Table 1.

Molecular targets and protective effects of curcumin on pathogenic pathways [41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75]. ▼ = “decrease”, ▲ = “increase”.

Biological Effects	References	Molecular Targets/Pathogenic Pathways	Conclusions
Immunomodulator	Yang, et al. [41]	Reduces the receptor activator of nuclear factor-kappa-B ligand (RANKL) ▼ Akt/NF-κB/NFATc1 pathways ▼	Curcumin ameliorated the RANKL-mediated differentiation, fusion and maturation of osteoclasts and had an immunomodulatory effect on macrophage polarization; the protective effect of curcumin on osteoclast genesis was mediated by attenuating the up-regulation of Akt and p65 phosphorylation and the activation of the downstream transcription factor NFATc1 (Nuclear Factor of Activated T-cells, cytoplasmic 1).
	Wu, et al. [42]	NF-κB, MAPK, Akt and pBAD pathways ▼	Curcumin treatment reduced activation of the NF-κB, MAPK (mitogen-activated protein kinase), Akt and pBAD (systematically araBp, a promoter found in bacteria) pathways either systemically, or within the inflamed kidneys. These findings suggest that natural food supplements could become an alternative approach to ameliorating immune-mediated kidney diseases.
	Tuyaerts, et al. [43]	COX-2 expression in B cells, NK and T cells. Myeloid -Derived Suppressor Cell (MDSC): CD15+ & CD33+ granulocytic, and CD33+ monocytic. Expression of HLA-DR/CD45+ leukocytes	It is observed a downregulation of MHC expression by leukocytes, a reduction in the frequency of monocytes and a decreased inducible co-stimulator (ICOS) expression by CD8+ T cells upon Curcumin Phytosome (CP) intake, while the level of CD69 on CD16- NK cells was upregulated; did not find significant changes in inflammatory biomarker levels, frequencies of other immune cell types, T cell activation and COX-2 expression.
	Mollazadeh, et al. [44]	Dendritic cells, macrophages, mast cells, natural killer cells, eosinophils, neutrophils, B cells, CD8+ T cells, TH1, TH2, TH17 & regulatory T cells	Curcumin is a natural anti-inflammatory compound able to induce the expression and production of IL-10 and enhancing its action on many tissues.
	Boroumand, et al. [45]	Neutrophils, macrophages, monocytes, NK cells, dendritic cells (DCs), T and B cells Down regulating the expression of growth and survival promoting genes including c-Myc, BCL-XL and NF-κB ▼	This review discusses current knowledge on the immunomodulatory, anti-inflammatory and antioxidant roles of curcumin, with the hope of recruiting curcumin as a therapeutic agent in the future therapeutic regimen.
	Bai, et al. [46]	Inhibition of nuclear factor-kappa B (NF-κB) ▼	Curcumin is a potent inducer of apoptosis—an effector mechanism used by macrophages to kill intracellular Mycobacterium tuberculosis (MTB). Curcumin enhanced the clearance of MTB in differentiated THP-1 human monocyte and in primary human alveolar macrophages. Curcumin was an inducer of caspase-3-dependent apoptosis and autophagy.
	Antiga, et al. [47]	Th22 cells, a subpopulation of T cells ▼	In conclusion, curcumin was demonstrated to be effective as an adjuvant therapy for the treatment of psoriasis vulgaris and to significantly reduce serum levels of IL-22.
	Castro, et al. [48]	NF-kB, iNOS IL-6, TNF-alfa, IL-1 beta ▼	Curcumin modulates the T lymphocyte response impairing proliferation and interferon (IFN)-γ production through modulation of T-box expressed in T cells (T-bet), a key transcription factor for proinflammatory T helper type 1 (Th1) lymphocyte differentiation, both at the transcriptional and translational levels. Reduces nuclear factor (NF)-κB activation in T cell receptor (TCR)-stimulated NOD lymphocytes and secretion of proinflammatory cytokines and nitric oxide (NO).
Anti-inflammatory	Lee, et al. [49]	IFN-γ, TNF alfa, IL1 beta, 6, 10, 13. 17 ▼ NF-κB/COX-2 pathway and iNOS ▼	Authors conclude that C. longa and A. hookeri co-treatment synergistically inhibit inflammation by regulating the NF-κB/COX-2/iNOS pathway.
	Li, et al. [50]	Macrophage (M); Lipopolysaccharide (LPS), IFN-γ promote M1-type macrophage; IL-4, 10 and IL-13 promote M2-type macrophage polarization	Macrophages play a pivotal role in non-alcoholic fatty liver disease (NASH) development. Evidence for natural products or their active ingredients in the modulation of macrophage activation, recruitment, and polarization, as well as the metabolic status of macrophages were assessed.
	Almatroodi, et al. [51]	TNF-α, IL-6 ▼ p53 expression▼ Glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT) Total Antioxidant Capacity (TAC)%▲	Co-administration of curcumin (50 mg/kg) with BaP (50 mg/kg) exhibited significant reduction in TNF-α and the IL-6 level; significantly decreased the number of TUNEL-positive cells. Curcumin plus BaP decreased the p53 protein expression as compared with the BaP group and intensity of positivity was low as compared to the BaP only treated group. In addition, curcumin administered to BaP induced rats confirmed the improvement in SOD, CAT and GPx, total antioxidant capacity, and oxidative stress biomarker; significantly decreased the accumulation of cells in the G2/M phase and reduced the apoptotic cell death level increased by BaP.
	Vitali, et al. [52]	IL-6, TNF-α and MCP-1 transcription factor NF-κB ▼	Results show that delivery of curcumin nanoparticles directly into the vaginal tract of mice infected with HSV-2 abrogated CpG-oligodeoxynucleotide (ODN) induced inflammatory vaginal pathology and diminished the production of pro-inflammatory cytokines IL-6, TNF-α and MCP-1 in vaginal and cervical tissues.
	Ullah, et al. [53]	Cycloxygenase-2 (COX-2)▼ Inhibitory kappa B Kinase (IKK) and TANK binding kinase-1 (TBK-1) of Toll Like Receptor 4 (TLR4) pathway ▲	A continuous computerized examination of 14 compounds comprising curcumin, its derivatives and analogues were investigated as inhibitors of signaling proteins: cyclooxygenase-2 (COX-2), Kappaβ kinase inhibitor (IKK) and TANK-1 binding kinase (TBK-1), and Toll Path Like Receptor 4 (TLR4) involved in inflammation. This study recommends 6-Gingerol, Yakuchinone A and Yakuchinone B as the best inhibitors of COX-2, IKK and TBK-1 respectively among the selected curcumin analogues, which could be considered as potential anti-inflammatory agents in the search for new medication against inflammation.
	Shimizu, et al. [54]	NF-kappa B TNF-alpha, IL-1beta myeloid differentiation protein 2-Toll-like receptor 4 co-receptor pathways▼ activates peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ▲	A number of studies have reported the efficacy of curcumin and the mechanisms by which its anti-inflammatory activity could treat various lifestyle-related conditions associated with chronic inflammation, including atherosclerosis, heart failure, obesity, diabetes and other related diseases, such as dementia. Most of these studies have involved animal experiments; however, there are several reports on the benefits of curcumin use in humans.
	Szebeni, et al. [55]	human PBMCs (peripheral blood mononuclear cells) NF-kB; TNF-alfa, IL4, IL6 ▼	The effects of treatment with curcumin analogues in the inflamed colon of rats demonstrated a significant reduction in total tissue myeloperoxidase (MPO) activity, like the biological agent infliximab. Mannich curcuminoids reported herein possess a powerful anti-inflammatory activity.
	Wal, et al. [56]	NF-κB, TNF-α▼ COX-2, inducible nitric oxide synthase (INS) and lipoxygenase (COX). INOs, LOX ▼	Curcumin has the potential for curing inflammatory diseases as it blocks the mechanism of reactive oxygen species generation via inhibiting oxidative stress. Curcumin has prominent effect on inflammatory mediators like cytokines as a result of which it blocks the oxidation process in mitochondria of the cell and reduces inflammation.
	Chen, et al. [57]	TNF-α, IL-1β and IL-6 as pro-inflammatory cytokines▼ NF-κB p65 ▼	After four weeks of administration of combined two natural products with curcumin resulted in a decrease in the inflammatory cell infiltration, less thickness of the synovium and less volumetric increase in the synovial space at collagen-induced rat model arthritis; the level of TNF-α, IL-1β and IL-6 was significantly decreased in serum. Curcumin combination was able to inhibit the expression of NF-κB p65 and TNF-α which were closely related to the inflammatory process.
	Panahi, et al. [58]	TNF-a, IL-6, TGF-b and MCP-1▼ macrophages monocytes NF-κBp65▼	Study suggests a significant decrease in serum concentrations of TNF-a, IL-6, TGF-b and chemoattractant protein-1 (MCP-1) cytokines following curcumin supplementation in subjects with metabolic syndrome.
Antioxidant	Paciello, et al. [59]	Nuclear factor (erythroid-derived 2)-like 2 ») or Nrf2/Heme oxygenase-1 (HO-1) pathway; ROS downregulating p53 phosphorylation ▼ NF-κB, STAT-3 ▼	The authors used two different polyphenols in adjuvant chemotherapy in several malignancies to avoid the chemoresistance and ototoxicity of the drug cisplatin. Both polyphenols had an antioxidant and self-protective action by up-regulating the Nrf-2/HO-1 pathways and down-regulating p53 phosphorylation; but only curcumin has been able to influence the inflammatory pathways that counteract NF-κB activation. In human cancer cells, curcumin transforms the antioxidant effect into a pro-oxidant and anti-inflammatory one. Curcumin has permissive and chemosensitive properties by targeting chemoresistant factors of cisplatin phosphorylation of Nrf-2, NF-κB and STAT-3. Therefore, polyphenols, mainly curcumin, which target ROS modulated pathways can be a promising tool for the treatment of cancer. Due to their biphasic antioxidant activity in normal cells under stress and pro-oxidant in cancer cells, these polyphenols are likely to involve an interaction between key factors Nrf-2, NF-κB, STAT-3 and p53.
	AlBasher, et al. [60]	(MDA) malondialdehyde, {NO} nitric oxide ▼, {GSH} reduced glutathione, {GPx} glutathione peroxidase, {SOD} superoxide dismutase, {CAT} catalase) ▲ Nrf2 ARE antioxidant response elements	This study was undertaken to assess the effects of resveratrol (RSV) and curcumin (CUR) on oxidative damage induced by insecticide fipronil (FPN). Co-treatment with RSV and CUR, mainly in combination, markedly alleviated the toxic effects and oxidative damage induced by FPN. Thus, liver enzyme activities, renal injury biomarkers, and lipid profiles in the sera, as well as the MDA, NO, and GSH concentrations and GPx, SOD, and CAT activities (liver, kidney, and brain), were normalized. RSV and CUR repaired oxidative disorders through the Nrf2 heterodimer that bound to antioxidant response elements (AER) and regulated the expression of antioxidant enzyme genes such as GPx, SOD and CAT.
	Konak, et al. [61]	SOD, CAT, GPx ▲ ROS, NO▼ total antioxidant capacity (TAC) total oxidant capacity (TOC)▲	Study investigated the antioxidant effect of curcumin, a phytochemical, on the blood tissue of rats. When the TAC and TOC levels of curcumin-supplemented feeding group were examined, the level was higher than the control group (P <0.05). Results of the study show that curcumin strengthens the antioxidant defense system.
	Nawab, et al. [62]	CAT, SOD, GSH-Px and T-AOC▼	The effects of increasing concentrations of dietary curcumin on the antioxidant parameters of layers maintained under high-temperature conditions for nine weeks were evaluated. Laying hens in all curcumin treatment groups had slightly higher activities of CAT, SOD, GSH-Px, and T-AOC in the liver, heart, and lungs, compared with heat stressed control group. It was concluded that dietary curcumin given to laying hens under heat stress may enhance their antioxidant status and alleviate the detrimental effects of stressful environmental conditions.
	Nawab, et al. [63]	IL-6, IL-1β, TNF-α, ▼ TLR4, NF-κB; PCNA (proliferating cell nuclear antigen) ▼	This study aimed to investigate the effect of curcumin supplementation on TLR4 mediated non-specific immune response in liver of laying hens under high-temperature conditions and heat stress. Authors showed that in the curcumin group treatment had reduced inflammatory responses (IL-6, IL-1β, TNF-α) as compared to control group. Furthermore, PCNA, TLR4 and its downstream gene expression as well as protein expression (TLR4, NF-κB and PCNA) were significantly downregulated in heat stress curcumin supplemented group as compared to control.
	Meshkibaf, et al. [64]	Methionine Sulfoxide Reductase A (MSRA) SOD, CAT, GPx ▲	Effect of curcumin on arthritis induced by adjuvant in rats, considering changes in methionine sulfoxide reductase A (MSRA) expression and antioxidant enzymes levels were analyzed. Curcumin can be used against inflammation. The increasing level of MSRA can be due to the antioxidant effect of curcumin. The enzymatic level changes (MSRA, SOD, CAT and GPx) may interfere with the aging process and delay it.
	Borra, et al. [65]	MDA: Malondialdehyde, PC: Protein carbonyls, GSH: Reduced glutathione TAC: Total Antioxidant Capacity ▲; ROS▼	Curcumin has the ability to protect the biomolecules like proteins, lipids and DNA from hydroxyl radical oxidation. These results demonstrate that exposure to OH in serum and plasma is a good experimental model for studying ROS-induced toxicity and evaluating the protective effects of various agents in vitro.
	Jat, et al. [66]	GSH▲ Lipid peroxidation (LPO)▼ Protein carbonyl▼; ROS▼	This study shows the strong anti-oxidative effects of curcumin and mitochondrially targeted curcumin against the lipid peroxidation, protein carbonylation and mitochondrial permeability transition induced by tert-butylhydroperoxide. Both curcumin and mitochondrially targeted curcumin significantly enhanced endogenous reduced glutathione level in the mitochondria thus preserving mitochondrial defense system against oxidative stress.
Anti-angiogenic	Norooznezhad, et al. [67]	CD68+ and CD11b+ cells; IL-1, IL-6, TNF-α, VEGF ▲ hypoxia-inducible factor 1α (HIF-1α) ▲	Curcumin has a strong antioxidant potential, can decrease oxidative stress and it is able to inhibit the mentioned inflammatory and angiogenic factors such as IL-1, IL-6, TNF-α, VEGF, MMPs, and HIF-1α.
	Mohapatra, et al. [68]	Glutathione (GSH) ▼ Malondialdehyde (MDA) ▼ Superoxide dismutase (SOD) ▲	The combination of curcumin and ASA (acetylsalicylic acid) significantly reduced foot edema and the formation of carrageenan-induced granuloma. Concomitant use of curcumin with ASA decreased malondialdehyde levels, while relatively increased superoxide dismutase and reduced glutathione, while proving protection against (histologically) induced hepatotoxicity by ASA.
Pro-Apoptotic/Antiproli-ferative	Hassan, et al. [69]	p53 level caspase activation ▲ tyrosine-regulated kinases (DYRKs) ▼ 26S proteasome activity ▼	Potent role of curcumin as epigenic modulator, influence on transcriptional factors, antioxidant effects, mediation of inflammatory cytokines and angiogenesis modulation was proved. Curcumin is a potent proteasome inhibitor that increases p53 level and induces apoptosis by mitochondrial caspase activation. Curcumin also disrupts 26S proteasome activity by inhibiting DYRK2 in different cancerous cells, resulting in the inhibition of cell proliferation.
	Rainey, et al. [70]	AMP-activated protein kinase NRF1 (Nuclear Respiratory Factor 1); Nuclear factor (erythroid-derived 2)- like 2, also known as NFE2L2, Mitochondrial transcription factor A (TFAM) TFEB (Transcription Factor EB) G2/M cell cycle Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) -related signaling pathway. Activator protein 1 (AP-1), Caspase-10	Multiple in vitro and in vivo preclinical studies have shown that curcumin is effective against various types of cancer. These potent the effects are determined by the ability of curcumin to induce G2/M cell cycle arrest, induction of autophagy, activation of apoptosis, disruption of molecules signaling, inhibition of invasion and metastasis and increasing the effectiveness of current chemotherapeutics. Low levels of curcumin enhance mitochondrial biogenesis in cells and tissues, mainly through the induction of the PGC-1α-related signaling pathway.
	Guo, et al. [71]	Telomerase reverse transcriptase (TERT) ▲; Malondialdehyde (MDA) ▼ glutathione (GSH); superoxide ▲; dismutase (SOD)▲; glutathione peroxidase (GSH-Px); TNF-α and IL-1β in the cerebral homogenates ▼ TERT mRNA expression level▲	Study evaluates the possible anti-apoptotic, antioxidant and anti-inflammatory effects of curcumin on the neurotoxicity caused by Acrylamide (ACR) in rats. Curcumin increased TERT mRNA expression level, suggesting curcumin might exert anti-apoptotic activity in ACR-induced neurotoxicity partly through maintaining TERT-related anti-apoptotic function. Curcumin at the dose of 100 mg/kg significantly decreased the levels MDA and IL-1β and TNF-α; increased levels GSH and SOD.
	Liu, et al. [72]	G2/M arrest via possible inhibition of cell cycle-related proteins including Cyclin-dependent kinase 1 (CDK1), cyclin B1, and “cell division cycle” (CDC25C). Extracellular signal-regulated kinase (ERK1/2) and Protein Kinase B (Akt) pathways. Transforming growth factor-β (TGF-β)/Smad pathway. Notch signaling pathway.	This study shows that curcumin could suppress the proliferation and epithelial-mesenchymal transition (EMT) in lens epithelial cells (LECs) and it might be a potential therapeutic protection against visual loss induced by posterior capsule opacification (PCO).
	Chen, et al. [73]	▼ miR-21 in SU-DHL-8 cells, regulating Von Hippel-Lindau (VHL) expression in diffuse large B-cell lymphoma (DLBCL) cell line.	Curcumin exerts its anti-cancer effects, partly by targeting special microRNAs, in human cancers. MiR-21 is a key oncomir in carcinogenesis of multiple human cancers. Curcumin exerted its anti-proliferation, anti-migration, anti-invasion, and pro-apoptosis functions, at least partly, by repressing miR-21 and regulating VHL expression in DLBCL cell line. Study proved a possible molecular mechanism of curcumin-mediated anti-cancer effect.
	Ma, et al. [74]	Caspase 3 and BAX (protein Bcl-2–associated X) ▲ reducing the expression of Bcl-2 in (human tongue squamous cell carcinoma) CAL 27 cells ▼	This study focused on the mechanism underlying the therapeutic effect of curcumin against tongue cancer (TC). The effects of curcumin at different concentrations on the proliferation, migration, apoptosis, and cell cycle for TC cells were verified in vitro. Study revealed the anti-proliferative and pro-apoptotic roles of curcumin in CAL 27 cells, probably due to its role in modulating oxygen production and metabolism. Curcumin might be explored as a promising therapeutic method to improve TC treatment.
	Muangnoi, et al. [75]	Caspase-3 and -9 activities and expression ▲ Bax and Bcl-2 protein expression LC3-II protein level ▲	The aims of the present study were to determine the anti-proliferative effects and mechanisms of curcumin diethyl disuccinate (CurDD), a succinate ester prodrug of Curcumin (Cur), in vitro, in comparison with Cur. These results indicated that the bioavailable fraction (BF) of CurDD had anti-proliferation effect on HepG2 cells by apoptosis induction in HepG2 cells at significantly higher levels than that of Cur. Incubation of HepG2 cells with the BF of Cur increased caspase-3 and -9 activities. These results indicated that treatment of HepG2 cells with the BF of CurDD increased and, respectively, decreased the expression of Bax and Bcl-2 proteins, to a higher extent than in the case of the BF of Cur. The BF of CurDD increased the level of LC3-II significantly higher than the BF of Cur.