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Nature Reviews. Gastroenterology &... Dec 2018Cell death represents a basic biological paradigm that governs outcomes and long-term sequelae in almost every hepatic disease condition. Acute liver failure is... (Review)
Review
Cell death represents a basic biological paradigm that governs outcomes and long-term sequelae in almost every hepatic disease condition. Acute liver failure is characterized by massive loss of parenchymal cells but is usually followed by restitution ad integrum. By contrast, cell death in chronic liver diseases often occurs at a lesser extent but leads to long-term alterations in organ architecture and function, contributing to chronic hepatocyte turnover, the recruitment of immune cells and activation of hepatic stellate cells. These chronic cell death responses contribute to the development of liver fibrosis, cirrhosis and cancer. It has become evident that, besides apoptosis, necroptosis is a highly relevant form of programmed cell death in the liver. Differential activation of specific forms of programmed cell death might not only affect outcomes in liver diseases but also offer novel opportunities for therapeutic intervention. Here, we summarize the underlying molecular mechanisms and open questions about disease-specific activation and roles of programmed cell death forms, their contribution to response signatures and their detection. We focus on the role of apoptosis and necroptosis in acute liver injury, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) and liver cancer, and possible translations into clinical applications.
Topics: Animals; Apoptosis; Cell Death; Humans; Liver; Liver Diseases; Necrosis
PubMed: 30250076
DOI: 10.1038/s41575-018-0065-y -
Journal of Natural Products Jul 2022Oxidative stress plays an important role in acetaminophen (APAP)-induced hepatotoxicity. Platanosides (PTSs) isolated from the American sycamore tree () represent a... (Review)
Review
Oxidative stress plays an important role in acetaminophen (APAP)-induced hepatotoxicity. Platanosides (PTSs) isolated from the American sycamore tree () represent a potential new four-molecule botanical drug class of antibiotics active against drug-resistant infectious disease. Preliminary studies have suggested that PTSs are safe and well tolerated and have antioxidant properties. The potential utility of PTSs in decreasing APAP hepatotoxicity in mice in addition to an assessment of their potential with APAP for the control of infectious diseases along with pain and pyrexia associated with a bacterial infection was investigated. On PTS treatment in mice, serum alanine aminotransferase (ALT) release, hepatic centrilobular necrosis, and 4-hydroxynonenal (4-HNE) were markedly decreased. In addition, inducible nitric oxide synthase (iNOS) expression and c-Jun--terminal kinase (JNK) activation decreased when mice overdosed with APAP were treated with PTSs. Computational studies suggested that PTSs may act as JNK-1/2 and Keap1-Nrf2 inhibitors and that the isomeric mixture could provide greater efficacy than the individual molecules. Overall, PTSs represent promising botanical drugs for hepatoprotection and drug-resistant bacterial infections and are effective in protecting against APAP-related hepatotoxicity, which decreases liver necrosis and inflammation, iNOS expression, and oxidative and nitrative stresses, possibly by preventing persistent JNK activation.
Topics: Acetaminophen; Animals; Chemical and Drug Induced Liver Injury; Drug Combinations; Glycosides; Kelch-Like ECH-Associated Protein 1; Liver; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Necrosis; Oxidative Stress; Phenols
PubMed: 35815804
DOI: 10.1021/acs.jnatprod.2c00324 -
Journal of Zhejiang University.... Apr 2022Acetaminophen, also known as -acetyl--aminophenol (APAP), is commonly used as an antipyretic and analgesic agent. APAP overdose can induce hepatic toxicity, known as... (Review)
Review
Acetaminophen, also known as -acetyl--aminophenol (APAP), is commonly used as an antipyretic and analgesic agent. APAP overdose can induce hepatic toxicity, known as acetaminophen-induced liver injury (AILI). However, therapeutic doses of APAP can also induce AILI in patients with excessive alcohol intake or who are fasting. Hence, there is a need to understand the potential pathological mechanisms underlying AILI. In this review, we summarize three main mechanisms involved in the pathogenesis of AILI: hepatocyte necrosis, sterile inflammation, and hepatocyte regeneration. The relevant factors are elucidated and discussed. For instance, -acetyl--benzoquinone imine (NAPQI) protein adducts trigger mitochondrial oxidative/nitrosative stress during hepatocyte necrosis, danger-associated molecular patterns (DAMPs) are released to elicit sterile inflammation, and certain growth factors contribute to liver regeneration. Finally, we describe the current potential treatment options for AILI patients and promising novel strategies available to researchers and pharmacists. This review provides a clearer understanding of AILI-related mechanisms to guide drug screening and selection for the clinical treatment of AILI patients in the future.
Topics: Acetaminophen; Analgesics, Non-Narcotic; Animals; Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Humans; Inflammation; Liver; Mice; Mice, Inbred C57BL; Necrosis
PubMed: 35403383
DOI: 10.1631/jzus.B2100977 -
Theranostics 2022Liver fibrosis affects millions of people worldwide without an effective treatment. Although multiple cell types in the liver contribute to the fibrogenic process,...
Liver fibrosis affects millions of people worldwide without an effective treatment. Although multiple cell types in the liver contribute to the fibrogenic process, hepatocyte death is considered to be the trigger. Multiple forms of cell death, including necrosis, apoptosis, and necroptosis, have been reported to co-exist in liver diseases. Mixed lineage kinase domain-like protein () is the terminal effector in necroptosis pathway. Although necroptosis has been reported to play an important role in a number of liver diseases, the function of MLKL in liver fibrosis has yet to be unraveled. Here we report that MLKL level is positively correlated with a number of fibrotic markers in liver samples from both patients with liver fibrosis and animal models. Mlkl deletion in mice significantly reduces clinical symptoms of CCl- and bile duct ligation (BDL) -induced liver injury and fibrosis. Further studies indicate that blocks liver fibrosis by reducing hepatocyte necroptosis and hepatic stellate cell (HSC) activation. AAV8-mediated specific knockdown of in hepatocytes remarkably alleviates CCl-induced liver fibrosis in both preventative and therapeutic ways. Our results show that MLKL-mediated signaling plays an important role in liver damage and fibrosis, and targeting MLKL might be an effective way to treat liver fibrosis.
Topics: Animals; Apoptosis; Fibrosis; Hepatic Stellate Cells; Hepatocytes; Humans; Liver Cirrhosis; Mice; Necroptosis; Necrosis; Protein Kinases
PubMed: 35836819
DOI: 10.7150/thno.71400 -
The Journal of Clinical Investigation Aug 2023The liver can fully regenerate after partial resection, and its underlying mechanisms have been extensively studied. The liver can also rapidly regenerate after injury,...
The liver can fully regenerate after partial resection, and its underlying mechanisms have been extensively studied. The liver can also rapidly regenerate after injury, with most studies focusing on hepatocyte proliferation; however, how hepatic necrotic lesions during acute or chronic liver diseases are eliminated and repaired remains obscure. Here, we demonstrate that monocyte-derived macrophages (MoMFs) were rapidly recruited to and encapsulated necrotic areas during immune-mediated liver injury and that this feature was essential in repairing necrotic lesions. At the early stage of injury, infiltrating MoMFs activated the Jagged1/notch homolog protein 2 (JAG1/NOTCH2) axis to induce cell death-resistant SRY-box transcription factor 9+ (SOX9+) hepatocytes near the necrotic lesions, which acted as a barrier from further injury. Subsequently, necrotic environment (hypoxia and dead cells) induced a cluster of complement 1q-positive (C1q+) MoMFs that promoted necrotic removal and liver repair, while Pdgfb+ MoMFs activated hepatic stellate cells (HSCs) to express α-smooth muscle actin and induce a strong contraction signal (YAP, pMLC) to squeeze and finally eliminate the necrotic lesions. In conclusion, MoMFs play a key role in repairing the necrotic lesions, not only by removing necrotic tissues, but also by inducing cell death-resistant hepatocytes to form a perinecrotic capsule and by activating α-smooth muscle actin-expressing HSCs to facilitate necrotic lesion resolution.
Topics: Humans; Actins; Liver; Hepatocytes; Macrophages; Hepatic Stellate Cells; Necrosis; Liver Neoplasms
PubMed: 37338984
DOI: 10.1172/JCI166954 -
International Journal of Molecular... Oct 2022Over the past few decades, mechanisms of programmed cell death have attracted the scientific community because they are involved in diverse human diseases. Initially,... (Review)
Review
Over the past few decades, mechanisms of programmed cell death have attracted the scientific community because they are involved in diverse human diseases. Initially, apoptosis was considered as a crucial mechanistic pathway for programmed cell death; recently, an alternative regulated mode of cell death was identified, mimicking the features of both apoptosis and necrosis. Several lines of evidence have revealed that dysregulation of necroptosis leads to pathological diseases such as cancer, cardiovascular, lung, renal, hepatic, neurodegenerative, and inflammatory diseases. Regulated forms of necrosis are executed by death receptor ligands through the activation of receptor-interacting protein kinase (RIPK)-1/3 and mixed-lineage kinase domain-like (MLKL), resulting in the formation of a necrosome complex. Many papers based on genetic and pharmacological studies have shown that RIPKs and MLKL are the key regulatory effectors during the progression of multiple pathological diseases. This review focused on illuminating the mechanisms underlying necroptosis, the functions of necroptosis-associated proteins, and their influences on disease progression. We also discuss numerous natural and chemical compounds and novel targeted therapies that elicit beneficial roles of necroptotic cell death in malignant cells to bypass apoptosis and drug resistance and to provide suggestions for further research in this field.
Topics: Humans; Necroptosis; Receptor-Interacting Protein Serine-Threonine Kinases; Protein Kinases; Necrosis; Cell Death; Apoptosis
PubMed: 36361505
DOI: 10.3390/ijms232112714 -
Thoracic Cancer Mar 2023The study aimed to fully understand small bowel necrosis, a rare but fatal complication after esophagectomy.
BACKGROUND
The study aimed to fully understand small bowel necrosis, a rare but fatal complication after esophagectomy.
METHODS
Patients who underwent esophagectomy for esophageal cancer at the Fudan University Shanghai Cancer Center from January 2013 to December 2021 were retrospectively reviewed. Clinical information on the demographics, presenting features, and outcomes of the cases were collected.
RESULTS
Of the 6607 patients during the study period, 11 (0.2%) underwent reoperation due to bowel necrosis, including nine males (81.8%) and two females (18.2%). Among them, eight cases (72.7%) had hypertension and seven (63.6%) suffered from lower thoracic esophageal cancer. Eight (72.7%) and three (27.3%) patients underwent the Ivor-Lewis and McKewon procedures, respectively. Jejunostomy was performed in nine patients (81.8%). The first signs of bowel necrosis appeared within 5 days after esophagectomy. Abdominal distension and deteriorating renal function were observed in seven patients (63.6%). There was no evidence of mesenteric vascular occlusion in any of the 11 cases, except for the hepatic portal venous gas found in seven patients on the computed tomography (CT) scan. Eight (72.7%) of the 11 patients underwent reoperation within 24 h due to the onset of the first symptoms. Eight (72.7%) had ileal necrosis, and three (27.3%) died.
CONCLUSION
Close attention should be paid to patients with abdominal distension, renal function damage, and portal hepatic venous gas after esophagectomy. These patients may suffer from small bowel necrosis, which may result in rapid disease progression. Exploratory laparotomy and bowel resection are effective treatments for such patients.
Topics: Male; Female; Humans; Esophagectomy; Retrospective Studies; China; Esophageal Neoplasms; Necrosis
PubMed: 36734100
DOI: 10.1111/1759-7714.14817 -
Cell Proliferation Mar 2022Chronic alcohol consumption can cause alcoholic liver disease (ALD), leading to morbidity and mortality worldwide. Complex disease progression of ALD varies from... (Review)
Review
Chronic alcohol consumption can cause alcoholic liver disease (ALD), leading to morbidity and mortality worldwide. Complex disease progression of ALD varies from alcoholic fatty liver to alcoholic steatohepatitis, eventually contributing to fibrosis and cirrhosis. Accumulating evidence revealed that necroptosis, a way of programmed cell death different from apoptosis and traditional necrosis, is involved in the underlying pathogenic molecular mechanism of ALD. Receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed-lineage kinase domain-like pseudokinase have been implicated as key mediators to execute necroptosis. Also, necroptosis has gained increasing attention due to its potential association with primary pathological hallmarks of ALD, including oxidative stress, hepatic steatosis and inflammation. This review summarizes the recent progress on the roles and mechanisms of necroptosis and focuses on the crosstalk between necroptosis and the other pathogenesis of ALD, providing a theoretical basis for targeting necroptosis as a novel treatment for ALD.
Topics: Animals; Hepatocytes; Humans; Liver; Liver Diseases, Alcoholic; Necroptosis; Necrosis; Oxidative Stress
PubMed: 35083817
DOI: 10.1111/cpr.13193 -
Journal of Veterinary Diagnostic... Mar 2020Clostridia can cause hepatic damage in domestic livestock, and wild and laboratory animals. type B causes infectious necrotic hepatitis (INH) in sheep and less... (Review)
Review
Clostridia can cause hepatic damage in domestic livestock, and wild and laboratory animals. type B causes infectious necrotic hepatitis (INH) in sheep and less frequently in other species. Spores of type B can be present in soil; after ingestion, they reach the liver via portal circulation where they persist in phagocytic cells. Following liver damage, frequently caused by migrating parasites, local anaerobic conditions allow germination of the clostridial spores and production of toxins. type B alpha toxin causes necrotizing hepatitis and extensive edema, congestion, and hemorrhage in multiple organs. causes bacillary hemoglobinuria (BH) in cattle, sheep, and rarely, horses. Beta toxin is the main virulence factor of , causing hepatic necrosis and hemolysis. , the causal agent of Tyzzer disease (TD), is the only gram-negative and obligate intracellular pathogenic clostridia. TD occurs in multiple species, but it is more frequent in foals, lagomorphs, and laboratory animals. The mode of transmission is fecal-oral, with ingestion of spores from a fecal-contaminated environment. In affected animals, proliferates in the intestinal mucosa, resulting in necrosis, and then disseminates to the liver and other organs. Virulence factors for this microorganism have not been identified, to date. Given the peracute or acute nature of clostridial hepatitis in animals, treatment is rarely effective. However, INH and BH can be prevented, and should be controlled by vaccination and control of liver flukes. To date, no vaccine is available to prevent TD.
Topics: Animals; Clostridiales; Clostridium; Clostridium Infections; Hemoglobinuria; Hepatitis, Animal; Necrosis
PubMed: 31735127
DOI: 10.1177/1040638719886567 -
Cellular and Molecular Gastroenterology... 2022Marked enhancement of neutrophil infiltration in the liver is a hallmark of acute liver failure (ALF), a severe life-threatening disease with varying etiologies....
BACKGROUND & AIMS
Marked enhancement of neutrophil infiltration in the liver is a hallmark of acute liver failure (ALF), a severe life-threatening disease with varying etiologies. However, the mechanisms and pathophysiological role corresponding to hepatic neutrophil infiltration during ALF development remain poorly characterized.
METHODS
Experimental ALF was induced in 10-week-old male microRNA-223 (miR-223) knockout (KO) mice, neutrophil elastase (NE) KO mice, and wild-type controls by intraperitoneal injection of galactosamine hydrochloride and lipopolysaccharide. Age-matched mice were injected with phosphate-buffered saline and served as vehicle controls.
RESULTS
Mouse liver with ALF showed evident formation of neutrophil extracellular traps (NETs), which were enhanced markedly in miR-223 KO mice. The blockade of NETs by pharmacologic inhibitor GSK484 significantly attenuated neutrophil infiltration and massive necrosis in mouse liver with ALF. ALF-related hepatocellular damage and mortality in miR-223 KO mice were aggravated significantly and accompanied by potentiated neutrophil infiltration in the liver when compared with wild-type controls. Transcriptomic analyses showed that miR-223 deficiency in bone marrow predominantly caused the enrichment of pathways involved in neutrophil degranulation. Likewise, ALF-induced hepatic NE enrichment was potentiated in miR-223 KO mice. Genetic ablation of NE blunted the formation of NETs in parallel with significant attenuation of ALF in mice. Pharmaceutically, pretreatment with the NE inhibitor sivelestat protected mice against ALF.
CONCLUSIONS
The present study showed the miR-223/NE axis as a key modulator of NETs, thereby exacerbating oxidative stress and neutrophilic inflammation to potentiate hepatocellular damage and liver necrosis in ALF development, and offering potential targets against ALF.
Topics: Animals; Extracellular Traps; Leukocyte Elastase; Liver Failure, Acute; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; Necrosis
PubMed: 35660025
DOI: 10.1016/j.jcmgh.2022.05.012