Ginsenoside Rb1 Alleviates Alcohol-Induced Liver Injury by Inhibiting Steatosis, Oxidative Stress, and Inflammation

Alcoholic liver disease (ALD) has become a heavy burden on health worldwide. Ginsenoside Rb1 (GRb1), extracted from Panax quinquefolium L., has protective effects on many diseases, but the effect and mechanisms of GRb1 on ALD remain unknown. This study aimed to investigate the protective effects of GRb1 on ALD and to discover the potential mechanisms. Zebrafish larvae were exposed to 350 mM ethanol for 32 h to establish a model of acute alcoholic liver injury, and the larvae were then treated with 6.25, 12.5, or 25 μM GRb1 for 48 h. The human hepatocyte cell line was stimulated by 100 mM ethanol and meanwhile incubated with 6.25, 12.5, and 25 μM GRb1 for 24 h. The lipid changes were detected by Oil Red O staining, Nile Red staining, and triglyceride determination. The antioxidant capacity was assessed by fluorescent probes in vivo, and the expression levels of inflammatory cytokines were detected by immunohistochemistry, immunofluorescence, and quantitative real-time PCR. The results showed that GRb1 alleviated lipid deposition in hepatocytes at an optimal concentration of 12.5 μM in vivo. GRb1 reversed the reactive oxygen species accumulation caused by alcohol consumption and partially restored the level of glutathione. Furthermore, GRb1 ameliorated liver inflammation by inhibiting neutrophil infiltration in the liver parenchyma and downregulating the expression of nuclear factor-kappa B pathway-associated proinflammatory cytokines, including tumor necrosis factor-α and interleukin-1β. This study revealed that GRb1 has a protective effect on alcohol-induced liver injury due to its resistance to lipid deposition as well as antioxidant and anti-inflammatory actions. These findings suggest that GRb1 may be a promising candidate against ALD.

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Ginsenoside Rb1, A Major Saponin from Panax ginseng, Exerts Protective Effects Against Acetaminophen-Induced Hepatotoxicity in Mice

The American Journal of Chinese Medicine ◽

10.1142/s0192415x19500927 ◽

2019 ◽

Vol 47 (08) ◽

pp. 1815-1831 ◽

Cited By ~ 4

Author(s):

Shen Ren ◽

Jing Leng ◽

Xing-Yue Xu ◽

Shuang Jiang ◽

Ying-Ping Wang ◽

...

Keyword(s):

Liver Injury ◽

Panax Ginseng ◽

Inflammatory Responses ◽

Interleukin 1 ◽

Protective Effects ◽

Ginsenoside Rb1 ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Oxide Synthase

Acute liver injury (ALI) induced by acetaminophen (APAP) is the main cause of drug-induced liver injury. Previous reports indicated liver failure could be alleviated by saponins (ginsenosides) from Panax ginseng against APAP-induced inflammatory responses in vivo. However, validation towards ginsenoside Rb1 as a major and marker saponin may protect liver from APAP-induced ALI and its mechanisms are poorly elucidated. In this study, the protective effects and the latent mechanisms of Rb1 action against APAP-induced hepatotoxicity were investigated. Rb1 was administered orally with 10[Formula: see text]mg/kg and 20[Formula: see text]mg/kg daily for 1 week before a single injection of APAP (250[Formula: see text]mg/kg, i.p.) 1[Formula: see text]h after the last treatment of Rb1. Serum alanine/aspartate aminotransferases (ALT/AST), liver glutathione (GSH) depletion, as well as the inflammatory cytokines, such as tumor necrosis factor-[Formula: see text] (TNF-[Formula: see text]), interleukin-1[Formula: see text] (IL-1[Formula: see text]), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), were analyzed to indicate the underlying protective effects of Rb1 against APAP-induced hepatotoxicity with significant inflammatory responses. Histological examination further proved Rb1’s protective effects. Importantly, Rb1 mitigated the changes in the phosphorylation of MAPK and PI3K/Akt, as well as its downstream factor NF-[Formula: see text]B. In conclusion, experimental data clearly demonstrated that Rb1 exhibited a remarkable liver protective effect against APAP-induced ALI, partly through regulating MAPK and PI3K/Akt signaling pathways-mediated inflammatory responses.

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Differential protective effects of Bcl-xL and Bcl-2 on apoptotic liver injury in transgenic mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1999.277.3.g702 ◽

1999 ◽

Vol 277 (3) ◽

pp. G702-G708 ◽

Cited By ~ 12

Author(s):

Alix de la Coste ◽

Monique Fabre ◽

Nathalie McDonell ◽

Arlette Porteu ◽

Helène Gilgenkrantz ◽

...

Keyword(s):

Liver Injury ◽

Transgenic Mice ◽

Fas Ligand ◽

Dependent Manner ◽

Protective Effects ◽

Tnf Α ◽

Apoptotic Pathways ◽

Induced Apoptosis ◽

Factor Α

Fas ligand (CD95L) and tumor necrosis factor-α (TNF-α) are pivotal inducers of hepatocyte apoptosis. Uncontrolled activation of these two systems is involved in several forms of liver injury. Although the broad antiapoptotic action of Bcl-2 and Bcl-xL has been clearly established in various apoptotic pathways, their ability to inhibit the Fas/CD95- and TNF-α-mediated apoptotic signal has remained controversial. We have demonstrated that the expression of BCL-2 in hepatocytes protects them against Fas-induced fulminant hepatitis in transgenic mice. The present study shows that transgenic mice overexpressing[Formula: see text]in hepatocytes are also protected from Fas-induced apoptosis in a dose-dependent manner. Bcl-xL and Bcl-2 were protective without any change in the level of endogenous[Formula: see text]or Bax and inhibited hepatic caspase-3-like activity. In vivo injection of TNF-α caused massive apoptosis and death only when transcription was inhibited. Under these conditions,[Formula: see text]mice were partially protected from liver injury and death but PK-BCL-2 mice were not. A similar differential protective effect of Bcl-xL and Bcl-2 transgenes was observed when Fas/CD95 was activated and transcription blocked. These results suggest that apoptosis triggered by activation of both Fas/CD95 and TNF-α receptors is to some extent counteracted by the transcription-dependent protective effects, which are essential for the antiapoptotic activity of Bcl-2 but not of Bcl-xL. Therefore, Bcl-xL and Bcl-2 appear to have different antiapoptotic effects in the liver whose characterization could facilitate their use to prevent the uncontrolled apoptosis of hepatocytes.

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TGR5-dependent hepatoprotection through the regulation of biliary epithelium barrier function

Gut ◽

10.1136/gutjnl-2018-316975 ◽

2019 ◽

Vol 69 (1) ◽

pp. 146-157 ◽

Cited By ~ 11

Author(s):

Grégory Merlen ◽

Nicolas Kahale ◽

Jose Ursic-Bedoya ◽

Valeska Bidault-Jourdainne ◽

Hayat Simerabet ◽

...

Keyword(s):

Liver Injury ◽

Barrier Function ◽

Bile Leakage ◽

Liver Parenchyma ◽

Knock Out ◽

Epithelial Barrier Function ◽

Biliary Epithelium ◽

Duct Ligation

ObjectiveWe explored the hypothesis that TGR5, the bile acid (BA) G-protein-coupled receptor highly expressed in biliary epithelial cells, protects the liver against BA overload through the regulation of biliary epithelium permeability.DesignExperiments were performed under basal and TGR5 agonist treatment. In vitro transepithelial electric resistance (TER) and FITC-dextran diffusion were measured in different cell lines. In vivo FITC-dextran was injected in the gallbladder (GB) lumen and traced in plasma. Tight junction proteins and TGR5-induced signalling were investigated in vitro and in vivo (wild-type [WT] and TGR5-KO livers and GB). WT and TGR5-KO mice were submitted to bile duct ligation or alpha-naphtylisothiocyanate intoxication under vehicle or TGR5 agonist treatment, and liver injury was studied.ResultsIn vitro TGR5 stimulation increased TER and reduced paracellular permeability for dextran. In vivo dextran diffusion after GB injection was increased in TGR5-knock-out (KO) as compared with WT mice and decreased on TGR5 stimulation. In TGR5-KO bile ducts and GB, junctional adhesion molecule A (JAM-A) was hypophosphorylated and selectively downregulated among TJP analysed. TGR5 stimulation induced JAM-A phosphorylation and stabilisation both in vitro and in vivo, associated with protein kinase C-ζ activation. TGR5 agonist-induced TER increase as well as JAM-A protein stabilisation was dependent on JAM-A Ser285 phosphorylation. TGR5 agonist-treated mice were protected from cholestasis-induced liver injury, and this protection was significantly impaired in JAM-A-KO mice.ConclusionThe BA receptor TGR5 regulates biliary epithelial barrier function in vitro and in vivo through an impact on JAM-A expression and phosphorylation, thereby protecting liver parenchyma against bile leakage.

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Protective Effects of Peroxiredoxin 4 (PRDX4) on Cholestatic Liver Injury

International Journal of Molecular Sciences ◽

10.3390/ijms19092509 ◽

2018 ◽

Vol 19 (9) ◽

pp. 2509 ◽

Cited By ~ 3

Author(s):

Jing Zhang ◽

Xin Guo ◽

Taiji Hamada ◽

Seiya Yokoyama ◽

Yuka Nakamura ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Injury ◽

Critical Role ◽

Therapeutic Modality ◽

Protective Effects ◽

Fibrotic Liver ◽

Intrahepatic Bile Ducts ◽

Duct Ligation ◽

Cholestatic Liver Injury

Accumulating evidence indicates that oxidative stress plays a critical role in initiating the progression of inflammatory and fibrotic liver diseases, including cholestatic hepatitis. Peroxiredoxin 4 (PRDX4) is a secretory antioxidase that protects against oxidative damage by scavenging reactive oxygen species (ROS) in both the intracellular compartments and extracellular space. In this study, we examined the in vivo net effects of PRDX4 overexpression in a murine model of cholestasis. To induce cholestatic liver injury, we subjected C57BL/6J wild-type (WT) or human PRDX4 (hPRDX4) transgenic (Tg) mice to sham or bile duct ligation (BDL) surgery for seven days. Our results showed that the liver necrosis area was significantly suppressed in Tg BDL mice with a reduction in the severity of liver injuries. Furthermore, PRDX4 overexpression markedly reduced local and systemic oxidative stress generated by BDL. In addition, suppression of inflammatory cell infiltration, reduced proliferation of hepatocytes and intrahepatic bile ducts, and less fibrosis were also found in the liver of Tg BDL mice, along with a reduced mortality rate after BDL surgery. Interestingly, the composition of the hepatic bile acids (BAs) was more beneficial for Tg BDL mice than for WT BDL mice, suggesting that PRDX4 overexpression may affect BA metabolism during cholestasis. These features indicate that PRDX4 plays an important role in protecting against liver injury following BDL and might be a promising therapeutic modality for cholestatic diseases.

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circ-CBFB upregulates p66Shc to perturb mitochondrial dynamics in APAP-induced liver injury

Cell Death and Disease ◽

10.1038/s41419-020-03160-y ◽

2020 ◽

Vol 11 (11) ◽

Author(s):

Zhecheng Wang ◽

Yan Zhao ◽

Ruimin Sun ◽

Yu Sun ◽

Deshun Liu ◽

...

Keyword(s):

Liver Injury ◽

Mitochondrial Dynamics ◽

Circular Rna ◽

Protective Effects ◽

Bioinformatics Analyses ◽

Hepatocyte Injury ◽

Rna Immunoprecipitation ◽

Competitive Endogenous Rna

Abstract p66Shc, a master regulator of mitochondrial reactive oxygen species (mtROS), is a crucial mediator of hepatocyte oxidative stress. However, its functional contribution to acetaminophen (APAP)-induced liver injury and the mechanism by which it is modulated remain unknown. Here, we aimed to assess the effect of p66Shc on APAP-induced liver injury and to evaluate if circular RNA (circRNA) functions as a competitive endogenous RNA (ceRNA) to mediate p66Shc in APAP-induced liver injury. p66Shc-, miR-185-5p-, and circ-CBFB-silenced mice were injected with APAP. AML12 cells were transfected with p66Shc, miR-185-5p, and circ-CBFB silencing or overexpression plasmids or siRNAs prior to APAP stimulation. p66Shc was upregulated in liver tissues in response to APAP, and p66Shc silencing in vivo protected mice from APAP-induced mitochondrial dynamics perturbation and liver injury. p66Shc knockdown in vitro attenuated mitochondrial dynamics and APAP-induced hepatocyte injury. Mechanically, p66Shc perturbs mitochondrial dynamics partially by inhibiting OMA1 ubiquitination. miR-185-5p, which directly suppressed p66Shc translation, was identified by microarray and bioinformatics analyses, and its overexpression attenuated mitochondrial dynamics and hepatocyte injury in vitro. Furthermore, luciferase, pull-down and RNA immunoprecipitation assays demonstrated that circ-CBFB acts as a miRNA sponge of miR-185-5p to mediate p66Shc in APAP-induced liver injury. circ-CBFB knockdown also alleviated APAP-induced mitochondrial dynamics perturbation and hepatocyte injury. More importantly, we found that the protective effects of circ-CBFB knockdown on p66Shc, mitochondrial dynamics and liver injury were abolished by miR-185-5p inhibition both in vivo and in vitro. In conclusion, p66Shc is a key regulator of APAP-induced liver injury that acts by triggering mitochondrial dynamics perturbation. circ-CBFB functions as a ceRNA to regulate p66Shc during APAP-induced liver injury, which may provide a potential therapeutic target.

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Milk osteopontin, a nutritional approach to prevent alcohol-induced liver injury

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00014.2013 ◽

2013 ◽

Vol 304 (10) ◽

pp. G929-G939 ◽

Cited By ~ 26

Author(s):

Xiaodong Ge ◽

Yongke Lu ◽

Tung-Ming Leung ◽

Esben S. Sørensen ◽

Natalia Nieto

Keyword(s):

Liver Disease ◽

Liver Injury ◽

Neutrophil Infiltration ◽

Therapeutic Interventions ◽

High Concentration ◽

Intestinal Integrity ◽

Enterocyte Proliferation ◽

Factor Α ◽

Key Events ◽

Necrosis Factor

Alcohol consumption is a leading cause of liver disease worldwide; thus, there is an urgent need to develop novel therapeutic interventions. Key events for the onset and progression of alcoholic liver disease result in part from the gut-to-liver interaction. Osteopontin is a cytokine present at high concentration in human milk, umbilical cord, and infants' plasma with beneficial potential. We hypothesized that dietary administration of milk osteopontin could prevent alcohol-induced liver injury perhaps by maintaining gut integrity and averting hepatic inflammation and steatosis. Wild-type mice were fed either the control or the ethanol Lieber-DeCarli diets alone or in combination with milk osteopontin for 3 wk, and parameters of gut and liver damage were measured. Milk osteopontin protected the stomach and the gut by increasing gland height, crypt cell plus enterocyte proliferation, and mucin content in addition to lowering macrophages, plasmacytes, lymphocytes, and neutrophils in the mucosa and submucosa in alcohol-fed mice. Milk osteopontin targeted the gut-liver axis, preserving the expression of tight-junction proteins in alcohol-fed mice thus maintaining intestinal integrity and permeability. There was protection from liver injury since transaminases, the activity scores, triglyceride levels, neutrophil infiltration, 3-nitrotyrosine residues, lipid peroxidation end products, translocation of gram-negative bacteria, lipopolysaccharide levels, and tumor necrosis factor-α were lower in cotreated than in ethanol-fed mice. Furthermore, milk osteopontin diminished ethanol-mediated liver injury in OPN knockout mice. Milk osteopontin could be a simple effective nutritional therapeutic strategy to prevent alcohol hepatotoxicity due, among others, to gut protective, anti-inflammatory, and anti-steatotic actions.

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Grape-Leaf Extract Attenuates Alcohol-Induced Liver Injury via Interference with NF-κB Signaling Pathway

Biomolecules ◽

10.3390/biom10040558 ◽

2020 ◽

Vol 10 (4) ◽

pp. 558 ◽

Cited By ~ 1

Author(s):

Yhiya Amen ◽

Asmaa E. Sherif ◽

Noha M. Shawky ◽

Rehab S. Abdelrahman ◽

Michael Wink ◽

...

Keyword(s):

Liver Injury ◽

Secondary Metabolites ◽

Nuclear Factor Κb ◽

Sprague Dawley ◽

Leaf Extracts ◽

Underlying Mechanisms ◽

Grape Leaf ◽

Factor Α ◽

Antioxidant Effects

Grape (Vitis vinifera) leaf extracts (GLEs) are known to be rich in phenolic compounds that exert potent antioxidant effects. Given the vulnerability of the liver to oxidative damage, antioxidants have been proposed as therapeutic agents and coadjuvant drugs to ameliorate liver pathologies. The current study was designed to characterize secondary metabolites and investigate the hepatoprotective effects of GLE and its underlying mechanisms. The secondary metabolites were profiled using HPLC–PDA–ESI-MS, and forty-five compounds were tentatively identified. In experimental in vivo design, liver injury was induced by oral administration of high doses of ethanol (EtOH) for 12 days to male Sprague Dawley rats that were split into five different groups. Blood samples and livers were then collected, and used for various biochemical, immunohistochemical, and histopathological analyses. Results showed that GLE-attenuated liver injury and promoted marked hepatic antioxidant effects, in addition to suppressing the increased heat-shock protein-70 expression. Moreover, GLE suppressed EtOH-induced expression of nuclear factor-κB (NF-κB) p65 subunit and proinflammatory cytokine tumor necrosis factor-α. Caspase-3 and survivin were enhanced by EtOH intake and suppressed by GLE intake. Finally, EtOH-induced histopathological changes in liver sections were markedly normalized by GLE. In conclusion, our results suggested that GLE interferes with NF-κB signaling and induces antioxidant effects, which both play a role in attenuating apoptosis and associated liver injury in a model of EtOH-induced liver damage in rats.

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TLR2 and TLR9 contribute to alcohol-mediated liver injury through induction of CXCL1 and neutrophil infiltration

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00031.2015 ◽

2015 ◽

Vol 309 (1) ◽

pp. G30-G41 ◽

Cited By ~ 63

Author(s):

Yoon Seok Roh ◽

Bi Zhang ◽

Rohit Loomba ◽

Ekihiro Seki

Keyword(s):

Liver Injury ◽

Alcoholic Hepatitis ◽

Early Stage ◽

Neutrophil Infiltration ◽

Wild Type ◽

Ethanol Feeding ◽

Binge Ethanol ◽

Deficient Mice ◽

Cxcl1 Expression

Although previous studies reported the involvement of the TLR4-TRIF pathway in alcohol-induced liver injury, the role of TLR2 and TLR9 signaling in alcohol-mediated neutrophil infiltration and liver injury has not been elucidated. Since alcohol binge drinking is recognized to induce more severe form of alcohol liver disease, we used a chronic-binge ethanol-feeding model as a mouse model for early stage of alcoholic hepatitis. Whereas a chronic-binge ethanol feeding induced alcohol-mediated liver injury in wild-type mice, TLR2- and TLR9-deficient mice showed reduced liver injury. Induction of neutrophil-recruiting chemokines, including Cxcl1, Cxcl2, and Cxcl5, and hepatic neutrophil infiltration were increased in wild-type mice, but not in TLR2- and TLR9-deficient mice. In vivo depletion of Kupffer cells (KCs) by liposomal clodronate reduced liver injury and the expression of Il1b, but not Cxcl1, Cxcl2, and Cxcl5, suggesting that KCs are partly associated with liver injury, but not neutrophil recruitment, in a chronic-binge ethanol-feeding model. Notably, hepatocytes and hepatic stellate cells (HSCs) produce high amounts of CXCL1 in ethanol-treated mice. The treatment with TLR2 and TLR9 ligands synergistically upregulated CXCL1 expression in hepatocytes. Moreover, the inhibitors for CXCR2, a receptor for CXCL1, and MyD88 suppressed neutrophil infiltration and liver injury induced by chronic-binge ethanol treatment. Consistent with the above findings, hepatic CXCL1 expression was highly upregulated in patients with alcoholic hepatitis. In a chronic-binge ethanol-feeding model, the TLR2 and TLR9-dependent MyD88-dependent pathway mediates CXCL1 production in hepatocytes and HSCs; the CXCL1 then promotes neutrophil infiltration into the liver via CXCR2, resulting in the development of alcohol-mediated liver injury.

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Pharmacological Effects and Toxicogenetic Impacts of Omeprazole: Genomic Instability and Cancer

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/3457890 ◽

2020 ◽

Vol 2020 ◽

pp. 1-21

Author(s):

Márcia Fernanda Correia Jardim Paz ◽

Marcus Vinícius Oliveira Barros de Alencar ◽

Rodrigo Maciel Paulino de Lima ◽

André Luiz Pinho Sobral ◽

Glauto Tuquarre Melo do Nascimento ◽

...

Keyword(s):

Genomic Instability ◽

Neutrophil Infiltration ◽

Protective Effects ◽

Pharmacological Effects ◽

Self Medication ◽

Study Objective ◽

Anti Inflammatory

Omeprazole (OME) is commonly used to treat gastrointestinal disorders. However, long-term use of OME can increase the risk of gastric cancer. We aimed to characterize the pharmacological effects of OME and to correlate its adverse effects and toxicogenetic risks to the genomic instability mechanisms and cancer-based on database reports. Thus, a search (till Aug 2019) was made in the PubMed, Scopus, and ScienceDirect with relevant keywords. Based on the study objective, we included 80 clinical reports, forty-six in vitro, and 76 in vivo studies. While controversial, the findings suggest that long-term use of OME (5 to 40 mg/kg) can induce genomic instability. On the other hand, OME-mediated protective effects are well reported and related to proton pump blockade and anti-inflammatory activity through an increase in gastric flow, anti-inflammatory markers (COX-2 and interleukins) and antiapoptotic markers (caspases and BCL-2), glycoprotein expression, and neutrophil infiltration reduction. The reported adverse and toxic effects, especially in clinical studies, were atrophic gastritis, cobalamin deficiencies, homeostasis disorders, polyp development, hepatotoxicity, cytotoxicity, and genotoxicity. This study highlights that OME may induce genomic instability and increase the risk of certain types of cancer. Therefore, adequate precautions should be taken, especially in its long-term therapeutic strategies and self-medication practices.

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Neuroprotective Effects of Ginsenosides against Cerebral Ischemia

Molecules ◽

10.3390/molecules24061102 ◽

2019 ◽

Vol 24 (6) ◽

pp. 1102 ◽

Cited By ~ 15

Author(s):

Zhekang Cheng ◽

Meng Zhang ◽

Chengli Ling ◽

Ying Zhu ◽

Hongwei Ren ◽

...

Keyword(s):

Cerebral Ischemia ◽

Ischemia Reperfusion ◽

Ischemic Injury ◽

Neurological Dysfunction ◽

Control Group ◽

Protective Effects ◽

Ginsenoside Rb1 ◽

Neuroprotective Effects

Ginseng has been used worldwide as traditional medicine for thousands of years, and ginsenosides have been proved to be the main active components for their various pharmacological activities. Based on their structures, ginsenosides can be divided into ginseng diol-type A and ginseng triol-type B with different pharmacological effects. In this study, six ginsenosides, namely ginsenoside Rb1, Rh2, Rg3, Rg5 as diol-type ginseng saponins, and Rg1 and Re as triol-type ginseng saponins, which were reported to be effective for ischemia-reperfusion (I/R) treatment, were chosen to compare their protective effects on cerebral I/R injury, and their mechanisms were studied by in vitro and in vivo experiments. It was found that all ginsenosides could reduce reactive oxygen species (ROS), inhibit apoptosis and increase mitochondrial membrane potential in cobalt chloride-induced (CoCl2-induced) PC12 cells injury model, and they could reduce cerebral infarction volume, brain neurological dysfunction of I/R rats in vivo. The results of immunohistochemistry and western blot showed that the expression of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), silencing information regulator (SIRT1) and nuclear transcription factor P65 (NF-κB) in hippocampal CA1 region of some ginsenoside groups were also reduced. In general, the effect on cerebral ischemia of Rb1 and Rg3 was significantly improved compared with the control group, and was the strongest among all the ginsenosides. The effect on SIRT1 activation of ginsenoside Rb1 and the inhibition effect of TLR4/MyD88 protein expression of ginsenoside Rb1 and Rg3 were significantly stronger than that of other groups. The results indicated that ginsenoside Rg1, Rb1, Rh2, Rg3, Rg5 and Re were effective in protecting the brain against ischemic injury, and ginsenoside Rb1 and Rg3 have the strongest therapeutic activities in all the tested ginsenosides. Their neuroprotective mechanism is associated with TLR4/MyD88 and SIRT1 activation signaling pathways, and they can reduce cerebral ischemic injury by inhibiting NF-κB transcriptional activity and the expression of proinflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6).

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