TABLE 3.
Summary of pharmacological studies on extracts/metabolites isolated from liriopogons included in this review.
| Activity | Plant resource | Metabolite tested pharmacologically | Model | Effect | Dosage | References |
|---|---|---|---|---|---|---|
| Cardiovascular protection (this activity has been tested on O. japonicus and L. muscari) | O. japonicus | Steroidal saponins extract | DOX-induced SD rats | ↓ values of LVEDP, LVESD and LVEDD; levels of IL-6, TNF-α, IL-1β, MDA; the relative activity of p38 MAPK ↑values of LVESP, +2dP/dtmax, –dP/dtmax, EF and FS; activities of SOD, CAT and GSH-Px | 100 mg/kg (p.o.) | Wu et al. (2019) |
| Aqueous extract | ICR mice SD rats | ↓ length of tail thrombus ↓ arterial-venous shunt | 12.5 and 25.0 mg/kg; 6.25 and 12.5 mg/kg (p.o.) | Kou et al. (2006) | ||
| Ethanol extract | SD rats HL-60 cells and ECV304 cells | ↓ the dried weight of thrombus (36.0 and 70.6%); endothelium injury, adherent or transmigrated leukocytes ↓ adhesion of HL-60 cells to ECV304 cells | 12.5 and 25.0 mg/kg; (p.o) 0.1, 1.0 and 10 μg/ml | Kou et al. (2005b) | ||
| Ruscogenin | (MCAO/R)-injured mice | ↓ infarct size; brain water; ICAM-1, iNOS, COX-2, TNF-α, IL-1β; NF-κB p65 and phosphorylation ↑ neurological deficits | 5 and 10 mg/kg (i.g.) | Guan et al. (2013) | ||
| Ruscogenin | (MCAO/R)-injured mice | ↓ brain infarction and edema, EB leakage ↑ neurological deficits, cerebral brain flow CBF, ameliorated histopathological damage; expression of TJs | 10 mg/kg | Cao et al. (2016) | ||
| OGD/R-injured bEnd.3 cells | ↓ sodium fluorescein leakage, expression of TJs, IL-1β and caspase-1, NLRP3 and TXNIP ↑ cell viability and TEER value | 0.1–10 μM | ||||
| Ophiopogonin D | H9c2 cells 5C7BL/6J mice | ↓ LC3-II/LC3-I ratio, activation of JNK and ERK in H9c2 cells ↓ DOX-induced cardiac dysfunction in mice | 1 μM 10 mg/kg (i.p.) | Zhang et al. (2015c) | ||
| Ophiopogonin D | H9c2 cells Ang II-induced H9c2 cells | ↑ CYP2J3 expression and 14,15-DHET levels in normal H9c2 cells ↓ angiotensin II-induced abnormalities in Ca2+ homeostasis, ER stress | 100, 250 and 500 nM | You et al. (2016) | ||
| Ophiopogonin D | DOX-induced H9c2 cell DOX-induced rats | ↓ ROS accumulation and up-regulation of ERS related proteins ↓ cardiac ultrastructural abnormalities in rats | 1 μM 10 mg/kg (i.p.) | Meng et al. (2014) | ||
| Ophiopogonin D | Ang II-infused H9c2 cells Ang II-infused rats | ↓ ANP, BNP, β-MHC, p-IκBα, p-REL-A, and REL-A proteins ↑ LVESD and LVEDD | 0.1, 0.25, and 0.5 μM 5 or 10 mg/kg (i.p.) | Wang et al. (2018) | ||
| DT-13 | Rat ventricular myocytes | ↓ cardiac intracellular Ca2+ ↑ current voltage curve | 0.1 μM | Tao et al. (2005) | ||
| Methylophiopogonanone A (MONA) | MCAO-induced rats ODG/R -induced bEND.3 cells THP-1 cells | ↓ infarct volume and brain edema, body weight decreases, ROS production, MMP-9 release, ICAM-1 and VCAM-1 expression ↑ neurological deficit scores, survival time, TJ | 1.25, 2.50 or 5.00 mg/kg (i.v.) 2.5, 5.0 or 10 μM | Lin et al. (2015) | ||
| Methylophiopogonanone A (MONA) | I/R-induced mice H/R-induced H9C2 cells | ↓ infarct size (by 60.7%) and myocardial apoptosis (by 56.8%), cell apoptosis and cleaved caspase-3 expression ↑ cardiac function; PI3K, p-Akt, p-eNOS, Bcl-2/Bax ratio and restored NO production | 10 mg/kg (p.o.) 10 μM | He et al. (2016) | ||
| Methylophiopogonanone B (MONB) | H2O2-induced HUVECs | ↓ production of MDA and ROS, H2O2-induced apoptosis, p22phox ↑ SOD activity | 10, 20, 40 and 50 μM | Wang et al. (2019) | ||
| L. muscari | DT-13 | C57BL/6 mice HUVECs | ↓ ROS, TNFR, IL-8, MCP-1 and NO (dose dependent) ↓ NO production, phosphorylation of endothelial NO synthase | 4 mg/kg (i.v.) 0.01, 0.1, 1 μM | Fan et al. (2018) | |
| DT-13 | SD rats | ↓ mRNA expression levels of IL-6 and TF | 1.0, 2.0 and 4.0 mg/kg (p.o.) | Tian et al. (2013) | ||
| DT-13 | HUVECs | ↓ cleaved caspase-3 and cleaved PARP ↑ mitochondrial membrane potential, Akt phosphorylation | 1, 2, 5 μM | Qiu et al. (2014) | ||
| Metabolite 209 and 210 (Flavonoids) | Plates | ↓ platelet aggregation at IC50 value of 11.59 and 10.69 μM | - | Tsai et al. (2013) | ||
| Anti-inflammatory effects (this activity has tested on O. japonicus, L. muscari and L. spicata) | O. japonicus | ROJ-ext (Aquesous extract) | ICR mice and SD rats; HL-60 and ECV304 cells | ↓ ear swelling, pawedema, pleural leukocyte migration, peritoneal total leukocyte and neutrophil migration ↓ adhesion of HL-60 cells to ECV304 cells, with IC50 of 42.85 μg/ml | 25 and 50 mg/kg (p.o.) - | Kou et al. (2005a) |
| Ruscogenin | LPS-induced mice | ↓ lung wet/dry weight ratio, LPS-induced MPO activity and nitrate/nitrite content; expression of TF, iNOS, procoagulant activity; NF-κB p-p65 | 0.3, 1.0 and 3.0 mg/kg (p.o.) | Sun et al. (2012) | ||
| Ruscogenin | MCT-rats | ↓ endothelial cell apoptosis ↑ eNOS, caveolin-1, and CD31 | 0.1, 0.4 and 0.7 mg/kg (p.o.) | Bi et al. (2013) | ||
| Ophiopogonin D | TNF-α- inflamed HaCaT cell; DNCB-treated mice | ↓ spleen/body weight ratio; TNF-α, IL-4, and IL-5; p38 and ERK protein activation and NF-κB nuclear translocation | 1 and 10 μM; 125 and 250 nM | An et al. (2020) | ||
| DT-13 | HUVECs THP-1 TNF-α induced mice | ↓ vascular inflammation, expression of ICAM-1 and VCAM-1; NF-кB p65 phosphorylation, p38 phosphorylation and Src degradation | 0.01, 0.1and 1 μM 4 mg/kg (i.g.) | Zhang et al. (2015b) | ||
| 4′-O-Demethylophiopogonanone E | LPS-induced RAW 264.7 cell | ↓ production of NO with IC50 value of 80.2 μg/ml; production of IL-1β and IL-6 with the IC50 value of 32.5 μg/ml and 13.4 μg/ml, respectively | 0–50 μg/ml | Zhao et al. (2017) | ||
| Methylophiopogonone A; Ophiopogonone E; Methylophiopogonanone B; Ophiopogonanone H | LPS-induced murine microglial cell BV-2 | ↓ NO production with IC50 of 19.2, 14.4, 7.8 and 20.1 μM, respectively | - | Li et al. (2012a) | ||
| Ophiopogonanone G; Ophiopogoside A; Ophiopogoside B | human bronchial epithelial BEAS- 2B cell | ↓ IL-4-induced eotaxin production and eotaxin expression | 25.0 μM | Hung et al. (2010) | ||
| MDG-1 | HUVECs | ↓ Bax/Bcl-2 protein ratio, caspase-3, TNF-α, IL-1β, IL-6 and Cox-2 | 5, 10 or 50 mM | Li et al. (2017) | ||
| Metabolite 289; Metabolite 290 (phenols) | LPS-induced RAW 264.7 macrophage cells | ↑ LPS-induced NO production in RAW264.7 cells with the IC50 value of 11.4 and 29.1 μM, respectively | - | Dang et al. (2017b) | ||
| L. muscari | DT-13 | Mice; HL-60/ECV304 | ↓ acute paw edema induced by histamine in mice; adhesion of HL-60 to ECV304 cells induced by TNF-α or PMA | 4.6 mg/kg (p.o.) 0.01, 0.1 and 1 μM | Tian et al. (2011) | |
| L. spicata | Metabolite 279, 280 (phenols) | Neutrophils | ↓ neutrophil respiratory burst stimulated by PMA with IC50 value of 5.96 and 4.15 μM, respectively | - | Hu et al. (2011) | |
| Effects on the endocrine system (this activity has been tested on O. japonicus and L. spicata) | O. japonicus | Methylophiopogonanone A (MONA) | HFD-induced obese rat model | ↓ expression of ACC and SREBP-1C ↑ activities of lipoprotein lipase and hepatic lipase in serum and liver; expression of LDLR and PPAR α | 10 mg/kg (i.g.) | Li et al. (2020) |
| Ruscogenin | STZ-induced diabetic rat | ↓ macrophage influx; expression of TNF-α, IL-6 and IL-1β | 3.0 mg/kg (p.o.) | Lu et al. (2014) | ||
| Ophiopogonin D | HFD male mice | ↓ Firmicutes/Bacteroidetes ratios and endotoxin-bearing Proteobacteria levels | 1 mg/kg (i.g.) | Chen et al. (2018b) | ||
| Ophiopogonin D | STZ-induced DN rats | ↑ serum albumin and creatinine clearance, serum creatinine, blood urea nitrogen, kidney hypertrophy; TGF-β1, and, GSH, SOD, CAT ↓ MDA, IL-6, IL-1β | 2.5, 5 and 10 mg/kg (p.o.) | Qiao et al. (2020) | ||
| L. spicata | LSP1, LSP2 | STZ-induced diabetic mice | ↓ fasting blood glucose, TC, TG, LDL-C, HDL-C/TC ↑ glucose tolerance, insulin resistance | 100 and 200 mg/kg (p.o.) | Chen et al. (2009a) | |
| Aqueous ethanol extract | STZ-diabetic rats | ↓ creatinine clearance, ICAM-1, MCP-1, and fibronectin protein, TNF- α and IL-1β ↑ histological architecture, blood urea nitrogen and proteinuria | 100 or 200 mg/kg (p.o.) | Lu et al. (2013) | ||
| LSP1, LSP2 | KKAy diabetic mice | ↓ fasting blood glucose, lipid accumulation, hepatic gluconeogenesis ↑ insulin resistance and serum lipid metabolism, glycolysis and hepatic glycogen content; expression of InsR, IRS-1, phosphatidylinositol 3-kinase, and PPAR γ | 100 and 200 mg/kg (i.g.) | Liu et al. (2013) | ||
| Immunomodulation (this activity has been tested on O. japonicus and L. muscari) | O. japonicus | Polysaccharides | C57BL/6 mouse | ↓ SMG index, spleen index, IFN-γ level and IFN-γ/IL-4 ratio ↑ salivary flow, body weight; water intake | 5 and 10 mg/kg (p.o.) | Wang et al. (2007) |
| L. muscari | DT-13, ruscogenin | ICR mice; nonparenchymal cells; hepatocytes and spleen cells | ↓ ALT level, hepatocelluar necrosis and adipose degeneration ↓ release of ALT innonparenchymal cells with IC50 of 6.3 × 10–10 M and 3.9 × 10–7 M, lympho proliferation | 10 or 20 mg/kg (i.p.); 10−5–10–4 μM | Wu et al. (2001) | |
| Water extract | LPS-induced mouse | ↓ NO, IL-6, IL-10, IL-12p40, IP-10, KC, MCP-1, VEGF, GM-CSF, PDGF-BB, intracellular calcium, NF-κB and CREB | 25–200 μg/ml | Kim et al. (2012) | ||
| Anti-oxidation (this activity has been tested on O. japonicus) | O. japonicus | Ophiopogonin D | HUVECs | ↓ H2O2-induced oxidative stress, apoptosis and ERK1/2 activation | 0.6–60.0 μM | Qian et al. (2010) |
| Ophiopogonin D | MC3T3-E1cells and RAW264.7 cells; BALB/c female mice | ↓ induced MC3T3-E1 dysfunction, H2O2-induced MC3T3-E1 dysfunction ↓ CTX-1, TRAP activities, MDA, ROS generation, expression of β-catenin, mRNA expressions of Axin2 and OPG | 1, 10,100 μM 5 and 25 mg/kg (i.p.) | Huang et al. (2015) | ||
| 8-formylophiopogonanone B (FOB-8) | PQ-induced mice | ↓ PQ-induced elevation in MDA, GSH and SOD levels | 20 mg/kg (i.g.) | Qian et al. (2019) | ||
| Anti-cancer (this activity has been tested on O. japonicus and L. muscari) | O. japonicus | Ophiopogonin D′ | PC3 and DU145 cells (prostate cancer); BALB/c nude mice implanted with PC3 and DU145 cells | ↓ levels of cleaved-RIPK1, caspase 8, cleaved-caspase 8, Bid, caspase 10, and cleaved-caspase 10 ↑ cell apoptosis, expression levels of RIPK1 and Bim ↓ PC3 and DU145 xenograft tumors in BALB/c nude mice | 1, 2.5, 5, 10, 25, and 50 μM 2.5 or 5.0 mg/kg (i.p.) | Lu et al. (2018) |
| DT-13 | 95D cells (lung cancer); Orthotopic implantation mouse model | ↓ 95D cells metastasis, expression of paxillin, p-paxillin, p-c-Raf, total c-Raf, p-ERK1/2, total ERK1/2 and β-actin ↑ non-muscle myosin IIA | 0.01, 0.1 and 1 μM 2.5 or 10 mg/kg (i.g.) | Wei et al. (2016) | ||
| DT-13 | HCT-15, HT-29 cells (colorectal cancer); Orthotopic implantation mouse model of colorectal cancer; C57BL/6J APCmin mice model | ↓ glucose uptake, ATP generation, lactate production, m-TOR ↑ AMPK ↓ expression of GLUT1, colorectal cancer growth | 2.5, 5 and 10 μM 0.625, 1.25, 2.5 mg/kg (i.g.) 10 mg/kg (i.g.) | Wei et al. (2019) | ||
| Ruscogenin | SMMC-7721 and HCCLM3 (liver cancer); nude mice implanted with HCCLM3 cells | ↓ cell migration and invasion; levels of MMP-2, MMP-9, urokinase-type plasminogen activator, VEGF and HIF-1α; phosphorylation of Akt, mTOR | 0–100 μM; 0.3, 1.0, or 3.0 mg/kg (i.v.) | Hua et al. (2018) | ||
| Sprengerinin C | HUVECs, HepG-2/BEL7402 cells; nude mice implanted with HepG-2 cells | ↓ VEGF-induced vascular endothelial cell proliferation, invasion and tube formation; VEGFR2 activation, MMP-2/9 and VEGF expression ↑ G2/M phase arrest, NADPH oxidase activity, reactive oxygen species, cleaved caspase-3 and cleaved PARP ↓ tumor growth in a nude mouse | 0.5, 1.0 and 2.0 μM; 7.5 and 15 mg/kg (i.p.) | Zeng et al. (2013) | ||
| Metabolite 26 (saponin) | HUVECs C57/BL mice | ↓ HUVECs invasion and tube formation; expression of Src tyrosine kinase ↓ angiogenesis and MMPs/VEGF expression | 1.25, 2.5, 5.0 and 10.0 μM 5.0 μM (SC) | Zeng et al. (2015) | ||
| L. muscari | Ophiopogon Saponin C1 | A549 cells; mice | ↓ cell migration ↓ degradation and breakage of the ZO-1 protein, PKCδ and Src | 0.01, 0.1, 1 μM 4.0 mg/kg (i.g.) | Zhang et al. (2020) | |
| Anti-viral | L. muscari | Metabolite 207 (falvonoid) | HBV-transfected Huh7 cells | ↓ pCore-Luc, pS-Luc, pPreS-Luc activities; binding activity of NF- κB protein to CS1 element; CS1 containing promoter activity ↓ expression of p65/p50 NF- κB protein, phosphorylated NF-κB p65 ↑ cytoplasmic I κB αprotein levels | 0–10 μg/ml | Huang et al. (2014) |
| Spicatoside A | Huh 7.5 (hepatocellular carcinoma cell) | ↓ replication of the genotype 3 HEV replicon ↓ HEV genotype 3 strain 47832c ↓ expression of HEV ORF2 | 0.5, 1 and 2 μg/ml; 2 μg/ml 0.2, 0.5, 1 and 2 μg/ml | Park et al. (2019) | ||
| Anti-tussive | O. japonicus | Ophiopogonin D | Paratracheal neurones | hyperpolarized the paratracheal neurones from a resting membrane potential of -65.7 to -73.5 mV | 10 μM | Ishibashi et al. (2001) |
| Neuroprotection | L. muscari | Ethanol extract | H2O2-induced injury in SH-SY5Y cells (neuroblastoma cell) | ↓ intracellular oxidative stress, mitochondrial dysfunction; poly (ADP ribose) polymerase and caspase-3 cleavage | 0.5–50 μg/ml | Park et al. (2015) |
| Acute myeloid leukemia (anti-AML) | L. muscari | DT-13 | Human leukemia cell lines; NOD/SCID mice with the engraftment of HL-60 cells | ↑ apoptosis of HL-60 and Kasumi-1 cells ↑ Fas, FasL, DR5, TRAIL, the cleaved-PARP and cleaved-caspase 3 and 8, differentiation markers CD11b and CD14, level of C/EBPα and C/EBPβ ↑ NOD/SCID mice survival time | 0–18 μM; 10 and 20 mg/kg (p.o.) | Wang et al. (2020a) |
| Hepatoprotection | O. japonicus | 58-F | CCl4-induced mouse; H2O2-induced BNL CL.2 hepatocyte cell | ↓ lysosome membrane permeabilization, cathepsin B, cathepsin D ↑ lysosomal enzyme translocation to the cytosol, fluorescence intensity of the LysoTracker Green, cell viability | 15 mg/kg (i.g.) 50 μM | Yan et al. (2016) |
Abbreviations: ABTS, 2,2′-azino-bis (3-ethylbenzthiazoline-6-sulfonicacid); ACC, acetyl CoA carboxylase; AMPK, adenosine 5′-monophosphate (AMP)-activated protein kinase; Ang II, Angiotensin II; ANP, atrial natriuretic peptide; ALT, alanine transaminase; AST, aspartate transaminase; BBB, blood brain barrier; BBMV, intestinal brush border membrane vesicles; bFGF, basic fibroblast growth factor; BNP, B-type natriuretic peptide; CREB, cyclic adenosine monophosphate response element-binding protein; CAT, catalase; CBF, cerebral flow; CCR3, C-C motif chemokine receptor 3; CHF, chronic heart failure; COX-2, cyclooxygenase; CTGF, connective tissue growth factor; DN, diabetic nephropathy; DPPH, 2,2-diphenyl-1-picrylhydrazyl; DT-13, 25 (R,S)-ruscogenin1-O-[β-d-glucopyranosyl-(1→2)]-[β-d-xylopyranosyl-(1→3)]-β-d-fucopyranoside; EB, evans blue; EETs, epoxyeicosatrienoic acids; eNOS, endothelial nitric oxide synthase; Egr-1, Early growth response gene-1; EF, ejection fraction; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; ET-1, endothelin-1; FAS, fatty acid synthase; FasL, fas ligand; FS, fractional shortening; GLP-1, glucagon-like peptide-1; GLUT1, glucose transporter 1; GM-CSF, granulocyte macrophage colony-stimulating factor; GPx, glutathione peroxidase; GSH, glutathione; hBSM, human bronchial smooth muscle cells; HEV, hepatitis e virus; HFD, high fat diet; HDL-C, high density lipoprotein cholesterol; HMEC-1, microvascular endothelial cells; HUVECs, human umbilical vein endothelial cells; ICAM, intercellular adhesion molecules; IFN-γ, interferon-γ; iNOS, inducible nitric oxide synthase; IL, interleukin; LVESP, left ventricular end-systolic pressure; InsR, insulin receptor; ISO, isoproterenol; JNK, c-Jun N-terminal kinase; KC, keratinocyte-derived chemokine; LVESD, left ventricular end systolic diameter; LVEDD, left ventricular end diastolic diameter; LVEDP, left ventricular end-diastolic pressure; LPS, lipopolysaccharide; mAChRs, muscarinic acetylcholine receptors; MAPK, mitogen-activated protein kinase; MCAO, middle cerebral artery occlusion; MCAO/R, middle cerebral artery occlusion/reperfusion; MCP-1, monocyte chemoattractant protein-1; MCT, monocrotaline; MDA, malondialdehyde; MHC, myosin heavy chain; MLE, mouse lung epithelial cells; MMP, matrix metalloproteinase; MPO, myeloperoxidase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-κB; NOD, nucleotide-binding domain; NOD/SCID, nonobese diabetic/severe combined immunodeficiency; NSCLC, non-smallcell lung cancer; NLRP3, pyrin domain containing 3; OGD/R, oxygen–glucose deprivation/reoxygenation; OGTT, oral glucose tolerance test; ORF, open reading frame; PDGF-BB, platelet derived growth factor; PI3-Kp85, phosphoinositide 3-kinase p85 subunit; ROS, reactive oxygen species; PKC, protein kinase C; PMA, phorbol myristate acetate; PPAR, peroxisome proliferator-activated receptor; PSA, prostate-specific antigen; PTP1B, protein-tyrosine phosphatase 1B; S1P, sphingosine 1-phosphate; SCr, serum creatinine; SD, Sprague-Dawley; sICAM-1, human soluble intercellular adhesion molecule-1; SMG, submandibular gland; SOD, superoxide dismutase; SPHK1, sphingosine kinase-1; SREBP-1C, sterol regulatory element-binding protein 1c; STZ, streptozotocin; TEER, trans-endothelial electeical resistance; TC, total cholesterol; TF, tissue factor; TG, triglycerides; THP-1, human monoblastic leukemia cells; TJ, tight junction; TNF- α, tumour necrosis factor- α; TNFR, tumor necrosis factor receptor; TXNIP, thiredoxin-interactive protein; UA, uric acid; VCA,-1, vascular adhesion molecule-1; VEGF, vascular endothelial growth factor.