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.

Elucidating the role of 4-hydroxy-2(3H)-benzoxazolone in chronic alcoholic liver disease via transcriptomics and metabolomics.

Background: Chronic alcoholic liver disease (CALD) is a global health problem which includes multiple pathological processes such as immune inflammation and oxidative stress. 4-hydroxy-2(3H)-benzoxazolone (HBOA), an alkaloid isolated from Acanthus ilicifolius L, has been shown to exert hepatoprotective and immunomodulatory effects. However, its effects on CALD remain unclear. This study aimed to investigate the effects and underlying mechanisms of HBOA on CALD. Methods: Rats were administered alcohol by gavage continuously for 12 weeks to establish the CALD model, and then treated with HBOA by gavage for 4 weeks. Transcriptomics and metabolomics were used to predict the potential mechanisms of the effects of HBOA on CALD. Liver histology and function, oxidative stress, inflammatory cytokines, and the TLR4/NF-κB pathway components were evaluated. Results: HBOA significantly improved alcohol-induced liver injury and steatosis. It decreased the expression levels of pro-inflammatory cytokines (tumour necrosis factor-α [TNF-α], interleukin (IL)-1ß, and IL-6), and increased the activities of antioxidant enzymes (superoxide dismutase [SOD], glutathione [GSH], and glutathione peroxidase [GSH-Px]). Western blotting confirmed that HBOA treatment largely diminished NF-κBp65 nuclear translocation. Comprehensive transcriptomics and metabolomics analyses indicated that HBOA regulated the glycerophospholipid metabolism pathway to achieve therapeutic effects in rats with CALD. Conclusion: HBOA has a therapeutic effect on rats with CALD. Its mechanism of action mainly affects the glycerophospholipid metabolic pathway to promote lipid metabolism homeostasis by regulating the expression of Etnppl, Gpcpd1, and Pla2g4c. In addition, it may also inhibit the TLR4/NF-κB signaling pathway, thereby reducing the immune-inflammatory response.

Ge-Zhi-Jie-Jiu decoction alleviates alcoholic liver disease through multiple signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Alcoholic liver disease (ALD) is a growing public health concern caused by excessive alcohol consumption, but effective treatments are limited. Ge-Zhi-Jie-Jiu decoction (JJY) is a modified traditional Chinese herbal remedy that aims to alleviate ALD. This formula contains various components such as Ge Hua, Ge Gen, Zhi Ju Zi, and other medicinal-food herbs. However, the specific pharmacotherapeutic compounds of JJY and its pharmacological mechanisms remain unclear. AIM OF THE STUDY: This study aimed to elucidate the molecular mechanism and pharmacodynamic basis of JJY in treating ALD. MATERIALS AND METHODS: UPLC-Q-Orbitrap HRMS, HPLC fingerprinting, and LC-MS techniques were used for the composition identification and quality control of JJY. The pharmacological components and molecular mechanisms of JJY in anti-ALD were then predicted using network pharmacology and molecular docking approaches. Ultimately, an acute alcoholic liver injury mouse model was developed, and the potential mechanisms were verified by hematoxylin-eosin (H&E), Oil Red O, and TUNEL staining, real-time fluorescence quantitative PCR (RT-qPCR), Western blot (WB) and molecular docking analysis. RESULTS: The results showed that the main components of JJY are organic acids, flavonoids, and isoflavonoids, in which puerarin, daidzein, glycitein, ononin, quercetin, and tectorigenin can be used as the indicator components of JJY. In addition, JJY might ameliorate ALD through several pathways, including potentially promoting alcohol metabolism via alcohol-metabolizing enzymes, and possibly inhibiting oxidative stress, inflammation and apoptosis via the Nrf2/Keap1/HO-1 and MAPK signaling pathways. Furthermore, JJY may also alleviated hepatic lipid accumulation through the PPARα signaling pathway. CONCLUSIONS: JJY has significant anti-ALD efficacy with multiple mechanisms. This study offers a solid experimental foundation for JJY's development as a medicine with anti-ALD characteristics and elucidates its probable active components.

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.

Metabolomics combined with network pharmacology reveals the protective effect of astragaloside IV on alcoholic liver disease.

BACKGROUND: Alcoholic liver disease (ALD) is a significant contributor to liver damage. However, the clinical options for the treatment of ALD are limited. Astragaloside IV (AST-IV) is a saponin isolated from Astragalus membranaceus (AM). This study aimed to explore the underlying mechanisms of action of AST-IV in ALD by integrating metabolomics and network pharmacology. METHODS: Sprague-Dawley (SD) rats were used to establish a rat model of ALD. AST-IV and polyene phosphatidyl choline (PPC; a positive control drug) were administered to rats with ALD for 4 weeks. We measured the body weight, liver index, ALT, AST, TC, TG, inflammatory markers (IL-1ß, IL-6, and TNF-α), and oxidative stress markers (SOD, MDA) and used H&E and ORO staining to evaluate the hepatoprotective effect of both AST-IV and PPC on ALD. Subsequently, we performed untargeted metabolomics to predict the influence of AST-IV on lipid metabolism in rats with ALD. We then used a network pharmacology approach to identify the core targets through which AST-IV corrected lipid metabolism disorders and validated these targets through molecular docking, qRT-PCR and western blot analyses. Finally, we calculated the relationships between ALD-related biochemical markers, differential liver metabolites, and core targets using Spearman's correlation analysis. RESULTS: AST-IV improved pathological damage and reduced lipid accumulation in the hepatocytes of rats with ALD. Furthermore, AST-IV inhibited oxidative stress and inflammatory responses in rats with ALD. The metabolomic results showed that AST-IV corrected hepatic lipid metabolism disorders by targeting linoleic acid, necrosis, sphingolipid, and glycerophospholipid metabolism. The Network pharmacology analysis revealed that the core targets of AST-IV exerting the above effects were p-RIPK3, p-MLKL, CYP1A2, CYP2C19, PPARα, PCSK9. Spearman's correlation analysis showed a strong correlation between ALD-related serum biochemical indices, core targets, and liver differential metabolites. CONCLUSION: AST-IV corrects the metabolic disorders of linoleic acid, sphingolipid, and glycerophospholipid, and alleviates necrosis in rats with ALD through the core targets p-RIPK3, p-MLKL, CYP1A2, CYP2C19, PPARα, and PCSK9. This study is the first to reveal the mechanism of ALD protection through AST-IV from the perspective of metabolomics and network pharmacology. Therefore, a novel target has been identified to exert protection against ALD. This study provides a reference for ALD treatment.

Aromatic Abietane-Type Diterpenoids from the Roots of Salvia prattii and Their Protective Activity Against alcoholic liver disease.

Eighteen aromatic abietane-type diterpenes, including three previously unreported compounds, Salkanoids A-C (1-3), were isolated from the roots of Salvia prattii. Their stuctures were extensively elucidated using 1D/2D NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS) data, and ECD calculation. Among these, compounds 1, 6 and 7 belong to a class of diterpenes featuring a [5, 5]-oxaspirolactones moiety, a rare structure isolated from the Salvia plants. All the isolates were assessed for their protective effects against alcoholic liver disease using ethanol-induced AML-12 cell lines. The findings revealed that compounds 2, 5, 8 and 15 demonstrated potential protective activity.

Protective effect of Acanthus ilicifolius extracts against acute alcoholic liver injury via suppressing TLR4/NF-κB signal pathway and modulating intestinal microbiota in mice.

Excessive alcohol consumption is leading to increased rates of liver injury and disease. A new research strategy focuses on manipulating gut microbiota to lessen alcohol-induced harm. This study examined the hepatoprotective effects of extracts from Acanthus ilicifolius (EAI) on acute alcoholic liver injury by inhibiting the TLR4/NF-κB signalling pathway and modulating intestinal microbiota in mice. The results showed that EAI dose-dependently reduced alcohol-induced elevations of AST, ALT, and ALP levels. EAI showed significant inhibitory effects on the expressions of TLR4, NF-κB, and pNF-κB proteins. Furthermore, EAI caused a notable reduction in hepatic levels of IL-1ß, IL-6, and TNF-α. Supplementation with EAI could ameliorate alcohol-induced dysbiosis of intestinal bacteria. The levels of ALT, AST, and ALP levels were negatively correlated with Ligilactobacillus, Lactobacillus, and Alistipes, but positively correlated with Helicobacter and Bacteroides. Overall, EAI alleviated alcoholic liver injury in mice by inhibiting the TLR4/NF-κB signalling pathway and modulating intestinal bacteria.

Refining the Rab7-V1G1 axis to mitigate iron deposition: protective effects of quercetin in alcoholic liver disease.

Iron overload is a common feature of alcoholic liver disease (ALD) and contributes significantly to disease progression. Quercetin, a flavonoid known for its iron-chelating properties, has emerged as a potential protective compound against ALD. However, research on quercetin's regulatory effects on iron levels in ALD is limited. To address this, we conducted a study using male C57BL/6J mice were subjected to a Lieber De Carli liquid diet containing ethanol (28% energy replacement) with or without quercetin supplementation (100 mg/kg.BW) for 12 weeks. Additionally, HepG2 cells, after transfection with the CYP2E1 plasmid, were incubated with ethanol and/or quercetin. Our findings revealed that ethanol consumption led to iron overload in both hepatocytes and lysosomes. Interestingly, despite the increase in iron levels, cells exhibited impaired iron utilization, disrupting normal iron metabolism. Further analysis identified a potential mechanism involving the Rab7-V1G1 (V-ATPase subunit) axis. Inhibition of V-ATPase by Concanamycin A caused elevated ROS levels, impaired lysosomal and mitochondria function, and increased expression of HIF1α and IRP2. Ultimately, this disruption in cellular processes led to iron overload and mitochondrial iron deficiency. Quercetin supplementation mitigated ethanol-induced hepatocyte damage by reversing iron overload through modulation of the Rab7-V1G1 axis and improving the interaction between lysosomes and mitochondria. In conclusion, this study elucidates a novel pathophysiological mechanism by which quercetin protects against ALD through its regulation of iron homeostasis.

Epidemiology of gastrointestinal cancers: a systematic analysis from the Global Burden of Disease Study 2021.

BACKGROUND: Gastrointestinal cancers comprise nearly one-third of global mortality from cancer, yet the comprehensive global burden of these cancers remains uninvestigated. OBJECTIVE: We aimed to assess the global, regional and national burden of gastrointestinal cancers. DESIGNS: Data on oesophagus, gastric, colorectal, liver, pancreas and biliary tract cancers were extracted from the Global Burden of Disease 2021 database. Age-standardised incidence rate (ASIR) and age-standardised death rate (ASDR) were calculated by sex, region and Sociodemographic Index (SDI). RESULTS: In 2021, there were 5.26 million incidences and 3.70 million deaths from gastrointestinal cancer. The greatest burden is from colorectal, followed by gastric, oesophageal, pancreatic, liver and biliary tract cancer. We noted geographical and socioeconomic differences in ASIR and ASDR across all types of cancers. From 2000 to 2021, ASIR increased for colorectal cancer (annual percent change (APC): 0.10%, 95% CI 0.05% to 0.14%), pancreatic cancer (APC: 0.27%, 95% CI 0.14% to 0.41%), and liver cancer from metabolic dysfunction-associated steatotic liver disease (APC: 0.62%, 95% CI 0.58% to 0.67%) and alcohol-related liver disease (APC: 0.26%, 95% CI 0.22% to 0.30%). ASDR increased for pancreatic cancer (APC: 0.18%, 95% CI 0.02% to 0.34%). Higher SDI countries had higher incidence rates for most types of gastrointestinal cancer. CONCLUSIONS: Although the ASIR of oesophageal, gastric and biliary tract cancer has decreased, the ASIR still increased in colorectal, pancreatic and liver cancer from steatotic liver disease. Public policies are important for controlling gastrointestinal cancers-most importantly, reducing alcohol consumption, hepatitis B immunisation and tackling the burden of metabolic diseases.

Impact of keratins 8 and 18 genetic variants on the severity of alcoholic liver disease.

Alcohol-related liver disease (ALD) affects approximately 30 % of heavy drinkers and is characterised by liver steatosis, fibrosis, and steatohepatitis. The aggregation of keratins 8 (KRT8) and 18 (KRT18) plays a key role in the formation of Mallory-Denk bodies, a hallmark of ALD. Circulating levels of keratin 18 fragments are elevated during ALD and several KRT8/18 genetic variants have been linked to an increased risk of liver disease. In this study, we explored the relationship between the histologic features of ALD and genetic variants of KRT8/18 in 106 severe ALD patients from the Hôpitaux Universitaires de Genève. We found a significant over-representation of several KRT8 (rs2070910, rs137898974, rs1065306) and KRT18 (rs17120866, rs1492241) variants located in the non-coding regions of these genes. Increased circulating level of keratins 18 fragments were associated with rs17120866 and alcoholic hepatitis. The combination of several KRT18 variants appeared associated with a poorer prognosis. These results highlight the possible role of KRT18 variants in ALD.

Exploring the impact of inflammatory cytokines on alcoholic liver disease: a Mendelian randomization study with bioinformatics insights into potential biological mechanisms.

Background: Alcoholic liver disease (ALD) significantly contributes to global morbidity and mortality. The role of inflammatory cytokines in alcohol-induced liver injury is pivotal yet not fully elucidated.Objectives: To establish a causal link between inflammatory cytokines and ALD using a Mendelian Randomization (MR) framework.Methods: This MR study utilized genome-wide significant variants as instrumental variables (IVs) for assessing the relationship between inflammatory cytokines and ALD risk, focusing on individuals of European descent. The approach was supported by comprehensive sensitivity analyses and augmented by bioinformatics tools including differential gene expression, protein-protein interactions (PPI), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and analysis of immune cell infiltration.Results: Our findings reveal that increased levels of stem cell growth factor beta (SCGF-ß, beta = 0.141, p = .032) and interleukin-7 (IL-7, beta = 0.311, p = .002) are associated with heightened ALD risk, whereas higher levels of macrophage inflammatory protein-1α (MIP-1α, beta = -0.396, p = .004) and basic fibroblast growth factor (bFGF, beta = -0.628, p = .008) are linked to reduced risk. The sensitivity analyses support these robust causal relationships. Bioinformatics analyses around inflammatory cytokine-associated SNP loci suggest multiple pathways through which cytokines influence ALD.Conclusion: The genetic evidence from this study convincingly demonstrates that certain inflammatory cytokines play directional roles in ALD pathogenesis. These findings provide insights into the complex biological pathways involved and underscore the potential for developing targeted therapies that modulate these inflammatory responses, ultimately improving clinical outcomes for ALD patients.

microRNAs and Other Serological Markers of Liver Fibrosis in Patients with Alcohol-Related Liver Cirrhosis.

Background: It is essential to identify novel non-invasive markers of liver fibrosis for clinical and scientific purposes. Thus, the goal of our survey was to assess the serological expression of selected microRNAs (miRNAs) in patients with alcohol-related liver cirrhosis (ALC) and to correlate them with other existing markers. Methods: Two hundred and thirty-nine persons were enrolled in the study: one hundred and thirty-nine with ALC and one hundred healthy controls. Serological expression of miR-126-3p, miR-197-3p and miR-1-3p was evaluated in all participants. Direct markers of liver fibrosis (PICP, PIIINP, PDGF-AB, TGF-α and laminin) together with indirect indices (AAR, APRI, FIB-4 and GPR) were also assessed. The additional evaluation concerned hematological parameters: MPV, PDW, PCT, RDW, MPR, RPR NLR, PLR and RLR. Results: The expression of miR-197-3p was lower in ALC compared to controls (p < 0.0001). miR-126-3p correlated negatively with AST (p < 0.05) and positively with miR-197-3p (p < 0.001). miR-197-3p correlated with direct markers of liver fibrosis-positively with PDGF-AB (p < 0.005) and negatively with TGF-α (p < 0.01). Significant negative relationships were noticed between miR-1-3p and the number of neutrophils (p < 0.05), TGF-α (p < 0.05) and laminin (p < 0.05). Conclusions: The achieved results and observed correlations prove the potential involvement of the examined miRNAs in the process of liver fibrosis, giving a novel insight into the diagnostics of liver cirrhosis.

Elucidating hydroxysafflor yellow A's multi-target mechanisms against alcoholic liver disease through integrative pharmacology.

BACKGROUND: Alcoholic liver disease (ALD) significantly contributes to global liver-related morbidity and mortality. Natural products play a crucial role in the prevention and treatment of ALD. Hydroxysafflor yellow A (HSYA), a unique and primary component of Safflower (Carthamus tinctorius l.), exhibits diverse pharmacological activities. However, the impact and mechanism of HSYA on ALD have not been fully elucidated. PURPOSE: The purpose of this study was to employ an integrative pharmacology approach to assess the multi-targeted mechanism of HSYA against ALD. METHODS: Network pharmacology and molecular docking techniques were used to analyze the potential therapeutic signaling pathways and targets of HSYA against ALD. An ALD model in zebrafish larvae was established. Larvae were pretreated with HSYA and then exposed to ethanol. Liver injury was measured by fluorescence expression analysis in the liver-specific transgenic zebrafish line Tg (fabp10a:DsRed) and liver tissue H&E staining. Liver steatosis was determined by whole-mount oil red O staining and TG level. Additionally, an ethanol-induced hepatocyte injury model was established in vitro to observe hepatocyte damage (cell viability, ALT level), lipid accumulation (oil red O staining, TC and TG), and oxidative stress (ROS, MDA, GPx and SOD) in HepG2 cells treated with or without HSYA. Finally, qRT-PCR combined with network pharmacology and molecular docking was employed to validate the effects of HSYA on targets. RESULTS: HSYA exhibited a significant, dose-dependent improvement in ethanol-induced liver injury in zebrafish larvae and HepG2 cells. Network pharmacology analysis revealed that HSYA may exert pharmacological effects against ALD through 341 potential targets. These targets are involved in various signaling pathways, including lipid metabolism and atherosclerosis, PI3K-Akt signaling pathway, MAPK signaling pathway, and ALD itself. Molecular docking studies displayed that HSYA had a strong binding affinity toward the domains of IL1B, IL6, TNF, PPARA, PPARG, HMGCR and ADH5. qRT-PCR assays demonstrated that HSYA effectively reversed the ethanol-induced aberrant gene expression of SREBF1, FASN, ACACA, CPT1A, PPARA, IL1B, IL6, TNFα, ADH5, and ALDH2 in vivo and in vitro. CONCLUSION: This study offers a comprehensive investigation into the anti-ALD mechanisms of HSYA using an integrative pharmacology approach. The potential targets of HSYA may be implicated in enhancing ethanol catabolism, reducing lipid accumulation, mitigating oxidative stress, and inhibiting inflammatory response.

Oxidative stress in alcoholic liver disease, focusing on proteins, nucleic acids, and lipids: A review.

Oxidative stress is one of the important factors in the development of alcoholic liver disease. The production of reactive oxygen species and other free radicals is an important feature of alcohol metabolism in the liver and an important substance in liver injury. When large amounts of ROS are produced, the homeostasis of the liver REDOX system will be disrupted and liver injury will be caused. Oxidative stress can damage proteins, nucleic acids and lipids, liver dysfunction. In addition, damaging factors produced by oxidative damage to liver tissue can induce the occurrence of inflammation, thereby aggravating the development of ALD. This article reviews the oxidative damage of alcohol on liver proteins, nucleic acids, and lipids, and provides new insights and summaries of the oxidative stress process. We also discussed the relationship between oxidative stress and inflammation in alcoholic liver disease from different perspectives. Finally, the research status of antioxidant therapy in alcoholic liver disease was summarized, hoping to provide better help for learning and developing the understanding of alcoholic liver disease.

Key regulators of hepatic stellate cell activation in alcohol liver Disease: A comprehensive review.

Alcoholic liver disease (ALD) is a broad category of disorders that begin with liver injury, lead to liver fibrosis, and ultimately conclude in alcohol-induced liver cirrhosis, the most chronic and irreversible liver damage. Liver fibrosis (LF) is a common pathological characteristic observed in most chronic liver inflammatory conditions that involve prolonged inflammation. In this review, we have summarized ethanol-mediated hepatic stellate cell (HSCs) activation and its role in liver fibrosis progression. We highlight important molecular mechanisms that are modulated by ethanol, play a role in the activation of HSCs and the progression of liver fibrosis and identifying potential targets to ameliorate liver fibrosis.

Pueraria lobata-Prunus mume Complex Alleviates Alcoholic Liver Disease by Regulating Lipid Metabolism and Inhibiting Inflammation: A Transcriptome and Gut Microbiota Analysis.

BACKGROUND: Lipid metabolism disorder appears to be one of the early features of alcoholic liver disease (ALD), which can be speculated via omics analysis including liver transcriptomics and gut microbiota. A complex consisting of the roots of Pueraria lobata and dried fruits of Prunus mume (PPC), which possesses hepatoprotective effects, could serve as a drug or functional food. The lack of non-polysaccharide compounds in PPC with their moderation effects on gut microbiota suggests the necessity for a relevant study. METHODS: Six groups of Kunming mice (control, Baijiu injury, silybin, low, medium, and high) were modelled by gavage with Baijiu (for 14 days) and PPC (equivalent to a maximum dose of 9 g/kg in humans). The liver transcriptome data were analyzed to predict gene annotation, followed by the verification of gut microbiota, serum, tissue staining, immunohistochemistry, and Western blotting. Liquid chromatography-mass spectrometry was used to detect the components. RESULTS: PPC normalized serum ALT (40 U/L), down-regulated TLR4-NF-κB signaling pathway to inhibit the release of TNF-α (90 pg/mL), improved the expression of occludin, claudin-4, and ZO-1, and restored the abundance of Muribaculaceae, Bacteroides and Streptococcus. CONCLUSION: PPC can alleviate ALD by regulating the gut microbiota with an anti-inflammatory and intestinal barrier, and has an application value in developing functional foods.

The protective effects of aqueous extract of Schisandra sphenanthera against alcoholic liver disease partly through the PI3K-AKT-IKK signaling pathway.

Purpose: This study aimed to investigated the key chemical components and the effect of the aqueous extract of Schisandra sphenanthera (SSAE) on alcoholic liver disease (ALD) and the related molecular mechanism. Methods: This study employed UPLC-Q-TOF-MS/MS to identify the chemical compositions in SSAE. ALD rat model was established through oral administration of white spirit. Transcriptome sequencing, weighted gene co-expression network construction analysis (WGCNA), and network pharmacology were used to predict key compositions and pathways targeted by SSAE for the treatment of ALD. Enzyme-linked immunosorbent assay (ELISA), biochemical kits, hematoxylin-eosin (HE) staining, Western blotting (WB) analysis, and immunohistochemical analysis were used to validate the mechanism of action of SSAE in treating ALD. Results: Active ingredients such as schisandrin A, schisandrol A, and schisandrol B were found to regulate the PI3K/AKT/IKK signaling pathway. Compared to the model group, the SSAE group demonstrated significant improvements in cellular solidification and tissue inflammation in the liver tissues of ALD model rats. Additionally, SSAE regulated the levels of a spartate aminotransferase (AST), alanine aminotransferase (ALT), alcohol dehydrogenase (ADH), and aldehyde Dehydrogenase (ALDH) in serum (P < 0.05); Western blotting and immunohistochemical analyses showed that the expression levels of phosphorylated PI3K, AKT, IKK, NFκB, and FOXO1 proteins were significantly reduced in liver tissues (P < 0.05), whereas the expression level of Bcl-2 proteins was significantly increased (P < 0.05). Conclusion: The active components of SSAE were schisandrin A, schisandrol A, and schisandrol B, which regulated the phosphorylation levels of PI3K, AKT, IKK, and NFκB and the expression of FOXO1 protein and upregulated the expression of Bcl-2 protein in the liver tissues of ALD rats. These findings indicate that SSAE acts against ALD partly through the PI3K-AKT-IKK signaling pathway. This study provided a reference for future research and treatment of ALD and the development of novel natural hepatoprotective drugs.

No causal relationship between serum vitamin D levels and alcoholic liver disease: a two-sample bidirectional Mendelian randomization study.

Background: Numerous observational studies have presented an association between Vitamin D (VD) and Alcoholic Liver Disease (ALD). However, sufficient evidence from Randomized Controlled Trials (RCTs) substantiating this correlation is scarce, thus leaving the causality of this relationship ambiguous. To overcome the shortcomings of traditional observational studies, we performed a two-sample bidirectional Mendelian randomization (MR) analysis to ascertain the causal relationship between VD and ALD. Methods: We utilized summary statistics datasets from Genome-Wide Association Studies (GWAS) for VD and ALD. We selected genetic instruments that measure circulating VD levels (n = 64,979), and retrieved ALD statistics from GWASs, inclusive of 1,416 cases and 217,376 healthy controls, while excluding chronic liver diseases such as nonalcoholic fatty liver disease, toxic liver disease, and viral hepatitis. Subsequent, MR analyses were performed to obtain effect estimates using inverse variance weighted (IVW) random effect models. Cochran's Q statistic and MR-Egger regression intercept analyses were used to assess pleiotropy. Sensitivity analyses using the MR Egger, weighted median, simple mode, and weighted mode methods were also performed. Leave-one-out analysis was used to identify SNPs with potential effect. Reverse MR analysis was also performed. Results: In IVW, our MR analysis incorporated 21 independent SNPs, circulating VD levels had no causal effect on ALD [OR = 0.624 (0.336-1.160), p = 0.136] and ALD had no causal effect on circulating VD [OR = 0.997 (0.986-1.008), p = 0.555]. No heterogeneity or pleiotropy was observed (p > 0.05). Other MR methods also agreed with IVW results. Conclusion: This study provides the causal relationship between genetically predicted circulating Vitamin D levels and ALD and provides new insights into the genetics of ALD.