American Journal of Pathology最新文献

{"title":"Selective Depletion of Gut Gram-Negative Bacteria Attenuates Alcohol Binge-Induced Cardiovascular Dysfunction by Lowering Cardiac Anandamide Levels","authors":"Sarah E. Cohen ,&nbsp;Meagan E. Donovan ,&nbsp;Davin J. Gardner ,&nbsp;Danielle Sambo ,&nbsp;Seray B. Karagoz ,&nbsp;Resat Cinar ,&nbsp;David Goldman ,&nbsp;Jason D. Gardner ,&nbsp;Pal Pacher ,&nbsp;Janos Paloczi","doi":"10.1016/j.ajpath.2025.10.010","DOIUrl":"10.1016/j.ajpath.2025.10.010","url":null,"abstract":"<div><div>Binge drinking contributes to an increasing number of emergency department visits in the United States. Previous work demonstrated that an alcohol binge impairs cardiac performance and exerts complex hemodynamic effects through the activation of the endocannabinoid-mediated cannabinoid type 1 receptor (CB1R) signaling pathway. Anandamide (AEA), an endogenous CB1R agonist, is synthesized in response to various stressors and tissue injury. However, the role of binge drinking in increasing myocardial AEA levels, which leads to CB1R-dependent cardiodepression, remains unclear. This work studied how endotoxins from intestinal Gram-negative bacteria affect myocardial AEA levels, which further induce CB1R-dependent cardiac dysfunction following acute alcohol intoxication. Using a murine model of a single alcohol binge (5 g/kg orally), reduced mesenteric microcirculation concurrent with elevated circulating endotoxin levels was observed. Selective depletion of gut Gram-negative bacteria by antibiotics partially ameliorated alcohol-induced gut barrier dysfunction, significantly lowered circulating endotoxins, coinciding with reduced cardiac AEA levels at 3 hours after binge. These changes were paralleled with moderately improved cardiac performance and vascular tone. Cardiac RNA levels of genes involved in AEA synthesis increased after alcohol binge, but not in antibiotic-pretreated mice. However, acute alcohol-induced cardiac AEA formation was unrelated to toll-like receptor-4 signaling. These findings provide novel insights that highlight the pivotal role of intestinal Gram-negative bacteria in modulating cardiac AEA levels after an alcohol binge, leading to cardiovascular dysfunction.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 192-208"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145476766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current Clinical Trials for Alcohol-Associated Hepatitis","authors":"Elias D. Rady,&nbsp;Ahmad Anouti,&nbsp;Mack C. Mitchell,&nbsp;Thomas G. Cotter","doi":"10.1016/j.ajpath.2025.03.009","DOIUrl":"10.1016/j.ajpath.2025.03.009","url":null,"abstract":"<div><div>Alcohol-associated hepatitis (AH) is a severe form of alcohol-associated liver disease characterized by acute-onset jaundice and liver failure. AH carries a high mortality risk, particularly in severe cases. Although glucocorticoids have been the primary pharmacologic intervention for decades, their use is limited by a lack of long-term efficacy and significant side effects, and relative contraindications. For patients who do not respond to glucocorticoids, early liver transplantation is a life-saving option. However, only a few patients qualify for this intervention. In recent years, advances in translational medicine have uncovered key mechanisms in AH pathophysiology, including microbiome interactions, proinflammatory signaling, and disruptions in hepatocyte function. These insights have led to the exploration of innovative pharmacologic treatments, targeting pathways such as the gut–liver axis, oxidative stress, inflammation, and liver regeneration. Despite promising results from ongoing clinical trials, several challenges persist, including low patient recruitment and retention rates, heterogeneity in trial design, and the lack of standardized endpoints. This review assesses the current pharmacologic landscape of AH, with a focus on emerging therapies and the ongoing challenges in AH clinical trials.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 182-191"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of Perivascular Adipose Tissue, White Adipose Tissue, and Brown Adipose Tissue in the Pathophysiological Effects of Ethanol","authors":"Thales M.H. Dourado ,&nbsp;Carlos R. Tirapelli","doi":"10.1016/j.ajpath.2025.07.012","DOIUrl":"10.1016/j.ajpath.2025.07.012","url":null,"abstract":"<div><div>Adipose tissue plays a crucial role in energy storage, but it also acts as an endocrine organ by secreting hormones and proinflammatory molecules. It regulates various processes, including adipogenesis, metabolism, and inflammation. White and brown adipose tissue (WAT and BAT) consists of white and brown adipocytes, respectively, which differ in cellular structure and function. Adipocytes also make up a significant part of perivascular adipose tissue (PVAT), which forms a sheath-like structure around blood vessels. Current research indicates that WAT, BAT, and PVAT are negatively affected by ethanol (ethyl alcohol). The changes induced by ethanol in the storage, metabolic, and secretory functions of PVAT and WAT are linked to vascular and hepatic dysfunction. In this context, while adipose tissue is a target of the harmful effects of ethanol, it also contributes to its pathophysiological consequences. Although the function of BAT is impacted by ethanol, BAT exhibits a protective role against ethanol-induced liver disease. This review highlights both past and recent efforts to identify the mechanisms through which ethanol consumption alters adipocyte function, with a focus on findings from studies that explain the detrimental effects of ethanol on WAT and BAT, and discusses the interplay between adipose tissue and the liver, particularly its implications for alcoholic liver disease. Additionally, new data that elucidate the mechanisms underlying ethanol-induced dysfunction in PVAT are summarized.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 172-181"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144939057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alcohol-Associated Hepatocarcinogenesis","authors":"Yuhua Xue,&nbsp;Tian Tian,&nbsp;Melak Ottallah,&nbsp;Mahfuza Mannan,&nbsp;Joshua Barkin,&nbsp;Brady Jin-Smith,&nbsp;Liya Pi","doi":"10.1016/j.ajpath.2025.04.016","DOIUrl":"10.1016/j.ajpath.2025.04.016","url":null,"abstract":"<div><div>Long-term alcohol consumption is a leading global health concern, primarily due to its deleterious effects on liver function and its well-established association with hepatocellular carcinoma. Alcohol-related liver disease (ALD) encompasses a continuum—from reversible hepatic steatosis and steatohepatitis through progressive fibrosis and cirrhosis to overt hepatocellular carcinoma. Accumulating studies have revealed that the Wnt/β-catenin signaling pathway is an essential regulator in ALD pathogenesis, orchestrating diverse molecular, immunologic, and epigenetic processes. Aberrant β-catenin activity disrupts redox homeostasis, promotes chronic inflammation, drives extracellular matrix remodeling, and alters hepatocyte cell fate, thereby creating a microenvironment that is highly conducive to carcinogenesis. This article provides a systematic review of the significant function of Wnt/β-catenin signaling in ALD, emphasizing its regulatory impact on liver fat accumulation, its inflammatory role in steatohepatitis, its involvement in fibrogenesis, and its tumor-promoting effects in alcohol-related hepatocellular carcinoma. In addition, emerging therapeutic strategies that offer potential for early identification and tailored therapy of ALD are explored—including direct Wnt modulators, combinatory therapeutics, and precision medicine approaches.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 151-160"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cholestasis in Alcohol-Associated Liver Disease","authors":"Shengmin Yan,&nbsp;Xiao-Ming Yin","doi":"10.1016/j.ajpath.2025.04.015","DOIUrl":"10.1016/j.ajpath.2025.04.015","url":null,"abstract":"<div><div>Alcohol-associated liver disease (ALD) is a leading cause of liver-related morbidity and mortality. ALD covers a spectrum of diseases, ranging from mild and reversible hepatic steatosis to the development of fibrosis, cirrhosis, and alcohol-associated hepatitis (AH). AH is marked by a rapid onset of jaundice and elevated serum levels of aspartate aminotransferase in individuals with heavy alcohol use. It can progress to acute-on-chronic liver failure, with a mortality rate of approximately 30% within the first month. Unfortunately, treatment options for AH are still limited. Cholestasis refers to an impairment in bile formation or flow, leading to clinical symptoms, such as fatigue, pruritus, and jaundice. Cholestasis and biliary dysfunction are commonly seen in patients with AH and can significantly worsen the prognosis. However, the mechanisms and roles of cholestasis in ALD are not yet fully understood. In this review, we will summarize recent findings and explore the potential roles and mechanisms of cholestasis in the progression of ALD.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 35-49"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Update on Animal Models of Alcohol-Associated Liver Disease","authors":"Peng Cao ,&nbsp;Xiaojuan Chao ,&nbsp;Hong-Min Ni ,&nbsp;Wen-Xing Ding","doi":"10.1016/j.ajpath.2024.11.011","DOIUrl":"10.1016/j.ajpath.2024.11.011","url":null,"abstract":"<div><div>Alcohol-associated liver disease (ALD) is a significant global health concern and a leading cause of liver disease-related deaths. However, the treatment options are limited due to the lack of animal models that accurately replicate ALD pathogenesis. An ideal ALD animal model should have pathological characteristics similar to those of human ALD, with a clear pathological process and ease of drug intervention. Over the years, researchers have focused on developing ideal ALD preclinical animal models by testing various methods, such as <em>ad libitum</em> drinking water with ethanol, acute, single large doses of ethanol gavage, multiple alcohol gavages in a short period, the Lieber-DeCarli liquid diet feeding model, the intragastric infusion model, and the Gao-binge model. With the increasing occurrence of obesity and metabolic dysfunction–associated steatotic liver disease, a new category of metabolic and alcohol-associated liver disease (MetALD) is also emerging. Studies have investigated the combined effects of a high-fat diet combined with binge alcohol or drinking water containing ethanol to mimic MetALD. In addition to mice, other species such as rats, guinea pigs, zebrafish, and non-human primates have also been tested to establish ALD preclinical models. This review aims to summarize current animal ALD models, particularly the emerging MetALD models, with the hope of providing a valuable reference for establishing more effective animal models in ALD studies in the future.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 4-19"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nonalcoholic Steatohepatitis Exacerbates Inflammatory Bone Destruction and Macrophage NLR Family Pyrin Domain-Containing 3 Inflammasome Activation in Ligature-Induced Periodontitis","authors":"Zijun Wang,&nbsp;Xiaoyue Sun,&nbsp;ZhaoJun Chen,&nbsp;Jingjing Yu,&nbsp;Qing Nie,&nbsp;Zihan Ma,&nbsp;Shuhui Zhou,&nbsp;Ting Li,&nbsp;Hantao Yao,&nbsp;Boxuan Zhao,&nbsp;Yaoting Ji,&nbsp;Li Wang,&nbsp;Minquan Du,&nbsp;Lingxin Zhu","doi":"10.1016/j.ajpath.2025.10.011","DOIUrl":"10.1016/j.ajpath.2025.10.011","url":null,"abstract":"<div><div>Metabolic disorders and accompanying complications pose considerable risks to systemic organ health. Clinical studies have revealed a significant correlation between nonalcoholic steatohepatitis (NASH) and increased severity of periodontitis. However, directed mechanistic insights remain limited. This study aimed to elucidate the direct impact of NASH on periodontitis progression and to investigate the underlying mechanisms using both <em>in vivo</em> and <em>in vitro</em> models. In mice, a NASH diet induced severe liver damage and steatosis compared with chow-fed controls. Furthermore, NASH significantly exacerbated ligature-induced periodontitis, as evidenced by enhanced alveolar bone loss, inflammatory infiltration, and osteoclast activity. Notably, NASH was associated with elevated macrophage NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation in periodontitis relative to lean controls. Mechanistic <em>in vitro</em> experiments revealed that metabolic stimuli, palmitic acid and cholesterol, synergistically promoted NLRP3 inflammasome activation in <em>Porphyromonas gingivalis</em>, <em>P. gingivalis</em> lipopolysaccharide, as well as <em>Escherichia coli</em> lipopolysaccharide-conditioned macrophages. Importantly, macrophage conditioned medium generated with the combination of palmitic acid and cholesterol markedly potentiated osteoclast differentiation and function, as evidenced by enhanced osteoclastogenesis, F-actin ring assembly, and bone resorptive activity in receptor activator of NF-κΒ ligand–stimulated bone marrow–derived macrophages. This study suggests that NASH exacerbates experimental periodontitis by priming periodontal macrophages through the metabolic activation of the NLRP3 inflammasome. These collective data uncover a novel mechanism linking systemic metabolic dysregulation and osteoimmune responses, providing important insights into the comorbidity of inflammatory diseases.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 288-305"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145476735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alcohol Provokes Multi-Organ Injury through Multi-Mechanisms","authors":"Xiao-Ming Yin ,&nbsp;Wen-Xing Ding","doi":"10.1016/j.ajpath.2025.09.018","DOIUrl":"10.1016/j.ajpath.2025.09.018","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 1-3"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145802277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-6 trans-Signaling Regulates Neutrophilic Inflammation in Alcohol-Associated Hepatitis","authors":"Gaurav Sarode ,&nbsp;Ming-Fo Hsu ,&nbsp;Fawaz G. Haj ,&nbsp;Sergio Barace ,&nbsp;Josepmaria Argemi ,&nbsp;Mengfei Liu ,&nbsp;Prisha Pandita ,&nbsp;Sheng Cao ,&nbsp;Vijay H. Shah ,&nbsp;Dorina Gui ,&nbsp;Ramon Bataller ,&nbsp;Vikrant Rachakonda","doi":"10.1016/j.ajpath.2025.05.023","DOIUrl":"10.1016/j.ajpath.2025.05.023","url":null,"abstract":"<div><div>Alcohol-associated hepatitis (AH) is a form of acute-on-chronic liver failure characterized by intrahepatic neutrophilic inflammation. In hepatocytes, IL-6 signals through either membrane-bound (classical signaling) or soluble (<em>trans</em>-signaling; TS) IL-6 receptors (IL-6Rs) to regulate liver injury responses. This study investigated the role of IL-6TS in the pathophysiology of AH. RNA sequencing of liver biopsies from patients with alcohol-related liver disease demonstrated a progressive decline in IL-6R expression correlating with increasing AH severity. Transforming growth factor (TGF)-β1 emerged as the most potent negative regulator of IL-6R expression. Notably, STAT3-dependent gene expression was increased in severe AH. <em>In vitro</em>, treatment of HepG2 cells with TGF-β1 suppressed IL-6R expression. Subsequent treatment with either IL-6 to stimulate classical signaling, or hyper–IL-6, a recombinant IL-6/IL-6R α peptide, to activate <em>trans</em>-signaling activated STAT3. Hyper–IL-6, but not IL-6, restored STAT3 activation in the face of suppressed IL-6R. RNA sequencing of hyper–IL-6 stimulated cells identified a gene signature that stratified a subset of AH patients with: i) enhanced IL-6TS activity, ii) increased intrahepatic neutrophilic infiltration, and iii) transcriptional enrichment of leukocyte migration pathways. Female mice treated with 10-day chronic-plus-binge ethanol exhibited enhanced STAT3 activation despite reduced hepatic IL-6R expression, leading to increased expression of neutrophilic activators, with colocalization of Ly6G⁺ leukocytes and STAT3⁺ hepatocytes. Collectively, these results indicate that IL-6TS preserves hepatocyte STAT3-dependent gene expression and promotes neutrophilic inflammation in AH.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 223-240"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding How Alcohol Induces Human Acute Alcoholic Pancreatitis","authors":"Isto Nordback ,&nbsp;Hannu Paajanen ,&nbsp;Stephen Pandol","doi":"10.1016/j.ajpath.2025.03.008","DOIUrl":"10.1016/j.ajpath.2025.03.008","url":null,"abstract":"<div><div>Why only a minority of heavy alcohol drinkers develop acute alcoholic pancreatitis has been a puzzle. In this review, the sparse data available from published studies were collected and, based on them, a hypothesis was formed. Long-term high alcohol consumption results in lowered cholecystokinin and cholinergic stimulus of the pancreas, and causes concentration and acidification of pancreatic fluid, predisposing to protein secretion. Early during the withdrawal period when returning to a normal or high-fat nonalcoholic diet, there is a relative hyperstimulation of the pancreas, a well-established mechanism that results in experimental acute pancreatitis. Lower, physiological stimulation is enough to start acute pancreatitis, when the secretions cause temporary obstruction in the duct system. The stimulation against temporary obstruction results in experimental acute pancreatitis. Finally, the magnitude of alcohol-induced deficits in acinar cell defense mechanisms determines the onset of pancreatitis.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 68-77"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}