The promising therapeutic potentials of ginsenosides mediated through p38 MAPK signaling inhibition.

In this part, we reviewed studies displaying the role of p38 MPAK inhibition in mediating the pharmacological activities of ginsenosides. Only ginsenosides (compound K, F1, Rb1, Rb3, Rc, Rd, Re, Rf, Rg1, Rg2, Rg3, Rg5, Rh1, Rh2, Ro, notoginsenoside R1, and PPD) reported to inhibit p38 MPAK were included in this section and their chemical structure was shown in Table 1 . In addition, their promising effects and therapeutic potentials regarding p38 MAPK inhibition were summarized in Table 2 . Table 1 Structure of selected ginsenosides. Table 1 Compound name CID IUPAC name Structure Ginsenoside Compound K 9852086 (2S,3R,4S,5S,6R)-2-[(2S)-2-[(3S,5R,8R,9R,10R, 12R,13R,14R,17S)-3,12-dihydroxy-4,4,8,10,14-pentamethyl-2,3,5,6,7,9,11,12,13,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]-6-methylhept-5-en-2-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Image 1 Ginsenoside F1 9809542 (2 R ,3 S ,4 S ,5 R ,6 S )-2-(hydroxymethyl)-6-[(2 S )-6-methyl-2-[(3 S ,5 R ,6 S ,8 R ,9 R ,10 R ,12 R ,13 R ,14 R , 17 S )-3,6,12-trihydroxy-4,4,8,10,14-pentamethyl-2,3,5,6,7,9,11,12,13,15,16,17-dodecahydro-1 H -cyclopenta[a]phenanthren-17-yl]hept-5-en-2-yl]oxyoxane-3,4,5-triol Image 2 Ginsenoside Rb1 9898279 (2R,3R,4S,5S,6R)-2-[[(2R,3S,4S,5R,6S)-6-[(2S)-2-[(3S,5R,8R,9R, 10R,12R,13R,14R, 17S)-3-[(2R,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxy- methyl)-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-12-hydroxy-4,4,8,10,14-pentamethyl-2,3,5,6,7,9,11, 12,13,15,16,17-dodecahydro-1H-cyclopenta[a] phenanthren-17-yl]-6-methylhept-5-en-2-yl]oxy-3,4,5-trihydroxyoxan-2-yl]methoxy]-6-(hydroxy-methyl)oxane-3,4,5-triol Image 3 Ginsenoside Rb3 12912363 (2S,3R,4S,5S,6R)-2-[(2R,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxyl methyl)-2-[[(3S,5R,8R, 9R,10R,12R,13R,14R,17S)-12-hydroxy-4,4,8,10,14-pentamethyl-17-[(2S)-6-methyl-2-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-[[(2S,3R,4S,5R)-3,4,5-trihydroxyoxan-2-yl]oxymethyl]oxan-2-yl]oxyhept-5-en-2-yl]-2,3,5,6,7,9,11,12, 13,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]oxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Image 4 Ginsenoside Rc 12855889 (2S,3R,4S,5S,6R)-2-[(2R,3R,4S,5S,6R)-2-[[(3S,5R,8R,9R,10R, 12R,13R,14R,17S)-17-[(2S)-2-[(2S,3R,4S,5S,6R)-6-[[(2R,3R,4R,5S)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxymethyl]-3,4,5-trihydroxyoxan-2-yl]oxy-6-methylhept-5-en-2-yl]-12-hydroxy-4,4,8,10,14-pentamethyl-2,3,5,6,7,9,11, 12,13,15,16,17-dodeca-hydro-1H-cyclopenta [a]phenanthren-3-yl]oxy]-4,5-dihydroxy-6-(hydroxyl methyl)oxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Image 5 Ginsenoside Rd 24721561 (2S,3R,4S,5S,6R)-2-[(2R,3R,4S,5S,6R)-2-[[(3S, 5R,6S,8R,9R,10R,12R, 13R,14R,17S)-3,12-dihydroxy-4,4,8,10,14-pentamethyl-17-[(2S)-6-methyl-2-[(2S,3R, 4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyhept-5-en-2-yl]-2,3,5,6, 7,9,11,12,13,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-6-yl]oxy]-4,5 dihydroxy-6-(hydroxymethyl)oxan-3-yl]oxy-6-(hydroxy- methyl)oxane-3,4,5-triol Image 6 Ginsenoside Re 441921 2S,3R,4R,5R,6S)-2-[(2R,3R,4S,5S,6R)-2-[[(3S,5R,6S,8R,9R,10R,12R,13R,14R,17S)-3,12-dihydroxy-4,4,8,10,14-pentamethyl-17-[(2S)-6-methyl-2-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyhept-5-en-2-yl]-2,3,5,6,7,9,11,12,13,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-6-yl]oxy]-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]oxy-6-methyloxane-3,4,5-triol Image 7 Ginsenoside Rf 441922 (2S,3R,4S,5S,6R)-2-[(2R,3R,4S,5S,6R)-2-[[(3S,5R, 6S,8R,9R,10R,12R, 13R,14R,17S)-3,12-dihydroxy-17-[(2S)-2-hydroxy-6-methylhept-5-en-2-yl]-4,4,8,10,14-pentamethyl-2,3,5,6,7,9,11,12,13, 15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-6-yl]oxy]-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Image 8 Ginsenoside Rg1 441923 2-[[3,12-dihydroxy-4,4,8,10,14-pentamethyl-17-[6-methyl-2-[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyhept-5-en-2-yl]-2,3,5,6,7,9,11,12,13,15, 16,17-dodecahydro-1H-cyclopenta[a]phenanthren-6-yl]oxy]-6-(hydroxymethyl)oxane-3,4,5-triol Image 9 Ginsenoside Rg2 21599924 (2S,3R,4R,5R,6S)-2-[(2R,3R,4S,5S,6R)-2-[[(6R,10R,12S,14R)-3,12-dihydroxy-17-[(E,2S)-2-hydroxy-6-methyloct-5-en-2-yl]-4,4,10,14-tetramethyl-1,2,3,5,6,7,8,9,11,12,13,15,16,17-tetradecahydrocyclopenta[a]phenanthren-6-yl]oxy]-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]oxy-6-methyloxane-3,4,5-triol Image 10 Ginsenoside Rg3 9918693 2-[4,5-dihydroxy-2-[[12-hydroxy-17-(2-hydroxy-6-methylhept-5-en-2-yl)-4,4,8,10,14-pentamethyl-2,3,5,6,7,9,11,12,13,15,16,17-dodecahydro-1H-cyclopenta [a]phenanthren-3-yl]oxy]-6-(hydroxy-methyl)oxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Image 11 Ginsenoside Rg5 11550001 (2S,3R,4S,5S,6R)-2-[(2R,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-2-[[(3S,5R,8R,9R, 10R,12R,13R,14R,17S)-12-hydroxy-4,4,8,10,14-pentamethyl-17-[(2E)-6-methylhepta-2,5-dien-2-yl]-2,3,5,6,7,9,11,12,13,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]oxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Image 12 Ginsenoside Rh1 12855920 2-[[3,12-dihydroxy-17-(2-hydroxy-6-methylhept-5-en-2-yl)-4,4,8,10, 14-pentamethyl-2,3,5,6,7,9,11, 12,13,15,16,17-dodecahydro-1H-cyclopenta [a]phenan-thren-6-yl]oxy]-6-(hydroxymethyl)oxane-3,4,5-triol Image 13 Ginsenoside Rh2 119307 (2R,3R,4S,5S,6R)-2-[[(3S,5R,8R,9R,10R,12R, 13R,14R,17S)-12-hydroxy-17-[(2S)-2-hydroxy-6-methylhept-5-en-2-yl]-4,4,8,10,14-pentamethyl-2,3, 5,6,7,9,11,12,13,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]-6-(hydroxymethyl)oxane-3,4,5-triol Image 14 Ginsenoside Ro 11815492 (2S,3S,4S,5R,6R)-6-[[(3S,4aR,6aR,6bS,8aS, 12aS,14aR,14bR)-4,4,6a, 6b,11,11,14b-heptamethyl-8a-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxylmethyl) oxan-2-yl]oxycarbonyl-1,2,3,4a, 5,6,7,8,9,10,12,12a,14,14a-tetradecahydropicen-3yl] oxy]-3,4-dihydroxy-5-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxane-2-carboxylic acid Image 15 Notoginsenoside R 1 441934 (2S,3R,4S,5S,6R)-2-[(2S)-2-[(3S,5R,6S,8R,9R,10R, 12R,13R, 14R,17S)-6-[(2R,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4S,5R)-3,4,5-trihydroxyoxan-2-yl]oxyoxan-2-yl]oxy-3,12-dihydroxy-4,4,8,10,14-pentamethyl-2,3,5,6,7, 9,11,12,13,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]-6-methylhept-5-en-2-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Image 16 Protopanaxadiol 11213350 ((3S,5R,8R,9R,10R,12R,13R,14R,17S)-17-[(2S)-2-hydroxy-6-methylhept-5-en-2-yl]-4,4,8,10,14-pentamethyl-2,3,5,6,7,9,11,12,13,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-3,12-diol) Image 17 Table 2 Summary of ginsenosides’ effects on p38 MAPK in different models. Table 2 Compound Disease/Model Effects Reference Ginsenoside compound K Development and invasion of brain tumors using U87MG and U373MG cells - Blocked the PMA-induced p38 MAPK, ERK, and JNK activation. - Downregulated MMP-9-induced by PMA. - Suppressed AP-1 binding. [ 69 ] Zymosan-induced inflammatory cytokine production using RAW264.7 macrophage - Decreased TNF-α and Interleukins - Suppressed p38 MAPK and ERK1/2 activation. - Decreased superoxide production - Decreased NADPH oxidase enzymatic activities - Suppressed Ser345-p47phox phosphorylation. [ 63 ] Angiogenesis-provoked by bFGF using HUVECs - Has an antiangiogenesis effect mediated by the suppression of p38 MAPK and Akt in HUVECs. [ 72 ] ox-LDL-induced injury in HUVECs - Prevented ox-LDL-induced injury through the inhibition of NF-κB, p38 MAPK, and JNK signals. [ 73 ] Colitis induced by TNBS in mice and in vitro murine peritoneal macrophages induced by LPS - Strongly inhibited TNF-α and interleukins expression. - Significantly augmented IL-10 level. - Effectively decreased both COX-2 and iNOS levels - Suppressed NF-κB activation. - Inactivated IRAK-1, IKK-β, and MAPKs and concluded that ginsenoside CK could be used effectively to treat inflammatory conditions like colitis. [ 62 ] Renal inflammation in diabetic nephropathy induced by HFD/STZ and rat glomerular mesangial cell line HBZY-1 exposed to high glucose. - Downregulated NLRP3 inflammasome components and cytokines; IL-1β and IL-18 in vivo and in vitro. - Inhibited kidney p38 MAPK phosphorylation. - Decreased NADHP oxidase level and ROS. [ 74 ] Atherosclerosis-induced by Ox-LDL in RAW264.7 - Potently suppressed NF-κB, p38MAPK, and JNK signals. [ 75 ] Ginsenoside F1 Age-related brain inflammation – SASP induced by d-galactose in Astrocytic CRT and U373-MG cells - Suppressed SASP induced by ​d-galactose through the inhibition of p38 MAPK-dependent NF-κB activity. - Downregulated IL-8 effectively. [ 86 ] Ginsenoside Rb1 Osteoporosis – RANKL-induced osteoclast differentiation using RAW264.7 cells - Exerted anti-osteoporotic action through preventing the distinction between RANKL-activated osteoclast and RAW264.7 macrophages. - Inhibited RANKL-induced p38 MAPK/NF-κB pathway. - Blocked the expression of c-Fos and NFAT C1, the important factors for osteoclasts distinction. [ 98 ] MPP(+)-induced apoptosis in PC12 cells - Increased phosphorylation levels of ERK1/2 or Akt in MPP(+)-treated PC12 cells, while it reduced the activation of p38 MAPK. [ 99 ] TNF-α-induced inflammation in HUVECs - Inhibits inflammatory response and decreases VCAM-1, ICAM-1, IL-6, IL-1β, VEGF, MMP-2, and MMP-9 levels. - Downregulated p38 MAPK and JNK signaling. - Suppressed ROS and MDA production, while it elevated SOD, CAT, and GSH-Px enzymatic activities. [ 100 ] Balloon injury-induced vascular neointimal hyperplasia in rats - Suppressed p-ERK1/2 and the mRNA expression of c-myc and downregulated the p38 MAPK gene. [ 101 ] Abdominal aortic aneurysm induced by angiotensin II in ApoE(−/−) mice - Protected against abdominal aortic aneurysm agent through inhibiting the JNK and p38 MAPK signaling pathways. - Attenuated Ang II-induced diameter enlargement, MMP production, and VSMC dysfunction. [ 102 ] Myocardial I/R in rats - Decreased caspase-3 activity and lowered TNF-α level in the myocardium. - Downregulated phospho-p38α MAPK. [ 103 ] In vivo using zymosan A in rat. In vitro using HUVECs and THP-1 cells from H 2 O 2 -mediated cytotoxicity - Protected endothelial cells cytotoxicity through the curbing of oxLDL-provoked p38 MAPK and VCAM-1 protein expression in addition to decreased TNF-α level. - Exhibited antioxidant activity mediated by PI3K/Akt/Nrf2 activation. [ 104 ] renal proximal tubular apoptosis induced by tacrolimus-induced apoptosis using LLC-PK1 cells - Decreased KIM-1 and cleaved-caspase-3 levels - Suppressed p38 MAPK phosphorylation. [ 105 ] Renal fibrosis and CKD using in vivo unilateral ureter obstruction in mice and in vitro HBSS-induced HK-2 cells. - Attenuated autophagy through the AMPK/mTOR pathway in HK-2 cells and in vivo mice model . - Effectively inhibited p38 and ERK activation in HK-2 cells exposed to HBSS. [ 106 ] Ginsenoside Rb3 Cigarette smoke-induced cell injury in WI-38 and 16HBE cells - Prevented the inflammatory response and oxidative stress caused by cigarette smoke extract as well as excessive accumulation of extracellular matrix. - Inhibited the p38 MAPK/NF-κB and TGF-β1/VEGF pathways. [ 110 ] Periodontitis-induced LPS in rats. - Effectively decreased p38 MAPK phosphorylation and NF-κB and decreased interleukins levels. - Decreased the expression of total Akt. [ 111 ] Ginsenoside Rc LPS-induced inflammation in RAW264.7 and HEK293 cells transfected with various inducers of inflammation . - Blocked the production of cytokines derived from macrophages for tumor necrosis. - Suppressed TANK-binding kinase 1/IκB kinase ε/IRF3, and p38 MAPK/ATF-2 signaling activation. [ 113 ] Ginsenoside Rd Cancer metastasis using HepG2 cells - Blocked MMP activation and MAPK signaling. [ 122 ] TNBS-induced colitis in rats - Potently inhibited the inflammatory perturbing evidenced by decreasing the MPO activity mediated by lowering cytokine production and suppressing of p38 MAPK and JNK phosphorylation. [ 123 ] Cartilage degradation of OA-induced by IL-1β using S12 cells - Suppressed cartilage degradation of OA by suppressing MMP3 through the inhibition of p-p38 MAPK activation. [ 121 ] Ginsenoside Re Neuroinflammation by LPS-induced inflammation in microglial cells - Delayed the progression of neuroinflammatory through the attenuation of LPS-induced MAPK phosphorylation. [ 128 ] Heart dysfunction induced by LPS in mice. - Significantly prevented cardiac dysfunction induced by LPS through the effective inhibition of phosphorylated MAPKs. [ 129 ] Ox-LDL-induced endothelial apoptosis using HUVECs - Restored the balanced redox state of the cells. - Inhibited the activation of NF-κB and the caspase cascade by activating the PI3K/Akt pathway and inhibiting the phosphorylation of p38 MAPK. - Downregulated lectin-like Ox-LDL receptor-1 and NADPH oxidase. - Upregulated the expression of estrogen receptor-alpha. [ 130 ] Angiotensin II-induced gap-junction remodeling in isolated beating rat atria. - Suppressed p38 MAPK, NF-κB, and AP-1 - Effectively upregulated PPARγ level. [ 131 ] Ginsenoside Rf TNF-α-stimulated HT-29 and RAW264.7 cells. - Reduced cytokines, TNF-α, IL-1β, IL-6, NO release, and suppressed ROS production that linked to p38 MAPK/NF-κB activation. [ 137 ] Ginsenoside Rg1 MPTP-induced Parkinson disease in mice - Reduced p-p38 MAPK, COX-2-, and PGE2-positive cells noticeably 6 h after the third injection of MPTP. [ 142 ] CSDS-induced depressive-like behaviors in rats - Inhibited p-p38 MAPK and NF-κB p65 subunit activation. - Inhibited neuronal apoptosis induced by CUMS exposure. - Upregulated Nrf2 expression. [ 143 ] CSDS-induced depressive-like behaviors in mice - Effectively decreased IL-6, TNF-α, and IL-1β production and both iNOS and COX2 enzymes. - Decreased caspase-9 and -3 level and inhibited hippocampal microglial activation. - Inactivated both p-p38 MAPK and p-JNK1/2 and inhibited NF-κB phosphorylation, thereby regulated SIRT1 and reduced acetylated p65 level. [ 144 ] LPS-induced microglial activation in mice - Suppressed microglial activation induced by LPS through suppressing Iba-1 and iNOS. - Suppressed IκB and nuclear translocation of p65 subunit of NF-κB phosphorylation through the effective suppression of p38 MAPK, ERK1/2, and JNK phosphorylation. [ 145 ] Neuroinflammation by LPS – in BV2 microglial cells - Significantly attenuated the LPS-induced expression of NF-κB and reduced cytokines TNF-α, IL-1β, iNOS, and COX-2 through the effective inhibition of p38 MAPK, IκB-α, CREB, ERK1/2, and JNK phosphorylation. [ 138 ] LPS-induced neuronal degeneration in rat - Protected against LPS-induced microglial inflammation in mesencephalic dopaminergic neurons through the inhibition of p38 MAPK signaling pathway. [ 139 ] Oxygen-glucose-deprivation in NSCs. - Downregulated p-p38 and p-JNK expression. - Suppressed apoptosis - Decreased oxidative stress [ 146 ] Ventricular remodeling model of myocardial infarction in rats - Activated PI3K/Akt signaling. - Inhibited p38 MAPK. [ 147 ] Insulin resistance induced by insulin – in HepG2 cells. - Raised glucose uptake through a decrease in ROS. - Suppressed p38 MAPK phosphorylation and GSK3β expression. - Effectively elevated Akt phosphorylation. [ 148 ] Left ventricular hypertrophy and cardiac dysfunction-induced by transverse aortic constriction in rats - Upregulated p-Akt level. - Potently inhibited p38 MAPK signaling. [ 149 ] RPE cells from CoCl2 and hypoxia assaults - Potently inhibited ROS production through effective suppression of p38 MAPK and JNK activation. [ 150 ] Podocytes from sMAC-induced injury - Attenuated F-actin damage. - Restored the antioxidant status mediated by the suppression of p38 MAPK activation. [ 151 ] Shear-induced inflammation - Suppressed p38 MAPK, ERK, and JNK phosphorylation is similar to that of specific chemical inhibitors for MAPK signal. [ 152 ] Ginsenoside Rg2 LPS-induced leukocyte adhesion into the vascular wall using HUVECs - Suppressed LPS-mediated p38 MAPK monocyte adhesion. - Downregulated VCAM-1 and ICAM-1 and NF-κB. [ 154 ] Ginsenoside Rg3 RANKL-induced osteoclasts differentiation in RAW264.7 cells - Showed the effective inhibition of Cat-K through p38 MAPK downregulation. [ 162 ] Hepatitis B virus replication - Decreased IL-8 and TNF-α levels. - Inhibited p38 MAPK. - Inhibited c-Jun N-terminal kinase phosphorylation and downregulated AP-1. [ 163 ] LLC cancer cell lines - Induce cell apoptosis mediated through the deactivation of the p38 MAPK pathway. [ 164 ] Ginsenoside Rg5 Diabetic nephropathy induced by high-fat diet/STZ-in mice - Suppressed the expression of NF-κB and the phosphorylation of p38 MAPK. - Effectively decreased IL-1β and IL-18 production and inflammatory response. - Restored oxidant/antioxidant balance. [ 220 ] Ginsenoside Rh1 Invasion and migration of THP-1 acute monocytic leukemia cells - Suppressed the phosphorylation of MAPKs. [ 183 ] Hepatocellular carcinoma using HepG2 cell lines - Suppressed ERK, JNK, and p38 MAPK activation. - Downregulated c-Jun and c-Fos. [ 185 ] Colon in vitro and tumor growth in vivo - Downregulated MMP1 and MMP3, promoted TIMP3 expression, and effectively decreased the ratios of p-pp38 MAPK/p38 MAPK, p-ERK1/2/ERK1/2, and p-JNK/JNK . [ 186 ] Ginsenoside Rh2 Allergic airway inflammation animal model - Suppressed phosphorylation of p38 MAPK and activation of NF-κB. [ 192 ] Human astroglioma cells - Repressed the expression of MMP-9 through the inhibition of p38 MAPK. [ 193 ] HepG2 cells - Ginsenoside Rh2 treatment alone, cotreatment with ginsenoside Rh2 and SB203580 (p38 MAPK inhibitor) resulted in cell death, which increased from 20% to 50%, suggesting that p38 MAPK inhibition can increase ginsenoside Rh2 apoptosis induction. [ 187 ] Ginsenoside Ro TXA2-associated thrombosis - Holds a significant antiplatelet potential and attenuated thromboxane-A2 production through suppressing p38-MAPK-mediated cPLA2a phosphorylation and AA release. [ 202 ] Notoginsenoside R1 I/R-induced myocardial injury in rabbits - Possessed a cardioprotective effect through p38 MAPK inhibition and suppressed apoptosis. - Inhibited TGF-β1-TAK1 signaling pathway-related proteins. [ 208 ] PASMCs exposed to hypoxia and hypercapnia - Alleviated hypoxia and HHPV and inhibiting the activation of ERK and p38 MAPK pathways. [ 209 ] Protopanaxadiol Triple-negative breast cancer metastasis in vivo and TNBC in vitro MDA-MB-231 and SUM159 cells - Inhibited EGFR phosphorylation and inactivated ERK1/2, p38, and JNK signaling. [ 216 ] Structure of selected ginsenosides. Summary of ginsenosides’ effects on p38 MAPK in different models. Blocked the PMA-induced p38 MAPK, ERK, and JNK activation. Downregulated MMP-9-induced by PMA. Suppressed AP-1 binding. Decreased TNF-α and Interleukins Suppressed p38 MAPK and ERK1/2 activation. Decreased superoxide production Decreased NADPH oxidase enzymatic activities Suppressed Ser345-p47phox phosphorylation. Has an antiangiogenesis effect mediated by the suppression of p38 MAPK and Akt in HUVECs. Prevented ox-LDL-induced injury through the inhibition of NF-κB, p38 MAPK, and JNK signals. Strongly inhibited TNF-α and interleukins expression. Significantly augmented IL-10 level. Effectively decreased both COX-2 and iNOS levels Suppressed NF-κB activation. Inactivated IRAK-1, IKK-β, and MAPKs and concluded that ginsenoside CK could be used effectively to treat inflammatory conditions like colitis. Downregulated NLRP3 inflammasome components and cytokines; IL-1β and IL-18 in vivo and in vitro. Inhibited kidney p38 MAPK phosphorylation. Decreased NADHP oxidase level and ROS. Potently suppressed NF-κB, p38MAPK, and JNK signals. Suppressed SASP induced by ​d-galactose through the inhibition of p38 MAPK-dependent NF-κB activity. Downregulated IL-8 effectively. Exerted anti-osteoporotic action through preventing the distinction between RANKL-activated osteoclast and RAW264.7 macrophages. Inhibited RANKL-induced p38 MAPK/NF-κB pathway. Blocked the expression of c-Fos and NFAT C1, the important factors for osteoclasts distinction. Increased phosphorylation levels of ERK1/2 or Akt in MPP(+)-treated PC12 cells, while it reduced the activation of p38 MAPK. Inhibits inflammatory response and decreases VCAM-1, ICAM-1, IL-6, IL-1β, VEGF, MMP-2, and MMP-9 levels. Downregulated p38 MAPK and JNK signaling. Suppressed ROS and MDA production, while it elevated SOD, CAT, and GSH-Px enzymatic activities. Suppressed p-ERK1/2 and the mRNA expression of c-myc and downregulated the p38 MAPK gene. Protected against abdominal aortic aneurysm agent through inhibiting the JNK and p38 MAPK signaling pathways. Attenuated Ang II-induced diameter enlargement, MMP production, and VSMC dysfunction. Decreased caspase-3 activity and lowered TNF-α level in the myocardium. Downregulated phospho-p38α MAPK. Protected endothelial cells cytotoxicity through the curbing of oxLDL-provoked p38 MAPK and VCAM-1 protein expression in addition to decreased TNF-α level. Exhibited antioxidant activity mediated by PI3K/Akt/Nrf2 activation. Decreased KIM-1 and cleaved-caspase-3 levels Suppressed p38 MAPK phosphorylation. Attenuated autophagy through the AMPK/mTOR pathway in HK-2 cells and in vivo mice model . Effectively inhibited p38 and ERK activation in HK-2 cells exposed to HBSS. Prevented the inflammatory response and oxidative stress caused by cigarette smoke extract as well as excessive accumulation of extracellular matrix. Inhibited the p38 MAPK/NF-κB and TGF-β1/VEGF pathways. Effectively decreased p38 MAPK phosphorylation and NF-κB and decreased interleukins levels. Decreased the expression of total Akt. Blocked the production of cytokines derived from macrophages for tumor necrosis. Suppressed TANK-binding kinase 1/IκB kinase ε/IRF3, and p38 MAPK/ATF-2 signaling activation. Blocked MMP activation and MAPK signaling. Potently inhibited the inflammatory perturbing evidenced by decreasing the MPO activity mediated by lowering cytokine production and suppressing of p38 MAPK and JNK phosphorylation. Suppressed cartilage degradation of OA by suppressing MMP3 through the inhibition of p-p38 MAPK activation. Delayed the progression of neuroinflammatory through the attenuation of LPS-induced MAPK phosphorylation. Significantly prevented cardiac dysfunction induced by LPS through the effective inhibition of phosphorylated MAPKs. Restored the balanced redox state of the cells. Inhibited the activation of NF-κB and the caspase cascade by activating the PI3K/Akt pathway and inhibiting the phosphorylation of p38 MAPK. Downregulated lectin-like Ox-LDL receptor-1 and NADPH oxidase. Upregulated the expression of estrogen receptor-alpha. Suppressed p38 MAPK, NF-κB, and AP-1 Effectively upregulated PPARγ level. Reduced cytokines, TNF-α, IL-1β, IL-6, NO release, and suppressed ROS production that linked to p38 MAPK/NF-κB activation. Reduced p-p38 MAPK, COX-2-, and PGE2-positive cells noticeably 6 h after the third injection of MPTP. Inhibited p-p38 MAPK and NF-κB p65 subunit activation. Inhibited neuronal apoptosis induced by CUMS exposure. Upregulated Nrf2 expression. Effectively decreased IL-6, TNF-α, and IL-1β production and both iNOS and COX2 enzymes. Decreased caspase-9 and -3 level and inhibited hippocampal microglial activation. Inactivated both p-p38 MAPK and p-JNK1/2 and inhibited NF-κB phosphorylation, thereby regulated SIRT1 and reduced acetylated p65 level. Suppressed microglial activation induced by LPS through suppressing Iba-1 and iNOS. Suppressed IκB and nuclear translocation of p65 subunit of NF-κB phosphorylation through the effective suppression of p38 MAPK, ERK1/2, and JNK phosphorylation. Significantly attenuated the LPS-induced expression of NF-κB and reduced cytokines TNF-α, IL-1β, iNOS, and COX-2 through the effective inhibition of p38 MAPK, IκB-α, CREB, ERK1/2, and JNK phosphorylation. Protected against LPS-induced microglial inflammation in mesencephalic dopaminergic neurons through the inhibition of p38 MAPK signaling pathway. Downregulated p-p38 and p-JNK expression. Suppressed apoptosis Decreased oxidative stress Activated PI3K/Akt signaling. Inhibited p38 MAPK. Raised glucose uptake through a decrease in ROS. Suppressed p38 MAPK phosphorylation and GSK3β expression. Effectively elevated Akt phosphorylation. Upregulated p-Akt level. Potently inhibited p38 MAPK signaling. Potently inhibited ROS production through effective suppression of p38 MAPK and JNK activation. Attenuated F-actin damage. Restored the antioxidant status mediated by the suppression of p38 MAPK activation. Suppressed p38 MAPK, ERK, and JNK phosphorylation is similar to that of specific chemical inhibitors for MAPK signal. Suppressed LPS-mediated p38 MAPK monocyte adhesion. Downregulated VCAM-1 and ICAM-1 and NF-κB. Showed the effective inhibition of Cat-K through p38 MAPK downregulation. Decreased IL-8 and TNF-α levels. Inhibited p38 MAPK. Inhibited c-Jun N-terminal kinase phosphorylation and downregulated AP-1. Induce cell apoptosis mediated through the deactivation of the p38 MAPK pathway. Suppressed the expression of NF-κB and the phosphorylation of p38 MAPK. Effectively decreased IL-1β and IL-18 production and inflammatory response. Restored oxidant/antioxidant balance. Suppressed the phosphorylation of MAPKs. Suppressed ERK, JNK, and p38 MAPK activation. Downregulated c-Jun and c-Fos. Downregulated MMP1 and MMP3, promoted TIMP3 expression, and effectively decreased the ratios of p-pp38 MAPK/p38 MAPK, p-ERK1/2/ERK1/2, and p-JNK/JNK . Suppressed phosphorylation of p38 MAPK and activation of NF-κB. Repressed the expression of MMP-9 through the inhibition of p38 MAPK. Ginsenoside Rh2 treatment alone, cotreatment with ginsenoside Rh2 and SB203580 (p38 MAPK inhibitor) resulted in cell death, which increased from 20% to 50%, suggesting that p38 MAPK inhibition can increase ginsenoside Rh2 apoptosis induction. Holds a significant antiplatelet potential and attenuated thromboxane-A2 production through suppressing p38-MAPK-mediated cPLA2a phosphorylation and AA release. Possessed a cardioprotective effect through p38 MAPK inhibition and suppressed apoptosis. Inhibited TGF-β1-TAK1 signaling pathway-related proteins. Alleviated hypoxia and HHPV and inhibiting the activation of ERK and p38 MAPK pathways. Inhibited EGFR phosphorylation and inactivated ERK1/2, p38, and JNK signaling. Ginsenoside CK is the principal by-product of PPD, the constituent of Panax ginseng [ 56 ]. Many researches evaluated the pharmacotherapeutic actions of ginsenoside CK such as anticancer in both in vitro cancer cells [ 57 ] and experimental animal models [ 58 ]. Ginsenoside CK has antioxidant [ 59 ], antidepressant [ 60 ], and anti-epileptic [ 61 ] effects. Traditionally, it has been claimed that ginsenoside CK's anti-inflammatory effects may rely on many mechanisms. Reducing the inducible nitric oxide synthase (iNOS), COX-2, and inflammatory mediators was the most common mechanism [ 62 , 63 , 64 ]. Joh et al. (2011) reported its ability to suppress the expression of proinflammatory cytokines by downregulating interleukin-1 receptor-associated kinase 1 (IRAK-1), MAPK, I kappa B kinase (IKK)-α, and NF-κB activities in peritoneal murine macrophages treated with LPS [ 65 ]. Furthermore, ginsenoside CK inhibited inflammatory responses in zymosan-treated cells by adversely controlling proinflammatory cytokine secretion, MAPK activation, and ROS generation [ 66 ]. Ginsenoside CK's anti-inflammatory action was observed in microglial cells activated by LPS, where ginsenoside CK hindered inflammatory responses by monitoring both ROS production and MAPKs, NF-κB, and activator protein 1 (AP-1) activities [ 67 ]. In addition, ginsenoside CK suppressed iNOS and COX2 expressions through the downregulation of NF-κB in LPS-activated inflammation in RAW264.7 cells [ 68 ]. Furthermore, ginsenoside CK downregulated intestinal inflammation by curbing NF-κB signaling in colitis instigated by 2,4,6-Trinitrobenzenesulfonic acid (TNBS) or sodium dextran sulfate [ 62 , 66 ] in rodents. Jung et al. (2006) concluded that ginsenoside CK has the ability to control brain cancers’ progression through repressing PMA-induced p38 MAPK, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) activation [ 69 ]. Hong et al. (2018) reported that BIOGF1K, ginsenoside CK-rich fraction obtained from Panax ginseng, has an antiphotoaging effect and can be used topically. This action is mediated by decreasing the activity of MAPKs [ 70 ]. Likewise, BIOGF1K decreased MAPKs activation in RBL-2H3 and HMC-1 cells, thereby supporting its promising potential for treating atopic dermatitis [ 71 ]. The correlation between the anti-inflammatory activities of ginsenoside CK and p38 MAPK suppression was postulated. An early study done by Cuong et al. (2009) reported that pretreatment with ginsenoside CK attenuated zymosan-instigated inflammatory cytokines through decreased TNF-α, IL-6, and IL-12 p40, while it suppressed p38 MAPK and ERK1/2 activation. Moreover, ginsenoside CK inhibited zymosan-mediated superoxide generation, nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) actions, and macrophages Ser345-p47phox phosphorylation [ 63 ]. Jeong et al. (2010) evaluated the ability of ginsenoside CK to regulate the expression of matrix metalloproteinases (MMPs) to inhibit the migration of human umbilical vein endothelial cells (HUVEC) by the modulation of p38 MAPK; hence, concluded that ginsenoside CK has an antiangiogenesis effect mediated by the suppression of p38 MAPK and protein kinase B (Akt) in HUVECs [ 72 ]. Another study done by Lu et al. (2019) reported that ginsenoside CK counteracts oxidized low-density lipoprotein (ox-LDL)- instigated damage through the suppression of NF-κB, p38 MAPK, and JNK signals in HUVECs [ 73 ]. Joh et al. (2011) reported that ginsenoside CK strongly curbed TNF-α, IL-1β, and IL-6 though it significantly augmented IL-10 levels. Additionally, ginsenoside CK effectively decreased both COX-2 and iNOS levels while it suppressed NF-κB activation. Interestingly, ginsenoside CK inactivated IRAK-1, IKK-β, and MAPKs (p38 MAPK, ERK, and JNK) and concluded that ginsenoside CK could be used effectively to treat inflammatory conditions like colitis [ 62 ]. Song et al. (2018) reported that ginsenoside CK effectively protects against diabetic nephropathy through controlling p38 MAPK/NF-κB signaling. In this study, ginsenoside CK downregulated NLRP3 inflammasome components and cytokines: IL-1β and IL-18 in-vivo and in-vitro. Significantly, ginsenoside CK inhibited kidney p38 MAPK phosphorylation. In addition, ginsenoside CK decreased NADPH oxidase level and ROS [ 74 ]. Furthermore, a recent study was done by Lu et al. (2020) concluded that ginsenoside CK potently suppressed NF-κB, p38MAPK, and JNK signals; thereby alleviating macrophage inflammation and foam cell and showing therapeutic potential for the treatment of atherosclerosis [ 75 ]. On the other side, the apoptotic effect of ginsenoside CK has been examined in different cancer cell lines through p38 MAPK activation [ 76 , 77 , 78 ]. Ginsenoside F1 is a protopanaxatriol, obtained from the Korean Red Ginseng [ 79 ]. Ginsenoside F1 has various pharmacological properties and is reported to protect against cerebral ischemia [ 80 ], Alzheimer's disease [ 81 ], and ultraviolet-B-induced apoptosis [ 82 ]. Ginsenoside F1 was also reported to increase NK cell function suggesting its chemotherapeutic potential in NK cell-based immunotherapy [ 83 ]. With regard to the anti-inflammatory activity of ginsenoside F1, Qin et al. (2017) reported that ginsenoside F1 attenuated endothelial cell inflammation in the mice model through the effective inhibition of cytokine production through the suppression of NF-κB; thereby, it can be used in the treatment of atherosclerosis [ 84 ]. An in-silico study proved that ginsenoside F1 can act as a nontoxic drug-like molecule and clearly defines its inhibitory action on p38 MAPK at the molecular level of interaction. Besides, molecular dynamics supported p38 MAPK and ginsenoside F1 structural stability [ 85 ]. Few studies have targeted the role of ginsenoside F1 against the p38 MAPK signaling pathway. However, Hou et al. (2018) proposed ginsenoside F1 as a potential therapeutic approach to alleviate senescent astrocytes' harmful influence in the aged brain and related diseases. This action is mediated through suppressing the senescence-associated secretory phenotype from astrocytes induced by d-galactose through the inhibition of p38 MAPK-dependent NF-κB activity [ 86 ]. Ginsenoside Rb1 was obtained from the classical Chinese medicine Panax ginseng C. A. [ 87 ]. Ginsenoside Rb 1 showed a significant role in the management of several ailments such as diabetes [ 88 ], CKD-associated vascular calcification [ 89 ], myocardial infarction [ 90 ], diabetic retinopathy [ 91 ], cognitive impairment [ 92 ], heart arrythmia [ 93 ], acetaminophen-induced hepatotoxicity [ 94 ], cisplatin-induced memory impairment [ 95 ] and others. The anti-inflammatory activity of ginsenoside Rb1 was previously evidenced, where it was revealed that ginsenoside Rb1 repressed TNF-α development of RAW264.7 macrophages stimulated by LPS [ 96 , 97 ]. Likewise, ginsenoside Rb1 suppressed the stimulation of NF-κB and TNF-α in LPS-activated macrophages, decreased stimulation of IRAK-1, IKK-α, NF-κB, and MAPKs, and inhibited the IRAK activation-mediated inflammatory responses induced by TNBS in a rat model of colitis [ 62 ]. Robust evidence demonstrated the ability of ginsenoside Rb1 to exert antiosteoporotic action through preventing the distinction between RANKL-activated osteoclast and macrophages and inhibiting RANKL-provoked p38 MAPK/NF-κB pathway, and thus potently suppressing c-Fos and NF of activated T cells (NFAT) C1 [ 98 ]. Hashimoto et al. (2012) revealed that ginsenoside Rb1 prevented the programmed cell death provoked by 1-methyl-4-phenylpyridinium ion (MPP (+)) in PC12 cells by inhibiting p38 MAPK and stress-activated protein kinase (SAPK)/JNK signals. In this study, treatment of the MPP(+)-treated PC12 cells with ginsenoside Rb1 resulted in an increase in ERK1/2 or Akt phosphorylation, while the p-p38 MAPK significantly decreased [ 99 ]. Zhou et al. (2017) similarly illustrated the ability of ginsenoside Rb1 to protect against TNF-α-instigated oxidative injury and inflammation through the suppression of p38 MAPK and JNK and signaling in HUVECs [ 100 ]. Several researchers reported the cardiovascular protective properties of ginsenoside Rb1 through p38 MAPK inhibition. Zhang et al. (2012) investigated its ability to suppress balloon injury-induced vascular neointimal hyperplasia in rats through the suppression of p-ERK1/2 and the mRNA expression of c-myc and downregulated the p38 MAPK gene [ 101 ]. Zhang et al. (2015) explained the beneficial role of ginsenoside Rb1 in abdominal aortic aneurysm through the suppression of the JNK and p38 MAPK signals [ 102 ]. Furthermore, the ability of ginsenoside Rb1 to ameliorate myocardial ischemia/perfusion (I/R) injury through the suppression of p38α MAPK phosphorylation was demonstrated by Li et al. (2016). In this study, caspase-3 activity and TNF-α levels were suppressed in the heart muscle. Phospho-p38α MAPK and not the total 38α MAPK levels were markedly upregulated in the I/R model, and these elevated levels were decreased by ginsenoside Rb1 [ 103 ]. Moreover, Fan et al. (2016) reported the ginsenoside Rb1 ability to protect endothelial cells (ECs) against cytotoxicity-induced by H 2 O 2 through the mitigation of oxLDL-induced p38 and vascular cell adhesion molecule 1(VCAM-1) expression, in addition to decreased TNF-α. It also exhibited antioxidant activity mediated by Nrf2 activation [ 104 ]. With regard to the renoprotective potential of ginsenoside Rb1 mediated by p38 MAPK signal inhibition, Lee et al. (2018) reported that ginsenoside Rb1 protects against tacrolimus-instigated cell death in kidney proximal tubular LLC-PK1 cells through the suppression of p38 MAPK phosphorylation [ 105 ]. Furthermore, Liu et al. (2020) reported that ginsenoside Rb1 attenuates autophagy through the MAPK/mammalian target of rapamycin (mTOR) signal in kidney tubular epithelial cells. In this study, ginsenoside Rb1 treatment successfully decreased p38 MAPK and ERK activation in HK-2 cells exposed to Hank's balanced salt solution (HBSS) and suggested that ginsenoside Rb1 can be used for the treatment of chronic kidney diseases (CKD) [ 106 ]. On the other hand, Xin et al. (2019) concluded the ability of ginsenoside Rb1 to increase macrophage phagocytosis mediated by p38 MAPK/Akt pathway, while curbing p38 MAPK phosphorylation by using SB203580, the specific p38 MAPK inhibitor, thus reducing phagocytosis [ 107 ]. Ginsenoside Rb3 was obtained from Panax ginseng C. A. Meyer [ 87 ]. The pharmacological role of ginsenoside Rb3 as an anti-inflammatory agent was studied by Ma et al. (2014), who stated that the ameliorative effect of ginsenoside Rb3 against oxygen-glucose deprivation-reperfusion damage was due to curbing JNK-instigated NF-κB stimulation, indicating that it might protect against myocardial I/R damage [ 108 ]. Liu et al. (2020) reported that treatment with ginsenoside Rb3/ginsenoside Rb2 attenuated myocardial I/R, as evidenced by improved cardiac function, decreased IL-6, and TNF-α serum levels as well as restoring antioxidant balance in myocardial tissues [ 109 ]. Ginsenoside Rb3 prevented the inflammatory response and ROS caused by cigarette smoke extract as well as the buildup of extracellular matrix in WI-38 and 16HBE cells to defend against cell damage through curbing p38 MAPK/NF-κB and transforming growth factor (TGF)-β1/vascular endothelial growth factor pathways [ 110 ]. Another recent study conducted by Sun et al. (2020) investigated that ginsenoside Rb3 potently suppressed LPS-induced cytokine production through MAPK/Akt/NF-κB signal and alleviated bone resorption. Ginsenoside Rb3 effectively decreased p38 MAPK and NF-κB phosphorylation and curbed IL-1β, IL-6, and IL-8 levels [ 111 ]. Ginsenoside Rc was isolated from Korean Panax ginseng [ 112 ]. It was found to block cytokines’ production derived from macrophages such as TNF-α and IL-1β. In activated HEK293 cells, RAW264.7 macrophages, and human synovial cells, ginsenoside Rc similarly showed a marked suppression in the activation of TANK-binding kinase 1/IκB kinaseε/interferon regulatory factor-3 and p38/activating transcription factor 2 ( ATF-2) pathway [ 113 ]. In contrast, ginsenoside Rc was reported to not prevent fibronectin expression induced by high glucose in mesangial cells mediated by p38 MAPK activation [ 114 ]. Ginsenoside Rd was obtained from Panax ginseng C. A. Meyer [ 87 ]. Ginsenoside Rd therapy has been investigated as anti-inflammatory in many studies, such as autoimmune encephalomyelitis [ 115 ], cardiac hypertrophy [ 116 ], acute ischemic stroke [ 117 ], ulcerative colitis [ 118 ], and others. Ginsenoside Rd showed an anti-inflammatory activity through a potent decrease in in the synthesis of NO and prostaglandin E2 (PGE2). Therefore, ginsenoside Rd's protective mechanisms might include interference with the expression iNOS and COX-2 [ 119 ]. Another study concluded the effectiveness of ginsenoside Rd to suppress poly(ADP-ribose) polymerase-1 and subsequently decreased apoptosis and NF-κB subunit nuclear accumulation in rats with arterial occlusion of the right middle brain [ 120 ]. Shin et al. (2009) demonstrated the suppressive effect of ginsenoside Rd on the main elements contributed in the cartilage degradation of osteoarthritis by suppressing MMP3 through the inhibition of p-p38 MAPK activation [ 121 ]. In addition, Yoon et al. (2012) showed the ability of ginsenoside Rd to mitigate metastasis mediated by blocking MMP activation and MAPK signal in HepG2 cells [ 122 ]. Furthermore, Yang et al. (2012) revealed that ginsenoside Rd potently inhibited colitis instigated by TNBS, evidenced by decreasing the MPO activity mediated through lowering cytokine production and suppressing p38 MAPK and JNK phosphorylation [ 123 ]. Ginsenoside Re was isolated from Panax ginseng [ 124 ]. Ginsenoside Re has a potent anti-inflammatory effect in different disease models such as amyotrophic lateral sclerosis [ 125 ], Parkinson's disease [ 126 ], and LPS-induced inflammation [ 127 ]. Lee et al. (2012) suggested that ginsenoside Re may display a possible therapeutic drug to delay the development of neuroinflammation through the attenuation of LPS-induced MAPK phosphorylation, which mediates microglial toxicity and inflammatory responses [ 128 ]. The cardioprotective activity of ginsenoside Re against LPS-induced heart dysfunction and inflammatory response was reported by Chen et al. (2016) who reported that ginsenoside Re significantly prevented cardiac dysfunction induced by LPS through the effective inhibition of p-ERK1/2, p-JNK, and p-p38 MAPK [ 129 ]. Additionally, ginsenoside Re has the ability to counteract Ox-LDL-instigated endothelial cell death through reinforcing the antioxidant status of the cells and inhibiting NF-κB provocation and apoptosis through the stimulation of the phosphatidylinositol-3-kinase (PI3K)/Akt signal and suppressing the p38 MAPK phosphorylation. These effects are mediated by mitigating the enzymatic activity of NADPH oxidase and lectin-like Ox-LDL receptor-1 expression, while boosting estrogen receptor-α expression. Therefore, ginsenoside Re successfully attenuates the endothelial apoptosis-induced by Ox-LDL through antioxidative and anti-inflammatory actions [ 130 ]. In addition, it halted angiotensin II-induced gap-junction remodeling. In this study, atrial activities of p38 MAPK, NF-κB, and AP-1 were markedly elevated by Ang II, while the level of peroxisome proliferator-activated receptor gamma (PPARγ) significantly decreased. These effects were attenuated by ginsenoside Re. Also, in this study, rosiglitazone, a PPARγ agonist, blocked these effects [ 131 ]. On the other side Shi et al. (2016) reported the antiangiopathy activities of ginsenoside Re in diabetes mediated by MAPKs activation [ 132 ]. Ginsenoside Rf was isolated from Panax ginseng [ 133 ]. Ginsenoside Rf has a promising neuroprotective effect in different models of neuronal injury [ 134 , 135 ]. In a rodent model of endometriosis, ginsenoside Rf relieved dysmenorrhea and inflammation through the brain-derived neurotrophic factor – tropomyosin receptor kinase – cyclic adenosine monophosphate (cAMP) response element-binding protein pathway [ 136 ]. In addition, in a rat model of incisional pain, ginsenoside Rf has potent antinociceptive/anti-inflammatory effects [ 133 ]. Ginsenoside Rf downregulated p38 MAPK signaling and has been supported by few studies. Ahn et al. (2016) assessed its suppressing actions on the inflammation cytokines downstream of p38 MAPK/NF-kB activation in colon and macrophage cells, which indicated a possible role of ginsenoside F1 for the management of ailments such as Irritable Bowel Diseases (IBD) [ 137 ]. Ginsenoside Rg1 was isolated from Korean Panax ginseng [ 112 ]. Many therapeutic benefits for ginsenoside Rg1 have been documented. Ginsenoside Rg1 downregulated NF-κB and curbed the amounts of TNF-α, iNOS, COX-2, and IL-1β in microglial cells, which were stimulated by LPS [ 138 , 139 ]. Ginsenoside Rg1's inhibitory effect on inflammation had been studied previously, through NF-κB curbing in LPS-instigated macrophages cells and mice peritoneal macrophages. Likewise, ginsenoside Rg1 downregulated IL-6 by regulating the NF-κB or Akt/mTOR signals. Another recent study demonstrated that ginsenoside Rg1 protected diverse tissues from I/R injury through the regulation of inflammation and apoptosis. Ginsenoside Rg1 was protected against hepatic I/R in rats through the suppression of NF-κB signaling and ROS-inducing factor [ 140 , 141 ]. It is worthy to note that the therapeutic use of ginsenoside Rg1, which relied on modulating p38 MAPK is the neuroprotective therapeutic potential which was studied by several researchers in experimental animal models and in in vitro cell lines. Wang et al. (2008) reported decreased COX-2 expression by ginsenoside Rg1 in Parkinson's animals provoked by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) through the inhibition of p38 MAPK. In this study, the number of phosphorylated p38 MAPK, COX-2, and PGE2 positive cells was markedly decreased by ginsenoside Rg1 6 h after the third injection of MPTP. [ 142 ]. Fan et al. (2018) reported the ability of ginsenoside Rg1 to prevent depression in rats, ginsenoside Rg1-inhibited neuronal programmed cell death provoked by chronic unpredictable mild stress exposure, and upregulated Nrf2 expression while it inhibited p-p38 MAPK and NF-κB p65 subunit activation [ 143 ]. Likewise, a recent study conducted by Jiang et al. (2020) investigated that ginsenoside Rg1 effectively treated depression caused by 4-week chronic social defeat stress exposure. Ginsenoside Rg1 treatment decreased IL-6, TNF-α, and IL-1β production and both iNOS and COX2 enzymes. Ginsenoside Rg1 decreased hippocampal caspase levels and inhibited microglial activation. Importantly, ginsenoside Rg1 inactivated both p-p38 MAPK and p-JNK1/2, and inhibited NF-κB phosphorylation, thereby regulated SIRT1, and reduced acetylated p65 expression [ 144 ]. In in vitro studies, an early study conducted by Hu et al. (2011) revealed that ginsenoside Rg1 suppressed microglial activation induced by LPS through the suppression of Iba-1 and iNOS. Ginsenoside Rg1 suppressed IκB and p65 subunit of NF-κB nuclear translocation through the effective inhibition of MAPKs phosphorylation [ 145 ]. Likewise, Zong et al. (2012) revealed the ability of ginsenoside Rg1 to significantly attenuate the LPS-provoked expression of NF-κB and reduced cytokines, iNOS, and COX-2 in BV-2 cells through the effective inhibition of p38 MAPK, IκB-α, cAMP response element-binding protein, JNK, and ERK1/2 phosphorylation [ 138 ]. Furthermore, Sun et al. (2016) highlighted that ginsenoside Rg1 has the ability to protect mesencephalic dopaminergic neurons from LPS-induced microglial inflammation and p38 MAPK signal suppression, which might contribute in ginsenoside Rg's anti-inflammatory effect [ 139 ]. Additionally, ginsenoside Rg1 not only protects against LPS-provoked injury in microglial cells but also protects against oxygen-glucose-deprivation in neural stem cells as reported by Li et al. (2017). In this study, ginsenoside Rg1 markedly suppressed the apoptosis in neural stem cells, decreased ROS, and downregulated p-p38 and p-JNK expressions [ 146 ]. Cross talk between p38 MAPK and Akt signaling has been studied in several literatures. In promoting angiogenesis and alleviating heart muscle fibrosis, ginsenoside Rg1 improved left ventricular function and the potential mechanisms include p38 MAPK inhibition and PI3K/Akt activation. [ 147 ]. Fan et al. (2019) reported that ginsenoside Rg1 alleviated insulin resistance in HepG2 cells. In this study, ginsenoside Rg1 increased glucose uptake through a decrease in ROS and the suppression of p38 MAPK phosphorylation and glycogen synthase kinase 3 beta expression while it effectively elevated Akt phosphorylation [ 148 ]. Zhang et al. (2013) reported ginsenoside Rg1's ability to treat left ventricular hypertrophy and heart failure provoked by transverse aortic constriction through p-Akt activation and p38 MAPK suppression [ 149 ]. Other models were also reported. Li et al. (2013) reported that ginsenoside Rg1 preserved the retinal pigment epithelium cells induced by cobalt chloride or hypoxia. In this study, ginsenoside Rg1 potently inhibited ROS production through the effective suppression of p38 MAPK and JNK activation [ 150 ]. Zhang et al. (2011) investigated the ability of ginsenoside Rg1 to protect podocytes from supramolecular activation cluster-induced injury through the suppression of F-actin damage and restoring the antioxidant status mediated by the suppression of p38 MAPK activation [ 151 ]. He and Li, (2015) reported that ginsenoside Rg1 prevents the shear-provoked inflammatory response by curbing the MAPK pathway, similar to the specific MAPK inhibitors [ 152 ]. Ginsenoside Rg2 was obtained from the root of Panax ginseng C. A. [ 153 ]. The anti-inflammatory and antioxidative effects of ginsenosides Rg2 through suppressing p38 MAPK signaling have been studied. Ginsenoside Rg2 has provided direct vascular benefits with the suppression of leukocyte adhesion into the vascular wall by the reduction of reduced LPS-mediated p38 MAPK monocyte adhesion to HUVEC [ 154 ]. Ginsenoside Rg 3 was isolated from Korean Panax ginseng [ 112 ]. Ginsenoside Rg3 had the effect of enhancing cardiac dysfunction caused by myocardial I/R and the ginsenoside Rg3 ′s pharmacological action mechanism was linked to its antiapoptotic and anti-inflammatory properties [ 155 ]. Guo et al. demonstrated the immunomodulatory function of ginsenoside Rg3 in promoting M2-type macrophages through PPARγ-dependent mechanism. They established its potentials in the management of atherosclerosis associated with diabetes [ 156 ]. Several studies reported the anticancer-related anti-inflammatory effects of ginsenoside Rg3. It induced apoptosis in breast cancer cells, by hindering NF-κB signals through inactivating ERK and Akt as well as by destabilizing the mutant p53 [ 157 ]. Ginsenoside Rg3 inhibited the development of colorectal tumors by the downregulation of NF-κB signal [ 158 ]. Furthermore, the anti-inflammatory properties of ginsenoside Rg3 were shown to be a potential candidate for the treatment of the aging process induced by chemotherapy and its inflammatory or paracrine side effects, which may show how ginsenoside Rg3 can suppress aging and its associated problems [ 159 ]. Additionally, Ginsenoside Rg3 prevented inflammatory neurotoxicity and microglial activation, it has exerted suppressive effects in neurodegenerative conditions. Ginsenoside Rg3 suppressed the expression of TNF-α and of NF-κB in microglial cells that were activated in the 42 amino acid form of beta amyloid (Abeta42). Pretreatment with ginsenoside Rg3 improved TNF-α-treated Neuro-2α-cell survival [ 160 ]. Also, through suppression of the hippocampal inflammatory mediators, production is induced by LPS in rat brains and memory impairments are alleviated [ 161 ]. Considerable studies were published on the anti-inflammatory effect of ginsenoside Rg3 in relation to p38 MAPK suppression. Ginsenoside Rg3 was shown to effectively decrease the receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced osteoclasts differentiation. This action involved a high-binding interaction with Cathepsin K (Cat-K) as well as the effective ability to decrease the RANKL-induced osteoclastogenesis differentiation through the suppression of Cat-K mediated by downregulating p38 MAPK signal [ 162 ]. Similarly, treatment with Rg3 showed anti-hepatitis B activity through the degradation of TNF receptor-associated factor 6/transforming growth factor activated kinase-1(TAK1) and the curbing of p38 MAPK activity [ 163 ]. Additionally, the anticancer activity of ginsenoside Rg3 mediated through the deactivation of the p38 MAPK pathway, explained its ability to provoke programmed cell death in many cancer cells including lung cancer [ 164 ]. On the other hand, some literatures demonstrated the ability of ginsenoside Rg3 to promote cell survival and insulin secretion through the activation of p38 MAPK and ERK phosphorylation against intermittent high glucose [ 165 ]. Similarly, Xin et al. (2019) reported that ginsenoside Rg3 enhances phagocytosis through ERK1/2 and p38 MAPK activation [ 166 ]. Ginsenoside Rg5 was isolated from red Panax ginseng [ 167 ]. Various studies have assessed the pharmacological effects of ginsenoside Rg5. Ginsenoside Rg5 induced apoptosis and autophagy in the mouse model against breast cancer by suppressing the PI3K/Akt [ 168 ]. Many studies investigated the ginsenoside Rg5 anti-inflammatory activities. Ginsenoside Rg5 decreased the IL-1β, TNFα, COX-2, iNOS expression and IRAK-1, IKK-α and NF-κB phosphorylation, and decrease IRAK-1 and IRAK4 degradation in the alveolar macrophages induced by LPS [ 169 ]. In addition, ginsenoside Rg5's anti-inflammatory activity was noted in TNF-α activated hepatic cells and in hepatocarcinoma through the suppression of NF-κB, COX2, and iNOS. Ginsenoside Rg5 suppressed streptozotocin (STZ)- induced COX-2 and iNOS expression, the essential neuroinflammatory enzymes [ 170 ]. Ginsenoside Rg5 dramatically inhibited thymus- and activation-regulated chemokine (TARC/CCL17) expression in HaCaT cells that were stimulated by TNF-α/IFN-γ. In RAW264.7 cells, the production of NO and ROS induced by LPS was likewise reduced by ginsenoside Rg5. Furthermore, ginsenoside Rg5 inhibited NF-κB/p38 MAPK/signal transducer and activator of transcription (STAT)-1 signal, which are involved in the expression of chemokine and NO production [ 171 ]. A very recent study illustrated that ginsenoside Rg5 could attenuate kidney damage in diabetic mice induced by oxidative stress through curbing NF-κB and p-p38 MAPK and effectively decreasing cytokines IL-1β and IL-18 production. Additionally, ginsenoside Rg5 restored oxidant/antioxidant balance, thereby protecting against diabetic nephropathy [ 172 ]. On the other hand, Liu and Fan (2019) revealed the potential use of ginsenoside Rg5 to treat gastric cancer, which was mediated by p38 MAPK activation and the p38 inhibitor SB203580, while the knockdown of p38 MAPK by siRNA reversed the apoptotic induction by ginsenoside Rg5 [ 173 ]. Ginsenoside Rh1 was isolated from Panax ginseng [ 174 ]. Numerous studies have attempted to explain the therapeutic role of ginsenoside Rh1. Administration of ginsenoside Rh1 for long-term improved learning and memory by promoting cell viability in the mouse's hippocampus [ 175 ]. Ginsenoside Rh1 has antifibrotic and hepatoprotective activities [ 176 ]. It ameliorated high-fat dietary obesity in mice through the suppression of the differentiation of adipocytes [ 177 ]. Ginsenoside Rh1 has potentiated dexamethasone's anti-inflammatory actions in chronic inflammatory disease by antagonizing the resistance induced by dexamethasone [ 178 ]. Ginsenoside Rh1 inhibited the high mobility group box 1 (HMGB1)-mediated hyperpermeability and leukocyte migration in mice as revealed by Lee et al. (2019). In addition, ginsenoside Rh1 treatment decreased the in vivo cecal ligation and puncture-induced release of HMGB1, sepsis-related mortality, and tissue injury [ 179 ]. Ginsenoside Rh1 exerted anti-inflammatory action through curbing COX-2 and iNOS expression by inhibiting the activation and downstream transcription of JAK/STAT and ERK signals, including NF-κB, interferon regulatory factor 1, and STAT1 in interferon gamma (IFN-γ)-stimulated microglial cells [ 180 , 181 ]. Ginsenoside Rh1 decreased immunoglobulin E and IL-6 levels in atopic dermatitis rodents, thereby significantly reducing inflammatory cell infiltration and mast cell granulation. In addition, ginsenoside Rh1 alleviated atopic dermatitis and ear-swelling symptoms [ 182 ]. Previous studies have explored the relationships between ginsenoside Rh1's anti-inflammatory activity and p38 MAPK downregulation. The suppressive effects of ginsenoside Rh1 on monocyte function was considered as a potent anti-inflammatory action through the attenuation of the phosphorylation of MAPKs [ 183 ]. In addition, it was found to prevent the invasion and migration of phorbol myristate acetate-simulated U87MG cells through the inhibition of MAPKs and DNA-binding activities: NF-κB and AP-1 [ 184 ]. Furthermore, ginsenoside Rh1 has been reported as a potential novel chemotherapy to treat malignant cancers through the inactivation of p38 MAPK signaling [ 185 ]. Likewise, Lyu et al. (2019) reported the ginsenoside Rh1 to inhibit colorectal carcinoma invasiveness both in vitro and in animal models. Rh1 downregulated MMP1 and MMP3 and promoted the tissue inhibitor of metalloproteinase 3 expression and effectively decreased the phosphorylation of MAPKs in vitro and in vivo , concluding that ginsenoside Rh1 mediated its action through MAPK-signaling inactivation [ 186 ]. Ginsenoside Rh2 was obtained from the root of Panax ginseng [ 187 ]. Ginsenoside Rh2 represented different pharmacological roles, including: antiproliferative and apoptotic role by regulating the TNF-α signaling pathway in human leukemia cells [ 188 ] and increasing mitochondrial ROS in human Jurkat leukemia cells [ 189 ]; Anti-allergic and anti-inflammatory activities by hindering the development of NO and PGE2 [ 190 ]; and anti-inflammatory actions in neuronal cells by the inhibition of LPS/IFN-γ-induced NO generation in murine BV-2 cells. Also, decreased TNF-α, iNOS, COX-2, and IL-1β, while curbing intercellular adhesion molecule 1 in astroglial cells mediated by curbing NF-κB and JNK/AP-1 signaling [ 191 ]. The anti-inflammatory properties of ginsenoside Rh2 in murine asthma model had been studied. Li et al. (2015) revealed that ginsenoside Rh2 inhibited peribronchiolar inflammation, cytokine production, airway inflammatory cell recruitment, in addition to the expression of IgE, and aryl hydrocarbon receptors in a murine asthma model by curbing of p38 MAPK and NF-κB activation. Therefore, ginsenoside Rh2 may be convenient for treating inflammatory disorders in the airways, such as asthma [ 192 ]. Kim et al. (2007) demonstrated that ginsenoside Rh2, acquired from PPD by gut flora, curbed the expression of MMP-9 by mitigating p38 MAPK [ 193 ]. Kim et al. (2014) also documented p38 MAPK as a survival factor in cancer cells. In this study, compared to ginsenoside Rh2 treatment alone, cotreatment with ginsenoside Rh2 and SB203580 resulted in cell death, which increased from 20% to 50%, suggesting that p38 MAPK inhibition can increase ginsenoside Rh2-provoked programmed cell death in hepatocellular carcinoma. Nevertheless, the effect of ERK or JNK mitigation on cytotoxicity has not been observed. [ 187 ]. In contrast, several researchers investigated that ginsenoside Rh2 exhibited anticancer activity mediated by p38 MAPK activation [ 187 , 194 , 195 , 196 ]. Ginsenoside Ro was isolated from the root of Panax ginseng [ 197 ]. Ginsenoside Ro exhibits various pharmacological activities, particularly antioxidant and anti-inflammatory activities. Ginsenoside Ro had a possible anti-photoaging skin property in fibroblasts against UV-B radiation [ 198 ]. Ginsenoside Ro prevented dose-dependent thrombin-provoked platelet aggregation and diminished fibrinogen attachment to αIIb/β3 by phosphorylated cAMP-dependent vasodilator-stimulated phosphoprotein (VASP; Ser157). Additionally, ginsenoside Ro mitigated the of the clot that represented thrombi intensification [ 199 ]. Ginsenoside Ro has inhibited in vivo tumor development of B16F10-transplanted tumors, and its anti-tumor effects are depending on its metabolites' biological action. Those metabolites' anti-tumor effectiveness was due to their antiangiogenic activity [ 200 ]. Ginsenoside Ro downregulated p-ERK/2 to mitigate thrombin-elevation [Ca2 +], which helped inhibiting ATP, 5-HT release, and p-selectin expression while positively regulating cAMP-dependent IP3RI (Ser1756) phosphorylation [ 201 ]. Up to now, no more studies highlighted the direct link between the ginsenoside subtype Ro's anti-inflammatory action and p38 MAPK signaling suppression. Only Shin et al. (2019) evidenced that ginsenoside Ro holds a significant antiplatelet potential and attenuates thromboxane-A2 production by suppressing p38-MAPK-mediated cytosolic phospholipase A2a (cPLA2a) phosphorylation and arachidonic acid release [ 202 ]. Notoginsenoside R1 was obtained from the root of Panax notoginseng [ 203 ]. Several studies reported that notoginsenoside R1 exhibited a strong anti-inflammatory [ 203 ] anticancer [ 204 ] and antioxidant [ 205 ] activities. Sun et al. (2019) demonstrated that notoginsenoside R1 relieved PC-12 cells from inflammatory damage caused by LPS through the elevation of miR-132 and subsequently suppression of the JNK pathway [ 206 ]. In another study, notoginsenoside R1 prevented acrylamide-induced mitochondrial apoptosis by upregulating thioredoxin-1 in rat adrenal chromaffin cell tumor (PC12) cells. Notoginsenoside R1 ameliorated I/R-provoked damage in different systems primarily by stimulating α-dependent 3-kinase phosphoinositide estrogen receptor [ 207 ]. The inhibitory effect of notoginsenoside R1 on p38 MAPK signaling has been well-studied by different researchers. The activation of TAK1 in mice might additionally activate p38 MAPK, therefore, upregulating inflammation and inducing myocardial programmed cell death. Notoginsenoside R1 possesses a cardioprotective effect through the modulation of this pathway [ 208 ]. Another study conducted by Qiu et al. (2016) reported the role of notoginsenoside R1 in the management of chronic obstructive pulmonary disease by alleviating hypoxia and hypercapnia-induced pulmonary vasoconstriction and suppression of ERK and p38 MAPK activation [ 209 ]. PPD is a major active metabolite from Panax ginseng [ 210 ]. It possesses a wide range of biological activities such as anti-inflammatory [ 211 , 212 ], antiapoptotic [ 212 ], anticancer [ 213 ], and antioxidant [ 214 , 215 ] activities. Peng et al. (2019) reported that PPD suppressed breast carcinoma metastasis in vivo through Epidermal Growth Factor Receptor (EGFR)-mediated MAPK pathway. This demonstrated that 20(S)-PPD treatment curbed EGFR phosphorylation and inactivated MAPK signaling [ 216 ]. Another study conducted by Jang et al. (2012) reported that PPD modulated the expression of COX-2, IκB-α, p-ERK 1/2, and p-SAPK/JNK levels and blocked apoptotic markers; caspases and cleaved poly (ADP-ribose) polymerase (PARP), such as in hepatic inflammation and apoptosis in hyperlipemic mice [ 217 ].

The molecular docking approach has been used widely to elucidate the binding modes of drug candidates to the active site of the target protein. We have utilized docking to obtain the potential binding energies of different ginsenosides with p38 MAPK. Molecular docking was performed by using Autodock vina 1.5.6 [ 218 ]. The complex crystal structure of p38 MAPK with its inhibitor was retrieved from a protein data bank with PDB ID: 3ZS5 . The water molecules and ligands were removed, and the PDBQT file was prepared accordingly. The binding residues of p38 MAPK with its inhibitor were identified and visualized ( Figure 2 ) [ 219 ]. Chimera 1.12 software was used to visualize the best-scored conformation of the different ginsenosides with the active site of p38 MAPK. To predict the binding affinity for the selected ginsenosides with p38 MAPK, the average of the lowest docking energy was utilized to predict the binding affinity for the selected ginsenosides. All the compounds' binding affinities with p38 MAPK were compared with SB2, the standard inhibitor for p38 MAPK, and cocrystallize with it. Interestingly, most of the compounds have shown promising binding affinities with p38 MAPK, and all the binding energies of docking were shown in Table 3 . The compounds of the highest binding affinities were further used to clarify their binding mechanism with p38 MAPK. Figure 2 The binding pocket of p38 MAPK. The following residues represent the binding site of p38 MAPK and were used for site-specific docking study: S32, Y35, V38, A51, K53, R67, E71, T106, M109, K152, N155, D168, F169, and G170 residues. Figure 2 Table 3 Molecular docking of ginsenosides as potential inhibitors of p38 MAPK. Table 3 Compounds Lowest energy of docking (kcal/mol) Ginsenoside Compound K -8.84 ± 0.28 Ginsenoside F1 -8.88 ± 0.40 Ginsenoside Rb1 -7.88 ± 0.38 Ginsenoside Rb3 -8.79 ± 0.27 Ginsenoside Rc -7.95 ± 0.36 Ginsenoside Rd -8.94 ± 0.33 Ginsenoside Re -8.56 ± 0.34 Ginsenoside Rf -8.31 ± 0.36 Ginsenoside Rg1 -8.20 ± 0.38 Ginsenoside Rg2 -8.50 ± 0.27 Ginsenoside Rg3 -8.30 ± 0.10 Ginsenoside Rg5 -8.83 ± 0.25 Ginsenoside Rh1 -7.15 ± 0.26 Ginsenoside Rh 2 -8.52 ± 0.20 Ginsenoside Ro -9.34 ± 0.39 Notoginsenoside R1 -8.47 ± 0.31 Protopanaxadiol -7.84 ± 0.33 SB2 (standard) -9.16 ± 0.64 Most promising ginsenosides regarding energy binding were written in bold and their docking models were presented in Figure 3 . The binding pocket of p38 MAPK. The following residues represent the binding site of p38 MAPK and were used for site-specific docking study: S32, Y35, V38, A51, K53, R67, E71, T106, M109, K152, N155, D168, F169, and G170 residues. Molecular docking of ginsenosides as potential inhibitors of p38 MAPK. Most promising ginsenosides regarding energy binding were written in bold and their docking models were presented in Figure 3 . All studied ginsenosides composed a well-fitted structure inside the binding cavity of p38 MAPK ( Figure 3 ). This promising inhibitory effect might be attributed to its unique structural features that combine the steroidal-like structure allowing ginsenosides to exhibit hydrophobic interaction with the hydrophobic residues in the active site, and the multiple bounded OH groups enabling them to form hydrogen bonds with the polar amino acids. These different noncovalent interactions could be the main reason for such promising binding between ginsenosides and p38 MAPK. Figure 3 Docking models of Ginsenoside Compound K (CK), Ginsenoside F1, Ginsenoside-Rb3, Ginsenoside-Rd, and Ginsenoside RO with p38 MAPK. Steroidal-like structure with multiple bounded OH groups of ginsenoside derivatives allowed them to form multiple hydrogen bonds with the polar amino acids and hydrophobic interaction with the hydrophobic residues in the active site. These different noncovalent interactions enable the derivatives to fit well in the binding pocket of p38 MAPK as shown in the surface map of the predicted complexes. Figure 3 Docking models of Ginsenoside Compound K (CK), Ginsenoside F1, Ginsenoside-Rb3, Ginsenoside-Rd, and Ginsenoside RO with p38 MAPK. Steroidal-like structure with multiple bounded OH groups of ginsenoside derivatives allowed them to form multiple hydrogen bonds with the polar amino acids and hydrophobic interaction with the hydrophobic residues in the active site. These different noncovalent interactions enable the derivatives to fit well in the binding pocket of p38 MAPK as shown in the surface map of the predicted complexes. As illustrated in Figure 3 , Ginsenoside Compound K (CK) forms two hydrogen bonds (H-bonds) with the side chains of K53 and T68. Ginsenoside F1 forms two hydrogen bonds with S56 and R67 and exhibit hydrophobic interface with L55 and L74. Ginsenoside Rb3 forms four H-bonds with K53, H64, and T68 and exhibit hydrophobic interaction with V30, V38, Y35, and F169 in the active site's vicinity. Ginsenoside Rd forms four hydrogen bonds with the side chains of Y35, K53, T68, and K152 and exhibited hydrophobic interaction with V38, L54, and F169. Ginsenoside Ro forms three hydrogen bonds with the side chain of K53, H64, and R70. It also exhibits hydrophobic interaction with V30, V38, and Y35.

Accumulating evidence indicates that p38 MAPK could play many roles in human disease pathophysiology. Therefore, great therapeutic benefits can be attained from p38 MAPK inhibitors. Ginseng is an exceptionally valued medicinal plant of the family Araliaceae ( Panax genus). Several studies and efforts have recently targeted the therapeutic effects on purified individual ginsenoside, ginseng's most active ingredient, and have investigated its molecular mechanism(s) rather than whole-plant extracts. Interestingly, several ginsenosides: ginsenosides compound K, F1, Rb1, Rb3, Rc, Rd, Re, Rf, Rg1, Rg2, Rg3, Rg5, Rh1, Rh2, Ro, notoginsenoside R1, and PPD, have shown to possess great therapeutic potentials mediated by its ability to downregulate p38 MAPK signaling in different cells and experimental animal models. Our review compiles the research findings of different ginsenosides as potent anti-inflammatory drugs, highlighting the key role of suppressing p38 MAPK in their pharmacological actions ( Table 2 ). In addition, in silico studies were conducted to explore the likely binding of these ginsenosides to p38 MAPK and evidenced the promising inhibitory effect of ginsenosides. This effect could be attributed to its unique structural features that combine the steroidal-like structure, which allowed ginsenosides to exhibit hydrophobic interaction with the hydrophobic residues in the active site and the multiple-bounded OH groups that enable them to form H-bonds with the polar amino acids. These different noncovalent interactions could be the main reason for such promising binding between ginsenosides and p38 MAPK. Notably, ginsenoside compound K, ginsenoside F1, ginsenoside Rb3, Ginsenoside Rd, and ginsenoside Ro produced energy of binding comparable with that of the standard p38 MAPK inhibitor SB2.

All authors listed have significantly contributed to the development and the writing of this article. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Data will be made available on request. The authors declare no conflict of interest. No additional information is available for this paper.

Ginseng is an exceptionally esteemed medicinal plant of the family Araliaceae ( Panax genus) [ 1 , 2 ]. The Panax genus consists of at least nine species [ 3 ]. P. ginseng, the most generally utilized, is indigenous to the far-eastern nations. P. quinquefolium is native to America and Canada [ 3 ]. P. ginseng has been substantially investigated because of its potential therapeutic effects on the human body. The name “ginseng” refers to the Chinese words Jen Sheng, signifying “man-herb” and Panax , meaning “all healing,” which communicate the conventional belief of ginseng to fix all human diseases. Ginsenosides represent the main constituents of ginseng obtained from different parts of the plant [ 4 ]. It is interesting to know that over 40 structurally differing ginsenosides from the root of P . ginseng were isolated and recognized [ 5 ]. Ginsenosides compose a diverse group of triterpene saponins [ 6 ], having a four-ring structure and a steroidal frame with sugar components [ 7 ]. The fundamental structure of ginsenosides is comparative in light of the fact that practically all ginsenosides comprise 30 carbon molecules organized in four rings of steroid cores [ 8 ]. No less than two (carbon-3 and -20) or three (carbon-3, -6, and -20) hydroxyl (OH) groups are free or attached to ginsenoside's sugars. Based on the location of the OH group on carbon-20, ginsenosides similarly occur as stereoisomers. As indicated by the distinction of position and amount of sugar, ginsenosides are subdivided into four groups: A-Protopanaxadiol (A-PPD), B-Protopanaxatriol, C-Oleanolic acid, and D- Ocotillol [ 9 , 10 , 11 ]. It is worthy to note that plant part, species, age, growing techniques, gathering term and storage affects the nature of ginsenosides in ginseng [ 12 , 13 ]. Ginsenoside Rf, for example, is distinctive to Far East ginseng, whereas F11 is found only in American ginseng. Therefore, the Rf/F11 proportion is utilized as a phytoconstituent marker to discriminate between different ginseng [ 14 , 15 ]. Ginseng's saponin amounts are legitimately relative to its growing stage, attaining the highest growth by the age of six years [ 12 , 16 ]. Almost all ginseng roots are either air-dried or vaporized for 2–4 h followed by drying at 100 °C, giving the ginseng known as red ginseng a dimmer appearance. The heat conversion and deglycosylation of ginsenosides, which occur naturally, grant the red ginseng a distinctive saponin profile [ 17 , 18 ]. The existence of these compounds confirms red ginseng's popular awareness of better therapeutic values over white ginseng [ 19 , 20 ]. Mitogen-activated protein kinases (MAPKs) are intracellular enzymes that play a key role in cell response to various stimuli, such as inflammatory cytokines, which will induce GTPase-stimulation of numerous upward kinases, the mitogen-activated protein kinase kinase kinases (MAPKKKs). These serine/threonine kinases phosphorylate and activate MAPK kinases, which consequently phosphorylate p38 mitogen-activated protein kinases (p38 MAPK) [ 21 , 22 , 23 ]. The MAPK superfamily p38 comprises four isoforms. p38α (named simply as “p38”) was initially described as being a MAPK aimed against toxin and increased osmotic pressure in the cells, it binds to pyridinyl imidazole enzymes inhibiting the inflammatory cytokine in monocytes, such as interleukin1 (IL-1), tumor necrosis factor-α (TNF-α), and the lipopolysaccharide (LPS) stimulant [ 24 , 25 ]. Gene database and the specified sequence tag reported having an identification of >70 percent to p38β and 60 percent to p38α [ 26 ]. P38α is thought to mainly regulate the inflammatory process; whereas the inflammatory roles of the others remain indefinable [ 27 ]. p38 MAPK represents a fundamental part in producing inflammatory mediators through both transcription-dependent and post-transcription control mechanisms. Many inflammatory response proteins rely for their development on the p38 MAPK signaling and the degree of this dependence differs based on the cell type. The inflammatory cytokines: TNF-α, IL-1β, and cyclooxygenase (COX)-2 were reported to significantly regulate p38 [ 28 ]. Suppression of the p38 MAPK signaling resulted in reduced inflammatory mediator release and consequently blockage of the inflammatory response [ 29 ]. In addition to mediating inflammatory molecular growth, p38 MAPK is activated significantly by cytokines; TNF-α and IL-1β show important cell retorts to these cytokines [ 30 ] ( Figure 1 ). The p38 MAPK also played a crucial part in immune cells’ differentiation [ 31 ]. All these mechanisms contribute to inflammation production. Therefore, p38 MAPK was presented as a therapeutic option for potential medicines to treat inflammatory diseases because of its essential role in inflammation [ 30 , 32 ]. Figure 1 p38 MAPK signaling and mediated inflammatory response. Figure 1 p38 MAPK signaling and mediated inflammatory response. In endothelial cells, the transcription factors nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is involved in TNF-α-induced upregulation of E-selectin via p38 MAPK and JNK [ 33 ].The pro-inflammatory cytokine TNF-α is regulated by LPS stimulation in neutrophils via the p38 pathway [ 34 ]. NF-κB regulates the transcription of adhesion molecules, enzymes, and cytokines involved in inflammatory diseases [ 35 ]. The activation of NF-κB has been linked to p38 MAPK. Several studies have shown that the p38 MAPK inhibitor SB203580 effectively inhibits NF-κB -dependent transcription. p38 MAPK has been implicated in the activation of NF-κB [ 34 , 35 , 36 ]. Therefore, the activation of protein kinases like MAPK is critical for the production and action of many pro-inflammatory cytokines in inflammation. As a result, protein kinases have become important drug targets. Importantly, ginsenosides possess anti-inflammatory effects. The anti-inflammatory mechanism of ginsenosides was discovered to be the negative regulation of pro-inflammatory cytokine expressions (TNF-α, IL-1β, and IL-6) and enzyme expressions (iNOS and COX-2) [ 11 , 37 ]. Kim et al. (2019) reviewed the anti-inflammatory effects of ginsenosides in different diseases associated with inflammation [ 11 ]. Mitochondria are a major source of reactive oxygen species (ROS) induced by oxidative stress, the mitochondrial respiration chain is the main site of ROS production [ 38 ]. Alterations in the respiratory chain and metabolic state typically increase ROS production. Disrupting the balance between ROS production and utilization can cause oxidative stress to develop [ 39 ]. When ROS is present in low concentrations in mitochondria, it acts as a protective agent. Increased ROS concentrations weaken this function, resulting in mitochondrial dysfunction. The greater the accumulation of ROS, the greater the oxidative damage to mitochondria, which produces more ROS, creating a vicious cycle [ 40 ]. In addition, p38 MAPK is considered to be a ROS sensor and may be induced by oxidative stress. The p38 MAPK activation's downstream effects depend on the actual assembly of the Nox subunits into the NAPDH oxidase complex responsible to deliver ROS [ 41 ]. Previously, ROS was reported to activate p38 MAPK in different models [ 42 , 43 , 44 , 45 ]. Suppressing LPS-induced mitochondrial ROS inhibited cytokines release by preventing MAPK and NF-κB activation [ 46 ]. Ginsenosides effectively regulate mitochondrial function in response to oxidative stress by inhibiting ROS production and maintaining mitochondrial membrane potential stability [ 47 ]. The inhibitor class pyridinyl imidazole targets p38ơ and p38β but does not target p38δ or p38 γ. These compounds effectively inhibit neutrophil, monocyte, and macrophage responses [ 48 ]. As certain cells express p38α, yet not p38β, p38α was reported to be the affected p38-isoform [ 49 ]. Activation of p38 MAPK is based on the activation of Thr180 and Tyr182 in the Thr-Gly-Tyr pattern [ 50 ]. p38 MAPK binds to adenosine triphosphate (ATP) until activated. Many target proteins in p38 pathway are significant kinases and gene expression regulators, which have fundamental functions in controlling various cell progressions, such as protein transcription, cell cycle progression, and apoptotic death [ 51 , 52 ]. The majority of p38 MAPK inhibitors are tailored to the ATP-binding site with high specificity to p38 MAPK and its various isoforms. Several compounds have shown to be effective in preclinical models and to have good biological activities. Despite the fact that a large number of people have enrolled in clinical trials, many of them have been stopped [ 53 , 54 ]. Some studies were halted because of the absence of the inhibitor's efficacy, while in other cases, it was discontinued due to the heart, GIT, brain and other adverse effects [ 55 ]. In view of that and based on the aforementioned explanation, targeting p38 MAPK signaling pathway as a potent mediator for inflammation, propose a powerful therapeutic hope for many inflammatory diseases.