Systematic review of p38 mitogen-activated kinase and its functional role in reproductive tissues

Abstract

Oxidative stress (OS) plays a role in uterine tissue remodeling during pregnancy and parturition. While p38 MAPK is an OS-response kinase, a precise functional role is unknown. Therefore, we conducted a systematic review of literature on p38 MAPK expression, activation, and function in reproductive tissues throughout pregnancy and parturition, published between January 1980-August 2017, using four electronic databases (Web of Science, Pubmed, Medline, and CoCHRANE). We identified 418 reports, 108 were selected for full text evaluation and 74 were included in final review. p38 MAPK was investigated using feto-maternal primary or immortalized cells, tissue explants, and animal models. Western blot was most commonly used to report phosphorylated (active) p38 MAPK. Human placenta (27), chorioamniotic membranes (14), myometrium (13), decidua (8) and cervix (1) were the studied tissues. p38 MAPK’s functions were tissue and gestational age dependent. Isoform specificity was hardly reported. p38 MAPK activity was induced by ROS or pro-inflammatory cytokines to promote cell signaling linked to cell fate, primed uterus, ripened cervix, and pro-inflammatory cytokine/chemokine production. In 35 years, reports on p38 MAPK’s role during pregnancy and parturition are scarce and current literature is insufficient to provide a comprehensive description of p38 MAPK’s mechanistic role during pregnancy and parturition.

Introduction

Reactive oxygen species (ROS) arising from intrauterine redox reactions play a dual role in reproductive tissues, specifically, uterine tissue remodeling during pregnancy when ROS are balanced and promoting parturition when there is a redox imbalance. The intrauterine oxidative status changes during various stages of gestation; it is mostly hypoxic during the first and third trimester, but it becomes hyperoxic during the second trimester and at term.^1,2 Reactive oxygen molecules generated from oxido-reductive reactions are essential for fetal and placental tissue growth and pregnancy maintenance. Recent studies have shown that increased oxidative stress is essential to trigger labor and delivery at term.³ Premature activation of oxidative stress during gestational periods can lead to adverse pregnancy events, like stillbirth, intrauterine growth restriction, preeclampsia, premature rupture of chorioamniotic membranes, and spontaneous preterm delivery. Excessive oxidative stress, if not balanced or controlled by uterine tissue antioxidant mechanisms, can damage cells and cellular organelles. Oxidative-stress-induced damage generate mechanistic pathways that trigger parturition either at term or prematurely at preterm. Understanding these mechanistic mediators and pathways are critical in preventing adverse pregnancy events.

One of the responders to oxidative stress damage is p38 mitogen-activated protein kinase (MAPK), which can trigger a variety of events in various tissues. Recent findings suggest that regulating p38 MAPK activation and its downstream pathologic effects may be beneficial in reducing the incidence of adverse pregnancies.⁴ However, a consensus has not emerged, and experimental evidence is still lacking to point to p38 MAPK as the molecule to regulate during pregnancy to avoid adverse events, partly because p38 MAPK can also function as a tissue remodeler through various pathways during pregnancy. Several reports have provided various functional roles for p38 MAPK in reproductive tissues at various stages of reproductive events^5–7; however, its origin, its mode of expression, signals that cause its induction and activation, and its specific role in various reproductive tissues are yet to emerge.

The family of MAP kinases has highly conserved regulation and function. There are 3 well-characterized subfamilies of MAPKs in mammals: the extracellular signal-regulated kinases (ERKs), the c-Jun NH2-terminal kinases (JNKs), and the p38 MAPKs. It has been demonstrated that targeted disruption of the p38 MAPK gene is embryonically lethal,⁸ indicating the function of p38 during embryogenesis is nonredundant, which is significantly different than JNK or ERK genes in which disruption is not lethal.⁹ The p38 MAPK pathway has been implicated in various cellular responses controlling cell proliferation, differentiation, apoptosis, embryogenesis, inflammatory responses, and stress responses in human reproductive tissues.^7,10 p38 MAPK is activated by most environmental stresses, such as oxidative stress, and pro-inflammatory cytokines, including interleukin 1 (IL-1) and tumor necrosis factor α (TNF­α); yet the functional role of p38 MAPK is cell-, tissue-, and stimulant-dependent.^11–13 Recently, we reported that activation of the p38 MAPK pathway by oxidative stress in human fetal membrane tissues causes cellular senescence and sterile inflammation, which are postulated to trigger parturition.^14–16 Animal model studies have also confirmed its potential role in the initiation of labor.^17,18 However, it is premature to state that p38 MAPK is the key mediator of parturition based on its activation in chorioamniotic membranes to various stimuli.

To examine the role of p38 MAPK, we conducted a systematic review of the literature. Our objectives are to 1) identify reports on p38 MAPK-associated function changes in human and animal reproductive tissues, 2) determine the mechanistic roles of p38 MAPK in human and animal reproductive tissues, and 3) determine the knowledge gaps in the functional role of p38 MAPK in human and animal reproductive tissues. Understanding the role of p38 MAPK in normal term pregnancies can provide insights into pathologic activation of its pathways that can cause adverse pregnancies. We expect that this systematic review will further characterize the role p38 MAPK plays in the initiation of labor, both at term and preterm, and lead to a better design and conduct of future experiments.

Methods

This systematic review was written following the standards set by the MOOSE group and PRISMA statements and was registered in PROSPERO: registration number 42016033380.

Search methods for identification of studies

Articles for this systematic review were published between January 1980 and August 2017 in English and came from 4 databases: Web of Science, Pubmed, Medline, and CoCHRANE. Articles were found with the help of a library liaison.

Search strategy

Our research strategy was designed to fill the knowledge gap of p38 MAPK’s role in the intrauterine compartments (placenta, chorioamniotic membranes, decidua, myometrium, and cervix) after implantation and through delivery (See Appendices 1–3 for full details of the search).

Selection criteria

Types of studies:

This review is restricted to studies focusing on p38 MAPK in humans and all animal models of pregnancy. Original research studies selected investigated p38 MAPK in various intrauterine compartments (placenta, chorioamniotic membranes, decidua, myometrium, and cervix) after implantation and during pregnancy and parturition. Studies were excluded if they were not related to p38 MAPK, not related to reproductive tissue, if they were review articles, if they had a below average quality score, or if no full text was available online (published as an abstract only) or the full text was not available from authors upon request.

Types of participants:

Studies that collected samples from female patients at full term gestation (≥ 37 weeks) who were either in labor or not in labor at the time of specimen collection for assay and analysis. Studies were also included if results were solely related to patients with preterm labor and delivery (both spontaneous and induced), chorioamnionitis, or studies that utilized cell lines from gestational tissues. Any age or patient ethnicity was included. Animal studies, including samples collected during and at the end of term or preterm birth studies, were also included.

Types of outcome measures:

This study measured p38 MAPK’s function and mechanistic role during pregnancy and parturition in human and animal models. Included studies assessed 1) changes in p38 MAPK RNA or protein expression, 2) its activators and repressors, 3) the mechanisms of activation or inactivation, and 4) biological pathways impacted in response to changes in p38 MAPK’s function (Table 1).

Table 1:

Full-text analysis.

Title	Author	Year Published	Journal Title	Species	Study type	in vivo or in vitro	Type of tissue	Inhibitors of p38 MAPK	Methods used to test p38 MAPK	p38 MAPK Isoform	Total or Phospho-p38 MAPK	Upstream	Downstream
Siglec-5 and Siglec-14 are polymorphic paired receptors that modulate neutrophil and amnion signaling responses to group B Streptococcus	Ali, S. R.	2014	Journal of Experimental Medicine	Human	PTB infection	in vitro	Amnion Epithelium	–	WB:P-p38 MAPK	–	Only P-p38 MAPK	Infection	Pro- Inflamatory Cytokines/Chemokines
Preimplantation factor (PIF) promoting role in embryo implantation: increases endometrial integrin-alpha2beta3, amphiregulin and epiregulin while reducing betacellulin expression via MAPK in decidua	Barnea, E. R.	2012	Reproductive Biology & Endocrinology	Human	Gestation	in vitro	Decidua and endometrium	–	BioPlex kit: P-p38 MAPK	–	Only P-p38 MAPK	Growth factors	Pro- Inflamatory Cytokines/Chemokines
Environmental Pollutant Polybrominated Diphenyl Ether, a Flame Retardant, Induces Primary Amnion Cell Senescence	Behnia, F.	2015	American Journal of Reproductive Immunology	Human	PTB	in vitro	Amnion Epithelium	–	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Oxidative stress	COX-2/ Cell fate
HMGB1 promotes a p38MAPK associated non-infectious inflammatory response pathway in human fetal membranes	Bredeson, S.	2014	PLoS ONE	Human	PTB	in vitro	Fetal Membranes and Amnionic Fluid	SB203580	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Oxidative stress	Pro- Inflamatory Cytokines/Chemokines
Arrestins differentially regulate histamine- and oxytocin-evoked phospholipase C and mitogen-activated protein kinase signalling in myometrial cells	Brighton, P. J.	2011	British Journal of Pharmacology	Human	Myometrial Activation/Quiesence	in vitro	Myometrium	–	WB:P-p38 MAPK	Alpha	Phospho and Total p38 MAPK	Arrestins	Cell fate
Tyrosine phosphorylation of caveolin 1 by oxidative stress is reversible and dependent on the c-src tyrosine kinase but not mitogen-activated protein kinase pathways in placental artery endothelial cells	Chen, D. B.	2005	Biology of Reproduction	Human	Gestation	in vitro	Placental Artery Endothelial Cells	SB203580	WB:P-p38 MAPK	Beta	Phospho and Total p38 MAPK	Oxidative stress	Cell fate
Secretion of adiponectin by human placenta: differential modulation of adiponectin and its receptors by cytokines	Chen, J.	2006	Diabetologia	Human	PTB	in vitro	Placenta Explants and Syncytiotrophoblast	–	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Adiponectin	Pro- Inflamatory Cytokines/Chemokines
Cyclic AMP increases COX-2 expression via mitogen-activated kinase in human myometrial cells	Chen, L.	2012	Journal of Cellular and Molecular Medicine	Human	Myometrial Activation/Quiesence	in vitro	Myometrium	SB203580	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	cAMP	COX-2/Prostaglandins/Primed uterus
Lysophosphatidic acid mediates interleukin-8 expression in human endometrial stromal cells through its receptor and nuclear factor-kappaB-dependent pathway: a possible role in angiogenesis of endometrium and placenta	Chen, S. U.	2008	Endocrinology	Human	Gestation	in vitro	Endometrial Stromal Cells	SB203580	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Lipid messangers	Pro- Inflamatory Cytokines/Chemokines
Lysophosphatidic acid up-regulates expression of growth-regulated oncogene-alpha, interleukin-8, and monocyte chemoattractant protein-1 in human first-trimester trophoblasts: possible roles in angiogenesis and immune regulation	Chen, S. U.	2010	Endocrinology	Human	Gestation	in vitro	Placenta Trophoblast	SB203580	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	–	Differentiation/Invation
Energy status and HIF signalling in chorionic villi show no evidence of hypoxic stress during human early placental development	Cindrova-Davies, T.	2015	Molecular Human Reproduction	Human	Gestation	in vitro	Placental Explants	PD169316	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Oxidative stress	transcriptional activity
Nuclear factor-kappa B, p38, and stress-activated protein kinase mitogen-activated protein kinase signaling pathways regulate proinflammatory cytokines and apoptosis in human placental explants in response to oxidative stress: effects of antioxidant…	Cindrova-Davies, T.	2007	American Journal of Pathology	Human	PTB	in vitro	Placental Explants	PD169316 and SB202190	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Oxidative stress	Differentiation/Invation/Pro- Inflamatory Cytokines/Chemokines
Genipa americana (Rubiaceae) fruit extract affects mitogen-activated protein kinase cell pathways in human trophoblast-derived BeWo cells: implications for placental development	da Conceicao, A. O.	2011	Journal of Medicinal Food	Human	Gestation	in vitro	Bewo Cells	PD169316 and SB202190	WB:P-p38 MAPK	Alpha, Beta, Gamma	Phospho and Total p38 MAPK	Genipa americana L. (Fruit extract)	Cell fate
ERK1/2 and p38 regulate trophoblasts differentiation in human term placenta	Daoud, G.	2005	Journal of Physiology	Human	Gestation	in vitro	Placenta Trophoblast	SB203580	WB:P-p38 MAPK	Alpha	Phospho and Total p38 MAPK	–	Differentiation/Invation
Interplay of cAMP and MAPK pathways in hCG secretion and fusogenic gene expression in a trophoblast cell line	Delidaki, M.	2011	Molecular & Cellular Endocrinology	Human	Gestation	in vitro	Bewo Cells	SB203580	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Forskolin	Cell fate/Differentiation/Invation
Inhibition of MAPK by prolactin signaling through the short form of its receptor in the ovary and decidua: involvement of a novel phosphatase	Devi, Y. S.	2011	Journal of Biological Chemistry	Mice	Gestation	in vivo and vitro	Decidua and ovaries	–	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Prostaglandins	Cell fate
Oxytocin-induced activation of eukaryotic elongation factor 2 in myometrial cells is mediated by protein kinase C	Devost, D.	2008	Endocrinology	Human	Myometrial Activation/Quiesence	in vitro	Myometrium	SB203580	WB:P-p38 MAPK	Alpha and Beta	Phospho and Total p38 MAPK	Oxytocin	Protein synthesis
Induction of PG G/H synthase-2 in bovine myometrial cells by interferon-tau requires the activation of the p38 MAPK pathway	Doualla-Bell, F.	2001	Endocrinology	Bovine	Myometrial Activation/Quiesence	in vitro	Uterus and Endometrial Cells	SB203580	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Pro- Inflamatory Cytokines/Chemokines	Prostaglandins
Role of atypical protein kinase C isozymes and NF-kappaB in IL-1beta-induced expression of cyclooxygenase-2 in human myometrial smooth muscle cells	Duggan, S. V.	2007	Journal of Cellular Physiology	Human	Myometrial Activation/Quiesence	in vitro	Myometrium	–	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Pro- Inflamatory Cytokines/Chemokines	Cox-2
The endocannabinoid anandamide induces apoptosis of rat decidual cells through a mechanism involving ceramide synthesis and p38 MAPK activation	Fonseca, B. M.	2013	Apoptosis	Rat	Gestation	in vivo and vitro	Decidua Cells	SB202190	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Lipid messangers	Cell fate
Cross talk between cAMP and p38 MAPK pathways in the induction of leptin by hCG in human placental syncytiotrophoblasts	Ge, Y. C.	2011	Reproduction	Human	Gestation	in vitro	Placenta Syncytiotrophoblast	SB203580	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	hCG/cAMP	Cell fate
Pregnancy reduces RhoA/Rho kinase and protein kinase C signaling pathways downstream of thromboxane receptor activation in the rat uterine artery	Goulopoulou, S.	2012	American Journal of Physiology-Heart and Circulatory Physiology	Rat	Myometrial Activation/Quiesence	in vivo and vitro	Uterine Artery and Mesenteric Artery	SB203580	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	TxA2	Primed uterus
Decidual NK cell-derived conditioned medium enhances capillary tube and network organization in an extravillous cytotrophoblast cell line	Hu, Y.	2010	Placenta	Human	Gestation	in vitro	Extravillous Cytotrophoblast and Decidual natural killer cells	SB202190	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	AKT	Differentiation/Invation
Function-specific intracellular signaling pathways downstream of heparin-binding EGF-like growth factor utilized by human trophoblasts	Jessmon, P.	2010	Biology of Reproduction	Human	Gestation	in vitro	Placenta Trophoblast	SB203580	WB:P-p38 MAPK	Alpha	Only P-p38 MAPK	Oxidative stress	Cell fate
EPO improves the proliferation and inhibits apoptosis of trophoblast and decidual stromal cells through activating STAT-5 and inactivating p38 signal in human early pregnancy	Ji, Y. Q.	2011	International Journal of Clinical & Experimental Pathology	Human	Gestation	in vitro	Extravillous Trophoblasts and Decidual Stromal Cells	–	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Hypoxia/Oxidative stress	Cell fate
Regulation of progesterone receptor A and B expression in human preterm, term, and postterm placental villi	Jiang, Z. Y.	2010	Acta Obstetricia Et Gynecologica Scandinavica	Human	Gestation	in vitro	postterm and preterm villous explants	–	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Progesterone	Receptor regulation
Epidermal growth factor stimulation of trophoblast differentiation requires MAPK11/14 (p38 MAP kinase) activation	Johnstone, E. D.	2005	Biology of Reproduction	Human	Gestation	in vitro	Villous cytotrophoblasts	SB202190 and SB203580	WB:P-p38 MAPK	Alpha and Beta	Only P-p38 MAPK	Epidermal growth factor	Cell fate
Multiple anti-apoptotic pathways stimulated by EGF in cytotrophoblasts	Johnstone, E. D.	2005	Placenta	Human	Gestation	in vitro	Placental Cytotrophoblast	SB203580	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Epidermal growth factor	Cell fate
Sphingosine 1-phosphate in amniotic fluid modulates cyclooxygenase-2 expression in human amnion-derived WISH cells	Kim, J. I.	2003	Journal of Biological Chemistry	Human	Parturition	in vitro	Amnion Wish Cells	SB203580	WB:P-p38 MAPK	Alpha	Phospho and Total p38 MAPK	Lipid messangers	COX-2
Oxytocin activates NF-kappaB-mediated inflammatory pathways in human gestational tissues	Kim, S. H.	2015	Molecular & Cellular Endocrinology	Human	Parturition	in vitro	Myometirum and Amnion Epithelium	SB203580	WB:P-p38 MAPK	Alpha	Only P-p38 MAPK	Oxytocin	Pro- Inflamatory Cytokines/Chemokines/COX-2/Primed uterus
Differential regulation of placental amino acid transport by saturated and unsaturated fatty acids	Lager, S.	2014	American Journal of Physiology - Cell Physiology	Human	Gestation	in vitro	Placental Cytotrophoblast	–	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Lipid messangers	Cell fate
Mechanisms in decorin regulation of vascular endothelial growth factor-induced human trophoblast migration and acquisition of endothelial phenotype	Lala, N.	2012	Biology of Reproduction	Human	Gestation	in vitro	Placenta Trophoblast	SB203580	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Decidn	Differentiation/Invation
Mitogen-activated protein kinase proteins regulate LPS-stimulated release of pro-inflammatory cytokines and prostaglandins from human gestational tissues	Lappas, M.	2007	Placenta	Human	Parturition	in vitro	Fetal Membranes and Placenta	SB202190	ELISA:P-p38 MAPK	–	Phospho and Total p38 MAPK	Oxidative stress	Pro- Inflamatory Cytokines/Chemokines
MAPK and AP-1 proteins are increased in term pre-labour fetal membranes overlying the cervix: regulation of enzymes involved in the degradation of fetal membranes	Lappas, M.	2011	Placenta	Human	Parturition	in vitro	Fetal Membranes and Amnion Epithelium	SB202190	WB and IHC:P-p38 MAPK	–	Phospho and Total p38 MAPK	Pro- Inflamatory Cytokines/Chemokines	Collagen remodeling
Differential actions of glycodelin-A on Th-1 and Th-2 cells: a paracrine mechanism that could produce the Th-2 dominant environment during pregnancy	Lee, C. L.	2011	Human Reproduction	Human	Gestation	in vitro	Amniotic fluid, seminal plasma, and cumulus matrix	–	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Glycodelin-A	Immunoregulation
NFkappaB and JNK/MAPK activation mediates the production of major macrophage- or dendritic cell-recruiting chemokine in human first trimester decidual cells in response to proinflammatory stimuli	Li, M.	2011	Journal of Clinical Endocrinology & Metabolism	Human	PTB	in vitro	Decidual Cells, Monocytes (primary and THP-1)	SB203580	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Pro- Inflamatory Cytokines/Chemokines	Pro- Inflamatory Cytokines/Chemokines
Effects of pulsatile shear stress on signaling mechanisms controlling nitric oxide production, endothelial nitric oxide synthase phosphorylation, and expression in ovine fetoplacental artery endothelial cells	Li, Y.	2004	Endothelium-Journal of Endothelial Cell Research	Ovine	PTB	in vitro	Artery endothelial cells	SB203580	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Oxidative stress	Vasodilatation
Interferon-gamma protects first-trimester decidual cells against aberrant matrix metalloproteinases 1, 3, and 9 expression in preeclampsia	Lockwood, C. J.	2014	American Journal of Pathology	Human	PTB	in vitro	Fetal Membranes and Decidua Cells	SB203580	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Pro- Inflamatory Cytokines/Chemokines and Interferon	Pro- Inflamatory Cytokines/Chemokines
The onset of labor alters corticotropin-releasing hormone type 1 receptor variant expression in human myometrium: putative role of interleukin-1beta	Markovic, D.	2007	Endocrinology	Human	Parturition	in vitro	Myometrium Myocytes and HEK293	–	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	cAMP	Hormones
Senescence of primary amniotic cells via oxidative DNA damage	Menon, R.	2013	PLoS ONE	Human	Parturition	in vitro	Amnion Epithelium	SB203580	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Oxidative stress	Cell fate
Histological evidence of oxidative stress and premature senescence in preterm premature rupture of the human fetal membranes recapitulated in vitro	Menon, R.	2014	American Journal of Pathology	Human	Parturition and PTB	in vitro	Fetal Membranes	–	WB and IHC:P-p38 MAPK	Alpha	Phospho and Total p38 MAPK	Oxidative stress	Cell fate
Macrophage-activating lipopeptide-2 induces cyclooxygenase-2 and prostaglandin E-2 via toll-like receptor 2 in human placental trophoblast cells	Mitsunari, M.	2006	Journal of Reproductive Immunology	Human	PTB Infection	in vitro	Placental Cytotrophoblast	SB202190	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Infection	Pro- Inflamatory Cytokines/Chemokines
Mitogen-activated protein kinases mediate stretch-induced c-fos mRNA expression in myometrial smooth muscle cells	Oldenhof, A. D.	2002	American Journal of Physiology - Cell Physiology	Rat	Parturition	in vivo and vitro	Myometrium	SB203580	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Strech	Primed uterus
Spatial and temporal expression of the myometrial mitogen-activated protein kinases p38 and ERK1/2 in the human uterus during pregnancy and labor	Otun, H. A.	2005	Journal of the Society for Gynecologic Investigation	Human	Parturition	in vivo and vitro	Myometrium	–	WB and IHC:Total p38 MAPK	–	Only Total	–	ATF2
Regulation of cyclooxygenase-2 expression by phospholipase D in human amnion-derived WISH cells	Park, D. W.	2002	Molecular Pharmacology	Human	Parturition	in vitro	Amnion Wish Cells	SB203580	WB:P-p38 MAPK	–	Only P-p38 MAPK	Oxidative stress	COX-2
Placental lactogen-I gene activation in differentiating trophoblast cells: extrinsic and intrinsic regulation involving mitogen-activated protein kinase signaling pathways	Peters, T. J.	2000	Journal of Endocrinology	Rat	Gestation	in vivo and vitro	Placental Trophoblast	SB203580	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Growth factors/Oxidative stress	Cell fate/Differentiation/Invation/Pro- Inflamatory Cytokines
Telomere Fragment Induced Amnion Cell Senescence: A Contributor to Parturition?	Polettini, J.	2015	PLoS ONE	Human and mouse	Parturition	in vivo and vitro	Fetal Membranes and Amnion Epithelium	SB203580	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Oxidative stress	Cell fate
Tumour necrosis factor alpha stimulates the production of monocyte chemoattractants by extravillous trophoblast cells via differential activation of MAPK pathways	Renaud, S. J.	2009	Placenta	Human	Gestation	in vitro	Extravillous Cytotrophoblast	SB203580	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Oxidative stress	Pro- Inflamatory Cytokines/Chemokines
Regulation of cyclooxygenase-2 induction in the mouse uterus during decidualization. An event of early pregnancy	Scherle, P. A.	2000	Journal of Biological Chemistry	Mice	Gestation	in vivo and vitro	Decidua	SB203580	WB and IHC:P-p38 MAPK	–	Only P-p38 MAPK	Corn Oil	Cox-2
Control of human endometrial stromal cell motility by PDGF-BB, HB-EGF and trophoblast-secreted factors	Schwenke, M.	2013	PLoS ONE	Human	Gestation	in vitro	Endometrial Cell Line and Extravillous Cytotrophoblast	SB202190	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Pro- Inflamatory Cytokines/Chemokines	Pro- Inflamatory Cytokines/Chemokines
Involvement of p38 MAP kinase in lipopolysaccharide-induced production of pro- and anti-inflammatory cytokines and prostaglandin E(2) in human choriodecidua	Shoji, T.	2007	Journal of Reproductive Immunolog	Human	PTB Infection	in vitro	Choriodecidual Explants	SB202190	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Oxidative stress	Pro- Inflamatory Cytokines/Chemokines
The mitogen-activated protein kinase dependent expression of prostaglandin H synthase-2 and interleukin-8 messenger ribonucleic acid by myometrial cells: the differential effect of stretch and interleukin-1{beta}	Sooranna, S. R.	2005	Journal of Clinical Endocrinology & Metabolism	Human	PTB	in vitro	Myometrium	SB203580	WB:P-p38 MAPK	–	Only P-p38 MAPK	Strech/Pro- Inflamatory Cytokines/Chemokines	Prostaglandins
Stretch and interleukin 1 beta: pro-labour factors with similar mitogen-activated protein kinase effects but differential patterns of transcription factor activation and gene expression	Sooranna, S. R.	2007	Journal of Cellular Physiology	Human	PTB	in vitro	Myometrium	SB239063	WB:P-p38 MAPK	–	Only P-p38 MAPK	Strech/Pro- Inflamatory Cytokines/Chemokines	Pro- Inflamatory Cytokines/Chemokines
Plasma membrane receptor mediated MAPK signaling pathways are activated in human uterine cervix at parturition	Wang, H.	2007	Reproductive Biology and Endocrinology	Human	Parturition	in vivo and vitro	Cervix	–	IHC:P-p38 MAPK	–	Only P-p38 MAPK	–	c-FOS and c-Jun cervical ripening
Corticotropin releasing hormone modulates endotoxin-induced inflammatory cytokine expression in human trophoblast cells	Wang, W.	2007	Placenta	Human	PTB Infection	in vitro	Extravillous Cytotrophoblast	SB203580	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Oxidative stress	Pro- Inflamatory Cytokines/Chemokines
Bradykinin-activated contractile signalling pathways in human myometrial cells are differentially regulated by arrestin proteins	Willets, J. M.	2015	Molecular & Cellular Endocrinology	Human	PTB Infection	in vitro	Myometrium Cell Line	SB203580	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Arrestins	Primed uterus
PGF2alpha modulates the output of chemokines and pro-inflammatory cytokines in myometrial cells from term pregnant women through divergent signaling pathways	Xu, C.	2015	Molecular Human Reproduction	Human	Parturition	in vitro	Uterine Smooth Muscle Cells	SB202190	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Prostaglandins	Pro- Inflamatory Cytokines/Chemokines
Prostaglandin F2alpha regulates the expression of uterine activation proteins via multiple signalling pathways	Xu, C.	2015	Reproduction	Human	Myometrial Activation/Quiesence	in vitro	Uterine Smooth Muscle Cells	SB202190	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Prostaglandins	Connexin-43/Primed uterus
Endometrial stromal cells undergoing decidualization down-regulate their properties to produce proinflammatory cytokines in response to interleukin-1 beta via reduced p38 mitogen-activated protein kinase phosphorylation	Yoshino, O.	2003	Journal of Clinical Endocrinology & Metabolism	Human	Gestation	in vitro	Endometrial Stromal Cells	SB202190	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Pro- Inflamatory Cytokines/Chemokines	Pro- Inflamatory Cytokines/Chemokines
Direct contribution of inducible nitric oxide synthase expression to apoptosis induction in primary smooth chorion trophoblast cells of human fetal membrane tissues	Yuan, B.	2009	International Journal of Biochemistry & Cell Biology	Human	Parturition	in vitro	Amnion and Chorion Cells	–	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Oxidative stress	Cell fate
Progesterone enhances immunoregulatory activity of human mesenchymal stem cells via PGE2 and IL-6	Zhao, X.	2012	American Journal of Reproductive Immunology	Human	Gestation	in vitro	Mesenchymal Stem Cells from Human Umbilical Cords	SB203580	WB:P-p38 MAPK	–	Only P-p38 MAPK	Hormones	Pro- Inflamatory Cytokines/Chemokines
Regulation of progesterone receptor A and B expression in human preterm, term, and postterm placental villi	Ziyan, J.	2010	Acta Obstetricia et Gynecologica Scandinavica	Human	Parturition	in vitro	Extravillous Cytotrophoblast	–	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Prostaglandins	PR-A;PR-B
Novel Noncompetitive IL-1 Receptor-Biased Ligand Prevents Infection- and Inflammation-Induced Preterm Birth	Nadeau-Vallée, M	2015	The Journal of Immunology	Human and mice	PTB	in vitro	Myometrial smooth muscle cell	–	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	IL-1B inhibitor	Pro- Inflamatory Cytokines/Chemokines
Reciprocal regulation of beta2-adrenoceptor-activated cAMP response-element binding protein signalling by arrestin2 and arrestin 3	Pearce, A.	2017	Cellular Signalling	Human	Myometrial Activation/Quiesence	in vitro	Uterine Smooth Muscle Cells	SB203580	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Arrestins	Cell fate
Differential senescence in feto-maternal tissues during mouse pregnancy.	Bonney, E.A.	2016	Placenta	Mice	Parturition	in vitro	Fetal Membranes, Placenta, Decidua, and Uterus	–	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Oxidative stress	Cell fate
Induction of pro-inflammatory genes by serum amyloid A1 in human amnion fibroblasts.	Li, W.	2017	Scientific Reports	Human	Parturition	in vitro	Amnion Epithelium and Fibroblast, Chorion Trophoblast Cells	SB203580	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Oxidative stress	Pro- Inflamatory Cytokines/Chemokines
Amnion-Epithelial-Cell-Derived Exosomes Demonstrate Physiologic State of Cell under Oxidative Stress.	Sheller, S.	2016	PLos One	Human	Parturition	in vitro	Amnion Epithelium	–	WB, IF, FLOW:P-p38 MAPK	–	Phospho and Total p38 MAPK	Oxidative stress	DAMPs in exosomes
Differential Effects of Oxytocin Receptor Antagonists, Atosiban and Nolasiban, on Oxytocin Receptor-Mediated Signaling in Human Amnion and Myometrium.	Kim, S. H.	2017	Molecular Pharmacology	Human	Parturition	in vitro	Myometirum and Amnion Epithelium	–	WB:P-p38 MAPK	Alpha	Only P-p38 MAPK	Oxytocin	COX-2/Pro- Inflamatory Cytokines/Chemokines/Primed uterus
Protein O-fucosyltransferase 1 promotes trophoblast cell proliferation through activation of MAPK and PI3K/Akt signaling pathways	Liu, C.	2017	Biomedicine & pharmacotherapy	Human	Gestation	in vitro	Chorioncarcinoma Cell Lines (JAR) and Placental Villi	SB203580	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	–	Cell fate
Placental membrane aging and HMGB1 signaling associated with human parturition	Menon, R.	2016	Aging	Human	Parturition	in vitro	Fetal Membranes and Amnion Epithelium	–	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Oxidative stress	Cell fate (senescence)
Sustained Endocannabinoid Signaling Compromises Decidual Function and Promotes Inflammation-induced Preterm Birth.	Sun, X.	2016	Journal of Biological Chemistry	Human	PTB	in vivo and vitro	Decidua	SB203580 or SR141716	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	LPS, endocannabinoid	senescence, PTB
The endocannabinoid 2-arachidonoylglycerol dysregulates the synthesis of proteins by the human syncytiotrophoblast	Costa, M.A.	2016	Biochimica et Biophysica Acta	Human	Gestation	in vitro	Placental Cytotrophoblasts	SB203580	WB:P-p38 MAPK	–	Phospho and Total p38 MAPK	Endocannabinoid	Collagen remodeling
Oxidative stress damage-associated molecular signaling pathways differentiate spontaneous preterm birth and preterm premature rupture of the membranes	Dutta, E.H.	2016	Molecular Human Reproduction	Human	PTB	in vitro	Fetal Membranes and Amniotic Fluid	–	WB:P-p38 MAPK, Luminex xMAP technology	–	Phospho and Total p38 MAPK	Oxidative stress	Cell fate
The oxytocin receptor antagonist, Atosiban, activates pro-inflammatory pathways in human amnion via G(alphai) signalling.	Kim, S.H.	2016	Molecular & Cellular Endocrinology	Human	Parturition	in vitro	Fetal Membranes	–	WB:P-p38 MAPK	–	Only P-p38 MAPK	Oxytocin	Pro- Inflamatory Cytokines/Chemokines

Data collection and analysis

Selection of studies:

All articles identified through the search strategy mentioned above were downloaded into a common folder, and duplicate articles were removed. Two authors (L.R., S. S-M.) independently screened the titles and abstracts, removing reviews and nonrelevant articles, and selecting those that were potentially appropriate for full text analysis.

Data extraction:

A data extraction form was created and information from the articles was collected including primary author, year and journal of publication, tissue, type of study, methods, inhibitor and isoform information, relevance to parturition, and key findings about p38 MAPK. Four authors (L.R., S. S-M., L.M, J.J.) independently collected data from the articles, discussed their findings, and created a single document containing all article information (Table 1).

Quality assessment:

No quality assessment tool for systematic reviews has been well defined for basic science research. Hence, we followed the guidelines outlined by Hadley et al,¹⁹ which specified criteria for quality assessment of such works and ranks them for quality. Areas, such as hypothesis, strength of study design, description of samples and reagents used, methods replication and reproducibility, experimental rigor as defined use of proper control, adequate power, assay and analytical approaches, appropriate use of statistical tests, sufficient explanation of results, and if the results support the conclusions (Appendix 3), were analyzed per article, and a score was given ranking them as poor, acceptable, or good quality.

Data synthesis

Based on our data extraction from all included articles, we present a better comprehensive understanding of p38 MAPK’s role throughout pregnancy in the intrauterine cavity (placenta, chorioamniotic membranes, decidua, myometrium, and cervix) of human and animal models. We also present the overlapping and unique functions of p38 MAPK in each of these tissues.

Results

p38 MAPK was first reported in reproductive tissue in 2000 when Peter et al and Scherle et al studied p38 MAPK’s role in trophoblast and endothelial cell differentiation.^20,21 Since then, more than 72 articles have been published highlighting p38 MAPK as the main regulator of many processes that occur throughout gestation and during preterm or term parturition. Specifically, the rate of publication increased 3.5-fold from 2000 to 2016 (Figure 2), including documentation of p38 MAPK in more than 31 different reproductive cells or tissues, supporting p38 MAPK’s diverse and important role during pregnancy (Figure 3).

Figure 2:

Article count. Number of p38 MAPK articles published between 2000 and August 2017*

*For 2017, we only analyzed articles published through August.

Figure 3:

Graphic summary of articles included in systematic review. Breakdown of p38 MAPK studies in species (inner circle), tissues (next to inner circle), cell types (outer circles), and number of articles (outer circle) identified in the systematic review.

Main characteristics of studies

The main characteristics and findings of the included studies are summarized in Table 1. Studies included in this systematic review discussed p38 MAPK function or mechanism of action in either the placenta, chorioamniotic membranes, decidua, myometrium, or cervix and various combinations of the gestational tissues (Figure 4A). Over the past 37 years, only 1 report (Wang et al) studied p38 MAPK expression, but not its function, in cervical tissues.¹⁰

Figure 4:

Main findings of p38 MAPK systematic review.

A. The most studied tissue for p38 MAPK was the placenta, followed by the chorioamniotic membranes, myometrium, decidua, and cervix.

B. The role of p38 MAPK in reproductive tissues has been studied predominantly in humans.

C. Of the methods used, Western blot was the most commonly used technique to investigate total p38 MAPK and its phosphorylated (active) form.

D. p38 MAPK has 4 different isoforms, and isoform expression is tissue specific. The majority of the studies in our review did not document the isoform studied. Among the reported ones, isoform α is the dominant isoform. Pharmaceutical inhibitors are also directed towards p38 MAPKα.

E. The majority of inhibitors of p38 being tested and reported are pharmaceutical compounds (SB203580, SB202190). Small interfering RNAs were used in a few reports. Interestingly, some studies reported p38’s function without scientific rigor by having inhibitors in experimental models.

F. The role of p38 MAPK has been studied during multiple stages of pregnancy. Its role in gestational stages other than term or preterm were the most studied.

Methods used for p38 MAPK function

Functional and mechanistic analysis of p38 MAPK in human and animal models (Figure 4B) were analyzed by a variety of techniques (often performing multiple approaches in the same study for confirmation purposes) including Western blot (71), immunostaining—histochemistry (5) or cytochemistry (1), flow cytometry (1), ELISA (1), and bioplex (2) (Figure 4C). Mechanistic participation of p38 MAPK was analyzed by studying what proteins or pathways lead to its activation, whereas functional changes associated with p38 MAPK activation were reported by measuring signaling pathways or the endpoint attained (eg, cell death, inflammation, and prostaglandin synthesis). Total forms of p38 MAPK were measured by Western blot, and immunohistochemistry, while phosphorylated active forms were measured by Western blot immunohistochemistry, flow cytometry, ELISA/bioplex, and immunocytochemistry. Though there are 4 different isoforms of p38 MAPK (alpha, beta, gamma, delta), 65 of the included studies did not document the specific isoform studied (Figure 4D). Additionally, 13 studies did not use total p38 MAPK to normalize phospho-p38 MAPK data when Western blot analysis was performed, making it difficult to properly interpret data. It is highly recommended to perform normalization of active p38/total p38 over other housekeeping genes for appropriate biological assessment of changes associated with p38 MAPK activation.

To add scientific rigor to experiments, most investigators have used inhibitors to p38 MAPK alpha or beta, such as PD169316 (3), SB203580 (35), SB202190 (13), SR141716 (1) or SB239063 (1), (Figure 4E). Surprisingly, no studies used p38 MAPK siRNA, leaving 19 of the studies in this systematic review to be mostly observational.

Quality assessment

The reports evaluated for this review are basic science or research laboratory-based studies, and no reference criteria exist to assess quality. However, based on the reported standards of quality assessment, we used a quality assessment tool established by Hadley, et al,¹⁹ which ranks articles by quality for each of the included articles (Appendix 3). Based on the criteria described in methods section, 55 articles were graded as above average quality, 42 as average quality, and 11 as below average quality. During the quality assessment, additional articles were identified that did not meet our inclusion criteria outlined in the methods (Not related to pregnancy or pregnancy timeline (9), Not related to p38 MAPK (11), Review articles (1), No full text available (2)) and were removed prior to the final analysis.

Main findings

Mechanisms and functions of p38 MAPK in various uterine tissues/cells were determined based on data extracted from 74 studies (Figure 4). The majority of included studies reported on a single cell or tissue type and used more than one assay type for analysis. As shown in Table 1, various gestational tissue types were studied: placenta (27), chorioamniotic membranes (14), decidua (8), myometrium (13), and cervix (1). Upon review, these reports suggested that p38 MAPK plays a role in gestation, specifically decidualization and trophoblast differentiation and invasion (28); parturition (21); adverse pregnancy outcomes like preterm birth, related and not related to infection (10); and myometrial quiescence or activation (8) (Figure 4F). All of these studies were carried out in vitro (cell culture or tissue explants) using human derived samples (65); however, some studies were carried out in vivo using rodent models (9).

p38 MAPK’s activation and function are stimulant, tissue, and time-dependent. The following findings determined the diversity and importance of p38 MAPK in the intrauterine cavity throughout pregnancy and during parturition. The most studied upstream activator of p38 MAPK was different for each tissue type, namely, oxidative stress in the placenta and chorioamniotic membranes, proinflammatory cytokines in the decidua, and oxytocin signaling in the myometrium. The most studied downstream effects of p38 MAPK were cell fate in the placenta and chorioamniotic membranes, prosenescence and inflammatory cytokine production in the decidua, transition from quiescent to active state of the myometrium, and cervical ripening in the cervix (Table 2).

Table 2:

p38 MAPK studies in reproductive tissues

Tissue	Upstream activators	Number of Articles	Downstream activators	Number of Articles
Placenta	Oxidative stress	10	Cell fate	10
	Epidermal growth factor	3	Proinflammatory cytokines / chemokines	6
	Endocannabinoid	2	Differentiation / invasion	5
Chorioamniotic Membranes	Oxidative stress	14	Cell fate	10
	Oxytocin	3	Proinflammatory cytokines / chemokines	9
	Proinflammatory cytokines / chemokines	2	COX-2	4
Decidua	Proinflammatory cytokines / chemokines	5	Proinflammatory cytokines / chemokines	7
	Oxidative stress	3	Cell fate	3
	Lipid messengers	2	COX-2	1
Uterus	Oxytocin	3	Primed uterus	5
	Stretch	3	Proinflammatory cytokines / chemokines	4
	Proinflammatory cytokines / chemokines	2	COX-2	3
Cervix	None	1	Cervical ripening	1
Other Tissues	Oxidative stress	3	Proinflammatory cytokines / chemokines	3
	Hormones	1	Cell fate	2
	Proinflammatory cytokines / chemokines	1	Immunoregulation	1

The cervix,¹⁰ ovaries,²² placental arteries,²³ and umbilical cord stromal cells²⁴ were understudied based on our review. Additionally, we did not examine vaginal expression of p38 MAPK as a part of this study. Tissue type breakdown and findings are discussed below.

Placenta

In studies related to placental cells, p38 MAPK was activated by hypoxia, LPS, and hydrogen peroxide^25–32 leading to the stimulation of cell fate pathways like cell survival^{21,25,31−39} (Table 2). The activation and function of p38 MAPK in the placenta was documented in villous explants and primary and immortalized cytotrophoblasts cells. Other p38 MAPK functions reported in placenta include cytotrophoblast differentiation and invasion during early gestation.^{21,35,39–43}

During differentiation, growth factors, such as epithelial and fibroblast growth factor (EGF & FGF),^21,44 can activate p38 MAPK,⁴⁵ potentially via protein kinase A (PKA),³⁵ increased placental lactogen-I,²¹ human chorionic gonadotropin (hCG), and fusion genes³⁵ to establish pregnancy. Conversely, Costa et al showed endocannabinoid 2-arachidonoylglycerol can block p38 MAPK activation and prevent protein expression in syncytiotrophoblast.⁴³ Maternal serum factors and immune cell derivatives activate p38 MAPK, causing cytotrophoblast cell invasion in vitro,^42,46 whereas decorin⁴¹ secreted by the decidua prevents cytotrophoblast migration by inhibiting p38 MAPK. Throughout gestation, p38 MAPK function is regulated to promote cell survival. Cindrova-Davies et al and Jessmon et al reported that hypoxia directly, or via heparin-binding EGF-like growth factor, activates p38 MAPK. This activation of p38 MAPK promoted anti-apoptotic factors^29,31 or promoted cytotrophoblast proliferation.^36,37 Besides hypoxia, p38 MAPK activation is also associated with hCG and leptin production in cytotrophoblast.^34,35,38

p38 MAPK is also reported to enhance placental immune response in vitro in inflammation models,²⁷ causing cytokine³⁰ and uterotonin production^28,47 at term and preterm parturition. Jiang et al found that prostaglandins activated a p38 MAPK-mediated increase in progesterone receptor A (PR-A) in the placenta,⁴⁸ a mechanism associated with functional progesterone withdrawal in the myometrium. However, this novel role of p38 MAPK has not yet been determined in the myometrium.

Chorioamniotic membranes

Studies on p38 MAPK’s role in chorioamniotic membranes has mostly been studied in association with parturition (Table 2), partly due to the impracticality of obtaining chorioamniotic membranes (chorioamniotic membranes) during gestation until after delivery. Placental studies have overcome this limitation by using placenta from aborted fetuses; however, membrane researchers have not attempted such early studies, thus creating a black box regarding p38 MAPK’s function during formation, development, remodeling, and expansion of the chorioamniotic membraness. Though chorioamniotic membranes researchers only study p38 MAPK activation and function in a short window of time, theirs are the only intrauterine tissue studies to document p38 MAPK using Western blots, RT-PCR, ELISAs, immunohistochemistry, and immunocytochemistry. This documentation should set the standard for researchers in other uterine tissues, which normally use only Western blots to determine p38 MAPK expression and function. Though chorioamniotic membranes comprise multiple layers, the prominent cell type studied is amnion epithelial cells (AECs). Higher natural levels of p38 MAPK are documented in cases of PTB⁴⁹ and in the region of the chorioamniotic membranes that overlap the cervix.⁷ Recently, multiple laboratories have reported OS induced pathways of parturition in chorioamniotic membranes directed by p38 MAPK. Regardless of species (mice⁵⁰ or humans^14,21,51,52) or pregnancy conditions (PTB^28,53 or term labor^14,21,51,52), all these conditions support a role for p38 MAPK. Studies showed OS causes p38 MAPK-mediated senescence of chorioamniotic membranes, sterile inflammation, and prostaglandin production²⁸ to facilitate parturition. In addition to the OS induced pathways, oxytocin,⁵⁰ environmental toxins,⁵⁴ and lipid mediators⁵⁵ were all reported to activate p38 MAPK. In chorion cells, OS induces p38 MAPK activation, leading to production of PGE2,⁵⁶ Heme oxygenase 1 downregulation,⁵⁷ pro-inflammatory cytokine increase,⁵⁶ and apoptosis.⁵⁷ In summary, multiple stimulants at term activate p38 MAPK in chorioamniotic membranes cells to affect labor-inducing pathways.

Decidua

p38 MAPK’s role in the maternal decidua during gestation and at parturition was documented in endometrial stromal cells that were undergoing or had undergone decidualization. The role of p38 MAPK in decidualization was reported by Yoshino et al, Lockwood et al, Scherle et al and many others (Table 1). In decidua cells, pro-inflammatory cytokines and chemokines induced p38 MAPK causing apoptosis,³³ cell survival,³² angiogenesis,⁵⁸ inflammation,⁵⁹ collagenolysis,⁵⁸ and senescence (Table 2). Therefore, p38 MAPK is reported to support cell survival and cell death, likely mediated by distinct stimuli. Only 2 reports documented decidual cells role at term and preterm parturition. In mice, Bonney et al showed association between p38 MAPK expression and decidual senescence at term,¹⁷ while Li et al reported lack of a role for decidual p38 MAPK in immune cell infiltration during preeclampsia.⁶⁰

Myometrium

The role of p38 MAPK in maintaining myometrial quiescence and inducing contractions was reported using primary and immortalized myocytes, myometrial tissue, and uterine artery cells. Oxytocin, a hormone released by the pituitary gland during labor, was a reported activator of p38 MAPK through the oxytocin receptor in the myometrium (Table 2). Kim et al reported that the oxytocin-oxytocin receptor complex activates p38 MAPK and induces COX-2 and IL-8 in myocytes. Xu et al validated these findings, showing PGF2α production mediated by p38 MAPK⁶¹ through the same mechanism. A new oxytocin receptor antagonist, nolasiban, was shown to inhibit NF-κB and p38 MAPK signaling, downregulating cytokine production in myometrial cells.⁶² Along with oxytocin, reports documented p38 MAPK activation by pro-inflammatory mediators that stimulates myometrial activation.^{38,50,61–65} Specifically, IL-1β and interferons⁶⁶ have been documented as activators of p38 MAPK in myometrial cells, which induces prostaglandin synthesis^67,68,69 and inflammation.⁶⁶ Activation of these signaling pathways creates a feed-forward loop, perpetuating pro-inflammatory cytokines and COX-2⁶⁹ production associated with parturition.^61,64,70

Arrestins are a small family of proteins important for regulating signal transduction of G protein-coupled receptors (GPCRs) upstream of MAPK activators. Brighton et al reported arrestin 2 and 3 negatively regulate oxytocin-induced p38 MAPK activation by downregulating oxytocin receptors in myometrial cells, thus maintaining a quiescent phenotype.⁷¹ Willets et al validated these findings using bradykinin, a potent pro-inflammatory peptide involved in infection-induced inflammation (to mimic preterm labor), to induce p38 MAPK signaling.⁶⁵

Though cyclic adenosine monophosphate (cAMP) is documented as a muscle relaxant⁶⁴ it has been shown to perform dual roles in myometrial activation and quiescence through p38 MAPK. Two reports have identified cAMP-mediated activation of p38 MAPK,^64,72 which in turn induces corticotropin-releasing hormone secretion and COX-2 expression; both are key components of labor initiation pathways.^64,72 These reports suggest p38 MAPK dependency of cAMP’s dual role in myometrial quiescence and activation.

In the myometrium, p38 MAPK activation induces a pro-inflammatory environment associated with parturition, and inhibition of p38 MAPK maintains myometrial quiescence. However, there are no current reports on potential interventions for preterm labor that inhibit p38 MAPK activation or function in the myometrium.

Discussion

Our systematic review documents p38 MAPK as a key intermediate kinase responsible for regulating signaling cascades during implantation, pregnancy, and parturition. These processes included decidualization, myometrial activation during parturition, placental growth, cervical ripening, and parturition at term and preterm. Our systematic review emphasizes challenges in determining the precise function of p38 MAPK due to redundancies in the activators and effectors in specific tissues, leading to contradictory reports on p38 MAPK function. Some of the challenges include 1) finding a specific upstream activator and downstream signaling molecule that correlate to the biological function of interest, 2) identifying the temporal activation of p38 MAPK in vitro and in vivo, 3) determining the functional isoform under a specific cellular environment, and 4) choosing the right inhibitor and model to study p38 MAPK’s functional role in different tissues and species. Knockout of p38 MAPK is embryonically lethal; therefore, functional studies using p38 MAPK knockout models are not attempted. Dependency on in vitro models alone to understand p38 MAPK function is challenging due to obvious limitations of such models in replicating the in vivo tissue microenvironment.

Though our reports document p38 MAPK’s role in many intrauterine tissues during pregnancy and parturition, we also identified several knowledge gaps that need to be filled through future research. The most commonly reported downstream function of p38 MAPK, regardless of tissue, was activation of proinflammatory cytokines; however, the pathways by which p38 MAPK induces inflammatory activation are still unclear. Interestingly, NF-κB activation by p38 MAPK is well reported in various other systems,^73–75 but this mechanism was not reported in any of the uterine tissues in this review. It has been shown that p38 MAPK causes placental PRA-PRB ratio switch to favor progesterone-PRA mediated action, a well-known proinflammatory mechanism. The role of p38 MAPK as a mediator of functional progesterone withdrawal in the myometrium, where this ratio switch is considered a prerequisite for labor initiation,^76–78 has not yet been reported.

p38 MAPK exists in 4 isoforms—alpha, beta, gamma, and delta—with tissue-specific functions. Isoform-specific function of p38 MAPK in reproductive tissues has yet to be fully elucidated, making it difficult to determine the exact functional form of p38 MAPK in a given cell. The gamma isoform may have a role in myometrial function as it is known to be expressed in muscle tissues⁷⁹ while the delta isoform might play a role in brain development. The knowledge of isoform function is essential in designing molecules that can inhibit p38 MAPK function to avoid any deleterious effects caused by its premature activation.

Knowledge gaps still exist in p38 MAPK’s role in placental growth and development and fetal membrane collagen and cellular remodeling during gestation. Additionally, cervix, ovaries, placental arteries, and umbilical cord stromal cells were understudied based on our review. Immediate research attention is needed in understanding the functional and mechanistic role of p38 MAPK in these tissues during pregnancy and parturition.

Conclusion

p38 MAPK is a multifunctional signaling kinase. It is a responder to stress stimuli performing various pleiotropic functions ranging from maintenance of cellular homeostasis to contributing to cellular dysfunction, depending on the tissue environment. p38 MAPK helps to maintain pregnancy and promote parturition, and its untimely activation or overactivation may cause adverse pregnancy outcomes. A better knowledge of p38 MAPK’s function in various uterine tissues during normal and abnormal conditions may increase its potential as a target for intervention in adverse pregnancy outcomes. While the number of p38 MAPK publications has increased recently, current literature is still insufficient to provide a comprehensive description of p38 MAPK’s role in gestation and parturition in various uterine tissues. More basic research is essential to generate a comprehensive functional role of p38 MAPK, especially in under-reported tissues, such as the cervix, ovaries, placental arteries, and umbilical cord stromal cells, where its expression, activation, and function are relatively unknown.

Figure 1:

PRISMA Chart. Systematic review of article and selection for data extraction and analysis.

Appendix 1: Articles reviewed for systematic review.

Title	Author	Year Published	Journal Title	Species	Tissue/ Cell Type	Exculsion criteria
Epidermal growth factor and interleukin-1beta utilize divergent signaling pathways to synergistically upregulate cyclooxygenase-2 gene expression in human amnion-derived WISH cells	Ackerman, W. E.	2004	Biology of Reproduction	Human	Amnion-derived (WISH) cells
Cardiac myocyte cell cycle control in development, disease, and regeneration	Ahuja, P.	2007	Physiological Reviews			Review
Siglec-5 and Siglec-14 are polymorphic paired receptors that modulate neutrophil and amnion signaling responses to group B Streptococcus	Ali, S. R.	2014	Journal of Experimental Medicine	Human	Aminon epithilium
Anandamide and decidual remodelling: COX-2 oxidative metabolism as a key regulator	Almada, M.	2015	Biochimica et Biophysica Acta	Rat	Decidua
Increased expression of a novel heat shock protein transcript in the mouse uterus during decidualization and in response to progesterone	Bany, B. M.	2001	Biology of Reproduction			Not related to p38 MAPK
Preimplantation factor (PIF) promoting role in embryo implantation: increases endometrial integrin-alpha2beta3, amphiregulin and epiregulin while reducing betacellulin expression via MAPK in decidua	Barnea, E. R.	2012	Reproductive Biology & Endocrinology	Human	Decidua and endometrium
Induction of cyclooxygenase-2 expression in human myometrial smooth muscle cells by interleukin-1beta: involvement of p38 mitogen-activated protein kinase	Bartlett, S. R.	1999	Journal of Physiology	Human	Human myometrial smooth muscle cells
Preeclampsia-related increase of interleukin-11 expression in human decidual cells	Basar, M.	2010	Reproduction	Human	Decidua
Environmental Pollutant Polybrominated Diphenyl Ether, a Flame Retardant, Induces Primary Amnion Cell Senescence	Behnia, F.	2015	American Journal of Reproductive Immunology	Human	Aminon epithilium
Haymaker gene expression in malignant and normal gynecologic tissues	Borowsky, M. E.	2006	Journal of Histochemistry & Cytochemistry			Not related to p38 MAPK
Late-gestation rat myometrial cells express multiple isoforms of phospholipase A2 that mediate PCB 50-induced release of arachidonic acid with coincident prostaglandin production	Brant, K.	2005	Toxicological Sciences	Rat	Uterus and myometrium
HMGB1 promotes a p38MAPK associated non-infectious inflammatory response pathway in human fetal membranes	Bredeson, S.	2014	PLoS ONE	Human	Fetal membranes and amniontic fluid
Arrestins differentially regulate histamine- and oxytocin-evoked phospholipase C and mitogen-activated protein kinase signalling in myometrial cells	Brighton, P. J.	2011	British Journal of Pharmacology	Human	Myometrium
Opposite effect of phorbol ester PMA on PTGS2 and PGDH mRNA expression in human chorion trophoblast cells	Casciani, V.	2008	Reproductive Sciences	Human	Chorion trophoblasts
Tyrosine phosphorylation of caveolin 1 by oxidative stress is reversible and dependent on the c-src tyrosine kinase but not mitogen-activated protein kinase pathways in placental artery endothelial cells	Chen, D. B.	2005	Biology of Reproduction	Human	Placental artery endothelial cells
Secretion of adiponectin by human placenta: differential modulation of adiponectin and its receptors by cytokines	Chen, J.	2006	Diabetologia	Human	Syncytiotrophoblast
Cyclic AMP increases COX-2 expression via mitogen-activated kinase in human myometrial cells	Chen, L.	2012	Journal of Cellular and Molecular Medicine	Human	Myometrium
Lysophosphatidic acid mediates interleukin-8 expression in human endometrial stromal cells through its receptor and nuclear factor-kappaB-dependent pathway: a possible role in angiogenesis of endometrium and placenta	Chen, S. U.	2008	Endocrinology	Human	Endometrial stromal cells
Lysophosphatidic acid up-regulates expression of growth-regulated oncogene-alpha, interleukin-8, and monocyte chemoattractant protein-1 in human first-trimester trophoblasts: possible roles in angiogenesis and immune regulation	Chen, S. U.	2010	Endocrinology	Human	Trophoblasts
Energy status and HIF signalling in chorionic villi show no evidence of hypoxic stress during human early placental development	Cindrova-Davies, T.	2015	Molecular Human Reproduction	Human	Placental explants
Nuclear factor-kappa B, p38, and stress-activated protein kinase mitogen-activated protein kinase signaling pathways regulate proinflammatory cytokines and apoptosis in human placental explants in response to oxidative stress: effects of antioxidant…	Cindrova-Davies, T.	2007	American Journal of Pathology	Human	Placental explants
Genipa americana (Rubiaceae) fruit extract affects mitogen-activated protein kinase cell pathways in human trophoblast-derived BeWo cells: implications for placental development	da Conceicao, A. O.	2011	Journal of Medicinal Food	Human	Trophoblast and bewo cells
ERK1/2 and p38 regulate trophoblasts differentiation in human term placenta	Daoud, G.	2005	Journal of Physiology	Human	Trophoblasts
Interplay of cAMP and MAPK pathways in hCG secretion and fusogenic gene expression in a trophoblast cell line	Delidaki, M.	2011	Molecular & Cellular Endocrinology	Human	Trophoblast and bewo cells
Inhibition of MAPK by prolactin signaling through the short form of its receptor in the ovary and decidua: involvement of a novel phosphatase	Devi, Y. S.	2011	Journal of Biological Chemistry	Mice	Decidua
Oxytocin receptor signalling	Devost, D.	2008	Progress in Brain Research/ Advances in Vasopressin and Oxytocin: from Genes to Behaviour to Disease			Review
Oxytocin-induced activation of eukaryotic elongation factor 2 in myometrial cells is mediated by protein kinase C	Devost, D.	2008	Endocrinology	Human	Myometrium
Induction of PG G/H synthase-2 in bovine myometrial cells by interferon-tau requires the activation of the p38 MAPK pathway	Doualla-Bell, F.	2001	Endocrinology	Bovine	Myometrium
MEK modulates force-fluctuation-induced relengthening of canine tracheal smooth muscle	Dowell, M. L.	2010	European Respiratory Journal			Not related to pregnancy or designated pregnancy timeline
Role of atypical protein kinase C isozymes and NF-kappaB in IL-1beta-induced expression of cyclooxygenase-2 in human myometrial smooth muscle cells	Duggan, S. V.	2007	Journal of Cellular Physiology	Human	Myometrium
Decidual NK cell-derived conditioned medium (dNK-CM) mediates VEGF-C secretion in extravillous cytotrophoblasts	Eastabrook, G. D.	2012	American Journal of Reproductive Immunology	Human	Decidual NK cells and extravillous cytotrophoblasts
The endocannabinoid anandamide induces apoptosis of rat decidual cells through a mechanism involving ceramide synthesis and p38 MAPK activation	Fonseca, B. M.	2013	Apoptosis	Rat	Decidua
Cross talk between cAMP and p38 MAPK pathways in the induction of leptin by hCG in human placental syncytiotrophoblasts	Ge, Y. C.	2011	Reproduction	Human	Syncytiotrophoblast
Pregnancy reduces RhoA/Rho kinase and protein kinase C signaling pathways downstream of thromboxane receptor activation in the rat uterine artery	Goulopoulou, S.	2012	American Journal of Physiology-Heart and Circulatory Physiology	Rat	Uterine artery
In anesthetized pigs human chorionic gonadotropin increases myocardial perfusion and function through a beta-adrenergic-related pathway and nitric oxide	Grossini, E.	2013	Journal of Applied Physiology			Not related to pregnancy or designated pregnancy timeline
Prostaglandin F-2 alpha induces expression of activating transcription factor 3 (ATF3) and activates MAPK signaling in the rat corpus luteum	Guo, N. N.	2015	Acta Histochemica	Rat	Ovaries
Multiple alternative splicing and differential expression pattern of the glycogen synthase kinase-3beta (GSK3beta) gene in goat (Capra hircus)	Hou, Y.	2014	PLoS ONE			Not related to p38 MAPK
Decidual NK cell-derived conditioned medium enhances capillary tube and network organization in an extravillous cytotrophoblast cell line	Hu, Y.	2010	Placenta	Human	Decidual NK cells and extravillous cytotrophoblasts
Role of activin-A and myostatin and their signaling pathway in human myometrial and leiomyoma cell function	Islam, M. S.	2014	Journal of Clinical Endocrinology & Metabolism	Human	Myometrium
Function-specific intracellular signaling pathways downstream of heparin-binding EGF-like growth factor utilized by human trophoblasts	Jessmon, P.	2010	Biology of Reproduction	Human	Trophoblasts
EPO improves the proliferation and inhibits apoptosis of trophoblast and decidual stromal cells through activating STAT-5 and inactivating p38 signal in human early pregnancy	Ji, Y. Q.	2011	International Journal of Clinical & Experimental Pathology	Human	Trophoblast and Decidual stromal cells
Regulation of progesterone receptor A and B expression in human preterm, term, and postterm placental villi	Jiang, Z. Y.	2010	Acta Obstetricia Et Gynecologica Scandinavica	Human	postterm and preterm villous explants
Epidermal growth factor stimulation of trophoblast differentiation requires MAPK11/14 (p38 MAP kinase) activation	Johnstone, E. D.	2005	Biology of Reproduction	Human	Trophoblasts
Multiple anti-apoptotic pathways stimulated by EGF in cytotrophoblasts	Johnstone, E. D.	2005	Placenta	Human	Cytotrophoblast
Regulation of interleukin-1alpha and tumor necrosis factor-alpha-induced interleukin-8 production by amnion-derived (WISH) cells	Kawano, Y.	2012	Clinical & Experimental Obstetrics & Gynecology	Human	Amnion-derived (WISH) cells
Pharmacological inhibition of inflammatory pathways for the prevention of preterm birth	Keelan, J. A.	2011	Journal of Reproductive Immunology			Review
Sphingosine 1-phosphate in amniotic fluid modulates cyclooxygenase-2 expression in human amnion-derived WISH cells	Kim, J. I.	2003	Journal of Biological Chemistry	Human	Amnion-derived (WISH) cells
Oxytocin activates NF-kappaB-mediated inflammatory pathways in human gestational tissues	Kim, S. H.	2015	Molecular & Cellular Endocrinology	Human	Myometirum and amnion cells
Regulation and signal transduction of toll-like receptors in human chorioncarcinoma cell lines	Klaffenbach, D.	2005	American Journal of Reproductive Immunology	Human	Chorioncarcinoma cell lines and placental villi
Expression and Prognostic Value of Activating Transcription Factor 2 (ATF2) and its Phosphorylated Form in Mammary Carcinomas	Knippen, S.	2009	Anticancer Research			Not related to pregnancy or designated pregnancy timeline
Altered Expression of Enzymes Regulating the Activity of Endothelin-1 in the Lower Segment of the Human Amnion During Labor	Kotani, T.	2013	Biology of Reproduction			Not related to p38 MAPK
Differential COX localization and PG release in Thy-1(+) and Thy-1(-) human female reproductive tract fibroblasts	Koumas, L.	2002	American Journal of Physiology - Cell Physiology			Not related to p38 MAPK
Differential regulation of placental amino acid transport by saturated and unsaturated fatty acids	Lager, S.	2014	American Journal of Physiology - Cell Physiology	Human	Trophoblasts
Mechanisms in decorin regulation of vascular endothelial growth factor-induced human trophoblast migration and acquisition of endothelial phenotype	Lala, N.	2012	Biology of Reproduction	Human	Trophoblasts
Mitogen-activated protein kinase proteins regulate LPS-stimulated release of pro-inflammatory cytokines and prostaglandins from human gestational tissues	Lappas, M.	2007	Placenta	Human	Fetal membrane and placenta
MAPK and AP-1 proteins are increased in term pre-labour fetal membranes overlying the cervix: regulation of enzymes involved in the degradation of fetal membranes	Lappas, M.	2011	Placenta	Human	Fetal membrane and amnion cells
Differential actions of glycodelin-A on Th-1 and Th-2 cells: a paracrine mechanism that could produce the Th-2 dominant environment during pregnancy	Lee, C. L.	2011	Human Reproduction	Human	Amniotic fluid, seminal plasma, and cumulus matrix
Chemokine CCL24 promotes the growth and invasiveness of trophoblasts through ERK1/2 and PI3K signaling pathways in human early pregnancy	Li, H.	2015	Reproduction	Human	Placenta villi and decidua
Induction of p38 mitogen-activated protein kinase-mediated apoptosis is involved in outgrowth of trophoblast cells on endometrial epithelial cells in a model of human trophoblast-endometrial interactions	Li, H. Y.	2003	Biology of Reproduction	Human	Bewo and amnion cells
Activation of decidual invariant natural killer T cells promotes lipopolysaccharide-induced preterm birth	Li, L.	2015	Molecular Human Reproduction	Mice	Decidual MNC, iNKC, DC
NFkappaB and JNK/MAPK activation mediates the production of major macrophage- or dendritic cell-recruiting chemokine in human first trimester decidual cells in response to proinflammatory stimuli	Li, M.	2011	Journal of Clinical Endocrinology & Metabolism	Human	decidual cells, monocytes (primary and THP-1)
Effects of pulsatile shear stress on signaling mechanisms controlling nitric oxide production, endothelial nitric oxide synthase phosphorylation, and expression in ovine fetoplacental artery endothelial cells	Li, Y.	2004	Endothelium-Journal of Endothelial Cell Research	Ovine	Artery endothelial cells
Regulation of interleukin-6 expression in human decidual cells and its potential role in chorioamnionitis	Lockwood, C. J.	2010	American Journal of Pathology	Human	Decidua
Interferon-gamma protects first-trimester decidual cells against aberrant matrix metalloproteinases 1, 3, and 9 expression in preeclampsia	Lockwood, C. J.	2014	American Journal of Pathology	Human	Fetal membranes and decidua
The onset of labor alters corticotropin-releasing hormone type 1 receptor variant expression in human myometrium: putative role of interleukin-1beta	Markovic, D.	2007	Endocrinology	Human	Myometrium
Structural determinants critical for localization and signaling within the seventh transmembrane domain of the type 1 corticotropin releasing hormone receptor: lessons from the receptor variant R1d	Markovic, D.	2008	Molecular Endocrinology	Human	Myocytes
Senescence of primary amniotic cells via oxidative DNA damage	Menon, R.	2013	PLoS ONE	Human	Amnion epithelial cells
Histological evidence of oxidative stress and premature senescence in preterm premature rupture of the human fetal membranes recapitulated in vitro	Menon, R.	2014	American Journal of Pathology	Human	fetal membranes
Oxidative stress damage as a detrimental factor in preterm birth pathology	Menon, R.	2014	Frontiers in Immunology			Review
Macrophage-activating lipopeptide-2 induces cyclooxygenase-2 and prostaglandin E-2 via toll-like receptor 2 in human placental trophoblast cells	Mitsunari, M.	2006	Journal of Reproductive Immunology	Human	Placental trophoblast cells
A maternal diet rich in fish oil may improve cardiac Akt-related signaling in the offspring of diabetic mother rats	Nasu-Kawaharada, R.	2013	Nutrition			Not related to pregnancy or designated pregnancy timeline
Drugs to block cytokine signaling for the prevention and treatment of inflammation-induced preterm birth	Ng, P. Y.	2015	Frontiers in Immunology			Review
Pathophysiology of thrombosis and pregnancy morbidity in the antiphospholipid syndrome	Oku, K.	2012	European Journal of Clinical Investigation			Review
Mitogen-activated protein kinases mediate stretch-induced c-fos mRNA expression in myometrial smooth muscle cells	Oldenhof, A. D.	2002	American Journal of Physiology - Cell Physiology	Rat	Myometrium
Progestin-inflammatory cytokine interactions affect matrix metalloproteinase-1 and -3 expression in term decidual cells: implications for treatment of chorioamnionitis-induced preterm delivery	Oner, C.	2008	Journal of Clinical Endocrinology & Metabolism	Human	Decidua
Spatial and temporal expression of the myometrial mitogen-activated protein kinases p38 and ERK1/2 in the human uterus during pregnancy and labor	Otun, H. A.	2005	Journal of the Society for Gynecologic Investigation	Human	Myometrium
MAPK14 cooperates with MAPK3/1 to regulate endothelin-1-mediated prostaglandin synthase 2 induction and survival in leiomyoma but not in normal myometrial cells	Oyeniran, C.	2011	Biology of Reproduction	Rat	Myometrium
Regulation of cyclooxygenase-2 expression by phospholipase D in human amnion-derived WISH cells	Park, D. W.	2002	Molecular Pharmacology	Human	Amnion-derived (WISH) cells
Placental lactogen-I gene activation in differentiating trophoblast cells: extrinsic and intrinsic regulation involving mitogen-activated protein kinase signaling pathways	Peters, T. J.	2000	Journal of Endocrinology	Rat	Rcho-1 trophoblast cells
Telomere Fragment Induced Amnion Cell Senescence: A Contributor to Parturition?	Polettini, J.	2015	PLoS ONE	Human and mouse	Fetal membrane
Species Comparison of the Role of p38 MAP Kinase in the Female Reproductive System	Radi, Z. A.	2009	Journal of Toxicologic Pathology			Review
Tumour necrosis factor alpha stimulates the production of monocyte chemoattractants by extravillous trophoblast cells via differential activation of MAPK pathways	Renaud, S. J.	2009	Placenta	Human	Extravillous trophoblast cells
C5a receptor-deficient mice are protected from thrombophilia and endothelial cell activation induced by some Antiphospholipid antibodies	Romay-Penabad, Z.	2007	Autoimmunity, Pt D: Autoimmune Disease, Annus Mirabilis			Not related to pregnancy or designated pregnancy timeline
Epidermal growth factor induces Ca2+ sensitization through Rho-kinase-dependent phosphorylation of myosin phosphatase target subunit 1 in vascular smooth muscle	Sasahara, T.	2015	European Journal of Pharmacology			Not related to pregnancy or designated pregnancy timeline
Regulation of cyclooxygenase-2 induction in the mouse uterus during decidualization. An event of early pregnancy	Scherle, P. A.	2000	Journal of Biological Chemistry	Mice	Decidua
Control of human endometrial stromal cell motility by PDGF-BB, HB-EGF and trophoblast-secreted factors	Schwenke, M.	2013	PLoS ONE	Human	Endometrium and trophoblast cell line
Involvement of p38 MAP kinase in lipopolysaccharide-induced production of pro- and anti-inflammatory cytokines and prostaglandin E(2) in human choriodecidua	Shoji, T.	2007	Journal of Reproductive Immunolog	Human	Choriodecidual explants
Phosphorylated HSP27 modulates the association of phosphorylated caldesmon with tropomyosin in colonic smooth muscle	Somara, S.	2006	American Journal of Physiology-Gastrointestinal and Liver Physiology			Not related to pregnancy or designated pregnancy timeline
The mitogen-activated protein kinase dependent expression of prostaglandin H synthase-2 and interleukin-8 messenger ribonucleic acid by myometrial cells: the differential effect of stretch and interleukin-1{beta}	Sooranna, S. R.	2005	Journal of Clinical Endocrinology & Metabolism	Human	Myometrium
Stretch and interleukin 1 beta: pro-labour factors with similar mitogen-activated protein kinase effects but differential patterns of transcription factor activation and gene expression	Sooranna, S. R.	2007	Journal of Cellular Physiology	Human	Myometrium
Effects of cytokine-suppressive anti-inflammatory drugs on inflammatory activation in ex vivo human and ovine fetal membranes	Stinson, L. F.	2014	Reproduction	Human and ovine	Fetal membrane
Interleukin-1beta induces the expression of insulin-like growth factor binding protein-1 during decidualization in the primate	Strakova, Z.	2000	Endocrinology	Baboon and human	Stromal cells and endometrial fibroblasts
IL-1beta during in vitro decidualization in primate	Strakova, Z.	2002	Journal of Reproductive Immunology			Review
Inhibition of matrix metalloproteinases prevents the synthesis of insulin-like growth factor binding protein-1 during decidualization in the baboon	Strakova, Z.	2003	Endocrinology	Baboon	Stromal fibroblasts
Possible involvement of p38 mitogen-activated protein kinase in decidual function in parturition	Takanami-Ohnishi, Y.	2001	Biochemical & Biophysical Research Communications	Human and mice	Uterus and decidua
Concurrent dinoprostone and oxytocin for labor induction in term premature rupture of membranes: a randomized controlled trial	Tan, P. C.	2009	Obstetrics & Gynecology			Not related to p38 MAPK
Growth restriction before and after birth increases kinase signaling pathways in the adult rat heart	Wadley, G. D.	2010	Journal of Developmental Origins of Health and Disease			Not related to pregnancy or designated pregnancy timeline
Calcitonin promotes mouse pre-implantation development: involvement of calcium mobilization and P38 mitogen-activated protein kinase activation	Wang, F. W.	2013	Reproduction in Domestic Animals	Mice	Uterus
Plasma membrane receptor mediated MAPK signaling pathways are activated in human uterine cervix at parturition	Wang, H.	2007	Reproductive Biology and Endocrinology	Human	Cervix
Corticotropin releasing hormone modulates endotoxin-induced inflammatory cytokine expression in human trophoblast cells	Wang, W.	2007	Placenta	Human	Extravillous trophoblast cell line HTR-8/SVneo.
Bradykinin-activated contractile signalling pathways in human myometrial cells are differentially regulated by arrestin proteins	Willets, J. M.	2015	Molecular & Cellular Endocrinology	Human	Myometrium
PGF2alpha modulates the output of chemokines and pro-inflammatory cytokines in myometrial cells from term pregnant women through divergent signaling pathways	Xu, C.	2015	Molecular Human Reproduction	Human	Myometrial smooth muscle cells
Prostaglandin F2alpha regulates the expression of uterine activation proteins via multiple signalling pathways	Xu, C.	2015	Reproduction	Human	Myometrial smooth muscle cells
Dynamic changes in mitogen-activated protein kinase (MAPK) activities in the corpus luteum of the bonnet monkey (Macaca radiata) during development, induced luteolysis, and simulated early pregnancy: a role for p38 MAPK in the regulation of luteal	Yadav, V. K.	2006	Endocrinology	Bonnet monkey (Macaca radiata)	Corpus luteum
Endometrial stromal cells undergoing decidualization down-regulate their properties to produce proinflammatory cytokines in response to interleukin-1 beta via reduced p38 mitogen-activated protein kinase phosphorylation	Yoshino, O.	2003	Journal of Clinical Endocrinology & Metabolism	Human	Endometrial stromal cells
Direct contribution of inducible nitric oxide synthase expression to apoptosis induction in primary smooth chorion trophoblast cells of human fetal membrane tissues	Yuan, B.	2009	International Journal of Biochemistry & Cell Biology	Human	Chorion and amnion cells
Progesterone enhances immunoregulatory activity of human mesenchymal stem cells via PGE2 and IL-6	Zhao, X.	2012	American Journal of Reproductive Immunology	Human	Umbilical cord mesenchymal stem cells
Paradoxical stimulation of cyclooxygenase-2 expression by glucocorticoids via a cyclic AMP response element in human amnion fibroblasts	Zhu, X. O.	2009	Molecular Endocrinology	Human	Amnion fibroblasts
Regulation of progesterone receptor A and B expression in human preterm, term, and postterm placental villi	Ziyan, J.	2010	Acta Obstetricia et Gynecologica Scandinavica	Human	Placental villi
Crystallin alphaB acts as a molecular guard in mouse decidualization: regulation and function during early pregnancy	Zuo, R. J.	2014	FEBS Letters	Mice	Stroma cells, endometrium, decidua
Computational identification of a p38SAPK-regulated transcription factor network required for tumor cell quiescence	Adam, A. P.	2009	Cancer Res			Not related to pregnancy or designated pregnancy timeline
Thiol depletion induces apoptosis in cultured lung fibroblasts	Aoshiba, K.	1999	American Journal Respir Cell Mol Biology			Not related to pregnancy or designated pregnancy timeline
Maintenance of quiescent hematopoietic stem cells in the osteoblastic niche	Arai, F.	2007	Ann N Y Acad Sci			Not related to pregnancy or designated pregnancy timeline
Comparison of H2O2-induced vasoconstriction in the abdominal aorta and mesenteric artery of the mouse	Ardanaz, N.	2007	Vascul Pharmacol			Not related to pregnancy or designated pregnancy timeline
Cell cycle control during liver development in the rat: evidence indicating a role for cyclin D1 posttranscriptional regulation	Awad, M. M.	2000	Cell Growth Differ			Not related to pregnancy or designated pregnancy timeline
Growth regulation via p38 mitogen-activated protein kinase in developing liver	Awad, M. M.	2000	J Biol Chem			Not related to pregnancy or designated pregnancy timeline
Hydrogen peroxide modulates the proliferation/quiescence switch in the liver during embryonic development and posthepatectomy regeneration	Bai, H.	2015	Antioxid Redox Signal			Not related to pregnancy or designated pregnancy timeline
Human muscle satellite cells show age-related differential expression of S100B protein and RAGE	Beccafico, S.	2011	Age			Not related to pregnancy or designated pregnancy timeline
Integration of Golgi trafficking and growth factor signaling by the lipid phosphatase SAC1	Blagoveshchenskaya, A.	2008	J Cell Biol			Not related to pregnancy or designated pregnancy timeline
The central role of muscle stem cells in regenerative failure with aging	Blau, H. M.	2015	Nat Med			Not related to pregnancy or designated pregnancy timeline
Dominant-negative TAK1 induces c-Myc and G(0) exit in liver	Bradham, C. A.	2001	Am J Physiol Gastrointest Liver Physiol			Not related to pregnancy or designated pregnancy timeline
Retinoblastoma suppression of matrix metalloproteinase 1, but not interleukin-6, through a p38-dependent pathway in rheumatoid arthritis synovial fibroblasts	Bradley, K.	2004	Arthritis Rheum			Not related to pregnancy or designated pregnancy timeline
The vascular NADPH oxidase subunit p47phox is involved in redox-mediated gene expression	Brandes, R. P.	2002	Free Radic Biol Med			Not related to pregnancy or designated pregnancy timeline
p27(Kip1) inhibits tissue factor expression	Breitenstein, A.	2013	Biochem Biophys Res Commun			Not related to pregnancy or designated pregnancy timeline
c-MYC protein is degraded in response to UV irradiation	Britton, S.	2008	Cell Cycle			Not related to pregnancy or designated pregnancy timeline
Sphingosine 1-phosphate stimulates proliferation and migration of satellite cells: role of S1P receptors	Calise, S.	2012	Biochim Biophys Acta			Not related to pregnancy or designated pregnancy timeline
Role of p38 in the regulation of renal cortical cyclooxygenase-2 expression by extracellular chloride	Cheng, H. F.	2000	J Clin Invest			Not related to pregnancy or designated pregnancy timeline
Inhibition of SAPK2/p38 enhances sensitivity to mTORC1 inhibition by blocking IRES-mediated translation initiation in glioblastoma	Cloninger, C.	2011	Mol Cancer Ther			Not related to pregnancy or designated pregnancy timeline
Hypoxia-induced proliferative response of vascular adventitial fibroblasts is dependent on g protein-mediated activation of mitogen-activated protein kinases	Das, M.	2001	J Biol Chem			Not related to pregnancy or designated pregnancy timeline
Transient expression of FRNK reveals stage-specific requirement for focal adhesion kinase activity in cardiac growth	DiMichele, L. A.	2009	Circ Res			Not related to pregnancy or designated pregnancy timeline
Resistin mediates the hepatic stellate cell phenotype	Dong, Z. X.	2013	World J Gastroenterol			Not related to pregnancy or designated pregnancy timeline
Vitamin E (alpha-tocopherol) attenuates cyclo-oxygenase 2 transcription and synthesis in immortalized murine BV-2 microglia	Egger, T.	2003	Biochem J			Not related to pregnancy or designated pregnancy timeline
The stress-activated protein kinase Hog1 develops a critical role after resting state	Escote, X.	2011	Mol Microbiol			Review
A male-specific role for p38 mitogen-activated protein kinase in germ cell sex differentiation in mice	Ewen, K.	2010	Biol Reprod			Not related to pregnancy or designated pregnancy timeline
Regulation of tyrosinase-related protein-2 (TYRP2) in human melanocytes: relationship to growth and morphology	Frost, P.	2009	Mol Cancer Ther			Not related to pregnancy or designated pregnancy timeline
Prostaglandin E(2) regulates the level and stability of cyclooxygenase-2 mRNA through activation of p38 mitogen-activated protein kinase in interleukin-1 beta-treated human synovial fibroblasts	Faour, W.H.	2001	Journal of Biological Chemistry			Not related to pregnancy or designated pregnancy timeline
Cytosolic phospholipase A2 activation by the p38 kinase inhibitor SB203580 in rabbit aortic smooth muscle cells	Fatima, S.	2001	Journal of Pharmacology and Experimental Therapeutics			Not related to pregnancy or designated pregnancy timeline
Globular adiponectin activates motility and regenerative traits of muscle satellite cells	Fiaschi, T.	2012	PLoS One			Not related to pregnancy or designated pregnancy timeline
The neurotrophic factor receptor RET drives haematopoietic stem cell survival and function	Fonseca-Pereira, D.	2014	Nature			Not related to pregnancy or designated pregnancy timeline
GATA-3 regulates the self-renewal of long-term hematopoietic stem cells	Frelin, C.	2013	Nature Immunology			Not related to pregnancy or designated pregnancy timeline
Regulation of D-cyclin translation inhibition in myeloma cells treated with mammalian target of rapamycin inhibitors: rationale for combined treatment with extracellular signal-regulated kinase inhibitors and rapamycin	Frost, P.	2009	Molecular Cancer Therapeutics			Not related to pregnancy or designated pregnancy timeline
ESE-3, an Ets family transcription factor, is up-regulated in cellular senescence	Fujikawa, M.	2007	Cancer Sci			Not related to pregnancy or designated pregnancy timeline
Cellular senescence and chromatin structure	Funayama, R.	2007	Chromosoma			Review
p38 MAPK mediates fibrogenic signal through Smad3 phosphorylation in rat myofibroblasts	Furukawa, F.	2003	Hepatology			Not related to pregnancy or designated pregnancy timeline
Decreased mitochondrial nitric oxide synthase activity and hydrogen peroxide relate persistent tumoral proliferation to embryonic behavior	Galli, S.	2003	Cancer Res			Not related to pregnancy or designated pregnancy timeline
Tumor cell phenotype is sustained by selective MAPK oxidation in mitochondria	Galli, S.	2008	PLoS One			Not related to pregnancy or designated pregnancy timeline
8-Amino-adenosine induces loss of phosphorylation of p38 mitogen-activated protein kinase, extracellular signal-regulated kinase 1/2, and Akt kinase: role in induction of apoptosis in multiple myeloma	Ghias, K.	2005	Mol Cancer Ther			Not related to pregnancy or designated pregnancy timeline
Gas6-mediated survival in NIH3T3 cells activates stress signalling cascade and is independent of Ras	Goruppi, S.	1999	Oncogene			Not related to pregnancy or designated pregnancy timeline
Cell density impacts epigenetic regulation of cytokine-induced E-selectin gene expression in vascular endothelium	Hamada, K.	2014	PLoS One			Not related to pregnancy or designated pregnancy timeline
Wounding activates p38 map kinase and activation transcription factor 3 in leading keratinocytes	Harper, E. G.	2005	J Cell Sci			Not related to pregnancy or designated pregnancy timeline
Post-transcriptional regulation of satellite cell quiescence by TTP-mediated mRNA decay	Hausburg, M. A.	2015	Elife			Not related to pregnancy or designated pregnancy timeline
Secretory phospholipase A2 activates the cascade of mitogen-activated protein kinases and cytosolic phospholipase A2 in the human astrocytoma cell line 1321N1	Hernandez, M.	1998	J Biol Chem			Not related to pregnancy or designated pregnancy timeline
All-trans-retinoic acid ameliorates carbon tetrachloride-induced liver fibrosis in mice through modulating cytokine production	Hisamori, S.	2008	Liver Int			Not related to pregnancy or designated pregnancy timeline
Function of oxidative stress in the regulation of hematopoietic stem cell-niche interaction	Hosokawa, K.	2007	Biochem Biophys Res Commun			Not related to pregnancy or designated pregnancy timeline
5-HT(2B) antagonism arrests non-canonical TGF-beta1-induced valvular myofibroblast differentiation	Hutcheson, J. D.	2012	J Mol Cell Cardiol			Not related to pregnancy or designated pregnancy timeline
Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells	Ito, K.	2006	Nat Med			Not related to pregnancy or designated pregnancy timeline
p38-MAPK- and caspase-3-mediated superoxide-induced apoptosis of rat hepatic stellate cells: reversal by retinoic acid	Jameel, N. M.	2009	J Cell Physiol			Not related to pregnancy or designated pregnancy timeline
A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche	Jang, Y. Y.	2007	Blood			Not related to pregnancy or designated pregnancy timeline
3′,4′-Dihydroxyflavonol down-regulates monocyte chemoattractant protein-1 in smooth muscle: role of focal adhesion kinase and PDGF receptor signalling	Jiang, F.	2009	Br J Pharmacol			Not related to pregnancy or designated pregnancy timeline
The p38alpha/beta MAPK functions as a molecular switch to activate the quiescent satellite cell	Jones, N. C.	2005	J Cell Biol			Not related to pregnancy or designated pregnancy timeline
Raf-1 is activated by the p38 mitogen-activated protein kinase inhibitor, SB203580	Kalmes, A.	1999	FEBS Lett			Not related to pregnancy or designated pregnancy timeline
Activation of extracellular signal-regulated kinase through B-cell antigen receptor in B-cell chronic lymphocytic leukemia	Kawauchi, K.	2002	Int J Hematol			Not related to pregnancy or designated pregnancy timeline
Hypoosmotic stress activates p38, ERK 1 and 2, and SAPK/JNK in rat hepatocytes	Kim, R. D.	200	J Surg Res			Not related to pregnancy or designated pregnancy timeline
High extracellular [Mg2+]-induced increase in intracellular [Mg2+] and decrease in intracellular [Na+] are associated with activation of p38 MAP kinase and ERK2 in guinea-pig heart	Kim, S. J.	2008	Exp Physiol			Not related to pregnancy or designated pregnancy timeline
The isoprostane 8-iso-PGF2alpha suppresses monocyte adhesion to human microvascular endothelial cells via two independent mechanisms	Kumar, A.	2005	Faseb j			Not related to pregnancy or designated pregnancy timeline
Inducible nitric oxide synthase gene deletion exaggerates MAPK-mediated cyclooxygenase-2 induction by inflammatory stimuli	Lamon, B. D.	2010	Am J Physiol Heart Circ Physiol			Not related to pregnancy or designated pregnancy timeline
Effects of ras transformation on the induction of the IL-1 receptor related T1 gene in response to mitogens, anisomycin, IL-1 and TNFalpha	Laursen, N. B.	1998	Oncogene			Not related to pregnancy or designated pregnancy timeline
Ultraviolet radiation (UVR) activates p38 MAP kinase and induces post-transcriptional stabilization of the C/EBPdelta mRNA in G0 growth arrested mammary epithelial cells	Li, B.	2008	J Cell Biochem			Not related to pregnancy or designated pregnancy timeline
Myocyte contractile activity modulates norepinephrine cytotoxicity and survival effects of neuregulin-1beta	Kuramochi, Y.	2004	Am J Physiol Cell Physiol			Not related to pregnancy or designated pregnancy timeline
CDK11(p58) promotes rat astrocyte inflammatory response via activating p38 and JNK pathways induced by lipopolysaccharide	Liu, X.	2012	Neurochem Res			Not related to pregnancy or designated pregnancy timeline
Initiation of caspase-independent death in mouse mesangial cells by Cd2+: involvement of p38 kinase and CaMK-II	Liu, Y.	2008	J Cell Physiol			Not related to pregnancy or designated pregnancy timeline
Differential activation of mitogenic signaling pathways in aortic smooth muscle cells deficient in superoxide dismutase isoforms	Madamanchi, N. R.	2005	Arterioscler Thromb Vasc Biol			Not related to pregnancy or designated pregnancy timeline
Tristetraprolin regulates Cyclin D1 and c-Myc mRNA stability in response to rapamycin in an Akt-dependent manner via p38 MAPK signaling	Marderosian, M.	2006	Oncogene			Not related to pregnancy or designated pregnancy timeline
Ligands of peroxisome proliferator-activated receptor gamma modulate profibrogenic and proinflammatory actions in hepatic stellate cells	Marra, F.	2000	Gastroenterology			Not related to pregnancy or designated pregnancy timeline
Urotensin II is an autocrine/paracrine growth factor for the porcine renal epithelial cell line, LLCPK1	Matsushita, M.	2003	Endocrinology			Not related to pregnancy or designated pregnancy timeline
Vitamin A inhibits pancreatic stellate cell activation: implications for treatment of pancreatic fibrosis	McCarroll, J. A.	2006	Gut			Not related to pregnancy or designated pregnancy timeline
The role of caldesmon in the regulation of endothelial cytoskeleton and migration	Mirzapoiazova, T.	2005	J Cell Physiol			Not related to pregnancy or designated pregnancy timeline
Foxo3a is essential for maintenance of the hematopoietic stem cell pool	Miyamoto, K.	2007	Cell Stem Cell			Not related to pregnancy or designated pregnancy timeline
Endotoxin priming of neutrophils requires NADPH oxidase-generated oxidants and is regulated by the anion transporter ClC-3	Moreland, J. G.	2007	J Biol Chem			Not related to pregnancy or designated pregnancy timeline
Involvement of stress-activated protein kinase and p38/RK mitogen-activated protein kinase signaling pathways in the enhanced phosphorylation of initiation factor 4E in NIH 3T3 cells	Morley, S. J.	1997	J Biol Chem			Not related to pregnancy or designated pregnancy timeline
Novel Noncompetitive IL-1 Receptor-Biased Ligand Prevents Infection- and Inflammation-Induced Preterm Birth	Nadeau-Vallée, M	2015	The Journal of Immunology	Human and mice	Myometrial smooth muscle cell
Oxidative stress-induced apoptosis in dividing fibroblasts involves activation of p38 MAP kinase and over-expression of Bax: resistance of quiescent cells to oxidative stress	Naderi, J.	2003	Apoptosis			Not related to pregnancy or designated pregnancy timeline
ROS detoxification and proinflammatory cytokines are linked by p38 MAPK signaling in a model of mature astrocyte activation	Nahirnyj, A.	2013	PLoS One			Not related to pregnancy or designated pregnancy timeline
Anti-apoptotic action of hepatocyte growth factor through mitogen-activated protein kinase on human aortic endothelial cells	Nakagami, H.	2000	J Hypertens			Not related to pregnancy or designated pregnancy timeline
Differential effect of simvastatin on activation of Rac(1) vs. activation of the heat shock protein 27-mediated pathway upon oxidative stress, in human smooth muscle cells	Negre-Aminou, P.	2002	Biochem Pharmacol			Not related to pregnancy or designated pregnancy timeline
Oxidative-stress and IL-6 mediate the fibrogenic effects of Kupffer cells on stellate cells	Nieto, N.	2006	Hepatology			Not related to pregnancy or designated pregnancy timeline
Regulation of tissue factor in microvascular dermal endothelial cells	O’Reilly, F. M.	2003	J Invest Dermatol			Not related to pregnancy or designated pregnancy timeline
Opposed effects of lithium on the MEK-ERK pathway in neural cells: inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms	Pardo, R.	2003	J Neurochem			Not related to pregnancy or designated pregnancy timeline
The flavonoid quercetin induces apoptosis and inhibits JNK activation in intimal vascular smooth muscle cells	Perez-Vizcaino, F.	2006	Biochem Biophys Res Commun			Not related to pregnancy or designated pregnancy timeline
Simultaneous Increases in Proliferation and Apoptosis of Vascular Smooth Muscle Cells Accelerate Diabetic Mouse Venous Atherosclerosis	Ping, S.	2015	PLoS One			Not related to pregnancy or designated pregnancy timeline
Interleukin-33 drives a proinflammatory endothelial activation that selectively targets nonquiescent cells	Pollheimer, J.	2013	Arterioscler Thromb Vasc Biol	Human	Umbilical vein endothelial cells
Stress-activated protein kinases in the activation of rat hepatic stellate cells in culture	Reeves, H. L.	2000	J Hepatol			Not related to pregnancy or designated pregnancy timeline
Effects of angiotensin II on rat pancreatic stellate cells	Reinehr, R.	2004	Pancreas			Not related to pregnancy or designated pregnancy timeline
p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF-1	Richard, D. E.	1999	J Biol Chem			Not related to pregnancy or designated pregnancy timeline
Efficient adult skeletal muscle regeneration in mice deficient in p38beta, p38gamma and p38delta MAP kinases	Ruiz-Bonilla, V.	2008	Cell Cycle			Not related to pregnancy or designated pregnancy timeline
Sphingolipid-mediated restoration of Mitf expression and repigmentation in vivo in a mouse model of hair graying	Saha, B.	2009	Pigment Cell Melanoma Res			Not related to pregnancy or designated pregnancy timeline
High Mda-7 expression promotes malignant cell survival and p38 MAP kinase activation in chronic lymphocytic leukemia	Sainz-Perez, A.	2006	Leukemia			Not related to pregnancy or designated pregnancy timeline
CREB downregulation in vascular disease: a common response to cardiovascular risk	Schauer, I. E.	2010	Arterioscler Thromb Vasc Biol			Not related to pregnancy or designated pregnancy timeline
ATF6alpha-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo	Schewe, D. M.	2008	Proc Natl Acad Sci U S A			Not related to pregnancy or designated pregnancy timeline
TAK1/JNK and p38 have opposite effects on rat hepatic stellate cells	Schnabl, B.	2001	Hepatology			Not related to pregnancy or designated pregnancy timeline
Analysis of R-Ras signalling pathways	Self, A. J.	2001	J Cell Sci			Not related to pregnancy or designated pregnancy timeline
Skeletal muscle cell activation by low-energy laser irradiation: a role for the MAPK/ERK pathway	Shefer, G.	2001	J Cell Physiol			Not related to pregnancy or designated pregnancy timeline
Cyclin D1 and c-myc internal ribosome entry site (IRES)-dependent translation is regulated by AKT activity and enhanced by rapamycin through a p38 MAPK- and ERK-dependent pathway	Shi, Y.	2005	J Biol Chem			Not related to pregnancy or designated pregnancy timeline
The MAP kinase pathway is involved in odontoblast stimulation via p38 phosphorylation	Simon, S.	2010	J Endod			Not related to pregnancy or designated pregnancy timeline
Osteopontin mediates hypoxia-induced proliferation of cultured mesangial cells: role of PKC and p38 MAPK	Sodhi, C. P.	2000	Kidney Int			Not related to pregnancy or designated pregnancy timeline
Hypoxia stimulates osteopontin expression and proliferation of cultured vascular smooth muscle cells: potentiation by high glucose	Sodhi, C. P.	2001	Diabetes			Not related to pregnancy or designated pregnancy timeline
ERK1/2 and p38alpha/beta signaling in tumor cell quiescence: opportunities to control dormant residual disease	Sosa, M. S.	2011	Clin Cancer Res			Not related to pregnancy or designated pregnancy timeline
Differential regulation of the mitogen-activated protein and stress-activated protein kinase cascades by adrenergic agonists in quiescent and regenerating adult rat hepatocytes	Spector, M. S.	1997	Mol Cell Biol			Not related to pregnancy or designated pregnancy timeline
Survival of retinal pigment epithelium after exposure to prolonged oxidative injury: a detailed gene expression and cellular analysis	Strunnikova, N.	2004	Invest Ophthalmol Vis Sci			Not related to pregnancy or designated pregnancy timeline
Redox regulation of vascular smooth muscle cell differentiation	Su, B.	2001	Circ Res			Not related to pregnancy or designated pregnancy timeline
Antinociceptive action of a p38alpha MAPK inhibitor, SD-282, in a diabetic neuropathy model	Sweitzer, S. M.	2004	Pain			Not related to pregnancy or designated pregnancy timeline
Activation of villous trophoblastic p38 and ERK1/2 signaling pathways in preterm preeclampsia and HELLP syndrome	Szabo, S.	2015	Pathology & Oncology Research			Not related to pregnancy or designated pregnancy timeline
Hematopoietic stem cell quiescence and function are controlled by the CYLD-TRAF2-p38MAPK pathway	Tesio, M.	2015	J Exp Med			Not related to pregnancy or designated pregnancy timeline
Expression and suppressive effects of interleukin-19 on vascular smooth muscle cell pathophysiology and development of intimal hyperplasia	Tian, Y.	2008	Am J Pathol			Not related to pregnancy or designated pregnancy timeline
Hypercholesterolemia induces oxidant stress that accelerates the ageing of hematopoietic stem cells	Tie, G.	2014	J Am Heart Assoc			Not related to pregnancy or designated pregnancy timeline
ERK1/2 and p38 cooperate to induce a p21CIP1-dependent G1 cell cycle arrest	Todd, D. E.	2004	Oncogene			Not related to pregnancy or designated pregnancy timeline
Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway	Todd, J. L.	1999	J Biol Chem			Not related to pregnancy or designated pregnancy timeline
Coordination of satellite cell activation and self-renewal by Par-complex-dependent asymmetric activation of p38alpha/beta MAPK	Troy, A.	2012	Cell Stem Cell			Not related to pregnancy or designated pregnancy timeline
Activation of extracellular signal-regulated kinases is essential for pressure-induced proliferation of vascular smooth muscle cells	Tsuda, Y.	2002	Eur J Pharmacol			Not related to pregnancy or designated pregnancy timeline
S100B in myoblasts regulates the transition from activation to quiescence and from quiescence to activation and reduces apoptosis	Tubaro, C.	2011	Biochim Biophys Acta			Not related to pregnancy or designated pregnancy timeline
Vitamin C promotes human endothelial cell growth via the ERK-signaling pathway	Ulrich-Merzenich, G.	2007	Eur J Nutr	Human	Umbilical cord venous endothelial cells
Role of mitogen-activated protein kinases in 4-hydroxy-2-nonenal-induced actin remodeling and barrier function in endothelial cells	Usatyuk, P. V.	2004	J Biol Chem			Not related to pregnancy or designated pregnancy timeline
Suppression of p38-stress kinase sensitizes quiescent leukemic cells to anti-mitotic drugs by inducing proliferative responses in them	Vaidya, A. A.	2008	Cancer Biol Ther			Not related to pregnancy or designated pregnancy timeline
Insulin-like growth factor 1 receptor and p38 mitogen-activated protein kinase signals inversely regulate signal transducer and activator of transcription 3 activity to control human dental pulp stem cell quiescence, propagation, and differentiation	Vandomme, J.	2014	Stem Cells Dev			Not related to pregnancy or designated pregnancy timeline
Impaired CD200-CD200R-mediated microglia silencing enhances midbrain dopaminergic neurodegeneration: roles of aging, superoxide, NADPH oxidase, and p38 MAPK	Wang, X. J.	2011	Free Radic Biol Med			Not related to pregnancy or designated pregnancy timeline
Vanadium-induced STAT-1 activation in lung myofibroblasts requires H2O2 and P38 MAP kinase	Wang, Y. Z.	2003	Free Radic Biol Med			Not related to pregnancy or designated pregnancy timeline
Down-regulation of intrinsic P-glycoprotein expression in multicellular prostate tumor spheroids by reactive oxygen species	Wartenberg, M.	2001	J Biol Chem			Not related to pregnancy or designated pregnancy timeline
Hyperplastic Growth of Pulmonary Artery Smooth Muscle Cells from Subjects with Pulmonary Arterial Hypertension Is Activated through JNK and p38 MAPK	Wilson, J. L.	2015	PLoS One			Not related to pregnancy or designated pregnancy timeline
Modulating the dysregulated migration of pulmonary arterial hypertensive smooth muscle cells with motif mimicking cell permeable peptides	Wilson, J. L.	2015	Curr Top Pept Protein Res			Not related to pregnancy or designated pregnancy timeline
Differential transcriptional responses of keloid and normal keratinocytes to serum stimulation	Xia, W.	2006	J Surg Res			Not related to pregnancy or designated pregnancy timeline
p38 mitogen-activated protein kinase and liver X receptor-alpha mediate the leptin effect on sterol regulatory element binding protein-1c expression in hepatic stellate cells	Yan, K.	2012	Mol Med			Not related to pregnancy or designated pregnancy timeline
Rapid isolation and culture of primary microglia from adult mouse spinal cord	Yip, P. K.	2009	J Neurosci Methods			Not related to pregnancy or designated pregnancy timeline
Modulation of endothelial cell growth arrest and apoptosis by vascular endothelial growth inhibitor	Yu, J.	2001	Circ Res			Not related to pregnancy or designated pregnancy timeline
Gene expression of cyclin-dependent kinase inhibitors and effect of heparin on their expression in mice with hypoxia-induced pulmonary hypertension	Yu, L.	2006	Biochem Biophys Res Commun			Not related to pregnancy or designated pregnancy timeline
c-Jun NH2-terminal kinase mediation of angiotensin II-induced proliferation of human mesangial cells	Zhang, A.	2005	Am J Physiol Renal Physiol			Not related to pregnancy or designated pregnancy timeline
Bacterial heat shock protein-60 increases epithelial cell proliferation through the ERK1/2 MAP kinases	Zhang, L.	2001	Exp Cell Res			Not related to pregnancy or designated pregnancy timeline
Gene suppression by tristetraprolin and release by the p38 pathway	Zhu, W.	2001	Am J Physiol Lung Cell Mol Physiol			Not related to pregnancy or designated pregnancy timeline
Is sprint exercise a leptin signaling mimetic in human skeletal muscle?	Guerra, B.	2011	Journal of applied physiology			Not related to pregnancy or designated pregnancy timeline
Heat stress enhances mTOR signaling after resistance exercise in human skeletal muscle.	Kakigi, R.	2011	The journal of physiological			Not related to pregnancy or designated pregnancy timeline
Inhibition of stress-activated MAP kinases induces clinical improvement in moderate to severe Crohn’s disease.	Hommes, D.	2002	Gastroenterology			Not related to pregnancy or designated pregnancy timeline
Increased atypical PKC activity in endurance-trained human skeletal muscle.	Nielsen, J.N.	2003	Biochemical and biophysical research communications			Not related to pregnancy or designated pregnancy timeline
Shear stress inhibits homocysteine-induced stromal cell-derived factor-1 expression in endothelial cells.	Sung, M.L.	2009	Circulation research			Not related to pregnancy or designated pregnancy timeline
Thiol-based antioxidant supplementation alters human skeletal muscle signaling and attenuates its inflammatory response and recovery after intense eccentric exercise.	Michailidis, Y.	2013	The American journal of clinical nutrition			Not related to pregnancy or designated pregnancy timeline
Exercise with low glycogen increases PGC-1? gene expression in human skeletal muscle.	Psilander, N.	2013	European journal of applied physiology			Not related to pregnancy or designated pregnancy timeline
Simvastatin reduces myocardial injury undergoing noncoronary artery cardiac surgery: a randomized controlled trial.	Almansob, M.A.	2012	Arteriosclerosis, thrombosis, and vascular biology			Not related to pregnancy or designated pregnancy timeline
Prognostic significance of phosphorylated P38 mitogen-activated protein kinase and HER-2 expression in lymph node-positive breast carcinoma.	Esteva, F.J.	2004	Cancer			Not related to pregnancy or designated pregnancy timeline
Insulin infusion suppresses while glucose infusion induces Toll-like receptors and high-mobility group-B1 protein expression in mononuclear cells of type 1 diabetes patients.	Dandona, P.	2013	American journal of physiology. Endocrinology and metabolism			Not related to pregnancy or designated pregnancy timeline
Carbohydrate feeding during recovery alters the skeletal muscle metabolic response to repeated sessions of high-intensity interval exercise in humans.	Cochran, A.J.	2010	Journal of applied physiology			Not related to pregnancy or designated pregnancy timeline
Inhibition of p38 mitogen-activated protein kinase: dose-dependent suppression of leukocyte and endothelial response after endotoxin challenge in humans.	Fijen, J.W.	2002	Critical care medicine			Not related to pregnancy or designated pregnancy timeline
Matched work high-intensity interval and continuous running induce similar increases in PGC-1? mRNA, AMPK, p38, and p53 phosphorylation in human skeletal muscle.	Bartlett, J.D.	2012	Journal of applied physiology			Not related to pregnancy or designated pregnancy timeline
Anti-inflammatory effects of a p38 mitogen-activated protein kinase inhibitor during human endotoxemia.	Branger, J.	2002	Journal of immunology			Not related to pregnancy or designated pregnancy timeline
An effector-reduced anti-?-amyloid (A?) antibody with unique a? binding properties promotes neuroprotection and glial engulfment of A?.	Adolfsson, O.	2012	The Journal of neuroscience : the official journal of the Society for Neuroscience			Not related to pregnancy or designated pregnancy timeline
Contribution of nonesterified fatty acids to mitogen-activated protein kinase activation in human skeletal muscle during endurance exercise.	Zbinden-Foncea, H.	2013	International journal of sport nutrition and exercise metabolism			Not related to pregnancy or designated pregnancy timeline
Time course of angiopoietin-2 release during experimental human endotoxemia and sepsis.	Kümpers, P.	2009	Critical care			Not related to pregnancy or designated pregnancy timeline
Cardiac contractility modulation electrical signals improve myocardial gene expression in patients with heart failure.	Butter, C.	2008	Journal of the American College of Cardiology			Not related to pregnancy or designated pregnancy timeline
Resveratrol, at concentrations attainable with moderate wine consumption, stimulates human platelet nitric oxide production.	Gresele, P.	2008	The Journal of nutrition			Not related to pregnancy or designated pregnancy timeline
Endotoxin increases plasma soluble tumor necrosis factor-related apoptosis-inducing ligand level mediated by the p38 mitogen-activated protein kinase signaling pathway.	Lub-de Hooge, M.N.	2004	Shock			Not related to pregnancy or designated pregnancy timeline
Increased HDL cholesterol and apoA-I in humans and mice treated with a novel SR-BI inhibitor.	Masson, D.	2009	Arteriosclerosis, thrombosis, and vascular biology			Not related to pregnancy or designated pregnancy timeline
Ischemic preconditioning by unstable angina reduces the release of CK-MB following CABG and stimulates left ventricular HSP-72 protein expression.	Vahlhaus, C.	2005	Journal of cardiac surgery			Not related to pregnancy or designated pregnancy timeline
Inhibition of coagulation, fibrinolysis, and endothelial cell activation by a p38 mitogen-activated protein kinase inhibitor during human endotoxemia.	Branger, J.	2003	Blood			Not related to pregnancy or designated pregnancy timeline
Single-dose pharmacokinetics and pharmacodynamics of RWJ 67657, a specific p38 mitogen-activated protein kinase inhibitor: a first-in-human study.	Parasrampuria, D.A.	2003	Journal of clinical pharmacology			Not related to pregnancy or designated pregnancy timeline
Cardiopulmonary and systemic effects of methylprednisolone in patients undergoing cardiac surgery.	Liakopoulos, O.J.	2007	The Annals of thoracic surgery			Not related to pregnancy or designated pregnancy timeline
Efficacy and safety of the oral p38 inhibitor PH-797804 in chronic obstructive pulmonary disease: a randomised clinical trial.	MacNee, W.	2013	Thorax			Not related to pregnancy or designated pregnancy timeline
A randomized, placebo-controlled study of the effects of the p38 MAPK inhibitor SB-681323 on blood biomarkers of inflammation in COPD patients.	Singh, D.	2010	Journal of clinical pharmacology			Not related to pregnancy or designated pregnancy timeline
Futsal and continuous exercise induce similar changes in specific skeletal muscle signalling proteins.	Serpiello, F.R.	2014	International journal of sports medicine			Not related to pregnancy or designated pregnancy timeline
Ammonia impairs neutrophil phagocytic function in liver disease.	Shawcross, D.L.	2008	Hepatology			Not related to pregnancy or designated pregnancy timeline
A Randomized Dose-Escalation Study of the Safety and Anti-Inflammatory Activity of the p38 Mitogen-Activated Protein Kinase Inhibitor Dilmapimod in Severe Trauma Subjects at Risk for Acute Respiratory Distress Syndrome.	Christie, J.D.	2015	Critical care medicine			Not related to pregnancy or designated pregnancy timeline
Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: results of two randomized, double-blind, placebo-controlled clinical studies.	Damjanov, N.	2009	Arthritis and rheumatism			Not related to pregnancy or designated pregnancy timeline
In silico and in vitro pharmacogenetics: aldehyde oxidase rapidly metabolizes a p38 kinase inhibitor.	Zhang, X.	2011	The pharmacogenomics journal			Not related to pregnancy or designated pregnancy timeline
Novel p38? mitogen-activated protein kinase inhibitor shows analgesic efficacy in acute postsurgical dental pain.	Tong, S.E.	2012	Journal of clinical pharmacology			Not related to pregnancy or designated pregnancy timeline
The effect of BMS-582949, a P38 mitogen-activated protein kinase (P38 MAPK) inhibitor on arterial inflammation: a multicenter FDG-PET trial.	Emami, H.	2015	Atherosclerosis			Not related to pregnancy or designated pregnancy timeline
An oral inhibitor of p38 MAP kinase reduces plasma fibrinogen in patients with chronic obstructive pulmonary disease.	Lomas, D.A.	2012	rnal of clinical pharmacology			Not related to pregnancy or designated pregnancy timeline
Anti-inflammatory properties of a novel N-phenyl pyridinone inhibitor of p38 mitogen-activated protein kinase: preclinical-to-clinical translation.	Hope, H.R.	2009	The Journal of pharmacology and experimental therapeutics			Not related to pregnancy or designated pregnancy timeline
A 24-week, randomized, double-blind, placebo-controlled, parallel group study of the efficacy of oral SCIO-469, a p38 mitogen-activated protein kinase inhibitor, in patients with active rheumatoid arthritis.	Genovese, M.C.	2011	The Journal of rheumatology			Not related to pregnancy or designated pregnancy timeline
Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double-blind, methotrexate-controlled study of patients with active rheumatoid arthritis.	Cohen, S.B.	2009	Arthritis and rheumatism			Not related to pregnancy or designated pregnancy timeline
Efficacy and safety of pamapimod in patients with active rheumatoid arthritis receiving stable methotrexate therapy.	Alten, R.E.	2010	of the rheumatic diseases			Not related to pregnancy or designated pregnancy timeline
Recombinant human activated protein C reduces human endotoxin-induced pulmonary inflammation via inhibition of neutrophil chemotaxis.	Nick, J.A.	2004	Blood			Not related to pregnancy or designated pregnancy timeline
Inhibition of p38 mitogen-activated protein kinase reduces inflammation after coronary vascular injury in humans.	Sarov-Blat, L.	2010	Arteriosclerosis, thrombosis, and vascular biology			Not related to pregnancy or designated pregnancy timeline
Impaired cardiometabolic responses to glucagon-like peptide 1 in obesity and type 2 diabetes mellitus.	Moberly, S.P.	2013	Basic research in cardiology			Not related to pregnancy or designated pregnancy timeline
Effects of p38 mitogen-activated protein kinase inhibition on vascular and systemic inflammation in patients with atherosclerosis.	Elkhawad, M.	2012	Cardiovascular imaging			Not related to pregnancy or designated pregnancy timeline
Clinical trial of the p38 MAP kinase inhibitor dilmapimod in neuropathic pain following nerve injury.	Anand, P.	2011	European journal of pain			Not related to pregnancy or designated pregnancy timeline
Adiponectin promotes the migration of circulating angiogenic cells through p38-mediated induction of the CXCR4 receptor.	Adams, V.	2013	International journal of cardiology			Not related to pregnancy or designated pregnancy timeline
Inhibition of p38 mitogen-activated protein kinase improves nitric oxide-mediated vasodilatation and reduces inflammation in hypercholesterolemia.	Cheriyan, J.	2011	Circulation			Not related to pregnancy or designated pregnancy timeline
Analgesic efficacy and safety of the novel p38 MAP kinase inhibitor, losmapimod, in patients with neuropathic pain following peripheral nerve injury: a double-blind, placebo-controlled study.	Ostenfeld, T.	2013	European journal of pain			Not related to pregnancy or designated pregnancy timeline
Rationale, design, and baseline characteristics in Evaluation of LIXisenatide in Acute Coronary Syndrome, a long-term cardiovascular end point trial of lixisenatide versus placebo.	Bentley-Lewis, R.	2015	American heart journal			Not related to pregnancy or designated pregnancy timeline
The study of LoSmapimod treatment on inflammation and InfarCtSizE (SOLSTICE): design and rationale.	Melloni, C.	2012	American heart journal			Not related to pregnancy or designated pregnancy timeline
A proof-of-concept and drug-drug interaction study of pamapimod, a novel p38 MAP kinase inhibitor, with methotrexate in patients with rheumatoid arthritis.	Zhang, X.	2010	Journal of clinical pharmacology			Not related to pregnancy or designated pregnancy timeline
Population pharmacokinetics of losmapimod in healthy subjects and patients with rheumatoid arthritis and chronic obstructive pulmonary diseases.	Yang, S.	2013	Clinical pharmacokinetics			Not related to pregnancy or designated pregnancy timeline
Rationale and design of the LosmApimod To Inhibit p38 MAP kinase as a TherapeUtic target and moDify outcomes after an acute coronary syndromE trial.	O’Donoghue, M.L.	2015	American heart journal			Not related to pregnancy or designated pregnancy timeline
Randomized, dose-escalation study of the p38? MAPK inhibitor SCIO-469 in patients with myelodysplastic syndrome.	Sokol, L.	2013	Leukemia			Not related to pregnancy or designated pregnancy timeline
Oral p38 mitogen-activated protein kinase inhibition with BIRB 796 for active Crohn’s disease: a randomized, double-blind, placebo-controlled trial.	Schreiber, S.	2006	Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association			Not related to pregnancy or designated pregnancy timeline
Efficacy and safety of the p38 MAPK inhibitor losmapimod for patients with chronic obstructive pulmonary disease: a randomised, double-blind, placebo-controlled trial.	Watz, H.	2014	The Lancet. Respiratory medicine			Not related to pregnancy or designated pregnancy timeline
Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial.	Newby, L.K.	2014	Lancet			Not related to pregnancy or designated pregnancy timeline
Programmed Fetal Membrane Senescence and Exosome-Mediated Signaling: A Mechanism Associated With Timing of Human Pregancy.	Menon, R.	2017	Frontiers in Endocrinology			Review
Reciprocal regulation of beta2-adrenoceptor-activated cAMP response-element binding protein signalling by arrestin2 and arrestin 3	Pearce, A.	2017	Cellular Signalling	Human	Myometrium
Differential senescence in feto-maternal tissues during mouse pregnancy.	Bonney, E.A.	2016	Placenta	Mice	Fetal membrane and placenta
Induction of pro-inflammatory genes by serum amyloid A1 in human amnion fibroblasts.	Li, W.	2017	Scientific Reports	Human	Fetal membrane
Human fetal membranes at term: Dead tissue or signalers of parturition?.	Menon, R.	2016	Placetna			Review
Amnion-Epithelial-Cell-Derived Exosomes Demonstrate Physiologic State of Cell under Oxidative Stress.	Sheller, S.	2016	PLos One	Human	Amnion cells
Novel concepts on pregnancy clocks and alarms: redundancy and synergy in human parturition.	Menon, R.	2016	Human Reproduction Update			Review
Preclinical evaluation of drugs to block inflammation-driven preterm birth.	Ireland, D.J.	2017	Innate Immunity	Human	Fetal membrane and placenta
p38 Mitogen activated protein kinase (MAPK): a new therapeutic target for reducing the risk of adverse pregnancy outcomes.	Menon, R.	2016	Expert Opinion on Therapeutic Targets			Review
Differential Effects of Oxytocin Receptor Antagonists, Atosiban and Nolasiban, on Oxytocin Receptor-Mediated Signaling in Human Amnion and Myometrium.	Kim, S. H.	2017	Molecular Pharmacology	Human	Fetal membrane, placenta, myometrium
Protein O-fucosyltransferase 1 promotes trophoblast cell proliferation through activation of MAPK and PI3K/Akt signaling pathways	Liu, C.	2017	Biomedicine & pharmacotherapy	Human	Trophoblast cell lines
Placental membrane aging and HMGB1 signaling associated with human parturition	Menon, R.	2016	Aging	Human	Amnion cells
Impact of Axis of GHRH and GHRH Receptor on Cell Viability and Apoptosis of the Placental Choriocarcinoma Cell Line.	Liu, A.X.	2016	Current Molecular Medicine	Human	Trophoblast cell lines
Sustained Endocannabinoid Signaling Compromises Decidual Function and Promotes Inflammation-induced Preterm Birth.	Sun, X.	2016	Journal of Biological Chemistry	Human	Decidua
The endocannabinoid 2-arachidonoylglycerol dysregulates the synthesis of proteins by the human syncytiotrophoblast	Costa, M.A.	2016	Biochimica et Biophysica Acta	Human	Cytotrophoblast
Oxidative stress damage-associated molecular signaling pathways differentiate spontaneous preterm birth and preterm premature rupture of the membranes	Dutta, E.H.	2016	Molecular Human Reproduction	Human	Amnion cells
The oxytocin receptor antagonist, Atosiban, activates pro-inflammatory pathways in human amnion via G(alphai) signalling.	Kim, S.H.	2016	Molecular & Cellular Endocrinology	Human	Fetal membrane
Restraint of Trophoblast Invasion of the Uterus by Decorin: Role in Pre-eclampsia	Nandi, P.	2016	American Journal of Reproductive Immunology			Review
Quercetin alleviates generalizaed hyperalgesia in mice with induced adenomyosis	Nie, J.C.	2017	Molecular medicine reports	Mice	Placenta
adiponectin stimulates lipid metabolism via AMPK in rabbit blastocysts	Schindler, M.	2017	Human Reproduction			Not related to pregnancy or designated pregnancy timeline
Mapping out p38MAPK	Bonney, EA	2017	American Journal of Reproductive Immunology			Review
Inhibitory effects of emodin, thymol, and astragalin on leptospira interrogans - induced inflammatory response in the uterine and endometrium epithelila cells of mice	Zhang, W.	2017	Inflammation	Mice	Uterus
Pioglitazone induces cell growth arrest and activates mitochondrial apoptosis in human uterine leiomyosrcomacells by a peroxisome proliferator-activated receptor gamma-independent mechanism	Lutzen, U.	2016	Naunyn-Schmiedeberg’s Archives of Pharmacology			Not related to pregnancy or designated pregnancy timeline
Mechanistic differences leading to infectious and sterile inflammation	Behnia, F.	2016	American Journal of Reproductive Immunology	Human	Fetal membrane
Involvment of p38/MMP9/TIMP1 in premature rupture of the human fetal membranes	Zonghua, L.	2016	International Journal of Clinical Experimental Pathology	Human	Fetal membrane

Appendix 2: Articles excluded after initial review of the systematic review articles

Title	Author	Year Published	Journal Title	Species	Tissue/ Cell Type	Exculsion criteria
Increased expression of a novel heat shock protein transcript in the mouse uterus during decidualization and in response to progesterone	Bany, B. M.	2001	Biology of Reproduction			Not related to p38 MAPK
Haymaker gene expression in malignant and normal gynecologic tissues	Borowsky, M. E.	2006	Journal of Histochemistry & Cytochemistry			Not related to p38 MAPK
Multiple alternative splicing and differential expression pattern of the glycogen synthase kinase-3beta (GSK3beta) gene in goat (Capra hircus)	Hou, Y.	2014	PLoS ONE			Not related to p38 MAPK
Altered Expression of Enzymes Regulating the Activity of Endothelin-1 in the Lower Segment of the Human Amnion During Labor	Kotani, T.	2013	Biology of Reproduction			Not related to p38 MAPK
Differential COX localization and PG release in Thy-1(+) and Thy-1(-) human female reproductive tract fibroblasts	Koumas, L.	2002	American Journal of Physiology - Cell Physiology			Not related to p38 MAPK
Concurrent dinoprostone and oxytocin for labor induction in term premature rupture of membranes: a randomized controlled trial	Tan, P. C.	2009	Obstetrics & Gynecology			Not related to p38 MAPK
Cardiac myocyte cell cycle control in development, disease, and regeneration	Ahuja, P.	2007	Physiological Reviews			Review
Oxytocin receptor signalling	Devost, D.	2008	Progress in Brain Research/ Advances in Vasopressin and Oxytocin: from Genes to Behaviour to Disease			Review
Pharmacological inhibition of inflammatory pathways for the prevention of preterm birth	Keelan, J. A.	2011	Journal of Reproductive Immunology			Review
Oxidative stress damage as a detrimental factor in preterm birth pathology	Menon, R.	2014	Frontiers in Immunology			Review
Drugs to block cytokine signaling for the prevention and treatment of inflammation-induced preterm birth	Ng, P. Y.	2015	Frontiers in Immunology			Review
Pathophysiology of thrombosis and pregnancy morbidity in the antiphospholipid syndrome	Oku, K.	2012	European Journal of Clinical Investigation			Review
Species Comparison of the Role of p38 MAP Kinase in the Female Reproductive System	Radi, Z. A.	2009	Journal of Toxicologic Pathology			Review
IL-1beta during in vitro decidualization in primate	Strakova, Z.	2002	Journal of Reproductive Immunology			Review
The stress-activated protein kinase Hog1 develops a critical role after resting state	Escote, X.	2011	Mol Microbiol			Review
Cellular senescence and chromatin structure	Funayama, R.	2007	Chromosoma			Review
Programmed Fetal Membrane Senescence and Exosome-Mediated Signaling: A Mechanism Associated With Timing of Human Pregancy.	Menon, R.	2017	Frontiers in Endocrinology			Review
Human fetal membranes at term: Dead tissue or signalers of parturition?.	Menon, R.	2016	Placetna			Review
Novel concepts on pregnancy clocks and alarms: redundancy and synergy in human parturition.	Menon, R.	2016	Human Reproduction Update			Review
p38 Mitogen activated protein kinase (MAPK): a new therapeutic target for reducing the risk of adverse pregnancy outcomes.	Menon, R.	2016	Expert Opinion on Therapeutic Targets			Review
Restraint of Trophoblast Invasion of the Uterus by Decorin: Role in Pre-eclampsia	Nandi, P.	2016	American Journal of Reproductive Immunology			Review
Mapping out p38MAPK	Bonney, EA	2017	American Journal of Reproductive Immunology			Review
MEK modulates force-fluctuation-induced relengthening of canine tracheal smooth muscle	Dowell, M. L.	2010	European Respiratory Journal			Not related to pregnancy or designated pregnancy timeline
In anesthetized pigs human chorionic gonadotropin increases myocardial perfusion and function through a beta-adrenergic-related pathway and nitric oxide	Grossini, E.	2013	Journal of Applied Physiology			Not related to pregnancy or designated pregnancy timeline
Expression and Prognostic Value of Activating Transcription Factor 2 (ATF2) and its Phosphorylated Form in Mammary Carcinomas	Knippen, S.	2009	Anticancer Research			Not related to pregnancy or designated pregnancy timeline
A maternal diet rich in fish oil may improve cardiac Akt-related signaling in the offspring of diabetic mother rats	Nasu-Kawaharada, R.	2013	Nutrition			Not related to pregnancy or designated pregnancy timeline
C5a receptor-deficient mice are protected from thrombophilia and endothelial cell activation induced by some Antiphospholipid antibodies	Romay-Penabad, Z.	2007	Autoimmunity, Pt D: Autoimmune Disease, Annus Mirabilis			Not related to pregnancy or designated pregnancy timeline
Epidermal growth factor induces Ca2+ sensitization through Rho-kinase-dependent phosphorylation of myosin phosphatase target subunit 1 in vascular smooth muscle	Sasahara, T.	2015	European Journal of Pharmacology			Not related to pregnancy or designated pregnancy timeline
Phosphorylated HSP27 modulates the association of phosphorylated caldesmon with tropomyosin in colonic smooth muscle	Somara, S.	2006	American Journal of Physiology-Gastrointestinal and Liver Physiology			Not related to pregnancy or designated pregnancy timeline
Growth restriction before and after birth increases kinase signaling pathways in the adult rat heart	Wadley, G. D.	2010	Journal of Developmental Origins of Health and Disease			Not related to pregnancy or designated pregnancy timeline
Computational identification of a p38SAPK-regulated transcription factor network required for tumor cell quiescence	Adam, A. P.	2009	Cancer Res			Not related to pregnancy or designated pregnancy timeline
Thiol depletion induces apoptosis in cultured lung fibroblasts	Aoshiba, K.	1999	American Journal Respir Cell Mol Biology			Not related to pregnancy or designated pregnancy timeline
Maintenance of quiescent hematopoietic stem cells in the osteoblastic niche	Arai, F.	2007	Ann N Y Acad Sci			Not related to pregnancy or designated pregnancy timeline
Comparison of H2O2-induced vasoconstriction in the abdominal aorta and mesenteric artery of the mouse	Ardanaz, N.	2007	Vascul Pharmacol			Not related to pregnancy or designated pregnancy timeline
Cell cycle control during liver development in the rat: evidence indicating a role for cyclin D1 posttranscriptional regulation	Awad, M. M.	2000	Cell Growth Differ			Not related to pregnancy or designated pregnancy timeline
Growth regulation via p38 mitogen-activated protein kinase in developing liver	Awad, M. M.	2000	J Biol Chem			Not related to pregnancy or designated pregnancy timeline
Hydrogen peroxide modulates the proliferation/quiescence switch in the liver during embryonic development and posthepatectomy regeneration	Bai, H.	2015	Antioxid Redox Signal			Not related to pregnancy or designated pregnancy timeline
Human muscle satellite cells show age-related differential expression of S100B protein and RAGE	Beccafico, S.	2011	Age			Not related to pregnancy or designated pregnancy timeline
Integration of Golgi trafficking and growth factor signaling by the lipid phosphatase SAC1	Blagoveshchenskaya, A.	2008	J Cell Biol			Not related to pregnancy or designated pregnancy timeline
The central role of muscle stem cells in regenerative failure with aging	Blau, H. M.	2015	Nat Med			Not related to pregnancy or designated pregnancy timeline
Dominant-negative TAK1 induces c-Myc and G(0) exit in liver	Bradham, C. A.	2001	Am J Physiol Gastrointest Liver Physiol			Not related to pregnancy or designated pregnancy timeline
Retinoblastoma suppression of matrix metalloproteinase 1, but not interleukin-6, through a p38-dependent pathway in rheumatoid arthritis synovial fibroblasts	Bradley, K.	2004	Arthritis Rheum			Not related to pregnancy or designated pregnancy timeline
The vascular NADPH oxidase subunit p47phox is involved in redox-mediated gene expression	Brandes, R. P.	2002	Free Radic Biol Med			Not related to pregnancy or designated pregnancy timeline
p27(Kip1) inhibits tissue factor expression	Breitenstein, A.	2013	Biochem Biophys Res Commun			Not related to pregnancy or designated pregnancy timeline
c-MYC protein is degraded in response to UV irradiation	Britton, S.	2008	Cell Cycle			Not related to pregnancy or designated pregnancy timeline
Sphingosine 1-phosphate stimulates proliferation and migration of satellite cells: role of S1P receptors	Calise, S.	2012	Biochim Biophys Acta			Not related to pregnancy or designated pregnancy timeline
Role of p38 in the regulation of renal cortical cyclooxygenase-2 expression by extracellular chloride	Cheng, H. F.	2000	J Clin Invest			Not related to pregnancy or designated pregnancy timeline
Inhibition of SAPK2/p38 enhances sensitivity to mTORC1 inhibition by blocking IRES-mediated translation initiation in glioblastoma	Cloninger, C.	2011	Mol Cancer Ther			Not related to pregnancy or designated pregnancy timeline
Hypoxia-induced proliferative response of vascular adventitial fibroblasts is dependent on g protein-mediated activation of mitogen-activated protein kinases	Das, M.	2001	J Biol Chem			Not related to pregnancy or designated pregnancy timeline
Transient expression of FRNK reveals stage-specific requirement for focal adhesion kinase activity in cardiac growth	DiMichele, L. A.	2009	Circ Res			Not related to pregnancy or designated pregnancy timeline
Resistin mediates the hepatic stellate cell phenotype	Dong, Z. X.	2013	World J Gastroenterol			Not related to pregnancy or designated pregnancy timeline
Vitamin E (alpha-tocopherol) attenuates cyclo-oxygenase 2 transcription and synthesis in immortalized murine BV-2 microglia	Egger, T.	2003	Biochem J			Not related to pregnancy or designated pregnancy timeline
A male-specific role for p38 mitogen-activated protein kinase in germ cell sex differentiation in mice	Ewen, K.	2010	Biol Reprod			Not related to pregnancy or designated pregnancy timeline
Regulation of tyrosinase-related protein-2 (TYRP2) in human melanocytes: relationship to growth and morphology	Frost, P.	2009	Mol Cancer Ther			Not related to pregnancy or designated pregnancy timeline
Prostaglandin E(2) regulates the level and stability of cyclooxygenase-2 mRNA through activation of p38 mitogen-activated protein kinase in interleukin-1 beta-treated human synovial fibroblasts	Faour, W.H.	2001	Journal of Biological Chemistry			Not related to pregnancy or designated pregnancy timeline
Cytosolic phospholipase A2 activation by the p38 kinase inhibitor SB203580 in rabbit aortic smooth muscle cells	Fatima, S.	2001	Journal of Pharmacology and Experimental Therapeutics			Not related to pregnancy or designated pregnancy timeline
Globular adiponectin activates motility and regenerative traits of muscle satellite cells	Fiaschi, T.	2012	PLoS One			Not related to pregnancy or designated pregnancy timeline
The neurotrophic factor receptor RET drives haematopoietic stem cell survival and function	Fonseca-Pereira, D.	2014	Nature			Not related to pregnancy or designated pregnancy timeline
GATA-3 regulates the self-renewal of long-term hematopoietic stem cells	Frelin, C.	2013	Nature Immunology			Not related to pregnancy or designated pregnancy timeline
Regulation of D-cyclin translation inhibition in myeloma cells treated with mammalian target of rapamycin inhibitors: rationale for combined treatment with extracellular signal-regulated kinase inhibitors and rapamycin	Frost, P.	2009	Molecular Cancer Therapeutics			Not related to pregnancy or designated pregnancy timeline
ESE-3, an Ets family transcription factor, is up-regulated in cellular senescence	Fujikawa, M.	2007	Cancer Sci			Not related to pregnancy or designated pregnancy timeline
p38 MAPK mediates fibrogenic signal through Smad3 phosphorylation in rat myofibroblasts	Furukawa, F.	2003	Hepatology			Not related to pregnancy or designated pregnancy timeline
Decreased mitochondrial nitric oxide synthase activity and hydrogen peroxide relate persistent tumoral proliferation to embryonic behavior	Galli, S.	2003	Cancer Res			Not related to pregnancy or designated pregnancy timeline
Tumor cell phenotype is sustained by selective MAPK oxidation in mitochondria	Galli, S.	2008	PLoS One			Not related to pregnancy or designated pregnancy timeline
8-Amino-adenosine induces loss of phosphorylation of p38 mitogen-activated protein kinase, extracellular signal-regulated kinase 1/2, and Akt kinase: role in induction of apoptosis in multiple myeloma	Ghias, K.	2005	Mol Cancer Ther			Not related to pregnancy or designated pregnancy timeline
Gas6-mediated survival in NIH3T3 cells activates stress signalling cascade and is independent of Ras	Goruppi, S.	1999	Oncogene			Not related to pregnancy or designated pregnancy timeline
Cell density impacts epigenetic regulation of cytokine-induced E-selectin gene expression in vascular endothelium	Hamada, K.	2014	PLoS One			Not related to pregnancy or designated pregnancy timeline
Wounding activates p38 map kinase and activation transcription factor 3 in leading keratinocytes	Harper, E. G.	2005	J Cell Sci			Not related to pregnancy or designated pregnancy timeline
Post-transcriptional regulation of satellite cell quiescence by TTP-mediated mRNA decay	Hausburg, M. A.	2015	Elife			Not related to pregnancy or designated pregnancy timeline
Secretory phospholipase A2 activates the cascade of mitogen-activated protein kinases and cytosolic phospholipase A2 in the human astrocytoma cell line 1321N1	Hernandez, M.	1998	J Biol Chem			Not related to pregnancy or designated pregnancy timeline
All-trans-retinoic acid ameliorates carbon tetrachloride-induced liver fibrosis in mice through modulating cytokine production	Hisamori, S.	2008	Liver Int			Not related to pregnancy or designated pregnancy timeline
Function of oxidative stress in the regulation of hematopoietic stem cell-niche interaction	Hosokawa, K.	2007	Biochem Biophys Res Commun			Not related to pregnancy or designated pregnancy timeline
5-HT(2B) antagonism arrests non-canonical TGF-beta1-induced valvular myofibroblast differentiation	Hutcheson, J. D.	2012	J Mol Cell Cardiol			Not related to pregnancy or designated pregnancy timeline
Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells	Ito, K.	2006	Nat Med			Not related to pregnancy or designated pregnancy timeline
p38-MAPK- and caspase-3-mediated superoxide-induced apoptosis of rat hepatic stellate cells: reversal by retinoic acid	Jameel, N. M.	2009	J Cell Physiol			Not related to pregnancy or designated pregnancy timeline
A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche	Jang, Y. Y.	2007	Blood			Not related to pregnancy or designated pregnancy timeline
3′,4′-Dihydroxyflavonol down-regulates monocyte chemoattractant protein-1 in smooth muscle: role of focal adhesion kinase and PDGF receptor signalling	Jiang, F.	2009	Br J Pharmacol			Not related to pregnancy or designated pregnancy timeline
The p38alpha/beta MAPK functions as a molecular switch to activate the quiescent satellite cell	Jones, N. C.	2005	J Cell Biol			Not related to pregnancy or designated pregnancy timeline
Raf-1 is activated by the p38 mitogen-activated protein kinase inhibitor, SB203580	Kalmes, A.	1999	FEBS Lett			Not related to pregnancy or designated pregnancy timeline
Activation of extracellular signal-regulated kinase through B-cell antigen receptor in B-cell chronic lymphocytic leukemia	Kawauchi, K.	2002	Int J Hematol			Not related to pregnancy or designated pregnancy timeline
Hypoosmotic stress activates p38, ERK 1 and 2, and SAPK/JNK in rat hepatocytes	Kim, R. D.	200	J Surg Res			Not related to pregnancy or designated pregnancy timeline
High extracellular [Mg2+]-induced increase in intracellular [Mg2+] and decrease in intracellular [Na+] are associated with activation of p38 MAP kinase and ERK2 in guinea-pig heart	Kim, S. J.	2008	Exp Physiol			Not related to pregnancy or designated pregnancy timeline
The isoprostane 8-iso-PGF2alpha suppresses monocyte adhesion to human microvascular endothelial cells via two independent mechanisms	Kumar, A.	2005	Faseb j			Not related to pregnancy or designated pregnancy timeline
Inducible nitric oxide synthase gene deletion exaggerates MAPK-mediated cyclooxygenase-2 induction by inflammatory stimuli	Lamon, B. D.	2010	Am J Physiol Heart Circ Physiol			Not related to pregnancy or designated pregnancy timeline
Effects of ras transformation on the induction of the IL-1 receptor related T1 gene in response to mitogens, anisomycin, IL-1 and TNFalpha	Laursen, N. B.	1998	Oncogene			Not related to pregnancy or designated pregnancy timeline
Ultraviolet radiation (UVR) activates p38 MAP kinase and induces post-transcriptional stabilization of the C/EBPdelta mRNA in G0 growth arrested mammary epithelial cells	Li, B.	2008	J Cell Biochem			Not related to pregnancy or designated pregnancy timeline
Myocyte contractile activity modulates norepinephrine cytotoxicity and survival effects of neuregulin-1beta	Kuramochi, Y.	2004	Am J Physiol Cell Physiol			Not related to pregnancy or designated pregnancy timeline
CDK11(p58) promotes rat astrocyte inflammatory response via activating p38 and JNK pathways induced by lipopolysaccharide	Liu, X.	2012	Neurochem Res			Not related to pregnancy or designated pregnancy timeline
Initiation of caspase-independent death in mouse mesangial cells by Cd2+: involvement of p38 kinase and CaMK-II	Liu, Y.	2008	J Cell Physiol			Not related to pregnancy or designated pregnancy timeline
Differential activation of mitogenic signaling pathways in aortic smooth muscle cells deficient in superoxide dismutase isoforms	Madamanchi, N. R.	2005	Arterioscler Thromb Vasc Biol			Not related to pregnancy or designated pregnancy timeline
Tristetraprolin regulates Cyclin D1 and c-Myc mRNA stability in response to rapamycin in an Akt-dependent manner via p38 MAPK signaling	Marderosian, M.	2006	Oncogene			Not related to pregnancy or designated pregnancy timeline
Ligands of peroxisome proliferator-activated receptor gamma modulate profibrogenic and proinflammatory actions in hepatic stellate cells	Marra, F.	2000	Gastroenterology			Not related to pregnancy or designated pregnancy timeline
Urotensin II is an autocrine/paracrine growth factor for the porcine renal epithelial cell line, LLCPK1	Matsushita, M.	2003	Endocrinology			Not related to pregnancy or designated pregnancy timeline
Vitamin A inhibits pancreatic stellate cell activation: implications for treatment of pancreatic fibrosis	McCarroll, J. A.	2006	Gut			Not related to pregnancy or designated pregnancy timeline
The role of caldesmon in the regulation of endothelial cytoskeleton and migration	Mirzapoiazova, T.	2005	J Cell Physiol			Not related to pregnancy or designated pregnancy timeline
Foxo3a is essential for maintenance of the hematopoietic stem cell pool	Miyamoto, K.	2007	Cell Stem Cell			Not related to pregnancy or designated pregnancy timeline
Endotoxin priming of neutrophils requires NADPH oxidase-generated oxidants and is regulated by the anion transporter ClC-3	Moreland, J. G.	2007	J Biol Chem			Not related to pregnancy or designated pregnancy timeline
Involvement of stress-activated protein kinase and p38/RK mitogen-activated protein kinase signaling pathways in the enhanced phosphorylation of initiation factor 4E in NIH 3T3 cells	Morley, S. J.	1997	J Biol Chem			Not related to pregnancy or designated pregnancy timeline
Oxidative stress-induced apoptosis in dividing fibroblasts involves activation of p38 MAP kinase and over-expression of Bax: resistance of quiescent cells to oxidative stress	Naderi, J.	2003	Apoptosis			Not related to pregnancy or designated pregnancy timeline
ROS detoxification and proinflammatory cytokines are linked by p38 MAPK signaling in a model of mature astrocyte activation	Nahirnyj, A.	2013	PLoS One			Not related to pregnancy or designated pregnancy timeline
Anti-apoptotic action of hepatocyte growth factor through mitogen-activated protein kinase on human aortic endothelial cells	Nakagami, H.	2000	J Hypertens			Not related to pregnancy or designated pregnancy timeline
Differential effect of simvastatin on activation of Rac(1) vs. activation of the heat shock protein 27-mediated pathway upon oxidative stress, in human smooth muscle cells	Negre-Aminou, P.	2002	Biochem Pharmacol			Not related to pregnancy or designated pregnancy timeline
Oxidative-stress and IL-6 mediate the fibrogenic effects of Kupffer cells on stellate cells	Nieto, N.	2006	Hepatology			Not related to pregnancy or designated pregnancy timeline
Regulation of tissue factor in microvascular dermal endothelial cells	O’Reilly, F. M.	2003	J Invest Dermatol			Not related to pregnancy or designated pregnancy timeline
Opposed effects of lithium on the MEK-ERK pathway in neural cells: inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms	Pardo, R.	2003	J Neurochem			Not related to pregnancy or designated pregnancy timeline
The flavonoid quercetin induces apoptosis and inhibits JNK activation in intimal vascular smooth muscle cells	Perez-Vizcaino, F.	2006	Biochem Biophys Res Commun			Not related to pregnancy or designated pregnancy timeline
Simultaneous Increases in Proliferation and Apoptosis of Vascular Smooth Muscle Cells Accelerate Diabetic Mouse Venous Atherosclerosis	Ping, S.	2015	PLoS One			Not related to pregnancy or designated pregnancy timeline
Stress-activated protein kinases in the activation of rat hepatic stellate cells in culture	Reeves, H. L.	2000	J Hepatol			Not related to pregnancy or designated pregnancy timeline
Effects of angiotensin II on rat pancreatic stellate cells	Reinehr, R.	2004	Pancreas			Not related to pregnancy or designated pregnancy timeline
p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF-1	Richard, D. E.	1999	J Biol Chem			Not related to pregnancy or designated pregnancy timeline
Efficient adult skeletal muscle regeneration in mice deficient in p38beta, p38gamma and p38delta MAP kinases	Ruiz-Bonilla, V.	2008	Cell Cycle			Not related to pregnancy or designated pregnancy timeline
Sphingolipid-mediated restoration of Mitf expression and repigmentation in vivo in a mouse model of hair graying	Saha, B.	2009	Pigment Cell Melanoma Res			Not related to pregnancy or designated pregnancy timeline
High Mda-7 expression promotes malignant cell survival and p38 MAP kinase activation in chronic lymphocytic leukemia	Sainz-Perez, A.	2006	Leukemia			Not related to pregnancy or designated pregnancy timeline
CREB downregulation in vascular disease: a common response to cardiovascular risk	Schauer, I. E.	2010	Arterioscler Thromb Vasc Biol			Not related to pregnancy or designated pregnancy timeline
ATF6alpha-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo	Schewe, D. M.	2008	Proc Natl Acad Sci U S A			Not related to pregnancy or designated pregnancy timeline
TAK1/JNK and p38 have opposite effects on rat hepatic stellate cells	Schnabl, B.	2001	Hepatology			Not related to pregnancy or designated pregnancy timeline
Analysis of R-Ras signalling pathways	Self, A. J.	2001	J Cell Sci			Not related to pregnancy or designated pregnancy timeline
Skeletal muscle cell activation by low-energy laser irradiation: a role for the MAPK/ERK pathway	Shefer, G.	2001	J Cell Physiol			Not related to pregnancy or designated pregnancy timeline
Cyclin D1 and c-myc internal ribosome entry site (IRES)-dependent translation is regulated by AKT activity and enhanced by rapamycin through a p38 MAPK- and ERK-dependent pathway	Shi, Y.	2005	J Biol Chem			Not related to pregnancy or designated pregnancy timeline
The MAP kinase pathway is involved in odontoblast stimulation via p38 phosphorylation	Simon, S.	2010	J Endod			Not related to pregnancy or designated pregnancy timeline
Osteopontin mediates hypoxia-induced proliferation of cultured mesangial cells: role of PKC and p38 MAPK	Sodhi, C. P.	2000	Kidney Int			Not related to pregnancy or designated pregnancy timeline
Hypoxia stimulates osteopontin expression and proliferation of cultured vascular smooth muscle cells: potentiation by high glucose	Sodhi, C. P.	2001	Diabetes			Not related to pregnancy or designated pregnancy timeline
ERK1/2 and p38alpha/beta signaling in tumor cell quiescence: opportunities to control dormant residual disease	Sosa, M. S.	2011	Clin Cancer Res			Not related to pregnancy or designated pregnancy timeline
Differential regulation of the mitogen-activated protein and stress-activated protein kinase cascades by adrenergic agonists in quiescent and regenerating adult rat hepatocytes	Spector, M. S.	1997	Mol Cell Biol			Not related to pregnancy or designated pregnancy timeline
Survival of retinal pigment epithelium after exposure to prolonged oxidative injury: a detailed gene expression and cellular analysis	Strunnikova, N.	2004	Invest Ophthalmol Vis Sci			Not related to pregnancy or designated pregnancy timeline
Redox regulation of vascular smooth muscle cell differentiation	Su, B.	2001	Circ Res			Not related to pregnancy or designated pregnancy timeline
Antinociceptive action of a p38alpha MAPK inhibitor, SD-282, in a diabetic neuropathy model	Sweitzer, S. M.	2004	Pain			Not related to pregnancy or designated pregnancy timeline
Activation of villous trophoblastic p38 and ERK1/2 signaling pathways in preterm preeclampsia and HELLP syndrome	Szabo, S.	2015	Pathology & Oncology Research			Not related to pregnancy or designated pregnancy timeline
Hematopoietic stem cell quiescence and function are controlled by the CYLD-TRAF2-p38MAPK pathway	Tesio, M.	2015	J Exp Med			Not related to pregnancy or designated pregnancy timeline
Expression and suppressive effects of interleukin-19 on vascular smooth muscle cell pathophysiology and development of intimal hyperplasia	Tian, Y.	2008	Am J Pathol			Not related to pregnancy or designated pregnancy timeline
Hypercholesterolemia induces oxidant stress that accelerates the ageing of hematopoietic stem cells	Tie, G.	2014	J Am Heart Assoc			Not related to pregnancy or designated pregnancy timeline
ERK1/2 and p38 cooperate to induce a p21CIP1-dependent G1 cell cycle arrest	Todd, D. E.	2004	Oncogene			Not related to pregnancy or designated pregnancy timeline
Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway	Todd, J. L.	1999	J Biol Chem			Not related to pregnancy or designated pregnancy timeline
Coordination of satellite cell activation and self-renewal by Par-complex-dependent asymmetric activation of p38alpha/beta MAPK	Troy, A.	2012	Cell Stem Cell			Not related to pregnancy or designated pregnancy timeline
Activation of extracellular signal-regulated kinases is essential for pressure-induced proliferation of vascular smooth muscle cells	Tsuda, Y.	2002	Eur J Pharmacol			Not related to pregnancy or designated pregnancy timeline
S100B in myoblasts regulates the transition from activation to quiescence and from quiescence to activation and reduces apoptosis	Tubaro, C.	2011	Biochim Biophys Acta			Not related to pregnancy or designated pregnancy timeline
Role of mitogen-activated protein kinases in 4-hydroxy-2-nonenal-induced actin remodeling and barrier function in endothelial cells	Usatyuk, P. V.	2004	J Biol Chem			Not related to pregnancy or designated pregnancy timeline
Suppression of p38-stress kinase sensitizes quiescent leukemic cells to anti-mitotic drugs by inducing proliferative responses in them	Vaidya, A. A.	2008	Cancer Biol Ther			Not related to pregnancy or designated pregnancy timeline
Insulin-like growth factor 1 receptor and p38 mitogen-activated protein kinase signals inversely regulate signal transducer and activator of transcription 3 activity to control human dental pulp stem cell quiescence, propagation, and differentiation	Vandomme, J.	2014	Stem Cells Dev			Not related to pregnancy or designated pregnancy timeline
Impaired CD200-CD200R-mediated microglia silencing enhances midbrain dopaminergic neurodegeneration: roles of aging, superoxide, NADPH oxidase, and p38 MAPK	Wang, X. J.	2011	Free Radic Biol Med			Not related to pregnancy or designated pregnancy timeline
Vanadium-induced STAT-1 activation in lung myofibroblasts requires H2O2 and P38 MAP kinase	Wang, Y. Z.	2003	Free Radic Biol Med			Not related to pregnancy or designated pregnancy timeline
Down-regulation of intrinsic P-glycoprotein expression in multicellular prostate tumor spheroids by reactive oxygen species	Wartenberg, M.	2001	J Biol Chem			Not related to pregnancy or designated pregnancy timeline
Hyperplastic Growth of Pulmonary Artery Smooth Muscle Cells from Subjects with Pulmonary Arterial Hypertension Is Activated through JNK and p38 MAPK	Wilson, J. L.	2015	PLoS One			Not related to pregnancy or designated pregnancy timeline
Modulating the dysregulated migration of pulmonary arterial hypertensive smooth muscle cells with motif mimicking cell permeable peptides	Wilson, J. L.	2015	Curr Top Pept Protein Res			Not related to pregnancy or designated pregnancy timeline
Differential transcriptional responses of keloid and normal keratinocytes to serum stimulation	Xia, W.	2006	J Surg Res			Not related to pregnancy or designated pregnancy timeline
p38 mitogen-activated protein kinase and liver X receptor-alpha mediate the leptin effect on sterol regulatory element binding protein-1c expression in hepatic stellate cells	Yan, K.	2012	Mol Med			Not related to pregnancy or designated pregnancy timeline
Rapid isolation and culture of primary microglia from adult mouse spinal cord	Yip, P. K.	2009	J Neurosci Methods			Not related to pregnancy or designated pregnancy timeline
Modulation of endothelial cell growth arrest and apoptosis by vascular endothelial growth inhibitor	Yu, J.	2001	Circ Res			Not related to pregnancy or designated pregnancy timeline
Gene expression of cyclin-dependent kinase inhibitors and effect of heparin on their expression in mice with hypoxia-induced pulmonary hypertension	Yu, L.	2006	Biochem Biophys Res Commun			Not related to pregnancy or designated pregnancy timeline
c-Jun NH2-terminal kinase mediation of angiotensin II-induced proliferation of human mesangial cells	Zhang, A.	2005	Am J Physiol Renal Physiol			Not related to pregnancy or designated pregnancy timeline
Bacterial heat shock protein-60 increases epithelial cell proliferation through the ERK1/2 MAP kinases	Zhang, L.	2001	Exp Cell Res			Not related to pregnancy or designated pregnancy timeline
Gene suppression by tristetraprolin and release by the p38 pathway	Zhu, W.	2001	Am J Physiol Lung Cell Mol Physiol			Not related to pregnancy or designated pregnancy timeline
Is sprint exercise a leptin signaling mimetic in human skeletal muscle?	Guerra, B.	2011	Journal of applied physiology			Not related to pregnancy or designated pregnancy timeline
Heat stress enhances mTOR signaling after resistance exercise in human skeletal muscle.	Kakigi, R.	2011	The journal of physiological			Not related to pregnancy or designated pregnancy timeline
Inhibition of stress-activated MAP kinases induces clinical improvement in moderate to severe Crohn’s disease.	Hommes, D.	2002	Gastroenterology			Not related to pregnancy or designated pregnancy timeline
Increased atypical PKC activity in endurance-trained human skeletal muscle.	Nielsen, J.N.	2003	Biochemical and biophysical research communications			Not related to pregnancy or designated pregnancy timeline
Shear stress inhibits homocysteine-induced stromal cell-derived factor-1 expression in endothelial cells.	Sung, M.L.	2009	Circulation research			Not related to pregnancy or designated pregnancy timeline
Thiol-based antioxidant supplementation alters human skeletal muscle signaling and attenuates its inflammatory response and recovery after intense eccentric exercise.	Michailidis, Y.	2013	The American journal of clinical nutrition			Not related to pregnancy or designated pregnancy timeline
Exercise with low glycogen increases PGC-1? gene expression in human skeletal muscle.	Psilander, N.	2013	European journal of applied physiology			Not related to pregnancy or designated pregnancy timeline
Simvastatin reduces myocardial injury undergoing noncoronary artery cardiac surgery: a randomized controlled trial.	Almansob, M.A.	2012	Arteriosclerosis, thrombosis, and vascular biology			Not related to pregnancy or designated pregnancy timeline
Prognostic significance of phosphorylated P38 mitogen-activated protein kinase and HER-2 expression in lymph node-positive breast carcinoma.	Esteva, F.J.	2004	Cancer			Not related to pregnancy or designated pregnancy timeline
Insulin infusion suppresses while glucose infusion induces Toll-like receptors and high-mobility group-B1 protein expression in mononuclear cells of type 1 diabetes patients.	Dandona, P.	2013	American journal of physiology. Endocrinology and metabolism			Not related to pregnancy or designated pregnancy timeline
Carbohydrate feeding during recovery alters the skeletal muscle metabolic response to repeated sessions of high-intensity interval exercise in humans.	Cochran, A.J.	2010	Journal of applied physiology			Not related to pregnancy or designated pregnancy timeline
Inhibition of p38 mitogen-activated protein kinase: dose-dependent suppression of leukocyte and endothelial response after endotoxin challenge in humans.	Fijen, J.W.	2002	Critical care medicine			Not related to pregnancy or designated pregnancy timeline
Matched work high-intensity interval and continuous running induce similar increases in PGC-1? mRNA, AMPK, p38, and p53 phosphorylation in human skeletal muscle.	Bartlett, J.D.	2012	Journal of applied physiology			Not related to pregnancy or designated pregnancy timeline
Anti-inflammatory effects of a p38 mitogen-activated protein kinase inhibitor during human endotoxemia.	Branger, J.	2002	Journal of immunology			Not related to pregnancy or designated pregnancy timeline
An effector-reduced anti-?-amyloid (A?) antibody with unique a? binding properties promotes neuroprotection and glial engulfment of A?.	Adolfsson, O.	2012	The Journal of neuroscience : the official journal of the Society for Neuroscience			Not related to pregnancy or designated pregnancy timeline
Contribution of nonesterified fatty acids to mitogen-activated protein kinase activation in human skeletal muscle during endurance exercise.	Zbinden-Foncea, H.	2013	International journal of sport nutrition and exercise metabolism			Not related to pregnancy or designated pregnancy timeline
Time course of angiopoietin-2 release during experimental human endotoxemia and sepsis.	Kümpers, P.	2009	Critical care			Not related to pregnancy or designated pregnancy timeline
Cardiac contractility modulation electrical signals improve myocardial gene expression in patients with heart failure.	Butter, C.	2008	Journal of the American College of Cardiology			Not related to pregnancy or designated pregnancy timeline
Resveratrol, at concentrations attainable with moderate wine consumption, stimulates human platelet nitric oxide production.	Gresele, P.	2008	The Journal of nutrition			Not related to pregnancy or designated pregnancy timeline
Endotoxin increases plasma soluble tumor necrosis factor-related apoptosis-inducing ligand level mediated by the p38 mitogen-activated protein kinase signaling pathway.	Lub-de Hooge, M.N.	2004	Shock			Not related to pregnancy or designated pregnancy timeline
Increased HDL cholesterol and apoA-I in humans and mice treated with a novel SR-BI inhibitor.	Masson, D.	2009	Arteriosclerosis, thrombosis, and vascular biology			Not related to pregnancy or designated pregnancy timeline
Ischemic preconditioning by unstable angina reduces the release of CK-MB following CABG and stimulates center ventricular HSP-72 protein expression.	Vahlhaus, C.	2005	Journal of cardiac surgery			Not related to pregnancy or designated pregnancy timeline
Inhibition of coagulation, fibrinolysis, and endothelial cell activation by a p38 mitogen-activated protein kinase inhibitor during human endotoxemia.	Branger, J.	2003	Blood			Not related to pregnancy or designated pregnancy timeline
Single-dose pharmacokinetics and pharmacodynamics of RWJ 67657, a specific p38 mitogen-activated protein kinase inhibitor: a first-in-human study.	Parasrampuria, D.A.	2003	Journal of clinical pharmacology			Not related to pregnancy or designated pregnancy timeline
Cardiopulmonary and systemic effects of methylprednisolone in patients undergoing cardiac surgery.	Liakopoulos, O.J.	2007	The Annals of thoracic surgery			Not related to pregnancy or designated pregnancy timeline
Efficacy and safety of the oral p38 inhibitor PH-797804 in chronic obstructive pulmonary disease: a randomised clinical trial.	MacNee, W.	2013	Thorax			Not related to pregnancy or designated pregnancy timeline
A randomized, placebo-controlled study of the effects of the p38 MAPK inhibitor SB-681323 on blood biomarkers of inflammation in COPD patients.	Singh, D.	2010	Journal of clinical pharmacology			Not related to pregnancy or designated pregnancy timeline
Futsal and continuous exercise induce similar changes in specific skeletal muscle signalling proteins.	Serpiello, F.R.	2014	International journal of sports medicine			Not related to pregnancy or designated pregnancy timeline
Ammonia impairs neutrophil phagocytic function in liver disease.	Shawcross, D.L.	2008	Hepatology			Not related to pregnancy or designated pregnancy timeline
A Randomized Dose-Escalation Study of the Safety and Anti-Inflammatory Activity of the p38 Mitogen-Activated Protein Kinase Inhibitor Dilmapimod in Severe Trauma Subjects at Risk for Acute Respiratory Distress Syndrome.	Christie, J.D.	2015	Critical care medicine			Not related to pregnancy or designated pregnancy timeline
Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: results of two randomized, double-blind, placebo-controlled clinical studies.	Damjanov, N.	2009	Arthritis and rheumatism			Not related to pregnancy or designated pregnancy timeline
In silico and in vitro pharmacogenetics: aldehyde oxidase rapidly metabolizes a p38 kinase inhibitor.	Zhang, X.	2011	The pharmacogenomics journal			Not related to pregnancy or designated pregnancy timeline
Novel p38? mitogen-activated protein kinase inhibitor shows analgesic efficacy in acute postsurgical dental pain.	Tong, S.E.	2012	Journal of clinical pharmacology			Not related to pregnancy or designated pregnancy timeline
The effect of BMS-582949, a P38 mitogen-activated protein kinase (P38 MAPK) inhibitor on arterial inflammation: a multicenter FDG-PET trial.	Emami, H.	2015	Atherosclerosis			Not related to pregnancy or designated pregnancy timeline
An oral inhibitor of p38 MAP kinase reduces plasma fibrinogen in patients with chronic obstructive pulmonary disease.	Lomas, D.A.	2012	rnal of clinical pharmacology			Not related to pregnancy or designated pregnancy timeline
Anti-inflammatory properties of a novel N-phenyl pyridinone inhibitor of p38 mitogen-activated protein kinase: preclinical-to-clinical translation.	Hope, H.R.	2009	The Journal of pharmacology and experimental therapeutics			Not related to pregnancy or designated pregnancy timeline
A 24-week, randomized, double-blind, placebo-controlled, parallel group study of the efficacy of oral SCIO-469, a p38 mitogen-activated protein kinase inhibitor, in patients with active rheumatoid arthritis.	Genovese, M.C.	2011	The Journal of rheumatology			Not related to pregnancy or designated pregnancy timeline
Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double-blind, methotrexate-controlled study of patients with active rheumatoid arthritis.	Cohen, S.B.	2009	Arthritis and rheumatism			Not related to pregnancy or designated pregnancy timeline
Efficacy and safety of pamapimod in patients with active rheumatoid arthritis receiving stable methotrexate therapy.	Alten, R.E.	2010	of the rheumatic diseases			Not related to pregnancy or designated pregnancy timeline
Recombinant human activated protein C reduces human endotoxin-induced pulmonary inflammation via inhibition of neutrophil chemotaxis.	Nick, J.A.	2004	Blood			Not related to pregnancy or designated pregnancy timeline
Inhibition of p38 mitogen-activated protein kinase reduces inflammation after coronary vascular injury in humans.	Sarov-Blat, L.	2010	Arteriosclerosis, thrombosis, and vascular biology			Not related to pregnancy or designated pregnancy timeline
Impaired cardiometabolic responses to glucagon-like peptide 1 in obesity and type 2 diabetes mellitus.	Moberly, S.P.	2013	Basic research in cardiology			Not related to pregnancy or designated pregnancy timeline
Effects of p38 mitogen-activated protein kinase inhibition on vascular and systemic inflammation in patients with atherosclerosis.	Elkhawad, M.	2012	Cardiovascular imaging			Not related to pregnancy or designated pregnancy timeline
Clinical trial of the p38 MAP kinase inhibitor dilmapimod in neuropathic pain following nerve injury.	Anand, P.	2011	European journal of pain			Not related to pregnancy or designated pregnancy timeline
Adiponectin promotes the migration of circulating angiogenic cells through p38-mediated induction of the CXCR4 receptor.	Adams, V.	2013	International journal of cardiology			Not related to pregnancy or designated pregnancy timeline
Inhibition of p38 mitogen-activated protein kinase improves nitric oxide-mediated vasodilatation and reduces inflammation in hypercholesterolemia.	Cheriyan, J.	2011	Circulation			Not related to pregnancy or designated pregnancy timeline
Analgesic efficacy and safety of the novel p38 MAP kinase inhibitor, losmapimod, in patients with neuropathic pain following peripheral nerve injury: a double-blind, placebo-controlled study.	Ostenfeld, T.	2013	European journal of pain			Not related to pregnancy or designated pregnancy timeline
Rationale, design, and baseline characteristics in Evaluation of LIXisenatide in Acute Coronary Syndrome, a long-term cardiovascular end point trial of lixisenatide versus placebo.	Bentley-Lewis, R.	2015	American heart journal			Not related to pregnancy or designated pregnancy timeline
The study of LoSmapimod treatment on inflammation and InfarCtSizE (SOLSTICE): design and rationale.	Melloni, C.	2012	American heart journal			Not related to pregnancy or designated pregnancy timeline
A proof-of-concept and drug-drug interaction study of pamapimod, a novel p38 MAP kinase inhibitor, with methotrexate in patients with rheumatoid arthritis.	Zhang, X.	2010	Journal of clinical pharmacology			Not related to pregnancy or designated pregnancy timeline
Population pharmacokinetics of losmapimod in healthy subjects and patients with rheumatoid arthritis and chronic obstructive pulmonary diseases.	Yang, S.	2013	Clinical pharmacokinetics			Not related to pregnancy or designated pregnancy timeline
Rationale and design of the LosmApimod To Inhibit p38 MAP kinase as a TherapeUtic target and moDify outcomes after an acute coronary syndromE trial.	O’Donoghue, M.L.	2015	American heart journal			Not related to pregnancy or designated pregnancy timeline
Randomized, dose-escalation study of the p38? MAPK inhibitor SCIO-469 in patients with myelodysplastic syndrome.	Sokol, L.	2013	Leukemia			Not related to pregnancy or designated pregnancy timeline
Oral p38 mitogen-activated protein kinase inhibition with BIRB 796 for active Crohn’s disease: a randomized, double-blind, placebo-controlled trial.	Schreiber, S.	2006	Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association			Not related to pregnancy or designated pregnancy timeline
Efficacy and safety of the p38 MAPK inhibitor losmapimod for patients with chronic obstructive pulmonary disease: a randomised, double-blind, placebo-controlled trial.	Watz, H.	2014	The Lancet. Respiratory medicine			Not related to pregnancy or designated pregnancy timeline
Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial.	Newby, L.K.	2014	Lancet			Not related to pregnancy or designated pregnancy timeline
adiponectin stimulates lipid metabolism via AMPK in rabbit blastocysts	Schindler, M.	2017	Human Reproduction			Not related to pregnancy or designated pregnancy timeline
Pioglitazone induces cell growth arrest and activates mitochondrial apoptosis in human uterine leiomyosrcoma cells by a peroxisome proliferator-activated receptor gamma-independent mechanism	Lutzen, U.	2016	Naunyn-Schmiedeberg’s Archives of Pharmacology			Not related to pregnancy or designated pregnancy timeline

Appendix 3: Articles used for full-text review

Title	Author	Year Published	Journal Title	Species	Tissue/ Cell Type	Score	Exclusion
Epidermal growth factor and interleukin-1beta utilize divergent signaling pathways to synergistically upregulate cyclooxygenase-2 gene expression in human amnion-derived WISH cells	Ackerman, W. E.	2004	Biology of Reproduction	Human	Amnion-derived (WISH) cells	14	score
Siglec-5 and Siglec-14 are polymorphic paired receptors that modulate neutrophil and amnion signaling responses to group B Streptococcus	Ali, S. R.	2014	Journal of Experimental Medicine	Human	Aminon epithilium	16
Anandamide and decidual remodelling: COX-2 oxidative metabolism as a key regulator	Almada, M.	2015	Biochimica et Biophysica Acta	Rat	Decidua	15	score
Preimplantation factor (PIF) promoting role in embryo implantation: increases endometrial integrin-alpha2beta3, amphiregulin and epiregulin while reducing betacellulin expression via MAPK in decidua	Barnea, E. R.	2012	Reproductive Biology & Endocrinology	Human	Decidua and endometrium	17
Induction of cyclooxygenase-2 expression in human myometrial smooth muscle cells by interleukin-1beta: involvement of p38 mitogen-activated protein kinase	Bartlett, S. R.	1999	Journal of Physiology	Human	Human myometrial smooth muscle cells	15	score
Preeclampsia-related increase of interleukin-11 expression in human decidual cells	Basar, M.	2010	Reproduction	Human	Decidua	15	score
Environmental Pollutant Polybrominated Diphenyl Ether, a Flame Retardant, Induces Primary Amnion Cell Senescence	Behnia, F.	2015	American Journal of Reproductive Immunology	Human	Aminon epithilium	18
Late-gestation rat myometrial cells express multiple isoforms of phospholipase A2 that mediate PCB 50-induced release of arachidonic acid with coincident prostaglandin production	Brant, K.	2005	Toxicological Sciences	Rat	Uterus and myometrium	18	Not directly p38 MAPK
HMGB1 promotes a p38MAPK associated non-infectious inflammatory response pathway in human fetal membranes	Bredeson, S.	2014	PLoS ONE	Human	Fetal membranes and amniontic fluid	18
Arrestins differentially regulate histamine- and oxytocin-evoked phospholipase C and mitogen-activated protein kinase signalling in myometrial cells	Brighton, P. J.	2011	British Journal of Pharmacology	Human	Myometrium	17
Opposite effect of phorbol ester PMA on PTGS2 and PGDH mRNA expression in human chorion trophoblast cells	Casciani, V.	2008	Reproductive Sciences	Human	Chorion trophoblasts	17	Not directly p38 MAPK
Tyrosine phosphorylation of caveolin 1 by oxidative stress is reversible and dependent on the c-src tyrosine kinase but not mitogen-activated protein kinase pathways in placental artery endothelial cells	Chen, D. B.	2005	Biology of Reproduction	Human	Placental artery endothelial cells	17
Secretion of adiponectin by human placenta: differential modulation of adiponectin and its receptors by cytokines	Chen, J.	2006	Diabetologia	Human	Syncytiotrophoblast	18
Cyclic AMP increases COX-2 expression via mitogen-activated kinase in human myometrial cells	Chen, L.	2012	Journal of Cellular and Molecular Medicine	Human	Myometrium	19
Lysophosphatidic acid mediates interleukin-8 expression in human endometrial stromal cells through its receptor and nuclear factor-kappaB-dependent pathway: a possible role in angiogenesis of endometrium and placenta	Chen, S. U.	2008	Endocrinology	Human	Endometrial stromal cells	16
Lysophosphatidic acid up-regulates expression of growth-regulated oncogene-alpha, interleukin-8, and monocyte chemoattractant protein-1 in human first-trimester trophoblasts: possible roles in angiogenesis and immune regulation	Chen, S. U.	2010	Endocrinology	Human	Trophoblasts	17
Energy status and HIF signalling in chorionic villi show no evidence of hypoxic stress during human early placental development	Cindrova-Davies, T.	2015	Molecular Human Reproduction	Human	Placental explants	19
Nuclear factor-kappa B, p38, and stress-activated protein kinase mitogen-activated protein kinase signaling pathways regulate proinflammatory cytokines and apoptosis in human placental explants in response to oxidative stress: effects of antioxidant…	Cindrova-Davies, T.	2007	American Journal of Pathology	Human	Placental explants	17
Genipa americana (Rubiaceae) fruit extract affects mitogen-activated protein kinase cell pathways in human trophoblast-derived BeWo cells: implications for placental development	da Conceicao, A. O.	2011	Journal of Medicinal Food	Human	Trophoblast and bewo cells	16
ERK1/2 and p38 regulate trophoblasts differentiation in human term placenta	Daoud, G.	2005	Journal of Physiology	Human	Trophoblasts	19
Interplay of cAMP and MAPK pathways in hCG secretion and fusogenic gene expression in a trophoblast cell line	Delidaki, M.	2011	Molecular & Cellular Endocrinology	Human	Trophoblast and bewo cells	20
Inhibition of MAPK by prolactin signaling through the short form of its receptor in the ovary and decidua: involvement of a novel phosphatase	Devi, Y. S.	2011	Journal of Biological Chemistry	Mice	Decidua	19
Oxytocin-induced activation of eukaryotic elongation factor 2 in myometrial cells is mediated by protein kinase C	Devost, D.	2008	Endocrinology	Human	Myometrium	17
Induction of PG G/H synthase-2 in bovine myometrial cells by interferon-tau requires the activation of the p38 MAPK pathway	Doualla-Bell, F.	2001	Endocrinology	Bovine	Myometrium	16
Role of atypical protein kinase C isozymes and NF-kappaB in IL-1beta-induced expression of cyclooxygenase-2 in human myometrial smooth muscle cells	Duggan, S. V.	2007	Journal of Cellular Physiology	Human	Myometrium	19
Decidual NK cell-derived conditioned medium (dNK-CM) mediates VEGF-C secretion in extravillous cytotrophoblasts	Eastabrook, G. D.	2012	American Journal of Reproductive Immunology	Human	Decidual NK cells and extravillous cytotrophoblasts	20	Not directly p38 MAPK
The endocannabinoid anandamide induces apoptosis of rat decidual cells through a mechanism involving ceramide synthesis and p38 MAPK activation	Fonseca, B. M.	2013	Apoptosis	Rat	Decidua	19
Cross talk between cAMP and p38 MAPK pathways in the induction of leptin by hCG in human placental syncytiotrophoblasts	Ge, Y. C.	2011	Reproduction	Human	Syncytiotrophoblast	20
Pregnancy reduces RhoA/Rho kinase and protein kinase C signaling pathways downstream of thromboxane receptor activation in the rat uterine artery	Goulopoulou, S.	2012	American Journal of Physiology-Heart and Circulatory Physiology	Rat	Uterine artery	20
Prostaglandin F-2 alpha induces expression of activating transcription factor 3 (ATF3) and activates MAPK signaling in the rat corpus luteum	Guo, N. N.	2015	Acta Histochemica	Rat	Ovaries	20	Not related to pregnancy or designated pregnancy timeline
Decidual NK cell-derived conditioned medium enhances capillary tube and network organization in an extravillous cytotrophoblast cell line	Hu, Y.	2010	Placenta	Human	Decidual NK cells and extravillous cytotrophoblasts	20
Role of activin-A and myostatin and their signaling pathway in human myometrial and leiomyoma cell function	Islam, M. S.	2014	Journal of Clinical Endocrinology & Metabolism	Human	Myometrium	19	Not related to pregnancy or designated pregnancy timeline
Function-specific intracellular signaling pathways downstream of heparin-binding EGF-like growth factor utilized by human trophoblasts	Jessmon, P.	2010	Biology of Reproduction	Human	Trophoblasts	19
EPO improves the proliferation and inhibits apoptosis of trophoblast and decidual stromal cells through activating STAT-5 and inactivating p38 signal in human early pregnancy	Ji, Y. Q.	2011	International Journal of Clinical & Experimental Pathology	Human	Trophoblast and Decidual stromal cells	20
Regulation of progesterone receptor A and B expression in human preterm, term, and postterm placental villi	Jiang, Z. Y.	2010	Acta Obstetricia Et Gynecologica Scandinavica	Human	postterm and preterm villous explants	20
Epidermal growth factor stimulation of trophoblast differentiation requires MAPK11/14 (p38 MAP kinase) activation	Johnstone, E. D.	2005	Biology of Reproduction	Human	Trophoblasts	18
Multiple anti-apoptotic pathways stimulated by EGF in cytotrophoblasts	Johnstone, E. D.	2005	Placenta	Human	Cytotrophoblast	20
Regulation of interleukin-1alpha and tumor necrosis factor-alpha-induced interleukin-8 production by amnion-derived (WISH) cells	Kawano, Y.	2012	Clinical & Experimental Obstetrics & Gynecology	Human	Amnion-derived (WISH) cells	18	No full text
Sphingosine 1-phosphate in amniotic fluid modulates cyclooxygenase-2 expression in human amnion-derived WISH cells	Kim, J. I.	2003	Journal of Biological Chemistry	Human	Amnion-derived (WISH) cells	17
Oxytocin activates NF-kappaB-mediated inflammatory pathways in human gestational tissues	Kim, S. H.	2015	Molecular & Cellular Endocrinology	Human	Myometirum and amnion cells	20
Regulation and signal transduction of toll-like receptors in human chorioncarcinoma cell lines	Klaffenbach, D.	2005	American Journal of Reproductive Immunology	Human	Chorioncarcinoma cell lines and placental villi	15	score
Differential regulation of placental amino acid transport by saturated and unsaturated fatty acids	Lager, S.	2014	American Journal of Physiology - Cell Physiology	Human	Trophoblasts	20
Mechanisms in decorin regulation of vascular endothelial growth factor-induced human trophoblast migration and acquisition of endothelial phenotype	Lala, N.	2012	Biology of Reproduction	Human	Trophoblasts	19
Mitogen-activated protein kinase proteins regulate LPS-stimulated release of pro-inflammatory cytokines and prostaglandins from human gestational tissues	Lappas, M.	2007	Placenta	Human	Fetal membrane and placenta	19
MAPK and AP-1 proteins are increased in term pre-labour fetal membranes overlying the cervix: regulation of enzymes involved in the degradation of fetal membranes	Lappas, M.	2011	Placenta	Human	Fetal membrane and amnion cells	20
Differential actions of glycodelin-A on Th-1 and Th-2 cells: a paracrine mechanism that could produce the Th-2 dominant environment during pregnancy	Lee, C. L.	2011	Human Reproduction	Human	Amniotic fluid, seminal plasma, and cumulus matrix	16
Chemokine CCL24 promotes the growth and invasiveness of trophoblasts through ERK1/2 and PI3K signaling pathways in human early pregnancy	Li, H.	2015	Reproduction	Human	Placenta villi and decidua	19	Not directly p38 MAPK
Induction of p38 mitogen-activated protein kinase-mediated apoptosis is involved in outgrowth of trophoblast cells on endometrial epithelial cells in a model of human trophoblast-endometrial interactions	Li, H. Y.	2003	Biology of Reproduction	Human	Bewo and amnion cells	20	No full text
Activation of decidual invariant natural killer T cells promotes lipopolysaccharide-induced preterm birth	Li, L.	2015	Molecular Human Reproduction	Mice	Decidual MNC, iNKC, DC	20	Not directly p38 MAPK
NFkappaB and JNK/MAPK activation mediates the production of major macrophage- or dendritic cell-recruiting chemokine in human first trimester decidual cells in response to proinflammatory stimuli	Li, M.	2011	Journal of Clinical Endocrinology & Metabolism	Human	decidual cells, monocytes (primary and THP-1)	18
Effects of pulsatile shear stress on signaling mechanisms controlling nitric oxide production, endothelial nitric oxide synthase phosphorylation, and expression in ovine fetoplacental artery endothelial cells	Li, Y.	2004	Endothelium-Journal of Endothelial Cell Research	Ovine	Artery endothelial cells	20
Regulation of interleukin-6 expression in human decidual cells and its potential role in chorioamnionitis	Lockwood, C. J.	2010	American Journal of Pathology	Human	Decidua	18	Not directly p38 MAPK
Interferon-gamma protects first-trimester decidual cells against aberrant matrix metalloproteinases 1, 3, and 9 expression in preeclampsia	Lockwood, C. J.	2014	American Journal of Pathology	Human	Fetal membranes and decidua	19
The onset of labor alters corticotropin-releasing hormone type 1 receptor variant expression in human myometrium: putative role of interleukin-1beta	Markovic, D.	2007	Endocrinology	Human	Myometrium	19
Structural determinants critical for localization and signaling within the seventh transmembrane domain of the type 1 corticotropin releasing hormone receptor: lessons from the receptor variant R1d	Markovic, D.	2008	Molecular Endocrinology	Human	Myocytes	19	Not directly p38 MAPK
Senescence of primary amniotic cells via oxidative DNA damage	Menon, R.	2013	PLoS ONE	Human	Amnion epithelial cells	20
Histological evidence of oxidative stress and premature senescence in preterm premature rupture of the human fetal membranes recapitulated in vitro	Menon, R.	2014	American Journal of Pathology	Human	fetal membranes	20
Macrophage-activating lipopeptide-2 induces cyclooxygenase-2 and prostaglandin E-2 via toll-like receptor 2 in human placental trophoblast cells	Mitsunari, M.	2006	Journal of Reproductive Immunology	Human	Placental trophoblast cells	20
Mitogen-activated protein kinases mediate stretch-induced c-fos mRNA expression in myometrial smooth muscle cells	Oldenhof, A. D.	2002	American Journal of Physiology - Cell Physiology	Rat	Myometrium	20
Progestin-inflammatory cytokine interactions affect matrix metalloproteinase-1 and -3 expression in term decidual cells: implications for treatment of chorioamnionitis-induced preterm delivery	Oner, C.	2008	Journal of Clinical Endocrinology & Metabolism	Human	Decidua	20	Not directly p38 MAPK
Spatial and temporal expression of the myometrial mitogen-activated protein kinases p38 and ERK1/2 in the human uterus during pregnancy and labor	Otun, H. A.	2005	Journal of the Society for Gynecologic Investigation	Human	Myometrium	18
MAPK14 cooperates with MAPK3/1 to regulate endothelin-1-mediated prostaglandin synthase 2 induction and survival in leiomyoma but not in normal myometrial cells	Oyeniran, C.	2011	Biology of Reproduction	Rat	Myometrium	16	Not related to pregnancy or designated pregnancy timeline
Regulation of cyclooxygenase-2 expression by phospholipase D in human amnion-derived WISH cells	Park, D. W.	2002	Molecular Pharmacology	Human	Amnion-derived (WISH) cells	17
Placental lactogen-I gene activation in differentiating trophoblast cells: extrinsic and intrinsic regulation involving mitogen-activated protein kinase signaling pathways	Peters, T. J.	2000	Journal of Endocrinology	Rat	Rcho-1 trophoblast cells	18
Telomere Fragment Induced Amnion Cell Senescence: A Contributor to Parturition?	Polettini, J.	2015	PLoS ONE	Human and mouse	Fetal membrane	20
Tumour necrosis factor alpha stimulates the production of monocyte chemoattractants by extravillous trophoblast cells via differential activation of MAPK pathways	Renaud, S. J.	2009	Placenta	Human	Extravillous trophoblast cells	20
Regulation of cyclooxygenase-2 induction in the mouse uterus during decidualization. An event of early pregnancy	Scherle, P. A.	2000	Journal of Biological Chemistry	Mice	Decidua	16
Control of human endometrial stromal cell motility by PDGF-BB, HB-EGF and trophoblast-secreted factors	Schwenke, M.	2013	PLoS ONE	Human	Endometrium and trophoblast cell line	18
Involvement of p38 MAP kinase in lipopolysaccharide-induced production of pro- and anti-inflammatory cytokines and prostaglandin E(2) in human choriodecidua	Shoji, T.	2007	Journal of Reproductive Immunolog	Human	Choriodecidual explants	20
The mitogen-activated protein kinase dependent expression of prostaglandin H synthase-2 and interleukin-8 messenger ribonucleic acid by myometrial cells: the differential effect of stretch and interleukin-1{beta}	Sooranna, S. R.	2005	Journal of Clinical Endocrinology & Metabolism	Human	Myometrium	17
Stretch and interleukin 1 beta: pro-labour factors with similar mitogen-activated protein kinase effects but differential patterns of transcription factor activation and gene expression	Sooranna, S. R.	2007	Journal of Cellular Physiology	Human	Myometrium	17
Effects of cytokine-suppressive anti-inflammatory drugs on inflammatory activation in ex vivo human and ovine fetal membranes	Stinson, L. F.	2014	Reproduction	Human and ovine	Fetal membrane	18	Not directly p38 MAPK
Interleukin-1beta induces the expression of insulin-like growth factor binding protein-1 during decidualization in the primate	Strakova, Z.	2000	Endocrinology	Baboon and human	Stromal cells and endometrial fibroblasts	14	score
Inhibition of matrix metalloproteinases prevents the synthesis of insulin-like growth factor binding protein-1 during decidualization in the baboon	Strakova, Z.	2003	Endocrinology	Baboon	Stromal fibroblasts	12	score
Possible involvement of p38 mitogen-activated protein kinase in decidual function in parturition	Takanami-Ohnishi, Y.	2001	Biochemical & Biophysical Research Communications	Human and mice	Uterus and decidua	11	score
Calcitonin promotes mouse pre-implantation development: involvement of calcium mobilization and P38 mitogen-activated protein kinase activation	Wang, F. W.	2013	Reproduction in Domestic Animals	Mice	Uterus	19	Not related to pregnancy or designated pregnancy timeline
Plasma membrane receptor mediated MAPK signaling pathways are activated in human uterine cervix at parturition	Wang, H.	2007	Reproductive Biology and Endocrinology	Human	Cervix	17
Corticotropin releasing hormone modulates endotoxin-induced inflammatory cytokine expression in human trophoblast cells	Wang, W.	2007	Placenta	Human	Extravillous trophoblast cell line HTR-8/SVneo.	17
Bradykinin-activated contractile signalling pathways in human myometrial cells are differentially regulated by arrestin proteins	Willets, J. M.	2015	Molecular & Cellular Endocrinology	Human	Myometrium	19
PGF2alpha modulates the output of chemokines and pro-inflammatory cytokines in myometrial cells from term pregnant women through divergent signaling pathways	Xu, C.	2015	Molecular Human Reproduction	Human	Myometrial smooth muscle cells	20
Prostaglandin F2alpha regulates the expression of uterine activation proteins via multiple signalling pathways	Xu, C.	2015	Reproduction	Human	Myometrial smooth muscle cells	17
Dynamic changes in mitogen-activated protein kinase (MAPK) activities in the corpus luteum of the bonnet monkey (Macaca radiata) during development, induced luteolysis, and simulated early pregnancy: a role for p38 MAPK in the regulation of luteal	Yadav, V. K.	2006	Endocrinology	Bonnet monkey (Macaca radiata)	Corpus luteum	18	Not related to pregnancy or designated pregnancy timeline
Endometrial stromal cells undergoing decidualization down-regulate their properties to produce proinflammatory cytokines in response to interleukin-1 beta via reduced p38 mitogen-activated protein kinase phosphorylation	Yoshino, O.	2003	Journal of Clinical Endocrinology & Metabolism	Human	Endometrial stromal cells	18
Direct contribution of inducible nitric oxide synthase expression to apoptosis induction in primary smooth chorion trophoblast cells of human fetal membrane tissues	Yuan, B.	2009	International Journal of Biochemistry & Cell Biology	Human	Chorion and amnion cells	17
Progesterone enhances immunoregulatory activity of human mesenchymal stem cells via PGE2 and IL-6	Zhao, X.	2012	American Journal of Reproductive Immunology	Human	Umbilical cord mesenchymal stem cells	18
Paradoxical stimulation of cyclooxygenase-2 expression by glucocorticoids via a cyclic AMP response element in human amnion fibroblasts	Zhu, X. O.	2009	Molecular Endocrinology	Human	Amnion fibroblasts	16	Not directly p38 MAPK
Regulation of progesterone receptor A and B expression in human preterm, term, and postterm placental villi	Ziyan, J.	2010	Acta Obstetricia et Gynecologica Scandinavica	Human	Placental villi	16
Crystallin alphaB acts as a molecular guard in mouse decidualization: regulation and function during early pregnancy	Zuo, R. J.	2014	FEBS Letters	Mice	Stroma cells, endometrium, decidua	15	score
Novel Noncompetitive IL-1 Receptor-Biased Ligand Prevents Infection- and Inflammation-Induced Preterm Birth	Nadeau-Vallée, M	2015	The Journal of Immunology	Human and mice	Myometrial smooth muscle cell	20
Interleukin-33 drives a proinflammatory endothelial activation that selectively targets nonquiescent cells	Pollheimer, J.	2013	Arterioscler Thromb Vasc Biol	Human	Umbilical vein endothelial cells	20	Not related to pregnancy or designated pregnancy timeline
Vitamin C promotes human endothelial cell growth via the ERK-signaling pathway	Ulrich-Merzenich, G.	2007	Eur J Nutr	Human	Umbilical cord venous endothelial cells	20	Not related to pregnancy or designated pregnancy timeline
Reciprocal regulation of beta2-adrenoceptor-activated cAMP response-element binding protein signalling by arrestin2 and arrestin 3	Pearce, A.	2017	Cellular Signalling	Human	Myometrium	20
Differential senescence in feto-maternal tissues during mouse pregnancy.	Bonney, E.A.	2016	Placenta	Mice	Fetal membrane and placenta	20
Induction of pro-inflammatory genes by serum amyloid A1 in human amnion fibroblasts.	Li, W.	2017	Scientific Reports	Human	Fetal membrane	20
Amnion-Epithelial-Cell-Derived Exosomes Demonstrate Physiologic State of Cell under Oxidative Stress.	Sheller, S.	2016	PLos One	Human	Amnion cells	19
Preclinical evaluation of drugs to block inflammation-driven preterm birth.	Ireland, D.J.	2017	Innate Immunity	Human	Fetal membrane and placenta	19	Not directly p38 MAPK
Differential Effects of Oxytocin Receptor Antagonists, Atosiban and Nolasiban, on Oxytocin Receptor-Mediated Signaling in Human Amnion and Myometrium.	Kim, S. H.	2017	Molecular Pharmacology	Human	Fetal membrane, placenta, myometrium	20
Protein O-fucosyltransferase 1 promotes trophoblast cell proliferation through activation of MAPK and PI3K/Akt signaling pathways	Liu, C.	2017	Biomedicine & pharmacotherapy	Human	Trophoblast cell lines	18
Placental membrane aging and HMGB1 signaling associated with human parturition	Menon, R.	2016	Aging	Human	Amnion cells	19
Impact of Axis of GHRH and GHRH Receptor on Cell Viability and Apoptosis of the Placental Choriocarcinoma Cell Line.	Liu, A.X.	2016	Current Molecular Medicine	Human	Trophoblast cell lines	15	score
Sustained Endocannabinoid Signaling Compromises Decidual Function and Promotes Inflammation-induced Preterm Birth.	Sun, X.	2016	Journal of Biological Chemistry	Human	Decidua	20
The endocannabinoid 2-arachidonoylglycerol dysregulates the synthesis of proteins by the human syncytiotrophoblast	Costa, M.A.	2016	Biochimica et Biophysica Acta	Human	Cytotrophoblast	18
Oxidative stress damage-associated molecular signaling pathways differentiate spontaneous preterm birth and preterm premature rupture of the membranes	Dutta, E.H.	2016	Molecular Human Reproduction	Human	Amnion cells	19
The oxytocin receptor antagonist, Atosiban, activates pro-inflammatory pathways in human amnion via G(alphai) signalling.	Kim, S.H.	2016	Molecular & Cellular Endocrinology	Human	Fetal membrane	18
Quercetin alleviates generalizaed hyperalgesia in mice with induced adenomyosis	Nie, J.C.	2017	Molecular medicine reports	Mice	Placenta	19	Not related to pregnancy or designated pregnancy timeline
Inhibitory effects of emodin, thymol, and astragalin on leptospira interrogans - induced inflammatory response in the uterine and endometrium epithelila cells of mice	Zhang, W.	2017	Inflammation	Mice	Uterus	19	Not related to pregnancy or designated pregnancy timeline
Mechanistic differences leading to infectious and sterile inflammation	Behnia, F.	2016	American Journal of Reproductive Immunology	Human	Fetal membrane	20	Review
Involvment of p38/MMP9/TIMP1 in premature rupture of the human fetal membranes	Zonghua, L.	2016	International Journal of Clinical Experimental Pathology	Human	Fetal membrane	14	score