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Extracellular vesicles (EVs) carrying functional cargoes are emerging as biomarkers and treatment strategies in multiple liver diseases. Nevertheless, the potential of EVs in liver failure remains indistinct. In this systematic review, we comprehensively analyzed the potential of EVs as biomarkers of liver failure and the therapeutic effects and possible mechanisms of EVs for liver failure. We conducted a systematic review by comprehensively searching the following electronic databases: PubMed, Web of Science, Embase and Cochrane Central Register of Controlled Trials from inception to March 2022. The used text words (synonyms and word variations) and database-specific subject headings included \"Extracellular Vesicles\", \"Exosomes\", \"Liver Failure\", \"Liver Injury\", etc. A total of 1479 studies were identified. After removing 680 duplicate studies and 742 irrelevant studies, 57 studies were finally retained and analyzed. Fourteen studies revealed EVs with functional cargoes could be used to make the diagnosis of liver failure and provide clues for early warning and prognostic assessment of patients with liver failure. Forty-three studies confirmed the administration of EVs from different sources alleviated hepatic damage and improved survival through inhibiting inflammatory response, oxidative stress as well as apoptosis or promoting hepatocyte regeneration and autophagy. EVs and their cargoes can be used not only as superior biomarkers of early warning, early diagnosis and prognostic assessments for liver failure, but also as potentially effective treatment options for liver failure. In the future, large-scale studies are urgently needed to verify the diagnostic, predictive and therapeutic value of EVs for liver failure.

We previously documented that M2-like macrophages exert a hepatoprotective effect in acute-on-chronic liver failure (ACLF) by inhibiting necroptosis signalling. Nevertheless, the molecular mechanism behind this hepatoprotection still needs to be further dissected. Galectin-3 (GAL3) has been reported to be critically involved in the pathogenesis of multiple liver diseases, whereas the potential role of GAL3 in ACLF remains to be explored. Herein, we hypothesised that GAL3 plays a pivotal role in the hepatoprotection conferred by M2-like macrophages in ACLF by inhibiting necroptosis. To test this hypothesis, we first assessed the expression of GAL3 in control and fibrotic mice with or without acute insult. Second, loss- and gain-of-function experiments of GAL3 were performed. Third, the correlation between GAL3 and M2-like macrophage activation was analysed, and the potential role of GAL3 in M2-like macrophage-conferred hepatoprotection was confirmed. Finally, the molecular mechanism underlying GAL3-mediated hepatoprotection was dissected. GAL3 was found to be obviously upregulated in fibrotic mice with or without acute insult but not in acutely injured mice. Depletion of GAL3 aggravated hepatic damage in fibrotic mice upon insult. Conversely, adoptive transfer of GAL3 provided normal mice enhanced resistance against acute insult. The expression of GAL3 is closely correlated with M2-like macrophage activation. Through adoptive transfer and depletion experiments, M2-like macrophages were verified to act as a major source of GAL3. Importantly, GAL3 was confirmed to hold a pivotal place in the hepatoprotection conferred by M2-like macrophages through loss- and gain-of-function experiments. Unexpectedly, the depletion and adoptive transfer of GAL3 resulted in significant differences in the expression levels of pyroptosis but not necroptosis signalling molecules. Taken together, GAL3 plays a pivotal role in the hepatoprotection conferred by M2-like macrophages in ACLF by inhibiting pyroptosis but not necroptosis signalling. Our findings provide novel insights into the pathogenesis and therapy of ACLF.

Disseminated intravascular coagulation (DIC) is considered to be the most common and lethal complication of sepsis. NLR-family pyrin domain-containing-3 (NLRP3) inflammasome plays an important role in host defense against microbial pathogens, and its deregulation may cause coagulation cascade and should be strictly managed. Here, we identified the deubiquitinase YOD1, which played a vital role in regulating coagulation in a NLRP3 inflammasome-dependent manner in sepsis induced by methicillin-resistant Staphylococcus aureus (MRSA). YOD1 interacted with NLRP3 to remove K33-linked ubiquitination of NLRP3 based on its deubiquitinating enzyme activity and specifically inhibited expression of NLRP3 as well as activation of NLRP3 inflammasome. Deficiency of YOD1 expression enhanced NLRP3 inflammasome activation and coagulation both in vitro and in vivo. In addition, pharmacological inhibition of the NLRP3 effectively improved coagulation and alleviated organ injury in Yod1 −/− mice infected with MRSA. Thus, our study reported that YOD1 is a key regulator of coagulation during MRSA infection, and provided YOD1 as a potential therapeutic target for the treatment of NLRP3 inflammasome-related diseases, especially MRSA sepsis-induced DIC.

Staphylococcus aureus ( S. aureus ) is a foodborne pathogen that causes severe diseases, such as endocarditis, sepsis, and bacteremia. As an important component of innate immune system, the NLR family pyrin domain-containing 3 (NLRP3) inflammasome plays a critical role in defense against pathogen infection. However, the cellular mechanism of NLRP3 inflammasome activation during S. aureus infection remains unknown. In the present study, we found that spleen tyrosine kinase (Syk) and c-Jun N-terminal kinase (JNK) were rapidly phosphorylated during S. aureus infection. Moreover, a Syk/JNK inhibitor and Syk/JNK siRNA not only reduced NLRP3 inflammasome-associated molecule expression at the protein and mRNA levels, apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) speck formation, and interleukin-1β (IL-1β), and IL-18 release but also rescued the decreased NIMA-related kinase 7 (NEK7) expression level following suppression of the NEK7-NLRP3 interaction in macrophages. Interestingly, Syk/JNK phosphorylation levels and NLRP3 inflammasome-associated molecule expression were decreased by blockade of K + efflux. Furthermore, activation of the NLRP3 inflammasome and a lower NEK7 protein level were found in vivo upon S. aureus infection. Taken together, our data indicated that S. aureus infection induces a K + efflux/Syk/JNK/NEK7-NLRP3 signaling pathway and the subsequent activation of the NLRP3 inflammasome for the release of proinflammatory cytokines. This study expands our understanding of the basic molecular mechanism regulating inflammation and provides potential value for anti-infective drug development against S. aureus infection.

Background Cells and tissues, such as macrophages, express inducible nitric oxide synthase (INOS) after stimulation by certain factors. INOS helps mediate the macrophage inflammatory reaction, but few studies have explored how INOS affects macrophage function in nonalcoholic fatty liver disease (NAFLD). Objective This study investigated the role of INOS‐mediated macrophage activity in NAFLD. Methods A high‐fat diet was used to establish an NAFLD mouse model. After 12 weeks, blood was collected for immune cell and lipid analyses, and liver tissues were collected for pathological analyses with hematoxylin and eosin and Oil Red O staining. Peritoneal macrophages were extracted in situ, cultured in Dulbecco's modified Eagle's medium, and stimulated with palmitic acid to mimic in vivo conditions for further assays. Real‐time polymerase chain reaction, western blot analysis, and immunofluorescence were used to verify the expression of target genes or proteins. Results In the NAFLD model, INOS expression in macrophages increased, and INOS knockdown significantly decreased the number of macrophages. Pathological examinations confirmed that INOS knockdown slowed NAFLD progression and macrophage infiltration during inflammation. INOS knockdown also enhanced phagocytosis and lipid transport by macrophages, and increased the expression of autophagy‐related molecules in macrophages, which improved the autophagy level, promoted apoptotic cell degradation, and maintained intracellular environment homeostasis. Conclusions These results indicate a correlation between INOS expression and macrophage function in NAFLD.

Introduction Acute liver inflammatory reactions contribute to many health problems; thus, it is critical to understand the underlying pathogenic mechanisms of acute hepatitis. In this study, an experimental in vivo model of concanavalin A (ConA)‐induced hepatitis was used. Materials and Methods C57BL/6 (wild‐type, WT) or inducible nitric oxide synthase‐deficient (iNOS−/−) mice were injected with PBS or 15 mg/kg ConA via tail vein. Detection of liver injury by histological examination and apoptosis, and flow cytometry to detect the effect of immune cells on liver injury. Results iNOS−/− mice had lower levels of the liver enzymes aspartate aminotransferase and alanine aminotransferase, suggesting that they were protected against ConA‐induced pathological liver injury and that iNOS participated in the regulation of hepatitis. Furthermore, iNOS deficiency was found to lower CD86 expression and suppressed the messenger RNA levels of inflammatory factors in the liver. In vitro experiments also demonstrated that iNOS deficiency suppressed the sequential phosphorylation of the mitogen‐activated protein kinase pathway cascade, thereby inhibiting the M1 polarization of macrophages and consequently suppressing the transcription of inflammation factors. Conclusion iNOS may contribute to ConA‐induced inflammation by promoting the activation of proinflammatory macrophages. We believe that our study makes a significant contribution to the literature because we identify that inducible nitric oxide synthase‐deficient may contribute to concanavalin A‐induced inflammation by promoting the activation of proinflammatory macrophages.

目的 探讨成体人肝源性干细胞外泌体(HLSC-exo)不同时间静脉注射对刀豆蛋白A(ConA)诱导的小鼠急性肝损伤的保护作用。 方法 差速离心法提取HLSC-exo，Western blot检测其标志蛋白CD9、CD63的表达，纳米颗粒跟踪分析粒径分布。将56只C57BL/6雄性小鼠随机分为3组，空白对照组、ConA模型组和HLSC-exo治疗组。根据给予磷酸盐缓冲液或HLSC-exo后再注射ConA间隔时间不同，分为3 h、6 h、12 h亚组；检测血清中ALT、AST、TNFα、IL-10水平；比较各组小鼠肝脏大体形态及病理组织变化。计量资料多组间比较采用单因素方差分析，进一步两两比较采用LSD-t检验。 结果 HLSC-exo是直径为90~110 nm的囊泡体，电镜下可见清晰的“茶托样”结构，其特异性标志蛋白CD9和CD63均有明显的表达；空白对照组小鼠ALT、AST水平分别为(31.81±6.74)U/L、(69.75±8.30)U/L。相较于空白对照组，ConA 3 h、6 h、12 h模型组小鼠ALT、AST水平明显升高(P值均＜0.001)；HLSC-exo 3 h、6 h治疗组ALT、AST水平较ConA 3 h、6 h模型组明显下降[(225.58±115.59)U/L vs (1989.32±347.67)U/L、(1174.71±203.30)U/L vs (2208.33±349.96)U/L，(303.53±126.68)U/L vs (2534.27±644.72)U/L、(1340.70±262.56)U/L vs (2437.13±288.13)U/L，P值均＜0.001]；与HLSC-exo 6 h治疗组相比，HLSC-exo 3 h治疗组下降更明显(P＜0.001)。空白对照组小鼠IL-10、TNFα水平分别为(313.51±10.97)pg/mL，(476.05±7.31)pg/mL。相较于空白对照组，ConA3 h、6 h、12 h模型组IL-10水平均明显下降(P值均＜0.001)；HLSC-exo 3 h、6 h治疗组IL-10水平相较于ConA 3 h、6 h模型组明显升高[(331.61±10.46)pg/mL vs (266.20±8.15)pg/mL、(288.13±10.74)pg/mL vs (264.41±9.12)pg/mL，P值均＜0.001]；且与H

摘要:目的探究益生菌干预对慢加急性肝衰竭 (ACLF) 大鼠的作用及其机制。方法采用随机数字表法将44只雄性SD大鼠随机分为6组,对照组1 (C1组,n=6,不做任何干预) 、模型组1 (M1组,n=8,40%CCl4油溶液腹腔注射10周,从第7周开始每天灌胃PBS溶液,10周末给予D-GalN急性攻击) 、益生菌干预组1 (Y1组,n=8,造模同M1组,灌胃剂为益生菌溶液) 、对照组2 (C2组,n=6,不做任何干预) 、模型组2 (M2组,n=8,腹腔注射40%CCl4油溶液,10周后给予D-GalN急性攻击,48 h后每天灌胃PBS溶液,持续到第12周末处死) 、益生菌干预组2 (Y2组,n=8,造模同M2组,灌胃剂为益生菌溶液) 。观察干预前后大鼠体质量、肝功能、肝组织病理学,采用ELISA法测血浆内毒素、肠道分泌型免疫球蛋白A (s IgA) ,Western Blot法测定肠道紧密连接蛋白occludin的水平,RT-PCR法检测肠道紧密连接蛋白occludin和ZO-1的mRNA水平,通过选择性培养基测定肠道菌群等指标的变化。计量资料多组间比较采用单因素方差分析,进一步两两比较采用SNK-q检验。结果 C1、...

Electricity prices are a central element of the electricity market, and accurate electricity price forecasting is critical for market participants. However, in the context of increasingly integrated economic markets, the complexity of the electricity system has increased. As a result, the number of factors required to consider in electricity price forecasting is growing. In addition, the high percentage of renewable energy penetration has increased the volatility of electricity generation, making it more challenging to predict prices accurately. In this paper, we propose a probabilistic forecasting method based on SHAP (SHapley Additive exPlanation) feature selection and LSTNet (long- and short-term time-series network) quantile regression. First, to reduce feature redundancy and overfitting, we use the SHAP method to perform feature selection in a high-dimensional input feature set, and specifically analyze the magnitude and manner in which features affect electricity prices. Second, we apply the LSTNet quantile regression model to predict the electricity value under different quantiles. Finally, the probability density function and the prediction interval of the predicted electricity prices are obtained by kernel density estimation. The case of the Danish electricity market validates the effectiveness and accuracy of our proposed method. The accuracy of the proposed method is better than that of other methods, and we assess the importance and direction of the impact of features on electricity prices.