Antioxidation and Hepatoprotection of Selenium Mycelium Polysaccharides Against Alcoholic Liver Diseases from the Cultivated Morel Mushroom Morchella esculenta (Ascomycota).

The liver was regarded as the most important metabolic and detoxification organ in vivo, and Morchella esculenta had been reported as the admittedly rare edible fungus belonging to Ascomycetes contributing to the abundant bioactivities. The objective of this study aimed to confirm the potential antioxidant activities of selenium mycelium polysaccharides (Se-MIP) from M. esculenta against alcoholic liver diseases (ALD) in mice. The results indicated that a selenium concentration of 25 µg/mL exhibited potential in vitro antioxidant capacities of Se-MIP. The in vivo mice results demonstrated that Se-MIP showed potential anti-ALD effects by improving the antioxidant activities and alleviating the hepatic dysfunctions. The present conclusions suggested that Se-MIP could be used as a candidate on improving ALD and its complications for further clinical investigations.

A polysaccharide from Alhagi honey protects the intestinal barrier and regulates the Nrf2/HO-1-TLR4/MAPK signaling pathway to treat alcoholic liver disease in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: According to the theory of traditional Chinese medicine, the main factors related to alcoholic liver disease (ALD) are qi stagnation and blood stasis of the five viscera. Previously, we showed that the bioactive components of Alhagi honey have various pharmacological effects in treating liver diseases, but the influence of Alhagi honey on ALD (and its mechanism of action) is not known. AIM OF THE STUDY: To determine the efficacy of the main active component of Alhagi honey, the polysaccharide AHPN80, in ALD and to explore the potential mechanism of action. MATERIALS AND METHODS: AHPN80 was isolated from dried Alhagi honey and identified by transmission electron microscopy, Fourier-transform infrared spectroscopy, and gas chromatography. Venous blood, liver tissue, and colon tissue were collected in a mouse model of alcohol-induced acute liver injury. Histology, staining (Oil Red O, Alcian Blue-Periodic Acid Schiff) and measurement of reactive oxygen species (ROS) levels were used to detect histopathologic and lipid-accumulation changes in the liver and colon. Lipopolysaccharide (LPS) levels and the content of proinflammatory cytokines in serum were measured by enzyme-linked immunosorbent assays. Commercial kits were employed to detect biochemistry parameters in serum and the liver. A terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining kit was used to identify hepatocyte apoptosis. Expression of tight junction-associated proteins in colon tissues and nuclear factor erythroid 2-related factor 2/heme oxygenase-1/toll-like receptor-4/mitogen-activated protein kinase (Nrf2/HO-1/TLR4/MAPK) pathway-related proteins in liver tissues and HepG2 cells were analyzed by immunofluorescence or western blotting. RESULTS: In a mouse model of alcohol-induced acute liver injury, AHPN80 therapy: significantly improved liver parameters (cytochrome P450 2E1, alcohol dehydrogenase, aldehyde dehydrogenase, superoxide dismutase, malondialdehyde, glutathione peroxidase, catalase, total cholesterol, triglycerides, alanine transaminase, aspartate transaminase); reduced serum levels of LPS, interleukin (IL)-1ß, IL-6, and tumor necrosis faction-α; increased levels of IL-10 and interferon-gamma. AHPN80 reduced ALD-induced lipid accumulation and ROS production, improved alcohol-induced inflammatory damage to hepatocytes, and inhibited hepatocyte apoptosis. Immunofluorescence staining and western blotting suggested that AHPN80 might eliminate hepatic oxidative stress by activating the Nrf2/HO-1 signaling pathway, repair the intestinal barrier, inhibit the LPS/TLR4/MAPK signaling pathway, and reduce liver inflammation. CONCLUSIONS: AHPN80 may activate the Nrf2/HO-1 pathway to eliminate oxidative stress, protect the intestinal barrier, and regulate the TLR4/MAPK pathway to treat ALD in mice. AHPN80 could be a functional food and natural medicine to prevent ALD and its complications.

Gentiana Scabra Bge Extract (GSE) Protects Against Alcoholic Liver Disease by Regulating the TLR4/NF-κB Pathway in Mice.

BACKGROUND: Alcohol abuse leads to alcoholic liver disease (ALD), for which no effective treatment is yet known. Gentiana Scabra Bge is a traditional Chinese medicine; its extract has a significant liver protection effect, but its effects on the mechanism of improving alcohol-induced toxicity remain unclear. Therefore, this study used cell and mouse models to investigate how Gentiana Scabra Bge extract (GSE) might affect the TLT4/NF-κB inflammation pathway in ALD. METHODS: In mice, we induced the alcoholic liver injury model by applying alcohol and induced the inflammatory cell model by lipopolysaccharide (LPS)-induced macrophages. Using an enzyme-linked immunosorbent assay (ELISA) kit, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and interleukin 1ß (IL-1ß), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) levels were measured in liver tissue; we also performed histological analysis of liver tissue sections to assess the hepatoprotective effect of GSE on alcohol. Using real-time fluorescence quantification, we determined the expression of toll-like receptor 4 (TLR4) and nuclear factor κB (NF-κB) mRNA levels; we used Western blotting to detect the expression of TLR4/NF-κB signaling pathway-related proteins. RESULTS: We demonstrate that GSE decreased AST and ALT activity, ameliorated liver dysfunction, decreased cytokine levels, and reduced LPS-induced cellular inflammation. In addition, GSE protected mouse liver cells from the inflammatory response by reducing alcohol-induced liver pathological damage and downregulating genes and proteins such as nuclear factors. CONCLUSIONS: GSE can attenuate liver injury in mice through the TLR4/NF-κB pathway by inhibiting the activation of nuclear factors.

Protective Effects and Mechanism of Polysaccharides from Edible Medicinal Plants in Alcoholic Liver Injury: A Review.

Alcohol use accounts for a large variety of diseases, among which alcoholic liver injury (ALI) poses a serious threat to human health. In order to overcome the limitations of chemotherapeutic agents, some natural constituents, especially polysaccharides from edible medicinal plants (PEMPs), have been applied for the prevention and treatment of ALI. In this review, the protective effects of PEMPs on acute, subacute, subchronic, and chronic ALI are summarized. The pathogenesis of alcoholic liver injury is analyzed. The structure-activity relationship (SAR) and safety of PEMPs are discussed. In addition, the mechanism underlying the hepatoprotective activity of polysaccharides from edible medicinal plants is explored. PEMPs with hepatoprotective activities mainly belong to the families Orchidaceae, Solanaceae, and Liliaceae. The possible mechanisms of PEMPs include activating enzymes related to alcohol metabolism, attenuating damage from oxidative stress, regulating cytokines, inhibiting the apoptosis of hepatocytes, improving mitochondrial function, and regulating the gut microbiota. Strategies for further research into the practical application of PEMPs for ALI are proposed. Future studies on the mechanism of action of PEMPs will need to focus more on the utilization of multi-omics approaches, such as proteomics, epigenomics, and lipidomics.

Proteomics and network pharmacology of Ganshu Nuodan capsules in the prevention of alcoholic liver disease.

Introduction: Ganshu Nuodan is a liver-protecting dietary supplement composed of Ganoderma lucidum (G. lucidum) spore powder, Pueraria montana (Lour.) Merr. (P. montana), Salvia miltiorrhiza Bunge (S. miltiorrhiza) and Astragalus membranaceus (Fisch.) Bunge. (A. membranaceus). However, its pharmacodynamic material basis and mechanism of action remain unknown. Methods: A mouse model of acute alcohol liver disease (ALD) induced by intragastric administration of 50% alcohol was used to evaluate the hepatoprotective effect of Ganshu Nuodan. The chemical constituents of Ganshu Nuodan were comprehensively identified by UPLC-QTOF/MS, and then its pharmacodynamic material basis and potential mechanism of action were explored by proteomics and network pharmacology. Results: Ganshu Nuodan could ameliorate acute ALD, which is mainly manifested in the significant reduction of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum and malondialdehyde (MDA) content in liver and the remarkably increase of glutathione (GSH) content and superoxide dismutase (SOD) activity in liver. Totally 76 chemical constituents were identified from Ganshu Nuodan by UPLC-QTOF/MS, including 21 quinones, 18 flavonoids, 11 organic acids, 7 terpenoids, 5 ketones, 4 sterols, 3 coumarins and 7 others. Three key signaling pathways were identified via proteomics studies, namely Arachidonic acid metabolism, Retinol metabolism, and HIF-1 signaling pathway respectively. Combined with network pharmacology and molecular docking, six key targets were subsequently obtained, including Ephx2, Lta4h, Map2k1, Stat3, Mtor and Dgat1. Finally, these six key targets and their related components were verified by molecular docking, which could explain the material basis of the hepatoprotective effect of Ganshu Nuodan. Conclusion: Ganshu Nuodan can protect acute alcohol-induced liver injury in mice by inhibiting oxidative stress, lipid accumulation and apoptosis. Our study provides a scientific basis for the hepatoprotective effect of Ganshu Nuodan in acute ALD mice and supports its traditional application.

Total saponins from Panax japonicus attenuate acute alcoholic liver oxidative stress and hepatosteatosis by p62-related Nrf2 pathway and AMPK-ACC/PPARα axis in vivo and in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax japonicus (T. Nees) C.A. Mey. (PJ) has been used as a tonic traditional Chinese medicine (TCM) for years. Based on its meridian tropism in liver, spleen, and lung, PJ was popularly used to enhance the function of these organs. It is originally recorded with detoxicant effect on binge drink in Ben Cao Gang Mu Shi Yi, a persuasive Chinese materia medica. And binge dink has a close relationship with alcoholic liver disease (ALD). Hence, it's meaningful to investigate whether PJ exerts liver protection against binge drink toxicity. AIM OF THE STUDY: This investigation was carried out not only to emphasize the right recognition of total saponins from PJ (SPJ), but also to study on its sober-up effectiveness and defensive mechanism against acute alcoholic liver injury in vivo and in vitro. MATERIALS AND METHODS: SPJ constituents were verified by HPLC-UV analysis. In vivo, acute alcoholic liver oxidative stress and hepatosteatosis were established by continuous ethanol gavage to C57BL/6 mice for 3 days. SPJ was pre-administered for 7 days to investigate its protective efficacy. Loss of righting reflex (LORR) assay was employed to assess anti-inebriation effect of SPJ. Transaminases levels and hematoxylin and eosin (H&E) staining were measured to indicate the alcoholic liver injury. Antioxidant enzymes were measured to evaluate the oxidative stress degree in liver. Measurement of hepatic lipid accumulation was based on Oil Red O staining. Levels of inflammatory cytokines were evaluated by enzyme-linked immunosorbent assay (ELISA). In vitro, HepG2 cells were treated with ethanol for 24 h, and SPJ was pre-administered for 2 h. 2,7-dichlorofluorescein diacetate (DCFH-DA) was used as a probe to indicate reactive oxygen species (ROS) generation. Nrf2 activation was verified by the favor of specific inhibitor, ML385. The nuclear translocation of Nrf2 was indicated with immunofluorescence analysis. Proteins expressions of related pathways were determined by Western blotting. RESULTS: Oleanane-type saponins are the most abundant constituents of SPJ. In this acute model, SPJ released inebriation of mice in a dose dependent manner. It decreased levels of serum ALT and AST, and hepatic TG. Besides, SPJ inhibited CYP2E1 expression and reduced MDA level in liver, with upregulations of antioxidant enzymes GSH, SOD and CAT. p62-related Nrf2 pathway was activated by SPJ with downstream upregulations of GCLC and NQO1 in liver. AMPK-ACC/PPARα axis was upregulated by SPJ to alleviate hepatic lipidosis. Hepatic IL-6 and TNF-α levels were downregulated by SPJ, which indicated a regressive lipid peroxidation in liver. In HepG2 cells, SPJ reduced ethanol-exposed ROS generation. Activated p62-related Nrf2 pathway was verified to contribute to the alleviation of alcohol-induced oxidative stress in hepatic cells. CONCLUSION: This attenuation of hepatic oxidative stress and steatosis suggested the therapeutic value of SPJ for ALD.

Study of Xuanhuang Pill in protecting against alcohol liver disease using ultra-performance liquid chromatography/time-of-flight mass spectrometry and network pharmacology.

Introduction: Xuanhuang Pill (XHP) is a traditional Chinese medicine oral formula composed of 10 herbs. This study aims to verify the hepatoprotective activity of XHP and explain its possible mechanism. Methods: The hepatoprotective activity of XHP was evaluated by constructing a mouse model of alcoholic liver disease, and the mechanism of XHP was preliminarily explained by utilizing ultra-performance liquid chromatography/time-of-flight mass spectrometry (UPLC-QTOF/MS), proteomics and network pharmacology. Results: The current study demonstrated that treatment with XHP ameliorated acute alcohol-induced liver injury in mice by significantly reducing alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and triglycerides (TGs) and malondialdehyde (MDA) content. Remarkably, treatment also increased superoxide dismutase (SOD) activity and glutathione (GSH) content. UPLC-QTOF/MS, 199 compounds were identified as within the make-up of the XHP. Network pharmacology analysis showed that 103 targets regulated by 163 chemical components may play an important role in the protective liver effect mediated by XHP. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis suggest that the HIF-1, FoxO, PI3K-Akt, insulin, and thyroid hormone signaling pathways are key modulators of XHP's effects. Finally, eight key targets including Mapk1, Mapk3, Akt1, Map2k1, Pik3ca, Pik3cg, Raf1, and Prkca were verified by molecular docking and proteomics analysis, which provide insight into the hepatoprotective effect observed with XHP treatment. Conclusion: In summary, these results improved upon knowledge of the chemical composition and the potential mechanisms of hepatoprotective action of oral XHP treatment, providing foundational support for this formulation as a viable therapeutic option for alcoholic liver disease.

Alleviating Effect of Lacticaseibacillus rhamnosus 1.0320 Combined with Dihydromyricetin on Acute Alcohol Exposure-Induced Hepatic Impairment: Based on Short-Chain Fatty Acids and Adenosine 5'-Monophosphate-Activated Protein Kinase-Mediated Lipid Metabolism Signaling Pathway.

Excessive drinking has been listed by the World Health Organization as the fifth major risk factor; especially the liver, as the core organ of alcohol metabolism, is prone to organic lesions. Probiotics have received attention due to their bioactivity for liver protection. The beneficial effects of probiotics on hosts are related to their physiological functions. Therefore, based on the concept of second-generation synbiotes, this study explored the protective effects of four dietary polyphenols on the stress tolerance, hydrophobicity, adhesion, and digestive characteristics of L. rhamnosus 1.0320. L. rhamnosus 1.0320 had the best synergistic effect with dihydromyricetin (DMY). Therefore, this combination was selected as a synbiotic supplement to explore the protective effect on acute alcohol exposure-induced hepatic impairment. The results showed that L. rhamnosus 1.0320 combined with DMY restored the intestinal barrier by upregulating short-chain fatty acid levels and activated the adenosine 5'-monophosphate-activated protein kinase-mediated lipid metabolism pathway to inhibit oxidative stress, inflammation, and lipid accumulation in the liver. Furthermore, 109 CFU/mouse/d L. rhamnosus 1.0320 and 50 mg/kg/d DMY by gavage were identified as the optimal doses for protection against acute alcohol expose-induced hepatic impairment. This study provides new insights into alleviating acute alcoholic hepatic impairment by targeting intestinal metabolites through the gut-liver axis.

A review on the protective effect of active components in Antrodia camphorata against alcoholic liver injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Antrodia camphorata is a genus of wood-rot basidiomycete in the family Fomitopsidaceae. It is a valuable medicinal fungus in China that contains more than 78 kinds of active compounds. A. camphorata has good protection effects on the liver, especially on alcoholic liver injury (ALI). AIM: This paper summarizes the complex occurrence and development of alcoholic liver disease (ALD). In addition, the effect of ALD on the intestine through the gut-liver axis is summarized. The protective mechanism of A. camphorata on ALI is reviewed to reveal its therapeutic potential, offering insights into future research. MATERIALS AND METHODS: A comprehensive search in the literature was obtained from books and online databases such as Web of Science, Google Scholar, PubMed, Scopus, Science direct, ACS Publications and Baidu Scholar. RESULTS: The pathogenesis of ALD mainly includes oxidative stress injury, intestinal microflora imbalance, inflammatory mediator injury and nutritional imbalance. A. camphorata contains rich active components (e.g. polysaccharides, triterpenoids, maleic and succinic acid derivatives, amino acids, superoxide dismutase, vitamins, lignin and sterols). These components have good antioxidant, anti-inflammatory and intestinal protection activities. Therefore, A. camphorata has a wide application in the prevention and treatment of ALI. CONCLUSIONS: ALD develops from a mild disease to alcoholic hepatitis and cirrhosis, which is the main reason of global morbidity and mortality. At present, there is no effective drug for the treatment of ALD. A. camphorata, as a valuable medicinal fungus unique to Taiwan, has a great protective effect on the liver. It is expected to be an effective drug for ALI treatment. Although many studies have performed the protective effects of A. camphorata on ALI, its regulatory effects on the gut-liver axis of ALD patients need to be further explored.

Morinda citrifolia Extract Prevents Alcoholic Fatty Liver Disease by Improving Gut Health.

Alcoholic liver disease (ALD) is a major chronic liver disease. Chronic alcohol consumption induces dysbiosis, disruption of gut barrier function, oxidative stress, inflammation, and changes in lipid metabolism, thereby leading to ALD. In this study, we investigated whether the commercial Morinda citrifolia extract Nonitri can ameliorate ALD symptoms through the gut-liver axis. We used mice chronically administered EtOH and found a marked increase in serum endotoxin levels and biomarkers of liver pathology. Moreover, the EtOH-treated group showed significantly altered gut microbial composition particularly that of Alistipes, Bacteroides, and Muribaculum and disrupted gut barrier function. However, Nonitri improved serum parameters, restored the microbial proportions, and regulated levels of zonula occludens1, occludin, and claudin1. Furthermore, Nonitri suppressed inflammation by inhibiting endotoxin-triggered toll-like receptor 4-signaling pathway and fat deposition by reducing lipogenesis through activating AMP-activated protein kinase in the liver. Furthermore, Pearson's correlation analysis showed that gut microbiota and ALD-related markers were correlated, and Nonitri regulated these bacteria. Taken together, our results indicate that the hepatoprotective effect of Nonitri reduces endotoxin levels by improving gut health, and inhibits fat deposition by regulating lipid metabolism.

The important role of glycerophospholipid metabolism in the protective effects of polyphenol-enriched Tartary buckwheat extract against alcoholic liver disease.

Alcoholic liver disease (ALD) is a mounting public health problem with significant medical, economic and social burdens. Tartary buckwheat (F. tataricum (L.) Gaertn, bitter buckwheat) is a kind of healthy and nutritious food, which has been demonstrated to protect against ALD, but the underlying mechanism has not been fully studied. Herein, we aimed to elucidate the beneficial effects of Tartary buckwheat extract (mainly composed of polyphenols including rutin, quercetin, kaempferol and kaempferol-3-O-rutinoside) in terms of lipid metabolism with the aid of lipidomic analysis. In our study, we employed C57BL/6J mice and a Lieber-DeCarli alcohol liquid diet to construct an ALD model and found that Tartary buckwheat extract was able to prevent ALD-induced histopathological lesions, liver injury and abnormal plasma lipid levels. These beneficial effects might be attributed to the regulation of energy metabolism-related genes (SIRT1, LKB1 and AMPK), lipid synthesis-related genes (ACC, SREBP1c and HMGR) and lipid oxidation-related genes (PPARα, CPT1 and CPT2). In addition, lipidomic profiling and KEGG pathway analysis showed that glycerophospholipid metabolism contributed the most to elucidating the regulatory mechanism of Tartary buckwheat extract. In specific, chronic ethanol intake reduced the level of phosphatidylcholines (PC) and increased the level of phosphatidylethanolamines (PE) in the liver, resulting in a decrease in the PC/PE ratio, which could be all significantly restored by Tartary buckwheat extract intervention, indicating that the Tartary buckwheat extract might regulate PC/PE homeostasis to exert its lipid-lowering effect. Overall, we demonstrated that Tartary buckwheat extract could prevent ALD by modulating hepatic glycerophospholipid metabolism, providing the theoretical basis for its further exploitation as a medical plant or nutritional food.

Rumex hanus by. Extract Protects Against Chronic Alcohol-Induced Liver Injury in Mice.

Alcoholic liver disease (ALD) has become a global health problem. The hepatoprotective effects of bioactive ingredients extracted from Rumex hanus by. on chronic alcoholic liver injury was investigated for the first time. The extract from R. hanus by. (ERHB) was obtained by 70% ethanol extraction, and the endotoxin antagonism rate of ERHB was 88.94 ± 1.24% in vitro. The animal experiments demonstrated that ERHB promoted hepatic function by significantly enhancing the activities of alcohol dehydrogenase and acetaldehyde dehydrogenase, and by reducing the activities of cytochrome P450 proteins, alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase. Furthermore, ERHB improved alcohol-induced dyslipidemia by regulating lipid metabolism. In addition, ERHB ameliorated the alcohol-induced liver injury by inhibiting endotoxin-caused inflammation. Seven compounds with antagonistic activity on endotoxin were identified in ERHB. These results demonstrated that ERHB had protective effects on ALD and if the results can be confirmed in humans, it might be useful as a functional food supplement for ALD treatment.

Identification of a protective Bacteroides strain of alcoholic liver disease and its synergistic effect with pectin.

The depletion of Bacteroides in the gut is closely correlated with the progression of alcoholic liver disease (ALD). This study aimed to identify Bacteroides strains with protective effects against ALD and evaluate the synergistic effects of Bacteroides and pectin in this disease. Mice were fed Lieber-DeCarli alcohol diet to establish an experimental ALD model and pre-treated with 4 Bacteroides strains. The severity of the liver injury, hepatic steatosis, and inflammation was evaluated through histological and biochemical assays. We found that Bacteroides fragilis ATCC25285 had the best protective effects against ALD strains by alleviating both ethanol-induced liver injury and steatosis. B. fragilis ATCC25285 could counteract inflammatory reactions in ALD by producing short-chain fat acids (SCFAs) and enhancing the intestinal barrier. In the subsequent experiment, the synbiotic combination of B. fragilis ATCC25285 and pectin was evaluated and the underlying mechanisms were investigated by metabolomic and microbiome analyses. The combination elicited superior anti-ALD effects than the individual agents used alone. The synergistic effects of B. fragilis ATCC25285 and pectin were driven by modulating gut microbiota, improving tryptophan metabolism, and regulating intestinal immune function. Based on our findings, the combination of B. fragilis ATCC25285 and pectin can be considered a potential treatment for ALD. KEY POINTS: • B. fragilis ATCC25285 was identified as a protective Bacteroides strain against ALD. • The synbiotic combination of B. fragilis and pectin has better anti-ALD effects. • The synbiotic combination modulates gut microbiota and tryptophan metabolism.

Folic acid intervention changes liver Foxp3 methylation and ameliorates the damage caused by Th17/Treg imbalance after long-term alcohol exposure.

Folic acid, as a key source of methyl donor in DNA methylation, has been proved to play a beneficial role in inflammation modulation, which is usually impaired in alcoholic liver disease (ALD). However, the role of folic acid in alcoholic liver inflammation and injury remain elusive. In this study, we sought to uncover the potential protective mechanism by which folic acid ameliorates alcoholic liver injury. 100 male C57BL/6J mice were randomly divided into 5 groups: normal saline group, folic acid control group (5 mg per kg BW), ethanol model group (56% v/v, 10 mL per kg BW), folic acid + ethanol group, and 5-Aza + ethanol group (0.1 mL per 20 g BW). Liquor (10 mL per kg BW) was orally administered 1 h after the folic acid treatment for 10 consecutive weeks. The results showed that folic acid-inhibited ethanol-induced serum TG, TC, and LDL elevation attenuated hepatic fat accumulation and maintained ALT at a normal level. 10 weeks of ethanol administration simultaneously upregulated the hepatic proportion of Th17 and Treg cells to different extents and broke the homeostasis of liver immunization. Folic acid limited ethanol-induced inflammatory injury by increasing the frequency of hepatic Treg cells. Importantly, this effect may be caused by decreased DNMT3a, which in turn downregulates the methylated levels of CPG2 and CPG3 in the Foxp3 promoter region, changing the abundance of Foxp3 expression and improving the Th17/Treg imbalance. In summary, our findings demonstrated that folic acid supplementation may relieve ethanol-induced Th17/Treg disbalance through altering Foxp3 promoter methylation patterns, suggesting that folic acid may be a feasible preventive strategy for ALD.

Stearic acid prevent alcohol-induced liver damage by regulating the gut microbiota.

The pathological characteristics of alcohol-associated liver damage (ALD) mainly include liver lipid accumulation, which subsequently leads to alcohol-associated steatohepatitis, fibrosis and cirrhosis. Dietary factors such as alcohol and fat may contribute to the development of ALD. A chronic alcohol-fed mouse model was used to investigate the effect of fatty acids in Jinhua ham on ALD. The fatty acids in Jinhua ham could prevent the occurrence of ALD from chronic alcohol consumption. In addition, the fatty acids in Jinhua ham with liver protective activity were long-chain saturated fatty acids (LCSFAs), including palmitic acid and stearic acid. In contrast, long-chain polyunsaturated fatty acids aggravated the pathogenesis of ALD. Furthermore, the mechanism underlying the prevention of ALD by fatty acids in Jinhua ham was ascribed to increasing relative abundances of Akkermansia muciniphila and Lactobacillus in the gut, which were beneficial to regulating intestinal homeostasis, ameliorating intestinal barrier dysfunction and reducing alcohol-associated hepatitis and oxidative stress damage. This study demonstrated that dietary supplementation with saturated fatty acids could prevent or mitigate ALD by regulating the gut microbiota (GM) and improving the intestinal barrier, while provided a more affordable dietary intervention strategy for the prevention of ALD.

Hepatoprotective effects of sea cucumber ether-phospholipids against alcohol-induced lipid metabolic dysregulation and oxidative stress in mice.

Sea cucumber is widely consumed as food and folk medicine in Asia, and its phospholipids are rich sources of dietary eicosapentaenoic acid enriched ether-phospholipids (ether-PLs). Emerging evidence suggests that ether-PLs are associated with neurodegenerative disease and steatohepatitis. However, the function and mechanism of ether-PLs in alcoholic liver disease (ALD) are not well understood. To this end, the present study sought to investigate the hepatoprotective effects of sea cucumber ether-PLs, including plasmenyl phosphatidylethanolamine (PlsEtn) and plasmanyl phosphatidylcholine (PlsCho), and their underlying mechanisms. Our results showed that compared with EtOH-induced mice, ether-PL treated mice showed improved liver histology, decreased serum ALT and AST levels, and reduced alcohol metabolic enzyme (ALDH2 and ADH1) expressions. Mechanistic studies showed that ether-PLs attenuated "first-hit" hepatic steatosis and lipid accumulation evoked by alcohol administration. Moreover, PlsEtn more effectively restored endogenous plasmalogen levels than PlsCho, thereby enhancing hepatic antioxidation against "second-hit" reactive oxygen species (ROS) due to the damaged mitochondria and abnormal ethanol metabolism. Taken together, sea cucumber ether-PLs show great potential to become a natural functional food against chronic alcohol-induced hepatic steatosis and lipid metabolic dysregulation.

Barriers to the management of alcohol use disorder and alcohol-associated liver disease: strategies to implement integrated care models.

Despite its increased recognition as a major public health issue, alcohol use disorder is mostly underdiagnosed and undertreated. The undertreatment and underdiagnosis of alcohol use disorder is most concerning in the management of patients with alcohol-associated liver disease, which is one of the main medical consequences of chronic and excessive alcohol use. Dual pathology (alcohol use disorder and alcohol-associated liver disease) requires multidisciplinary care involving hepatologists and addiction specialists. Such integrated care models are widely accepted as optimal care for treating comorbid medical and mental health conditions. However, the implementation of such models in clinical practice is challenging and often represents the exception, rather than the rule, in managing patients with alcohol use disorder and alcohol-associated liver disease. Barriers at the patient, clinician, and system levels are encountered in treating patients with alcohol use disorder and alcohol-associated liver disease. In this Viewpoint, we synthesise the emerging literature on the potential barriers encountered in caring for patients with alcohol-associated liver disease and alcohol use disorder and focus on how integrated models of care could overcome these barriers. We provide our perspective on why these barriers exist and propose strategies to overcome them.

Camel milk ameliorates inflammatory mechanisms in an alcohol-induced liver injury mouse model.

Camel milk (CM) is considered to protect the liver in the practice of traditional medicine in nomadic areas. The purpose of the present study was to investigate the effects of CM on the hepatic biochemical and multiple omics alterations induced by chronic alcoholic liver disease (ALD). An intragastric gavage mice Lieber DeCarli + Gao binge model (NIAAA model) was employed to investigate the inflammatory mechanism of camel milk on the liver tissue of mice. A gut microbiota of the feces of mice and transcriptomic and proteomic analyses of the liver of mice were performed. Analysis of serum and liver biochemical indexes revealed that camel milk not only prevents alcohol-induced colonic dysfunction and lipid accumulation, but also regulates oxidative stress and inflammatory cytokine production to protect against chronic ALD in mouse. The gut microbial community of mice treated with camel milk was more similar to the untreated control group than to the model group, indicating that the intake of camel milk pre- and post-alcohol gavage effectively prevents and alleviates the intestinal microbial disorder caused by chronic alcoholism in mice. Furthermore, the results of the transcriptomic and proteomic analyses of the liver tissue showed that camel milk can improve alcoholic liver injury in mice by regulating inflammatory factors and immune system disruptions. This study provides insights into the molecular mechanism by which camel milk can be developed as a potential functional food with no side effects and against liver injury.

Trehalose activates hepatic transcription factor EB (TFEB) but fails to ameliorate alcohol-impaired TFEB and liver injury in mice.

BACKGROUND: Recent evidence demonstrates that alcohol activates the mechanistic target of rapamycin (mTOR) and impairs hepatic transcription factor EB (TFEB) reducing autophagy and contributing to alcohol-induced liver injury. Trehalose, a disaccharide, activates TFEB and protects against diet-induced nonalcoholic fatty liver disease in mice. The aim of the present study was to investigate whether trehalose would reverse the impairment of TFEB induced by alcohol and protect against alcohol-induced liver injury. METHODS: Male C57BL/6J mice were subjected to chronic-plus-binge (Gao-binge) alcohol feeding with and without trehalose supplementation. Some mice were also administrered Alda-1, an aldehyde dehydrogenase 2 agonist. RESULTS: We found that Alda-1 did not affect Gao-binge alcohol-induced mTOR activation and impaired TFEB in mouse livers. Trehalose increased TFEB nuclear translocation, elevated levels of LC3-II and lysosomal proteins in mouse livers and cultured AML12 cells, confirming the activation of TFEB by trehalose. However, trehalose did not improve the impairment in TFEB induced by Gao-binge alcohol. Both Alda-1 and trehalose failed to protect against Gao-binge alcohol-induced steatosis and liver injury, based on the serum levels of alanine aminotransferase (ALT), histological analysis, and levels of hepatic triglyceride. Interestingly, trehalose increased expression of pro-inflammatory genes in mouse macrophage RAW264.7 cells and slightly increased the infiltration of hepatic neutrophils and inflammatory cytokine gene expression in Gao-binge alcohol-fed mice livers. CONCLUSIONS: Trehalose fails to improve the impaired TFEB induced by Gao-binge alcohol and does not protect against alcohol-induced liver injury.