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Oil red O staining of liver sections from the control and MCD-induced mice groups to validate the ameliorating effect of Gyp LXXV against hepatic lipid accumulation. (a) 100x magnification, scale bar 200 μm. Quantification of oil red O staining was performed using Fiji software (b). Error bars represent SEM. ** p < 0.01, *** p < 0.001 vs. MCD, two tailed unpaired t-test.
Source publication
Ginsenosides have offered a wide array of beneficial roles in the pharmacological regulation of hepatic metabolic syndromes, including non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), and obesity. Of the numerous ginsenosides, Rg3 has been widely investigated, but there have been few studies of gypenosides (Gyp). Par...
Contexts in source publication
Context 1
... oral administration of the compounds, the body weight of mice was measured every week. There was no weight change in groups of Gyp LXXV as well as Rg3 compared to the MCD diet mouse group that showed a significant decrease in weight ( Figure S5). It was confirmed that the liver tissue/weight ratio of the group administered with each compound was significantly reduced compared to the MCD group (Figure 3a,c). ...
Context 2
... this meets the preferred condition, meaning that it is safe to pursue low dosage-based administration to avoid any potential hepato-cytotoxicity and side effects when compared with results elsewhere on significantly high oral doses of Gyp extracts (200-800 mg/kg) to treat T2DM-NAFLD [30]. To confirm the lipid accumulation in the liver of MCD-fed mice, oil red O staining was used to measure fat loading in the hepatocytes (Figure 5a). Histological analysis revealed an increased intracellular lipid deposition in the liver of MCD group. ...
Context 3
... lipid droplets were markedly reduced in the livers of Rg3- or Gyp LXXV-treated mice. In particular, the reduction rate of fat accumulation in the Gyp LXXV-treated group at a low dose range (15 mg/kg) was apparently greater than that of the Rg3-treated group, as quantitated in Figure 5b. We have also monitored the level of lipid metabolic parameters such as triglycerides (TG), which remained unchanged ( Figure S6). ...
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Background
Non-alcoholic fatty liver disease (NAFLD) is rapidly becoming a global health problem. Cardiovascular diseases (CVD) are the most common cause of mortality in NAFLD patients. NAFLD and CVD share several common risk factors including obesity, insulin resistance, and type 2 diabetes (T2D). Atherogenic dyslipidemia, characterized by plasma...
Citations
... Some studies have shown that GPE can alleviate the NASH-related comorbidity sarcopenia, which is mainly characterized by weakness, fatigue, and energy loss [7,34,35]. It was reported that GYP LXXV, a GP saponin-type extract, exerted its hepatoprotective effects by ameliorating hepatic lipid accumulation and hepatic fibrosis in NASH mice [30]. The absence of gypenoside in GPE may be related to the extraction technique and the source of natural medicine. ...
NASH (non-alcoholic steatohepatitis) is a severe liver disease characterized by hepatic chronic inflammation that can be associated with the gut microbiota. In this study, we explored the therapeutic effect of Gynostemma pentaphyllum extract (GPE), a Chinese herbal extract, on methionine- and choline-deficient (MCD) diet-induced NASH mice. Based on the peak area, the top ten compounds in GPE were hydroxylinolenic acid, rutin, hydroxylinoleic acid, vanillic acid, methyl vanillate, quercetin, pheophorbide A, protocatechuic acid, aurantiamide acetate, and iso-rhamnetin. We found that four weeks of GPE treatment alleviated hepatic confluent zone inflammation, hepatocyte lipid accumulation, and lipid peroxidation in the mouse model. According to the 16S rRNA gene V3–V4 region sequencing of the colonic contents, the gut microbiota structure of the mice was significantly changed after GPE supplementation. Especially, GPE enriched the abundance of potentially beneficial bacteria such as Akkerrmansia and decreased the abundance of opportunistic pathogens such as Klebsiella. Moreover, RNA sequencing revealed that the GPE group showed an anti-inflammatory liver characterized by the repression of the NF-kappa B signaling pathway compared with the MCD group. Ingenuity Pathway Analysis (IPA) also showed that GPE downregulated the pathogen-induced cytokine storm pathway, which was associated with inflammation. A high dose of GPE (HGPE) significantly downregulated the expression levels of the tumor necrosis factor-α (TNF-α), myeloid differentiation factor 88 (Myd88), cluster of differentiation 14 (CD14), and Toll-like receptor 4 (TLR4) genes, as verified by real-time quantitative PCR (RT-qPCR). Our results suggested that the therapeutic potential of GPE for NASH mice may be related to improvements in the intestinal microenvironment and a reduction in liver inflammation.
... 16 Gypenoside LXXV can alleviate liver fibrosis and liver inflammation in NASH mice. 17 In this study, we establish a fatty liver cell model to investigate whether gypenoside XIII regulates the lipid metabolism of fatty liver cells and establish a NASH mouse model to evaluate whether gypenoside XIII has the ability to improve liver fibrosis and liver inflammation in NASH mice. ...
Gypenoside XIII is isolated from Gynostemma pentaphyllum (Thunb.) Makino. In mice, G. pentaphyllum extract and gypenoside LXXV have been shown to improve non‐alcoholic steatohepatitis (NASH). This study investigated whether gypenoside XIII can regulate lipid accumulation in fatty liver cells or attenuate NASH in mice. We used HepG2 hepatocytes to establish a fatty liver cell model using 0.5 mM oleic acid. Fatty liver cells were treated with different concentrations of gypenoside XIII to evaluate the molecular mechanisms of lipid metabolism. In addition, a methionine/choline‐deficient diet induced NASH in C57BL/6 mice, which were given 10 mg/kg gypenoside XIII by intraperitoneal injection. In fatty liver cells, gypenoside XIII effectively suppressed lipid accumulation and lipid peroxidation. Furthermore, gypenoside XIII significantly increased SIRT1 and AMPK phosphorylation to decrease acetyl‐CoA carboxylase phosphorylation, reducing fatty acid synthesis activity. Gypenoside XIII also decreased lipogenesis by suppressing sterol regulatory element‐binding protein 1c and fatty acid synthase production. Gypenoside XIII also increased lipolysis and fatty acid β‐oxidation by promoting adipose triglyceride lipase and carnitine palmitoyltransferase 1, respectively. In an animal model of NASH, gypenoside XIII effectively decreased the lipid vacuole size and number and reduced liver fibrosis and inflammation. These findings suggest that gypenoside XIII can regulate lipid metabolism in fatty liver cells and improve liver fibrosis in NASH mice. Therefore, gypenoside XIII has potential as a novel agent for the treatment of NASH.
... Notably, 6-shogaol did not induce significant alterations in these parameters in mice subjected to the MCD diet ( Figure 1A-C). As previously documented [16], liver tissue staining with oil red O revealed a substantial accumulation of triglycerides (TGs) in mice subjected to the MCD diet (p < 0.001; Figure 1D,E). A biochemical analysis of hepatic TG content confirmed the presence of MCD-diet-induced steatosis (p < 0.001; Figure 1F). ...
... For oil red O staining, frozen liver sections were quickly fixed in 4% paraformaldehyde. Subsequently, the cytoplasmic lipid droplets were stained using an oil red O solution (Sigma-Aldrich, St. Louis, MO, USA), with nuclei counterstained with hematoxylin [16]. Quantification of the area stained with oil red O or Masson's trichrome was performed using i-Solution DT software version 11.0 (IMT i-Solution, Coquitlam, BC, Canada) from ...
... For oil red O staining, frozen liver sections were quickly fixed in 4% paraformaldehyde. Subsequently, the cytoplasmic lipid droplets were stained using an oil red O solution (Sigma-Aldrich, St. Louis, MO, USA), with nuclei counterstained with hematoxylin [16]. Quantification of the area stained with oil red O or Masson's trichrome was performed using i-Solution DT software version 11.0 (IMT i-Solution, Coquitlam, BC, Canada) from five random fields (200× magnification for Masson's trichrome and 400× magnification for oil red O) for each sample. ...
Non-alcoholic steatohepatitis (NASH) is becoming an increasingly serious global health threat, distinguished by hepatic lipid accumulation, inflammation, and fibrosis. There is a lack of approved pharmaceutical interventions for this disease, highlighting the urgent need for effective treatment. This study explores the hepatoprotective potential of 6-shogaol, a natural compound derived from ginger, in a methionine- and choline-deficient (MCD) dietary mouse model of NASH. Male C57BL/6J mice were subjected to the MCD diet for 4 weeks to induce NASH, with concurrent intraperitoneal administration of 6-shogaol (20 mg/kg) three times a week. While 6-shogaol did not impact body weight, liver weight, or hepatic lipid accumulation, it effectively mitigated liver injury, inflammation, and fibrosis in MCD diet-fed mice. Mechanistically, 6-shogaol inhibited lipid and DNA oxidation, restored hepatic glutathione levels, and regulated the expression of pro-oxidant and antioxidant enzymes. Furthermore, 6-shogaol inhibited apoptosis and necroptosis, as indicated by a decrease in TUNEL-stained cells and downregulation of apoptosis- and necroptosis-associated proteins. Additionally, 6-shogaol alleviated endoplasmic reticulum (ER) stress, as demonstrated by decreased expression of molecules associated with unfolded protein response pathways. These findings underscore the potential of 6-shogaol as a therapeutic intervention for NASH by targeting pathways related to oxidative stress, cell death, and ER stress.
... This was achieved by reducing liver inflammation through the downregulation of cytokines like interleukin 1β (IL-1β) [53]. Furthermore, Treatment with Rg3 significantly reduced the level of mechanistic target of rapamycin complex 1 (mTORC1) and p-NF-κB expression, increased the marker for M2 (CD163 and IL-10), while decreased the marker for M1 such as chemokine C-C motif ligand 2(Ccl2), chemokine C-C motif ligand 5 (Ccl5), interleukin-6 (IL-6), iNos, IL-1β, and TNF-α in the inflammatory response induced by LPS [54,55]. ...
Liver diseases are a significant global health burden and are among the most common diseases. Ginssennoside Rg3 (Rg3), which is one of the most abundant ginsenosides, has been found to have significant preventive and therapeutic effects against various types of diseases with minimal side effects. Numerous studies have demonstrated the significant preventive and therapeutic effects of Rg3 on various liver diseases such as viral hepatitis, acute liver injury, nonalcoholic liver diseases (NAFLD), liver fibrosis and hepatocellular carcinoma (HCC). The underlying molecular mechanism behind these effects is attributed to apoptosis, autophagy, antioxidant, anti-inflammatory activities, and the regulation of multiple signaling pathways. This review provides a comprehensive description of the potential molecular mechanisms of Rg3 in the development of liver diseases. The article focuses on the regulation of apoptosis, oxidative stress, autophagy, inflammation, and other related factors. Additionally, the review discusses combination therapy and liver targeting strategy, which can accelerate the translation of Rg3 from bench to bedside. Overall, this article serves as a valuable reference for researchers and clinicians alike.
... Epidemiological investigation has shown that the incidence of NAFLD in China is about 15 %, while that in Europe and America is more than 20 %. Therefore, it is of great significance to explore effective therapies for NAFLD, and an in-depth study of the pathogenesis of NAFLD is crucial for the formulation of effective treatment strategies [11]. In this study, fucosterol improved palmitic acidinduced oxidative stress, lipid droplet formation, and insulin resistance in liver cells via mediating LCN13, suggesting that Fucosterol could serve as a promising drug of NAFLD. ...
Purpose: To determine the possible effects of fucosterol (FST) on non-alcoholic fatty liver disease (NAFLD), and the mechanisms involved. Methods: The NAFLD model was constructed using palmitic acid (PA) induction, and the expression of NF-E2-related factor 2 (Nrf2), lipocalin 13 (LCN13) and Keap1 were analyzed by immunoblot. The oxidative stress of hepatocytes was determined via ELISA assay. In addition, the role of FST on lipid content and metabolism were evaluated by Oil Red O staining and immunoblot, while the levels of p-AKT, p-IRS1, and p-PI3K were evaluated by immunoblot assay. Results: The data revealed that FST significantly increased the viability of PA-induced hepatocytes, and the expression levels of Nrf2 and LCN13 (p < 0.05). Fucosterol enhanced Keap1-Nrf2 mediated LCN13 expression, and alleviated PA-induced oxidative stress by contributing to Keap1-Nrf2-LCN13 axis. In addition, it significantly reduced (p < 0.05) lipid droplet formation, promoted lipid metabolism, and lowered insulin resistance by enhancing Keap1- Nrf2-LCN13 axis. Conclusion: Fucosterol regulates Keap1-Nrf2-mediated LCN13 to aid the ameliorate palmitic acid-induced oxidative stress, lipid droplet formation and insulin resistance in liver cells.
... Moreover, there was no difference in the hypoglycemic effect of Panax ginseng according to animal species (p in fasting blood glucose = 0.599) ( Figure 8C). [7,19,20,23,[27][28][29][30][31][32][35][36][37][38][39][40][41][43][44][45][47][48][49][50]52,[54][55][56]58]. (B) AST levels [19,23,[27][28][29][30][31][32][35][36][37][38][39][40][41]44,45,[47][48][49][50]52,[54][55][56]58]. ...
Although tremendous research has reported the protective effects of natural compounds in nonalcoholic fatty liver disease (NAFLD), there is still no approved drug. This study aimed to examine the efficacy of Panax ginseng in NAFLD in preclinical studies. A total of 41 studies were identified by searching the PubMed, Web of Science, and Cochrane Library databases. The methodological quality was assessed by the risk of bias tool from the Systematic Review Center for Laboratory Animal Experimentation. The standardized mean difference (SMD) with a 95% confidence interval was calculated, and the random effects model was used to examine overall efficacy or heterogeneity. The publication bias was analyzed by Egger’s test. The results showed that Panax ginseng treatment significantly reduced the systemic levels of alanine aminotransferase (SMD: −2.15 IU/L; p < 0.0001), aspartate aminotransferase (SMD: −2.86 IU/L; p < 0.0001), triglyceride (SMD: −2.86 mg/dL; p < 0.0001), total cholesterol (SMD: −1.69 mg/dL; p < 0.0001), low-density lipoprotein (SMD: −1.46 mg/dL; p < 0.0001), and fasting glucose (SMD: −1.45 mg/dL; p < 0.0001) while increasing high-density lipoprotein (SMD: 1.22 mg/dL; p = 0.0002) in NAFLD regardless of animal models or species. These findings may suggest that Panax ginseng is a promising therapeutic agent for NAFLD treatment.
... In recent years, studies have reported that Gypenoside XVII can exert anti-acute alcoholic liver injury effects in mice by activating the PI3K/Akt and Nrf2/NF-κB signaling pathways. Gypenoside LXXV has been used to treat non-alcoholic steatohepatitis and has protective effects against oxidative stress (18). Ginsenoside Rg2 could improve high-fatdiet-induced NAFLD, and its mechanism of action is related to the dependent upregulation of SIRT1 activity (19). ...
This study investigated the mechanism of characteristic non-volatile organic compounds (NVOCs) from ginseng Huang jiu (GH) in the treatment of alcoholic liver disease through UPLC-Q-Orbitrap-HRMS and network pharmacological analyses. Changes in NVOC contents in ginseng Huang jiu and ginseng-soaked wine fermented by different processing technologies were analyzed through liquid chromatography–mass spectrometry (LC-MS). A total of 96 ginsenosides were identified in ginseng Huang jiu throughout the fermentation process, which included 37 protopanaxadiol-type ginsenosides, 47 protopanaxatriol-type ginsenosides, and 4 oleanolic acid-type ginsenosides. Orthogonal partial least squares-discriminant analysis (OPLS-DA) revealed that 20(R)-Rg2, Gypenoside XVII, 20(S)-Rf3, CK, Rg5, Rh2, and other rare ginsenosides in ginseng Huang jiu could be the potential index for determining ginseng Huang jiu. In addition, ginseng Huang jiu could improve alcoholic liver disease by regulating the GSTP1, HRAS, AKR1B1, GSTA1, Androgen receptor (AR), GSR, and LDHB genes through bioinformatics analysis. This study provides new insights into improving the industrial production of ginseng Huang jiu and treating alcoholic liver disease with medicinal and food products.
... Previous studies have found that Fuzhenghuayu decoction and Jiangzhi granule, with GP as their main ingredient, could ameliorate hepatic fibrosis and steatohepatitis in vitro and in vivo (44,45). Moreover, the compound of Gypenosides LXXV could alleviate NASH by downregulating the inflammation and hepatic fibrosis markers such as TNF-a, IL-1b, and collagen 1 (46). In our study, we showed that GPP is effective in the prevention of steatohepatitis in a murine MCD model of NASH with dose-effect. ...
Recent studies have revealed the pivotal role of gut microbiota in the progress of liver diseases including non-alcoholic steatohepatitis (NASH). Many natural herbs, such as Gynostemma pentaphyllum (GP), have been extensively applied in the prevention of NASH, while the bioactive components and underlying mechanism remain unclear. The aim of this study was to investigate whether the polysaccharides of GP (GPP) have a protective effect on NASH and to explore the potential mechanism underlying these effects. C57BL/6 male mice were fed with a methionine-choline-deficient (MCD) diet for 4 weeks to induce NASH and administered daily oral gavage of sodium carboxymethylcellulose (CMC-Na), low dose of GPP (LGPP), high dose of GPP (HGPP), and polyene phosphatidylcholine capsules (PPC), compared with the methionine-choline-sufficient (MCS) group. Our results showed that the symptoms of hepatic steatosis, hepatocyte ballooning, liver fibrosis, and oxidative stress could be partially recovered through the intervention of GPP with a dose-dependent effect. Furthermore, gut microbiome sequencing revealed that HGPP altered the composition of gut microbiota, mainly characterized by the enrichment of genera including Akkermansia, Lactobacillus, and A2. Moreover, hepatic transcriptome analysis indicated that the anti-inflammatory effect of HGPP might be associated with toll-like receptor (TLR) and nod-like receptor (NLR) signaling pathways. HGPP could inhibit the expression of TLR2 and downregulate the expression of the NLRP3 inflammasome, as well as the pro-inflammatory cytokine tumor necrosis factor (TNF)-α and interleukin (IL)-1β. In summary, GPP could ameliorate NASH possibly mediated via the modulation of gut microbiota and the TLR2/NLRP3 signaling pathway, indicating that GPP could be tested as a prebiotic agent in the prevention of NASH.
... In NASH mouse models, several compound treatments were effective in downregulating α-SMA and inhibited HSC transdifferentiation into myofibroblasts, alleviating NASH features, including steatosis and fibrosis. Those compounds include resmetirom [79], liraglutide [80], eugenol [81], diosmin [82], amlexanox [83], L-carnitine [84], gypenoside LXXV [85], fermented black radish [86], zoledronic acid [87] ( Table 2) and many more. α-SMA expression in HSCs could also be lowered through overexpression of cytochrome P450 omega-hydroxylase 4a14 (CYP4A14) [88] or through knock-out of renalase in NASH mice fed a choline-deficient high-fat diet supplemented with 0.1% methionine [89]. ...
Background
Due to its extremely high prevalence and severity, non-alcoholic fatty liver disease (NALFD) is a serious health and economic concern worldwide. Developing effective methods of diagnosis and therapy demands a deeper understanding of its molecular basis. One of the strategies in such an endeavor is the analysis of alterations in the morphology of liver cells. Such alterations, widely reported in NAFLD patients and disease models, are related to the cytoskeleton. Therefore, the fate of the cytoskeleton components is useful to uncover the molecular basis of NAFLD, to further design innovative approaches for its diagnosis and therapy.
Main findings
Several cytoskeleton proteins are up-regulated in liver cells of NAFLD patients. Under pathological conditions, keratin 18 is released from hepatocytes and its detection in the blood emerges as a non-invasive diagnosis tool. α-smooth muscle actin is up-regulated in hepatic stellate cells and its down-regulation has been widely tested as a potential NALFD therapeutic approach. Other cytoskeleton proteins, such as vimentin, are also up-regulated.
Conclusions
NAFLD progression involves alterations in expression levels of proteins that build the liver cytoskeleton or associate with it. These findings provide a timely opportunity of developing novel approaches for NAFLD diagnosis and therapy.
