Leukocyte cell-derived chemotaxin 2(LECT2),initially identified as a multifunctional protein secreted by hepatocytes and involved in diverse hepatic pathophysiological processes(Yamagoe et al.,1998;Xie et al.,2022),is...Leukocyte cell-derived chemotaxin 2(LECT2),initially identified as a multifunctional protein secreted by hepatocytes and involved in diverse hepatic pathophysiological processes(Yamagoe et al.,1998;Xie et al.,2022),is also a prominent amyloid fibril protein in both renal and hepatic amyloidosis(Mann et al.,2022).Recently,LECT2 has been implicated in immune processes across various pathologies,including hepatocellular carcinoma(HCC),nonalcoholic fatty liver disease(NAFLD),sepsis,atherosclerosis,arthritis,and allergic diseases(Zhu et al.,2023).展开更多
Background and aim Hepatic ischemia–reperfusion injury(IRI)is a significant challenge in liver transplantation,trauma,hypovolemic shock,and hepatectomy,with limited effective interventions available.This study aimed ...Background and aim Hepatic ischemia–reperfusion injury(IRI)is a significant challenge in liver transplantation,trauma,hypovolemic shock,and hepatectomy,with limited effective interventions available.This study aimed to investigate the role of leukocyte cell-derived chemotaxin 2(LECT2)in hepatic IRI and assess the therapeutic potential of Lect2-short hairpin RNA(shRNA)delivered through adeno-associated virus(AAV)vectors.Materials and methods This study analyzed human liver and serum samples from five patients undergoing the Pringle maneuver.Lect2-knockout and C57BL/6J mice were used.Hepatic IRI was induced by clamping the hepatic pedicle.Treatments included recombinant human LECT2(rLECT2)and AAV-Lect2-shRNA.LECT2 expression levels and serum biomarkers including alanine aminotransferase(ALT),aspartate aminotransferase(AST),creatinine,and blood urea nitrogen(BUN)were measured.Histological analysis of liver necrosis and quantitative reverse-transcription polymerase chain reaction were performed.Results Serum and liver LECT2 levels were elevated during hepatic IRI.Serum LECT2 protein and mRNA levels increased post reperfusion.Lect2-knockout mice had reduced weight loss;hepatic necrosis;and serum ALT,AST,creatinine,and BUN levels.rLECT2 treatment exacerbated weight loss,hepatic necrosis,and serum biomarkers(ALT,AST,creatinine,and BUN).AAV-Lect2-shRNA treatment significantly reduced weight loss,hepatic necrosis,and serum biomarkers(ALT,AST,creatinine,and BUN),indicating therapeutic potential.Conclusions Elevated LECT2 levels during hepatic IRI increased liver damage.Genetic knockout or shRNA-mediated knockdown of Lect2 reduced liver damage,indicating its therapeutic potential.AAV-mediated Lect2-shRNA delivery mitigated hepatic IRI,offering a potential new treatment strategy to enhance clinical outcomes for patients undergoing liver-related surgeries or trauma.展开更多
Leukocyte cell-derived chemotaxin 2 (LECT2), a multifunctional hepatokine, is involved in many pathological conditi ons. However, its role in atherosclerosis remains undefined. In this study, we admimistered vehicle o...Leukocyte cell-derived chemotaxin 2 (LECT2), a multifunctional hepatokine, is involved in many pathological conditi ons. However, its role in atherosclerosis remains undefined. In this study, we admimistered vehicle or LECT2 to male Apoe^-/- mice fed a Western diet for 15 weeks. Atherosclerotic lesions were visualized and quantified with Oil-red O and hematoxylin staining. The mRNA expression levels of MCP-1, MMP-1, IL-8 IL-1β, and TNF-a were analyzed by quantitative real-time polymerase chain reaction. Serum TNF-a, IL-1β, IL-8, MCP-1, and MMP-1 concentrations were measured by en zyme-li nked immuno sorbent assay. CD68, CD31, and a-SMA, markers of macrophages, endothelial cells, and smooth muscle cells, respectively, were detected by immuno staining. Results showed that LECT2 reduced total cholesterol and low-density lipoprotein concentrations in serum and inhibited the development of atherosclerotic lesions, accompanied by reductions in inflammatory cytokines and lower MCP-1, MMP-1, TNF-a, IL-8, and IL-1β mRNA abundanee. Furthermore, LECT2 decreased CD68, but in creased cr SMA in atherosclerotic lesi ons, suggesting an in crease in smooth muscle cells and reduction in macrophages. In summary, LECT2 inhibited the development of atherosclerosis in mice, accompanied by reduced serum total cholesterol concentration and lower inflammatory responses.展开更多
基金funded by the National Natural Science Foundation of China(32170830)the Natural Science Foundation of Guangdong Province(2021A1515010422)。
文摘Leukocyte cell-derived chemotaxin 2(LECT2),initially identified as a multifunctional protein secreted by hepatocytes and involved in diverse hepatic pathophysiological processes(Yamagoe et al.,1998;Xie et al.,2022),is also a prominent amyloid fibril protein in both renal and hepatic amyloidosis(Mann et al.,2022).Recently,LECT2 has been implicated in immune processes across various pathologies,including hepatocellular carcinoma(HCC),nonalcoholic fatty liver disease(NAFLD),sepsis,atherosclerosis,arthritis,and allergic diseases(Zhu et al.,2023).
文摘Background and aim Hepatic ischemia–reperfusion injury(IRI)is a significant challenge in liver transplantation,trauma,hypovolemic shock,and hepatectomy,with limited effective interventions available.This study aimed to investigate the role of leukocyte cell-derived chemotaxin 2(LECT2)in hepatic IRI and assess the therapeutic potential of Lect2-short hairpin RNA(shRNA)delivered through adeno-associated virus(AAV)vectors.Materials and methods This study analyzed human liver and serum samples from five patients undergoing the Pringle maneuver.Lect2-knockout and C57BL/6J mice were used.Hepatic IRI was induced by clamping the hepatic pedicle.Treatments included recombinant human LECT2(rLECT2)and AAV-Lect2-shRNA.LECT2 expression levels and serum biomarkers including alanine aminotransferase(ALT),aspartate aminotransferase(AST),creatinine,and blood urea nitrogen(BUN)were measured.Histological analysis of liver necrosis and quantitative reverse-transcription polymerase chain reaction were performed.Results Serum and liver LECT2 levels were elevated during hepatic IRI.Serum LECT2 protein and mRNA levels increased post reperfusion.Lect2-knockout mice had reduced weight loss;hepatic necrosis;and serum ALT,AST,creatinine,and BUN levels.rLECT2 treatment exacerbated weight loss,hepatic necrosis,and serum biomarkers(ALT,AST,creatinine,and BUN).AAV-Lect2-shRNA treatment significantly reduced weight loss,hepatic necrosis,and serum biomarkers(ALT,AST,creatinine,and BUN),indicating therapeutic potential.Conclusions Elevated LECT2 levels during hepatic IRI increased liver damage.Genetic knockout or shRNA-mediated knockdown of Lect2 reduced liver damage,indicating its therapeutic potential.AAV-mediated Lect2-shRNA delivery mitigated hepatic IRI,offering a potential new treatment strategy to enhance clinical outcomes for patients undergoing liver-related surgeries or trauma.
基金supported by the National Natural Science Foundation of China(No.82204755,81960751,81960761)Guangxi Natural Science Youth Fund Project(No.2020GXNSFBA297094,2020GXNSFAA297119,2023GXNSFBA026274)+6 种基金the Basic Ability Enhancement Program for Young and Middle-aged Teachers of Guangxi(No.2022KY1667)the First-Class Discipline Project of Guangxi University of Chinese Medicine(No.2019XK141)the National Student Innovation and Entrepreneurship Training Program of Faculty of Chinese Medicine ScienceGuangxi University of Chinese Medicine(No.202213643011)Youth Fund Project of Guangxi University of Chinese Medicine(No.2020QN006,2022MS024,2022QN008)Research Projects of Faculty of Chinese Medicine ScienceGuangxi University of Chinese Medicine(No.2022MS002,2022MS008,2022QJ001)。
文摘脂肪堆积过多、生物钟失调、病毒感染、持续炎症反应等可造成肝脏炎症、纤维化、癌变,促进慢性肝病的发展。深入了解导致慢性肝病的病因,以及影响其发生和发展的基本机制,有助于确定潜在的治疗目标,进行靶向治疗。孤儿受体(orphan nuclear receptors,ONRs)是指无相应内源性配体与其结合的受体,对ONRs及其生物学特性的研究促进了合成配体的发展,对研究治疗多种疾病的有效靶点具有重要作用。近年来,研究发现ONRs对于维持正常的肝脏功能至关重要,其功能障碍可影响各种肝脏疾病。ONRs可通过调控激素、转录因子,影响生物钟、氧化应激等方式,影响肝脏脂质代谢、炎症反应、癌细胞增殖等病理生理学活动。基于此,本文重点介绍维甲酸相关孤儿受体(retinoid related orphan nuclear receptors,RORs)亚家族、孕烷X受体(pregnaneXreceptor,PXR)、白细胞衍生的趋化因子2(leukocytecellderivedchemotaxin2,LECT2)、核受体Nur77、肝细胞核因子4α(hepatocyte nuclear factor 4α,HNF4α)这些ONRs通过不同的方式调控不同类型慢性肝病的发生和发展,为基于ONRs调控慢性肝病治疗策略提供有益参考。
基金supported by the Program for the National Natural Science Foundation of China(31772876)Ningbo Municipal Bureau of Science and Technology(2018A610389)+1 种基金Scientific Innovation Team Project of Ningbo(2015C110018)K.C.Wong Magna Fund in Ningbo University
文摘Leukocyte cell-derived chemotaxin 2 (LECT2), a multifunctional hepatokine, is involved in many pathological conditi ons. However, its role in atherosclerosis remains undefined. In this study, we admimistered vehicle or LECT2 to male Apoe^-/- mice fed a Western diet for 15 weeks. Atherosclerotic lesions were visualized and quantified with Oil-red O and hematoxylin staining. The mRNA expression levels of MCP-1, MMP-1, IL-8 IL-1β, and TNF-a were analyzed by quantitative real-time polymerase chain reaction. Serum TNF-a, IL-1β, IL-8, MCP-1, and MMP-1 concentrations were measured by en zyme-li nked immuno sorbent assay. CD68, CD31, and a-SMA, markers of macrophages, endothelial cells, and smooth muscle cells, respectively, were detected by immuno staining. Results showed that LECT2 reduced total cholesterol and low-density lipoprotein concentrations in serum and inhibited the development of atherosclerotic lesions, accompanied by reductions in inflammatory cytokines and lower MCP-1, MMP-1, TNF-a, IL-8, and IL-1β mRNA abundanee. Furthermore, LECT2 decreased CD68, but in creased cr SMA in atherosclerotic lesi ons, suggesting an in crease in smooth muscle cells and reduction in macrophages. In summary, LECT2 inhibited the development of atherosclerosis in mice, accompanied by reduced serum total cholesterol concentration and lower inflammatory responses.
