Chronic alcohol consumption promotes hepatic steatosis, a key feature of alcohol-associated liver disease (ALD), yet the signaling mechanisms linking oxidative stress to lipid dysregulation remain incompletely understood. Here, we identify amyloid P component (APCS) as a previously unrecognized, alcohol-repressed hepatoprotective factor that is consistently suppressed during ALD progression. Transcriptomic, biochemical, and histological analyses revealed markedly reduced APCS expression in the livers of ALD patients and alcohol-fed mice, as well as in ethanol-treated hepatocytes. Functional studies demonstrated that liver-specific APCS deficiency increases susceptibility to alcohol-induced hepatic steatosis in vivo and promotes lipid accumulation in hepatocytes. Mechanistically, we identified miR-24-2-5p as an alcohol-inducible microRNA that directly targets Apcs. Manipulation of miR-24-2-5p reciprocally regulated APCS expression and hepatocellular lipid accumulation. Further analyses revealed that the miR-24-2-5p/APCS axis modulates AMPK activity, potentially through regulation of mitochondrial function, cellular redox homeostasis, and cAMP-associated signaling pathways. APCS depletion reduced AMPK phosphorylation and activity, whereas inhibition of miR-24-2-5p restored AMPK signaling. Pharmacological modulation confirmed AMPK as a critical downstream effector mediating the lipogenic effects associated with APCS deficiency. Importantly, antioxidant intervention with N-acetylcysteine (NAC) attenuated alcohol-induced miR-24-2-5p upregulation, restored APCS expression, and reactivated AMPK both in vivo and in vitro, whereas pro-oxidant stimuli recapitulated these regulatory effects. Collectively, these findings define an oxidative stress-driven miR-24-2-5p/APCS/AMPK regulatory axis that governs alcohol-induced hepatic steatosis and highlight a potential therapeutic target for ALD.

Introduction:Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by excessive lipid deposition in hepatocytes without a history of significant alcohol consumption. Pachymic acid (Pac), a bioactive triterpenoid from Poria cocos, has shown promise in treating MASLD due to its antioxidant and anti-inflammatory capabilities. This study aimed to elucidate the molecular impact and mechanisms of Pac in MASLD. Methods:Male C57BL/6J mice were subjected to a high-fat diet (HFD) for 8 weeks, followed by a 4 weeks treatment with the Pac. Comprehensive assessments including physiological, biochemical, and histomorphological evaluations were performed post-treatment. Transcriptomic analysis of liver samples from normal control (NC), HFD, and HFD + high-dose Pac (Pac-H) groups was conducted, with validation through Western blot, and immunofluorescence. Results:HFD induced biochemical abnormalities and liver injury, which were significantly reversed by Pac, as evidenced by decreased plasma levels of AST (Aspartate aminotransferase), ALT (Alanine aminotransferase), TG (Triglyceride), and TC (Total cholesterol), and reduced hepatic TG and TC levels. Pac also mitigated lipid accumulation, peroxidation, and ferroptosis. Pac modulated the expression of PPARα (Peroxisome proliferator-activated receptor α), MAPKs (Mitogen-activated protein kinases), and ferroptosis pathways, thereby ameliorating MASLD. Discussion:The study demonstrated that Pac inhibited the MAPKs signaling pathway and reduced hepatic ferroptosis, alleviated steatosis through PPARα regulation, offering a potential therapeutic strategy for MASLD.

BACKGROUND:Alisol B (AB) has been demonstrated to be a potential lead compound in improving obesity-related metabolic disorders. Nevertheless, the effects and mechanisms of AB on Metabolic dysfunction-associated steatotic liver disease (MASLD) remain unclear. PURPOSE:This study aimed to investigate the improvement of AB on MASLD and explore the intricate mechanism involving gut microbiota and liver metabolism. MATERIALS AND METHODS:The MASLD mice model was established by feeding a high-fat diet and oral treatment with AB. The effects of AB on lipid metabolism in MASLD were initially measured. Subsequently, 16S rRNA gene sequencing, untargeted metabolomics combined with network pharmacology analysis was used to unveil the potential mechanism of AB on MASLD. A series of molecular biology experiments was conducted to confirm the results of the multi-omics analysis and to elucidate the key mechanism. RESULTS:AB attenuated liver steatosis and improved liver injury in MASLD mice. AB treatment improved the diversity of gut microbiota and increased the abundance of Akkermansia, Escherichia-Shigella, and Muribaculu in MASLD mice. Based on correlation analysis between differential intestinal microbiota and metabolites, metabolites involving sodium oleate, helleolate acetate 3-acetate and oxaminate were identified as key metabolites. In addition, integrating metabolomics and network pharmacology showed that AB alleviated MASLD by regulating the purine metabolism pathway and de novo fatty acid biosynthesis. Then, we focused on the role of purine metabolism in the treatment of MASLD by AB. Notably, AB inhibited the urine acid level in serum and liver of MASLD mice and hepatic XO activity and expression. AB markedly reduced the hypoxanthine and allantoin levels, increased the inosine level in the livers of MASLD mice, indicating that AB significantly reversed the dysfunction of hepatic purine metabolism in MASLD. Moreover, Molecular docking and surface plasmon resonance (SPR) results demonstrated that AB directly binds to XO. Overexpressing XO abolished the effect of AB in lipid accumulations in AML-12 cells. AB may alleviate MASLD by directly targeting XO to inhibit purine metabolism disorders in the liver. CONCLUSION:Our results demonstrate that AB treatment attenuates HFD-induced MASLD through dual mechanisms involving gut microbiota modulation and restoration of hepatic metabolic homeostasis. Comprehensive mechanistic analysis revealed that AB ameliorates hepatic steatosis and corrects purine metabolism dysregulation in MASLD pathogenesis through specific inhibition of XO. These findings provide novel mechanistic insights into the hepatoprotective properties of AB and establish its therapeutic potential for MASLD intervention.

IntroductionAcetaminophen (APAP) is widely used as an analgesic and antipyretic. However overdose APAP can lead to acute liver injury (ALI), representing a significant challenge for public health due to limited treatment options. Current research highlights the need for safer and more effective therapies for APAP-induced liver injury, especially those that target oxidative and endoplasmic reticulum (ER) stress pathways. This study investigates the protective effects of Thonningianin A (TA), a flavonoid compound derived from Penthorum chinense Pursh, in mitigating APAP-induced hepatotoxicity.MethodsThe experimental design involved administering TA at doses of 20 mg/kg and 40 mg/kg to C57BL/6 mice prior to inducing hepatotoxicity with APAP.Results and discussionTA treatment significantly lowered plasma ALT and AST levels, inhibited the production of inflammatory cytokines, and reduced oxidative stress markers in liver tissues. Furthermore, TA modulated apoptosis-related proteins by increasing BCL-2 expression while decreasing CHOP and BAX levels. It alleviated endoplasmic reticulum (ER) stress by downregulating GRP78, p-PERK, and ATF4. Notably, liver-specific GPX4 knockdown, achieved through AAV-8-mediated shRNA delivery, abolished the hepatoprotective effects of TA, underscoring GPX4’s essential role in mediating TA-induced hepatoprotection. These findings suggest TA as a promising therapeutic agent in managing APAP-induced liver injury, with its unique action on both oxidative and ER stress pathways contributing to its hepatoprotective efficacy.

Ulcerative colitis (UC) is an idiopathic, relapsing inflammatory disorder of the colonic mucosa. Pyroptosis contributes significantly to UC. However, the molecular mechanisms of UC remain unexplained. Herein, using transcriptome data and animal experimental validation, we sought to explore pyroptosis-related molecular mechanisms, signature genes, and potential drugs in UC. Gene profiles (GSE48959, GSE59071, GSE53306, and GSE94648) were selected from the Gene Expression Omnibus (GEO) database, which contained samples derived from patients with active and inactive UC, as well as health controls. Gene Set Enrichment Analysis (GSEA), Weighted Gene Co-expression Network Analysis (WGCNA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on microarrays to unravel the association between UC and pyroptosis. Then, differential expressed genes (DEGs) and pyroptosis-related DEGs were obtained by differential expression analyses and the public database. Subsequently, pyroptosis-related DEGs and their association with the immune infiltration landscape were analyzed using the CIBERSORT method. Besides, potential signature genes were selected by machine learning (ML) algorithms, and then validated by testing datasets which included samples of colonic mucosal tissue and peripheral blood. More importantly, the potential drug was screened based on this. And these signature genes and the drug effect were finally observed in the animal experiment. GSEA and KEGG enrichment analyses on key module genes derived from WGCNA revealed a close association between UC and pyroptosis. Then, a total of 20 pyroptosis-related DEGs of UC and 27 pyroptosis-related DEGs of active UC were screened. Next, 6 candidate genes (ZBP1, AIM2, IL1β, CASP1, TLR4, CASP11) in UC and 2 candidate genes (TLR4, CASP11) in active UC were respectively identified using the binary logistic regression (BLR), least absolute shrinkage and selection operator (LASSO), random forest (RF) analysis and artificial neural network (ANN), and these genes also showed high diagnostic specificity for UC in testing sets. Specially, TLR4 was elevated in UC and further elevated in active UC. The results of the drug screen revealed that six compounds (quercetin, cyclosporine, resveratrol, cisplatin, paclitaxel, rosiglitazone) could target TLR4, among which the effect of quercetin on intestinal pathology, pyroptosis and the expression of TLR4 in UC and active UC was further determined by the murine model. These findings demonstrated that pyroptosis may promote UC, and especially contributes to the activation of UC. Pyroptosis-related DEGs offer new ideas for the diagnosis of UC. Besides, quercetin was verified as an effective treatment for pyroptosis and intestinal inflammation. This study might enhance our comprehension on the pathogenic mechanism and diagnosis of UC and offer a treatment option for UC.

The microbiota is strongly association with cancer. Studies have shown significant differences in the gastric microbiota between patients with gastric cancer (GC) patients and noncancer patients, suggesting that the microbiota may play a role in the development of GC. Although Helicobacter pylori (H. pylori ) infection is widely recognized as a primary risk factor for GC, recent studies based on microbiota sequencing technology have revealed that non-H. pylori microbes also have a significant impact on GC. A recent study discovered that Streptococcus anginosus (S. anginosus ) is more prevalent in the gastric mucosa of patients with GC than in that of those without GC. S. anginosus infection can spontaneously induce chronic gastritis, mural cell atrophy, mucoid chemotaxis, and heterotrophic hyperplasia, which promote the development of precancerous lesions of GC (PLGC). S. anginosus also disrupts the gastric barrier function, promotes the proliferation of GC cells, and inhibits apoptosis. However, S. anginosus is underrepresented in the literature. Recent reports suggest that it may cause precancerous lesions, indicating its emerging pathogenicity. Modern novel molecular diagnostic techniques, such as polymerase chain reaction, genetic testing, and Ultrasensitive Chromosomal Aneuploidy Detection, can be used to gastric precancerous lesions via microbial markers. Therefore, we present a concise summary of the relationship between S. anginosus and PLGC. Our aim was to further investigate new methods of preventing and treating PLGC by exploring the pathogenicity of S. anginosus on PLGC.

Precancerous Lesions of Gastric Cancer (PLGC) are an essential step in the advancement of Gastric cancer (GC). Early intervention represents the most effective strategy to impede the development of PLGC. However, additional research is necessary to comprehend the molecular mechanism of PLGC. YQHXD is originated from Si Wu Decoction, has been utilized as an empirical formula for the treatment of PLGC for several years. In this study, we employed network pharmacology, molecular docking, and experimental validation to examine the inhibitory and ameliorative properties of YQHXD on PLGC. Multiple databases were utilized to gather genetic information on drugs in PLGC and YQHXD, in order to obtain cross-targets. We discovered 142 common targets between YQHXD and PLGC. GO and KEGG enrichment analyses indicate that YQHXD treatment of PLGC might be linked with cellular response to oxygen levels and the HIF-1α signaling pathway. Finally, we performed in vitro experiments, of which the results reveal that YQHXD mitigates gastric mucosal atrophy, intestinalization, and heterogeneous hyperplasia, and reduces the expression of inflammatory factors in rats. Therefore, we considered that YQHXD has the potential to delay the PLGC process by inhibiting the HIF-1α signaling pathway.

Background:The diagnosis of Precancerous Lesions of Gastric Cancer (PLGC) is challenging in clinical practice. We conducted a clinical study by analyzing the information of relevant chromosome copy number variations (CNV) in the TCGA database followed by the UCAD technique to evaluate the value of Chromosomal Instability (CIN) assay in the diagnosis of PLGC.Methods:Based on the screening of gastric cancer related data in TCGA database, CNV analysis was performed to explore the information of chromosome CNV related to gastric cancer. Based on the gastroscopic pathology results, 12 specimens of patients with severe atrophy were screened to analyze the paraffin specimens of gastric mucosa by UCAD technology, and to explore the influence of related factors on them.Results:The results of CNV in TCGA database suggested that chromosome 7, 8, and 17 amplification was obvious in patients with gastric cancer. UCAD results confirmed that in 12 patients with pathologic diagnosis of severe atrophy, five of them had positive results of CIN, with a positive detection rate of 41.7%, which was mainly manifested in chromosome seven and chromosome eight segments amplification. We also found that intestinalization and HP infection were less associated with CIN. And the sensitivity of CIN measurement results was significantly better than that of tumor indicators.Conclusion:The findings suggest that the diagnosis of PLGC can be aided by UCAD detection of CIN, of which Chr7 and 8 may be closely related to PLGC.

Purpose: Atractylodes macrocephala Koidz is a widely used classical traditional Chinese herbal medicine, that has shown remarkable efficacy in cancers. Colorectal cancer (CRC) is the most common malignant tumor globally. Interferon (IFN)- gamma , a prominent cytokine involved in anti-tumor immunity that has cytostatic, pro-apoptotic, and immune-stimulatory properties for the detection and removal of transformed cells. Atractylenolides-II (AT-II) belongs to the lactone compound that is derived from Atractylodes macrocephala Koidz with anti-cancer activity. However, whether AT-II combined with IFN- gamma modulates CRC progression and the underlying mechanisms remain unclear. The present study aimed to elucidate the efficacy and pharmaceutical mechanism of action of AT-II combined with IFN- gamma synergistically against CRC by regulating the NF-kB p65/PD-L1 signaling pathway. Methods: HT29 and HCT15 cells were treated with AT-II and IFN- gamma alone or in combination and cell viability, migration, and invasion were then analyzed using Cell Counting Kit-8 (CCK-8) and Transwell assays, respectively. Furthermore, the underlying mechanism was investigated through western blot assay. The role of AT-II combined with IFN- gamma on tumor growth and lung metastases was estimated in vivo . Finally, the population of lymphocytes in tumor tissues of lung metastatic C57BL/6 mice and the plasma cytokine levels were confirmed by flow cytometry and enzyme-linked immunosorbent assay (ELISA). Results: AT-II or the combination IFN- gamma significantly inhibited the growth and migration abilities of CRC cells in vitro and in vivo . The biological mechanisms behind the beneficial effects of AT-II combined with IFN- gamma were also measured and inhibition of p38 MAPK, FAK, Wnt/ beta -catenin, Smad, and NF-kB p65/PD-L1 pathways was observed. Moreover, AT-II combined with IFN- gamma significantly inhibited HCT15 xenograft tumor growth and lung metastases in C57BL/6 mice, which was accompanied by lymphocyte infiltration into the tumor tissues and inflammatory response inactivation. Conclusions: The results showed that the AT-II in combination with IFN- gamma could be used as a potential strategy for tumor immunotherapy in CRC. More importantly, the mechanism by which AT-II suppressed CRC progressions was by inhibiting the NF-kB p65/PD-L1 signal pathway.

Gastric cancer (GC) is a prevalent malignant tumor within the digestive system, with over 40% of new cases and deaths related to GC globally occurring in China. Despite advancements in treatment modalities, such as surgery supplemented by adjuvant radiotherapy or chemotherapeutic agents, the prognosis for GC remains poor. New targeted therapies and immunotherapies are currently under investigation, but no significant breakthroughs have been achieved. Studies have indicated that GC is a heterogeneous disease, encompassing multiple subtypes with distinct biological characteristics and roles. Consequently, personalized treatment based on clinical features, pathologic typing, and molecular typing is crucial for the diagnosis and management of precancerous lesions of gastric cancer (PLGC). Current research has categorized GC into four subtypes: Epstein-Barr virus-positive, microsatellite instability, genome stability, and chromosome instability (CIN). Technologies such as multi-omics analysis and gene sequencing are being employed to identify more suitable novel testing methods in these areas. Among these, ultrasensitive chromosomal aneuploidy detection (UCAD) can detect CIN at a genome-wide level in subjects using low-depth whole genome sequencing technology, in conjunction with bioinformatics analysis, to achieve qualitative and quantitative detection of chromosomal stability. This editorial reviews recent research advancements in UCAD technology for the diagnosis and management of PLGC.

Gastric cancer (GC) metastasis is the main cause of poor prognosis for GC patients. In recent years, breakthroughs in immunotherapy have been made in the treatment of many kinds of cancers, providing new hope for patients with GC metastasis. This paper reviews the mechanism of immunotherapy in GC metastasis and its clinical application, and discusses and compares the research and efficacy of immunotherapy in patients with liver metastasis, lung metastasis, peritoneal metastasis and lymph node metastasis of GC. This study explores the challenges and future development directions of immunotherapy, and provides a theoretical basis and clinical guidance for the precise treatment of patients with GC metastasis.

Gardenia jasminoides Ellis, a staple in herbal medicine, has long been esteemed for its purported hepatoprotective properties. Its primary bioactive constituent, geniposide, has attracted considerable scientific interest owing to its multifaceted therapeutic benefits across various health conditions. However, recent investigations have unveiled potential adverse effects associated with its metabolite, genipin, particularly at higher doses and prolonged durations of administration, leading to hepatic injury. Determining the optimal dosage and duration of geniposide administration while elucidating its pharmacological and toxicological mechanisms is imperative for safe and effective clinical application.This study aimed to evaluate the safe dosage and administration duration of geniposide in mice and investigate its toxicological mechanisms within a comprehensive dosage-duration-efficacy/toxicity model. Four distinct mouse models were employed, including wild-type mice, cholestasis-induced mice, globally farnesoid X-activated receptor (FXR) knock out mice, and high-fat diet-induced (HFD) NAFLD mice. Various administration protocols, spanning one or four weeks and comprising two or three oral doses, were tailored to each model's requirements. Geniposide has positive effects on bile acid and lipid metabolism at doses below 220 mg/kg/day without causing liver injury in normal mice. However, in mice with NAFLD, this dosage is less effective in improving liver function, lipid profiles, and bile acid metabolism compared to lower doses. In cholestasis-induced mice, prolonged use of geniposide at 220 mg/kg/day worsened liver damage. Additionally, in NAFLD mice, this dosage of geniposide for four weeks led to intestinal pyroptosis and liver inflammation. These results highlight the lipid-lowering and bile acid regulatory effects of geniposide, but also warn of potential negative impacts on intestinal epithelial cells, particularly with higher doses and longer treatment durations. Therefore, achieving optimal therapeutic results requires a decrease in treatment duration as the dosage increases, in order to maintain a balanced approach to the use of geniposide in clinical settings.

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介绍王小奇教授从脾虚毒滞论治胃癌前病变经验.王小奇教授认为,胃癌前病变是以脾胃亏虚为本,毒邪郁滞为标,由于感受外邪或先天不足等因素导致中焦脾土亏虚,升降失常,气血运行受阻,痰浊、瘀血、湿热内生,诸邪积聚,郁久化毒(痰浊之毒、瘀血之毒、湿热之毒),毒邪阻滞胃腑所致.故在治疗上以固护脾胃为主,同时祛其浊毒;祛痰浊之毒,重在祛湿化痰,佐以温通;祛瘀血之毒,重在活血化瘀,兼以行气;祛湿热之毒,重在清热解毒,辅以温药.如此虚实兼顾,乃能正邪两治,直中其本.

Background: Current evidence indicates a rising global prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD), which is closely associated to conditions such as obesity, dyslipidemia, insulin resistance, and metabolic syndrome. The relationship between the gut microbiome and metabolites in NAFLD is gaining attention understanding the pathogenesis and progression of dysregulated lipid metabolism and inflammation. The Xie Zhuo Tiao Zhi (XZTZ) decoction has been employed in clinical practice for alleviating hyperlipidemia and symptoms related to metabolic disorders. However, the pharmacological mechanisms underlying the effects of XZTZ remain to be elucidated. Purpose: The objective of this study was to examine the pharmacological mechanisms underlying the hypolipidemic and anti-inflammatory effects of XZTZ decoction in a mouse model of NAFLD, as well as the effects of supplementing exogenous metabolites on PO induced cell damage and lipid accumulation in cultured hepatocytes. Methods: A high-fat diet (HFD) mouse model was established to examine the effects of XZTZ through oral gavage. The general condition of mice and the protective effect of XZTZ on liver injury were evaluated using histological and biochemical methods. Hematoxylin and eosin staining (H&E) staining and oil red O staining were performed to assess inflammatory and lipid accumulation detection, and cytokine levels were quantitatively analyzed. Additionally, the study included full-length 16S rRNA sequencing, liver transcriptome analysis, and non-targeted metabolomics analysis to investigate the relationship among intestinal microbiome, liver metabolic function, and XZTZ decoction. Results: XZTZ had a significant impact on the microbial community structure in NAFLD mice. Notably, the abundance of Ileibacterium valens, which was significantly enriched by XZTZ, exhibited a negative correlation with liver injury biomarkers such as, alanine transaminase (ALT) and aspartate transaminase (AST) activity. Moreover, treatment with XZTZ led to a significant enrichment of the purine metabolism pathway in liver tissue metabolites, with inosine, a purine metabolite, showing a significant positive correlation with the abundance of I. valens. XZTZ and inosine also significantly enhanced fatty acid beta-oxidation, which led to a reduction in the expression of pro-inflammatory cytokines and the inhibition of liver pyroptosis. These effects contributed to the mitigation of liver injury and hepatocyte damage, both in vivo and vitro. Furthermore, the utilization of HPLC fingerprints and UPLC-Q-TOF-MS elucidated the principal constituents within the XZTZ decoction, including naringin, neohesperidin, atractylenolide III, 23-o-Acetylalisol B, pachymic acid, and ursolic acid which are likely responsible for its therapeutic efficacy. Further investigations are imperative to fully uncover and validate the pharmacodynamic mechanisms underlying these observations. Conclusion: The administration of XZTZ decoction demonstrates a protective effect on the livers of NAFLD mice by inhibiting lipid accumulation and reducing hepatocyte inflammatory damage. This protective effect is mediated by the upregulation of I.valens abundance in the intestine, highlighting the importance of the gut-liver axis. Furthermore, the presesnce of inosine, adenosine, and their derivatives are important in promoting the protective effects of XZTZ. Furthermore, the in vitro approaching, we provide hitherto undocumented evidence indicating that the inosine significantly improves lipid accumulation, inflammatory damage, and pyroptosis in AML12 cells incubated with free fatty acids.

陈宝贵教授将大动脉炎归属于"脉痹"范畴,分为风寒客络、痰湿阻滞、热毒炽盛、瘀血阻滞、脾肾两虚证型,各证型之间相互兼夹,治疗过程总以"通法"贯穿始终,施以疏风散寒、行气化痰、清热解毒、活血化瘀以通络,同时兼顾正气,扶正祛邪.

胃癌是一种全球常见的消化道恶性肿瘤,有较高的发病率及病死率.何若苹主任中医师系全国老中医药专家学术经验继承工作指导老师,浙江省名中医,博士生导师,国医大师何任先生学术经验继承人.何师从医40余载,长期致力于内科杂病及肿瘤性疾病的中医治疗[1].笔者有幸跟从何师学习,现将何师诊治胃癌患者的就诊资料进行回顾分析,以探究何师治疗胃癌的用药规律和临床经验.

Background and aims Excessive alcohol consumption predisposes drinkers to develop alcoholic cardiomyopathy. Although cardiomyocyte loss is the hallmark of cardiomyopathy, the underlying mechanism remains elusive. This study examined the potential mechanism of alcohol-induced cardiomyocyte death in a mouse model of alcoholic cardiomyopathy. Methods We established the alcoholic cardiomyopathy mouse model using C57BL/6J mice and confirmed it via echocardiography and histological examination. The cardiac ceramide content and profile were analyzed with a triple-quadrupole mass spectrometer. The molecular mechanism underlying the accumulation of ceramide due to chronic alcohol consumption and ceramide-induced cardiomyocyte death were investigated by in vivo and in vitro models. Finally, we established a TLR4 mutation model to explore the function of TLR4 in CH3/HeJ mice. Results Cardiac lipotoxicity that followed alcohol exposure resulted mainly in C16:0-, C18:0-, and C24:1-ceramide aggregation. Genes encoding the sphingosine hydrolysis enzymes (SMPD1 and SMPD2) rather than de novo synthetic biomarkers were markedly upregulated. Exogenous ceramide mimics (C6-ceramide) werenderlying the accumulation of ceramide observed to cause H9C2 cardiomyocyte-like cell death, which was consistent with results under palmate acid (PA) treatment. As a ceramide precursor, PA induces intracellular ceramide generation through TLR4 signaling, which can be abolished by an inhibitor of ceramide synthesis. Furthermore, mechanistic investigations demonstrated that pharmacological or genetic inhibition of TLR4 attenuated PA-induced cell death and corresponding ceramide production. Moreover, global mutation of TLR4 in CH3/HeJ mice significantly reduced the accumulation of C24:0, C24:1, OH_C24:1, and total ceramide following alcohol challenge. Conclusions Our findings demonstrate that ceramide accumulation plays a crucial role in alcoholic cardiomyopathy, effects that are partially mediated through the TLR4-dependent pathway.

Excessive alcohol consumption predisposes drinkers to develop alcoholic cardiomyopathy. Although cardiomyocyte loss is the hallmark of cardiomyopathy, the underlying mechanism remains elusive. This study examined the potential mechanism of alcohol-induced cardiomyocyte death in a mouse model of alcoholic cardiomyopathy. We established the alcoholic cardiomyopathy mouse model using C57BL/6J mice and confirmed it via echocardiography and histological examination. The cardiac ceramide content and profile were analyzed with a triple-quadrupole mass spectrometer. The molecular mechanism underlying the accumulation of ceramide due to chronic alcohol consumption and ceramide-induced cardiomyocyte death were investigated by in vivo and in vitro models. Finally, we established a TLR4 mutation model to explore the function of TLR4 in CH3/HeJ mice. Cardiac lipotoxicity that followed alcohol exposure resulted mainly in C16:0-, C18:0-, and C24:1-ceramide aggregation. Genes encoding the sphingosine hydrolysis enzymes (SMPD1 and SMPD2) rather than de novo synthetic biomarkers were markedly upregulated. Exogenous ceramide mimics (C6-ceramide) werenderlying the accumulation of ceramide observed to cause H9C2 cardiomyocyte-like cell death, which was consistent with results under palmate acid (PA) treatment. As a ceramide precursor, PA induces intracellular ceramide generation through TLR4 signaling, which can be abolished by an inhibitor of ceramide synthesis. Furthermore, mechanistic investigations demonstrated that pharmacological or genetic inhibition of TLR4 attenuated PA-induced cell death and corresponding ceramide production. Moreover, global mutation of TLR4 in CH3/HeJ mice significantly reduced the accumulation of C24:0, C24:1, OH_C24:1, and total ceramide following alcohol challenge. Our findings demonstrate that ceramide accumulation plays a crucial role in alcoholic cardiomyopathy, effects that are partially mediated through the TLR4-dependent pathway.

目的 探讨运脾祛湿泄浊方治疗非酒精性脂肪性肝病(NAFLD)的临床疗效.方法 选取杭州市中医院2018年6月至2020年10月收治的非酒精性脂肪性肝病患者61例,按照随机数字表法分为观察组(32例)与对照组(29例).对照组予多烯磷脂酰胆碱胶囊(易善复)胶囊治疗,观察组在对照组基础上加用运脾祛湿泄浊方治疗.比较两组治疗前后症状改善积分、肝功能指标,以及临床疗效、不良反应情况.结果 两组患者经治疗后的临床症状积分均较治疗前降低(P<0.01);治疗后与对照组相比,观察组的临床症状积分显著降低(P<0.01);治疗后观察组血清丙氨酸转氨酶(ALT)、直接胆红素(DBIL)、甘油三酯(TG)、低密度脂蛋白(LDL)指标较治疗前明显降低(P<0.05).结论 运脾祛湿泄浊方治疗非酒精性脂肪性肝病有较好疗效,改善肝功能、降血脂效果显著,且安全性良好.