Cysteine triggered cascade reaction forming coumarin: Visualization of cysteine fluctuation in alcoholic liver disease by a NIR fluorescent probe.

Alcoholic liver disease (ALD) is a chronic toxic liver injury caused by long-term heavy drinking. Due to the increasing incidence, ALD is becoming one of important medical tasks. Many studies have shown that the main mechanism of liver damage caused by large amounts of alcohol may be related to antioxidant stress. As an important antioxidant, cysteine (Cys) is involved in maintaining the normal redox balance and detoxifying metabolic function of the liver, which may be closely related to the pathogenesis of ALD. Therefore, it is necessary to develop a simple non-invasive method for rapid monitoring of Cys in liver. Thus, a near-infrared (NIR) fluorescent probe DCI-Ac-Cys which undergoes Cys triggered cascade reaction to form coumarin fluorophore is developed. Using the DCI-Ac-Cys, decreased Cys was observed in the liver of ALD mice. Importantly, different levels of Cys were monitored in the livers of ALD mice taking silybin and curcumin with the antioxidant effects, indicating the excellent therapeutic effect on ALD. This study provides the important references for the accurate diagnosis of ALD and the pharmacodynamic evaluation of silybin and curcumin in the treatment of ALD, and support new ideas for the pathogenesis of ALD.

Causal relationships between the gut microbiota, inflammatory cytokines, and alcoholic liver disease: a Mendelian randomization analysis.

Objective: Previous studies have suggested a potential association between gut microbiota and the development of alcohol-related liver disease (ALD). However, the causal relationship between gut microbiota and ALD, as well as the role of inflammatory cytokines as mediators, remains unclear. This study aims to explore the causal relationship between gut microbiota and ALD using Mendelian randomization (MR) methods, and to analyze the mediating role of inflammatory cytokines. Methods: Gut microbiota, 91 inflammatory cytokines, and ALD were identified from summary data of large-scale genome-wide association studies (GWAS). MR was employed to investigate the causal relationship between gut microbiota, cytokines, and ALD, with the inverse variance-weighted method (IVW) as the primary statistical approach. Additionally, we examined whether inflammatory cytokines act as mediating factors in the pathway from gut microbiota to ALD. Results: The IVW results confirmed two positive and one negative causal effect between genetic liability in the gut microbiota and ALD. Escherichia coli (P= 0.003) was identified as a protective factor for ALD, while Roseburia hominis (P=0.023) and Family Porphyromonadaceae (P=0.038) were identified as risk factors for ALD. Furthermore, there were five positive and two negative causal effects between inflammatory cytokines and ALD, with CUB domain-containing protein 1 (P= 0.035), Macrophage colony-stimulating factor 1 (P=0.047), Cystatin D (P = 0.035), Fractalkine (P=0.000000038), Monocyte chemoattractant protein-1 (P=0.004) positively associated with ALD onset. CD40L receptor (P= 0.044) and Leukemia inhibitory factor (P = 0.024) exhibited protective effects against ALD. Mediation MR analysis indicated that CUB domain-containing protein 1 (mediation proportion=1.6%, P=0.035), Cystatin D (mediation proportion=1.5%, P=0.012), and Monocyte chemoattractant protein-1 (mediation proportion=3.3%, P=0.005) mediated the causal effect of Roseburia hominis on ALD. Conclusion: In conclusion, our study supports a causal relationship among gut microbiota, inflammatory cytokines and ALD, with inflammatory cytokines potentially acting as mediating factors in the pathway from gut microbiota to ALD.

Elafibranor: A promising treatment for alcoholic liver disease, metabolic-associated fatty liver disease, and cholestatic liver disease.

Liver diseases pose a significant threat to human health. Although effective therapeutic agents exist for some liver diseases, there remains a critical need for advancements in research to address the gaps in treatment options and improve patient outcomes. This article reviews the assessment of Elafibranor's effects on liver fibrosis and intestinal barrier function in a mouse model of alcoholic liver disease (ALD), as reported by Koizumi et al in the World Journal of Gastroenterology. We summarize the impact and mechanisms of Elafibranor on ALD, metabolic-associated fatty liver disease, and cholestatic liver disease based on current research. We also explore its potential as a dual agonist of PPARα/δ, which is undergoing Phase III clinical trials for metabolic-associated steatohepatitis. Our goal is to stimulate further investigation into Elafibranor's use for preventing and treating these liver diseases and to provide insights for its clinical application.

Lactobacillus helveticus attenuates alcoholic liver injury via regulation of gut microecology in mice.

Previous reports have demonstrated that alcohol consumption significantly reduces the abundance of Lactobacillus in the gut. In this study, we selected five species of the genus Lactobacillus, commonly found in fermented foods, and acknowledged them as safe, edible, and effective in preventing or treating certain diseases, to evaluate their effects on alcoholic liver disease (ALD). By comparing the liver damage indices in each group, we found that the type strain of Lactobacillus helveticus (LH, ATCC 15009) had the most marked alleviating effect on ALD-induced liver injury. Furthermore, experiments combining microbiomics and metabolomics were conducted to explore the mechanisms underlying the hepatoprotective effects of LH. Finally, we discovered that LH mitigated ethanol-induced liver steatosis and inflammation in ALD mice by altering the structure and function of the gut microbiome, increasing intestinal levels of short-chain fatty acids (SCFAs), and enhancing gut barrier integrity. These findings suggest a potential strategy for the clinical management of patients with ALD.

Selenium Attenuates Ethanol-induced Hepatocellular Injury by Regulating Ferroptosis and Apoptosis.

Ferroptosis is a newly identified type of cell death which is strongly linked to the development of several diseases. Whereas, the role of ferroptosis in the improvement of ethanol-induced hepatocytes injury by selenium has not been confirmed. In this study, an in vitro cell damage model was established using half inhibition concentration of ethanol to induce NCTC clone 1469. Cell activity, lipid peroxidation, apoptosis and the expression of markers related to ferroptosis pathway was determined. A mouse model of alcoholic liver disease (ALD) was constructed and the effectiveness of selenium and ferrostatin-1 in treating ALD in vivo was assessed by serum liver function tests, tissue staining and immunohistochemistry for ferroptosis related proteins. Pretreatment with selenomethionine and ebselen significantly improved ethanol-induced reduction in hepatocyte viability, elevated GSH levels and SOD enzyme activity, reduced MDA and iron content, while improving ethanol-induced changes in apoptosis levels and ferroptosis markers GPX4, SLC7A11, and ACSL4, with the effect of Selenomethionine being more significant. In vivo results also indicated that intervention with selenium or ferroptosis inhibitors significantly improved ethanol-induced liver tissue damage, significantly reduced serum ALT and AST levels, upregulated GPX4 and SLC7A11, but reduced ACSL4 protein levels in liver tissue. The process of ethanol damage to hepatocytes is regulated by the ferroptosis pathway. Selenium may exert a beneficial role in ethanol-induced hepatocyte injury by antagonizing oxidative stress and regulating apoptosis and ferroptosis pathways.

Oral supplementation of choline attenuates the development of alcohol-related liver disease (ALD).

BACKGROUND: Chronic alcohol intake is associated with alterations of choline metabolism in various tissues. Here, we assessed if an oral choline supplementation attenuated the development of alcohol-related liver disease (ALD) in mice. METHODS: Female C57BL/6 J mice (n = 8/group) were either pair-fed a liquid control diet, or a Lieber DeCarli liquid diet (5% ethanol) ± 2.7 g choline/kg diet for 29 days. Liver damage, markers of intestinal permeability and intestinal microbiota composition were determined. Moreover, the effects of choline on ethanol-induced intestinal permeability were assessed in an ex vivo model. RESULTS: ALD development as determined by liver histology and assessing markers of inflammation (e.g., nitric oxide, interleukin 6 and 4-hydroxynonenal protein adducts) was attenuated by the supplementation of choline. Intestinal permeability in small intestine being significantly higher in ethanol-fed mice was at the level of controls in ethanol-fed mice receiving choline. In contrast, no effects of the choline supplementation were found on intestinal microbiota composition. Choline also significantly attenuated the ethanol-induced intestinal barrier dysfunction in small intestinal tissue ex vivo, an effect almost entirely abolished by the choline oxidase inhibitor dimbunol. CONCLUSION: Our results suggest that an oral choline supplementation attenuates the development of ALD in mice and is related to a protection from intestinal barrier dysfunction.

Peroxisome proliferator-activated receptor agonists: A new hope towards the management of alcoholic liver disease.

In this editorial, we examine a paper by Koizumi et al, on the role of peroxisome proliferator-activated receptor (PPAR) agonists in alcoholic liver disease (ALD). The study determined whether elafibranor protected the intestinal barrier and reduced liver fibrosis in a mouse model of ALD. The study also underlines the role of PPARs in intestinal barrier function and lipid homeostasis, which are both affected by ALD. Effective therapies are necessary for ALD because it is a critical health issue that affects people worldwide. This editorial analyzes the possibility of PPAR agonists as treatments for ALD. As key factors of inflammation and metabolism, PPARs offer multiple methods for managing the complex etiology of ALD. We assess the abilities of PPARα, PPARγ, and PPARß/δ agonists to prevent steatosis, inflammation, and fibrosis due to liver diseases. Recent research carried out in preclinical and clinical settings has shown that PPAR agonists can reduce the severity of liver disease. This editorial discusses the data analyzed and the obstacles, advantages, and mechanisms of action of PPAR agonists for ALD. Further research is needed to understand the efficacy, safety, and mechanisms of PPAR agonists for treating ALD.

Mitochondrial quality control in alcohol-associated liver disease.

Excessive alcohol consumption is a leading cause of alcohol-associated liver disease (ALD), a significant global health concern with limited therapeutic options. Understanding the key factors contributing to ALD pathogenesis is crucial for identifying potential therapeutic targets. Central to ALD pathogenesis is the intricate interplay between alcohol metabolism and cellular processes, particularly involving mitochondria. Mitochondria are essential organelles in the liver, critical for energy production and metabolic functions. However, they are particularly vulnerable to alcohol-induced damage due to their involvement in alcohol metabolism. Alcohol disrupts mitochondrial function, impairing ATP production and triggering oxidative stress, which leads to cellular damage and inflammation. Mitochondrial quality control mechanisms, including biogenesis, dynamics, and mitophagy, are crucial for maintaining optimal mitochondrial function. Chronic alcohol consumption disrupts mitochondrial quality control checkpoints, leading to mitochondrial dysfunction that impairs fatty acid oxidation and contributes to hepatic steatosis in ALD. Moreover, alcohol promotes the accumulation of damaged mitochondria and the release of proinflammatory components, exacerbating liver damage and inflammation. Preserving mitochondrial health presents a promising therapeutic approach to mitigate ALD progression. In this review, we provide a comprehensive overview of the effects of alcohol on mitochondrial function and quality control mechanisms, highlighting their role in ALD pathogenesis. Understanding these mechanisms may pave the way for the development of novel therapeutic interventions for ALD.

AKR7A5 knockout promote acute liver injury by inducing inflammatory response, oxidative stress and apoptosis in mice.

Alcohol liver disease has become a worldwide critical health problem. The ingested alcohol could be converted into acetaldehyde or combined with free fatty acids to induce the endoplasmic reticulum oxidative stress in the liver. Coincidentally, AKR7A5 has both aldehyde detoxification and antioxidant effects. Therefore, we discuss the possible role and mechanism of AKR7A5 in the acute alcohol injury of mice liver. There were four experiment groups, the C57BL/6 mice of wild-type mice (WT) or AKR7A5-/- mice (KO) were intragastrically administrated with saline or 50% ethanol at 14 mL/kg, respectively. Compared to the WT + alcohol group, abnormal liver function, disordered hepatic cord, severe congestion in the hepatic sinus and the space of the hepatic cord, occurrence of oxidative stress, DNA damage and different expressions of apoptosis-related proteins were detected in the KO + alcohol group. Meanwhile, the biological process enrichment analysis showed that the down-regulated proteins were related to the metabolism of fatty acid, the up-regulated proteins positive regulation of reactive oxygen species metabolic process, negative regulation of coagulation and haemostasis. In conclusion, single ethanol binge combined with the absence of AKR7A5 caused more severe inflammatory response, oxidative stress, apoptosis of endogenous pathways, abnormal lipids metabolism and disordered coagulation in mice liver.

Dual peroxisome proliferator-activated receptor α/δ agonists: Hope for the treatment of alcohol-associated liver disease?

In this letter, we review the article "Effects of elafibranor on liver fibrosis and gut barrier function in a mouse model of alcohol-associated liver disease". We focus specifically on the detrimental effects of alcohol-associated liver disease (ALD) on human health. Given its insidious onset and increasing incidence, increasing awareness of ALD can contribute to reducing the prevalence of liver diseases. ALD comprises a spectrum of several different disorders, including liver steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. The pathogenesis of ALD is exceedingly complex. Previous studies have shown that peroxisome proliferator-activated receptors (PPARs) regulate lipid metabolism, glucose homeostasis and inflammatory responses within the organism. Additionally, their dysfunction is a major contributor to the progression of ALD. Elafibranor is an oral, dual PPARα and δ agonist. The effectiveness of elafibranor in the treatment of ALD remains unclear. In this letter, we emphasize the harm of ALD and the burden it places on society. Furthermore, we summarize the clinical management of all stages of ALD and present new insights into its pathogenesis and potential therapeutic targets. Additionally, we discuss the mechanisms of action of PPARα and δ agonists, the significance of their antifibrotic effects on ALD and future research directions.

Pueraria Extract Ameliorates Alcoholic Liver Disease via the Liver-Gut-Brain Axis: Focus on Restoring the Intestinal Barrier and Inhibiting Alcohol Metabolism.

Alcoholic liver disease (ALD) is one of the causes of hepatocellular carcinoma, accompanied by intestinal leakage and microbial changes. Pueraria has protective effects on liver injury. The aim of this study was to investigate the mechanism of pueraria in the treatment of ALD. UPLC-Q/TOF-MS was used to analyze the composition of the pueraria extract (PUE). Acute and chronic ALD models were established to evaluate the antialcoholic and hepatoprotective effects of PUE. As a result, PUE treatment reduced the serum levels of ALT, AST, TC, and TG and inflammatory factors and alleviated liver inflammation and drunk state. PUE decreased the gene expression of ADH1 and the serum level of acetaldehyde (ACH) to inhibit the generation of ACH from ethanol metabolism, increased the gene level of ALDH2 to accelerate the decomposition of ACH, and thereby alleviated liver inflammation and intestinal barrier damage. Meanwhile, 16 S rDNA revealed that PUE altered the microbiota composition, reduced the amount of Proteobacteria and Desulfobacterota, and thus inhibited the generation of lipopolysaccharide and its downstream-like TLR4/MyD88/NF-κB pathway. PUE also increased the abundance of Bacteroides, Ruminococcus, and Prevotella and producted short-chain fatty acids to protect the intestinal wall. Treatment with fecal microbiota transplantation further confirmed that PUE gut microbiota dependently alleviated ALD. Therefore, PUE regulated gut microbiota and inhibited ethanol metabolism to alleviate ALD through the liver-gut-brain axis. It has good prospects in the future.

Multiomics Studies on Metabolism Changes in Alcohol-Associated Liver Disease.

Metabolic dysfunction in the liver represents a predominant feature in the early stages of alcohol-associated liver disease (ALD). However, the mechanisms underlying this are only partially understood. To investigate the metabolic characteristics of the liver in ALD, we did a relative quantification of polar metabolites and lipids in the liver of mice with experimental ALD using untargeted metabolomics and untargeted lipidomics. A total of 99 polar metabolites had significant abundance alterations in the livers of alcohol-fed mice. Pathway analysis revealed that amino acid metabolism was the most affected by alcohol in the mouse liver. Metabolites involved in glycolysis and the TCA cycle were decreased, while glycerol 3-phosphate (G3P) and long-chain fatty acids were increased. Relative quantification of lipids unveiled an upregulation of multiple lipid classes, suggesting that alcohol consumption drives metabolism toward lipid synthesis. Results from enzyme expression and activity detection indicated that the decreased activity of mitochondrial glycerol 3-phosphate dehydrogenase contributed to the disordered metabolism.

Rice Protein Peptides Alleviate Alcoholic Liver Disease via the PPARγ Signaling Pathway: Through Liver Metabolomics and Gut Microbiota Analysis.

Alcoholic liver disease (ALD) is the predominant type of liver disease worldwide, resulting in significant mortality and a high disease burden. ALD damages multiple organs, including the liver, gut, and brain, causing inflammation, oxidative stress, and fat deposition. In this study, we investigated the effects of rice protein peptides (RPP) on ALD in mice with a primary focus on the gut microbiota and liver metabolites. The results showed that administration of RPP significantly alleviated the symptoms of ALD in mice including adiposity, oxidative stress, and inflammation. The KEGG pathway shows that RPP downregulates the liver metabolite of capric acid and the metabolism of fatty acid biosynthesis compared with the MOD group. Mechanistically, RPP downregulated the PPARγ signaling pathway and suppressed the expression of fatty acid biosynthesis genes (FASN, ACC1, ACSL1, and ACSL3). Furthermore, two active peptides (YLPTKQ and PKLPR) with potential therapeutic functions for ALD were screened by Caco-2 cell modeling and molecular docking techniques. In addition, RPP treatment alleviates gut microbiota dysbiosis by reversing the F/B ratio, increasing the relative abundance of Alloprevotella and Alistipes, and upregulating the level of short-chain fatty acids. In conclusion, RPP alleviates ALD steatosis through the PPARγ signaling pathway by YLPTKQ and PKLPR and regulates gut microbiota.

Enteromorpha prolifera Polysaccharide Alleviates Acute Alcoholic Liver Injury in C57 BL/6 Mice through the Gut-Liver Axis and NF-κB Pathway.

Enteromorpha prolifera polysaccharide (EP2) protection against acute alcoholic liver injury (AALI) in mice was investigated. By integration of physiological indicators, gut microbiota, and short-chain fatty acids (SCFAs), the mechanism of EP2 in alleviating AALI was disclosed. The results showed that EP2 significantly ameliorated alcohol-induced abnormal transaminase activities, liver and intestinal systemic inflammation, and intestinal environmental disorders. EP2 significantly reduces liver and serum LPS contents by 1.69-fold and 1.54-fold. Furthermore, inhibition of the NF-κB signaling pathway by EP2 reduced the production of proinflammatory cytokines such as TNF-α (1.83-fold), IL-6 (11.09-fold), and IL-1ß (1.99-fold). EP2 restored SCFAs to normal levels by upregulating the abundance of beneficial bacteria (Colidextribacter, Ruminococcus, unclassified_Lachnospiraceae, and Akkermansia). The alleviation of AALI by EP2 occurs through protection of the intestinal mucosal barrier and reduction of LPS permeating in serum. The decrease in LPS inactivates the NF-κB signaling pathway and prevents inflammation. In short, EP2 regulates the gut-liver axis and inflammation, alleviating effects in AALI mice.

A Butyrate-Yielding Dietary Supplement Prevents Acute Alcoholic Liver Injury by Modulating Nrf2-Mediated Hepatic Oxidative Stress and Gut Microbiota.

Alcoholic liver disease (ALD) is a globally prevalent form of liver disease for which there is no effective treatment. Recent studies have found that a significant decrease in butyrate was closely associated with ALD development. Given the low compliance and delivery efficiency associated with oral-route butyrate administration, a highly effective butyrate-yielding dietary supplement, butyrylated high-amylose maize starch (HAMSB), is a good alternative approach. Here, we synthesized HAMSB, evaluated the effect of HAMSB on acute ALD in mice, compared its effect with that of oral administration of butyrate, and further studied the potential mechanism of action. The results showed HAMSB alleviated acute ALD in mice, as evidenced by the inhibition of hepatic-function impairment and the improvement in liver steatosis and lipid metabolism; in these respects, HAMSB supplementation was superior to oral sodium butyrate administration. These improvements can be attributed to the reduction of oxidative stress though the regulation of Nrf2-mediated antioxidant signaling in the liver and the improvement in the composition and function of microbiota in the intestine. In conclusion, HAMSB is a safe and effective dietary supplement for preventing acute ALD that could be useful as a disease-modifying functional food or candidate medicine.

Ursolic Acid Ameliorates Alcoholic Liver Injury through Attenuating Oxidative Stress-Mediated Ferroptosis and Modulating Gut Microbiota.

Ursolic acid (UA), a triterpenoid found in plants, has many health benefits for liver function. However, understanding how UA intervenes in alcohol-induced ferroptosis remains unclear because of the lack of research. This study explored the protective effects of UA on alcohol-induced liver injury and further elucidated its mechanism of action. Using a mouse model, acute liver injury was induced via high-dose alcohol gavage, and UA's protective effects were assessed by analyzing serum and liver indicators. The results indicated that UA has a significant protective effect against alcohol-induced liver injury in mice. UA significantly decreased serum ALT, AST, TC, and TG levels. Histopathological examination revealed that UA significantly ameliorated liver damage. UA increased ADH, ALDH, and CYP2E1 enzyme expression levels and alleviated alcohol-induced oxidative damage by regulating alcohol metabolism. Moreover, UA increased SOD and GSH-Px levels and lowered the MDA levels in the liver. Furthermore, UA regulated ACC expression by activating the LKB1/AMPK pathway, thereby inhibiting lipid synthesis and peroxidation. UA also upregulated the expression of GPX4 and SLC7A11 in the liver and exerted hepatoprotective effects by inhibiting alcohol-induced ferroptosis. Additionally, 16S rRNA amplicon sequencing showed that excessive alcohol consumption significantly affected the composition of the mouse gut microbiota, with UA intervention proving to be beneficial for improving gut microbiota imbalance. We also validated the protective effects of UA on alcohol-treated HepG2 cells at the cellular level. In summary, these results revealed that UA can alleviate alcoholic liver injury by inhibiting oxidative stress-mediated ferroptosis and regulating gut microbiota. These findings suggest that UA may serve as a functional component in the prevention of alcoholic liver disease.

Near-Infrared Fluorescent Probe Reveals Elevated Mitochondrial Viscosity during Acute Alcoholic Liver Injury.

Acute alcoholic liver injury (AALI) has become an important cause of liver disease worldwide, and there is an urgent need to develop noninvasive and sensitive methods to detect and evaluate AALI. We report herein three novel but readily available mitochondrial targeting fluorescence probes (ICR, ICJ, and ICQ) for AALI detection. These probes contain different electron-donating groups, among which ICQ exhibits NIR fluorescence (740 nm), a large Stokes shift (110 nm), and a sensitive response to viscosity (73-fold enhancement in fluorescence from water to glycerol), making it suitable for in vivo imaging. ICQ also exhibits an excellent ability to image mitochondrial viscosity changes in cells. More importantly, ICQ can target the liver selectively and image the viscosity changes in the liver noninvasively. Through establishing an AALI mouse model, ICQ was successfully applied to the in situ imaging changes in liver viscosity during the AALI process. The results showed a significant increase in liver viscosity in AALI mice, indicating that viscosity can serve as a marker for AALI, and ICQ is a promising noninvasive and sensitive tool for detecting and evaluating AALI.

Nobiletin protects against alcohol-induced mitochondrial dysfunction and liver injury by regulating the hepatic NRF1-TFAM signaling pathway.

OBJECTIVES: Alcohol and its metabolites, such as acetaldehyde, induced hepatic mitochondrial dysfunction play a pathological role in the development of alcohol-related liver disease (ALD). METHODS: In this study, we investigated the potential of nobiletin (NOB), a polymethoxylated flavone, to counter alcohol-induced mitochondrial dysfunction and liver injury. RESULTS: Our findings demonstrate that NOB administration markedly attenuated alcohol-induced hepatic steatosis, endoplasmic reticulum stress, inflammation, and tissue damage in mice. NOB reversed hepatic mitochondrial dysfunction and oxidative stress in both alcohol-fed mice and acetaldehyde-treated hepatocytes. Mechanistically, NOB restored the reduction of hepatic mitochondrial transcription factor A (TFAM) at both mRNA and protein levels. Notably, the protective effects of NOB against acetaldehyde-induced mitochondrial dysfunction and cell death were abolished in hepatocytes lacking Tfam. Furthermore, NOB administration reinstated the levels of hepatocellular NRF1, a key transcriptional regulator of TFAM, which were decreased by alcohol and acetaldehyde exposure. Consistent with these findings, hepatocyte-specific overexpression of Nrf1 protected against alcohol-induced hepatic Tfam reduction, mitochondrial dysfunction, oxidative stress, and liver injury. CONCLUSIONS: Our study elucidates the involvement of the NRF1-TFAM signaling pathway in the protective mechanism of NOB against chronic-plus-binge alcohol consumption-induced mitochondrial dysfunction and liver injury, suggesting NOB supplementation as a potential therapeutic strategy for ALD.

Therapeutic Potential of Foodborne Indole Derived from Chinese Stinky Tofu in Reducing Intestinal Inflammation and Enhancing Barrier Function to Mitigate Alcoholic Liver Injury.

Indole, a compound in Chinese stinky tofu (ST), acts as a ligand for the aryl hydrocarbon receptor (AHR). Despite extensive research on prebiotic compounds, indole's specific role in ST remains unexplored. This study used an ethanol gavage method to create an ALD (alcoholic liver disease) mouse model and investigate dietary indole's effects on the intestinal barrier. Our findings indicate that after 6 weeks of being fed ST, the indole present (2 mg/day) robustly activated the intestinal AHR, upregulating its target gene, CYP1A1 (cytochrome P450 1A1 enzyme). This activation significantly reduced intestinal permeability, mitigated alcohol-induced oxidative stress and inflammation, and restored intestinal barrier function. Consequently, the study demonstrates that foodborne indole substantially reduces alcohol absorption and lowers the expression levels of liver inflammation-related factors, thereby slowing the progression of ALD. These results highlight indole's therapeutic potential for treating ALD and its role in developing functional foods.

Bergenin inhibits hepatic fat deposition by activating the AMPK signaling pathway, thereby attenuating alcoholic liver disease.

Alcoholic liver disease (ALD) is a prevalent liver condition that arises from prolonged and excessive alcohol intake. Bergenin (BER) is an effective phytotherapeutic agent that exhibits pharmacological properties, including anti-inflammatory and anti-oxidative effects. To establish an in vivo model of ALD, C57BL/6 mice were continuously fed a high-fat diet (HFD) and administered alcohol gavage for 8 weeks, while concurrently administering BER and evaluated for therapeutic effects. After modeling, the therapeutic effects of BER were evaluated by observing histopathological changes and the detection of relevant biochemical indicators in mice. In addition, RNA sequencing of liver tissues was performed to analyze differentially expressed genes and to investigate the associated signaling pathways in order to elucidate the protective mechanisms of BER. These differentially expressed genes were mainly enriched in lipid metabolism pathways and the cytochrome P450 metabolism of exogenous substances. Subsequently, HepG2 was co-treated with sodium oleate (NaOA) and ethanol to establish an in vitro model, and the specific mechanism by which BER ameliorates ALD was further analyzed in depth. AMPK inhibitor, Compound C (CC), was demonstrated to significantly inhibit the regulation of lipid metabolism by BER in vitro. Finally, the differentially expressed genes selected were validated through qRT-PCR and Western blot analysis. Collectively, our findings revealed that BER effectively alleviated liver injury caused by alcohol and HFD in mice, significantly suppressing lipid deposition in ALD, enhancing alcohol metabolism, and mitigating oxidative stress.