Journal of Advanced Research最新文献

{"title":"Astragaloside IV alleviates septic myocardial injury through DUSP1-Prohibitin 2 mediated mitochondrial quality control and ER-autophagy","authors":"Junyan Wang, Xiangyi Pu, Haowen Zhuang, Zhijiang Guo, Mengyuan Wang, Huaihong Yang, Chun Li, Xing Chang","doi":"10.1016/j.jare.2024.10.030","DOIUrl":"https://doi.org/10.1016/j.jare.2024.10.030","url":null,"abstract":"<h3>Introduction</h3>Septic cardiomyopathy (SCM) is a complication of myocardial injury in patients with severe sepsis.<h3>Objectives</h3>This study highlights the potential of Astragaloside IV(AS) in the treatment of septic cardiomyopathy and provides a reference for developing cardioprotective drugs targeting DUSP1-PHB2-related mitochondria-ER interaction.<h3>Methods</h3>Dual specificity phosphatase-1 (DUSP1)/Prohibitin 2 cardiomyocyte-specific knockout mice (DUSP1/PHB2^CKO) /DUSP1 transgenic mice (DUSP1/PHB2^TG) were used to generate LPS-induced sepsis models. The pathological mechanism by which AS-IV improves heart injury was detected using cardiac ultrasound, fluorescence staining, transmission electron microscopy, and western blotting. After siRNA treatment of cardiomyocytes with DUSP-1/PHB2, changes in mitochondrial function and morphology were determined using qPCR, western blotting, ELISA, and laser confocal microscopy, and the targeted therapeutic effects of AS-IV were further examined.<h3>Results</h3>SCM treatment leads to severe mitochondrial dysfunction. However, Astragaloside IV (AS) treatment normalizes mitochondrial homeostasis and ER function. Notably, the protective effect was blocked in DUSP1/Prohibitin 2 cardiomyocyte-specific knockout mice (DUSP1/PHB2^CKO) but remained unaffected in DUSP1 transgenic mice (DUSP1/PHB2^TG).<h3>Conclusion</h3>This study highlights the potential of AS in the treatment of septic cardiomyopathy and provides a reference for developing cardioprotective drugs targeting DUSP1-PHB2 related mitochondria-ER interaction.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"75 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oncogenic cholesterol rewires lipid metabolism in hepatocellular carcinoma via the CSNK2A1-IGF2R Ser2484 axis","authors":"Ren-yi Su, Chen-hao Xu, Hai-jun Guo, Li-jun Meng, Jian-yong Zhuo, Nan Xu, Hui-gang Li, Chi-yu He, Xuan-yu Zhang, Zheng-xin Lian, Shuai Wang, Chenhao Cao, Ruhong Zhou, Di Lu, Shu-sen Zheng, Xu-yong Wei, Xiao Xu","doi":"10.1016/j.jare.2024.11.021","DOIUrl":"https://doi.org/10.1016/j.jare.2024.11.021","url":null,"abstract":"<h3>Introduction</h3>Alcohol consumption and hepatitis B virus (HBV) infection are common risk factors for hepatocellular carcinoma (HCC). However, few studies have focused on elucidating the mechanisms of HCC with combined alcohol and HBV etiology.<h3>Objectives</h3>We aimed to investigate the molecular features of alcohol and HBV on HCC and to seek out potential therapeutic strategies.<h3>Methods</h3>Two independent cohorts of HCC patients (n = 539 and n = 140) were included to investigate HCC with synergetic alcohol and HBV (AB-HCC) background. Patient-derived cell lines, organoids, and xenografts were used to validate the metabolic fragile. High-throughput drug screening (1181 FDA-approved anticancer drugs) was leveraged to explore the potential therapeutic agents.<h3>Results</h3>Here, we delineated AB-HCC as a distinctive metabolic subtype, hallmarked by oncogenic cholesterol, through the integration of clinical cohorts, proteomics, phosphoproteomics, and spatial transcriptome. Mechanistically, our findings revealed that cholesterol directly binds to CSNK2A1 (Casein Kinase 2 Alpha 1), augmenting its kinase activity and leading to phosphorylation of IGF2R (Insulin-Like Growth Factor 2 Receptor) at Ser2484. This cascade rewires lipid-driven mitochondrial oxidative phosphorylation, spawns reactive oxygen species measured by malondialdehyde assay, and perpetuates a positive feedback loop for cholesterol biosynthesis, ultimately culminating in tumorigenesis. Initial transcriptional activation of CSNK2A1 is driven by upregulation of RAD21 in AB-HCC. Our cholesterol profiling exposes AB-HCC’s compensatory mechanism of AB-HCC, which capitalizes on both uptake and biosynthesis of cholesterol to confer survival edge. Moreover, high-throughput drug screening coupled with <em>in vivo</em> validation has uncovered the susceptibilities of AB-HCC, which can be effectively addressed by a combination of dietary cholesterol restriction and oral administration of Fostamatinib. The CSNK2A1-mediated cholesterol biosynthesis pathway has been implicated in various cancers characterized by cholesterol metabolism.<h3>Conclusion</h3>These findings not only pinpoint the oncogenic metabolite cholesterol as a hidden culprit in AB-HCC subtype, but also enlighten a novel combination strategy to rejuvenate tumor metabolism.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"98 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142609976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2′-Fucosyllactose ameliorates aging-related osteoporosis by restoring gut microbial and innate immune homeostasis","authors":"Ang Li, Ruixin Kou, Jin Wang, Bowei Zhang, Yan Zhang, Jingmin Liu, Yaozhong Hu, Shuo Wang","doi":"10.1016/j.jare.2024.11.017","DOIUrl":"https://doi.org/10.1016/j.jare.2024.11.017","url":null,"abstract":"<h3>Introduction</h3>Aging-related osteoporosis is considered as a serious public health concern for middle-aged and elderly people, with an intricated pathogenesis including the recently identified aging-induced immunological dysfunction and gut microbial disorder. The intervention based on dietary prebiotics is recommended to retain bone health and postpone the progression of osteoporosis.<h3>Objectives</h3>As a well-defined prebiotic, 2′-fucosyllactose (2′-FL) has been thoroughly validated with positive effect on systemic health and was proposed in this study to unveil its intervention on aging-related osteoporosis, as well as the underlying mechanisms involving the gut microecology and innate immunity.<h3>Methods</h3>The effects of dietary 2′-FL on osteoporosis phenotypes were identified by evaluating the severity of bone loss and microstructure damage in natural aging mice. The mechanisms relying on innate immune profile, intestinal barrier function, and gut microbial homeostasis, were analyzed to elucidate the signaling axis. The detailed molecular signaling was validated based on LPS-stimulated RAW 264.7 murine macrophages.<h3>Results</h3>The results indicated that 12-week 2′-FL intervention retrieved bone loss and microstructure damage in natural aging mice. Also, 2′-FL alleviated aging-induced colonic inflammation, gut barrier dysfunction, and abnormal expression of intestinal tight-junction protein. The impact of 2′-FL treatment on the aging-induced gut microbial dysbiosis was validated by restoring gut microbiota diversity, recovering the abundance of <em>Bifidobacterium, Prevotellaceae</em> and <em>Akkermansia</em>, and inhibiting the growth of <em>Stenotrophomonas</em>. Flow cytometry analysis revealed changes in dendritic cell (DC) and macrophage subsets with age, and a decrease in M1-polarized macrophages was observed in 2′-FL-treated aged mice and RAW264.7 cells potentially through the interaction with toll-like receptor 4 (TLR4) to suppress NF-κB signaling and the secretion of proinflammatory factors.<h3>Conclusion</h3>These findings highlight the preventive effect of 2′-FL on aging-associated osteoporosis by regulating gut microbial homeostasis and innate immune responses.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"9 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deficiency of myeloid NPC1 exacerbates liver injury and fibrosis by impairing macrophage efferocytosis","authors":"Dongwei Guan, Pengju Huang, Xinlei Liu, Qing Li, Xiaoxun Zhang, Nan Liu, Yong Wang, Ying Wan, Jin Chai, Shiying Cai, Rui Chen, Zhijia Ye","doi":"10.1016/j.jare.2024.11.020","DOIUrl":"https://doi.org/10.1016/j.jare.2024.11.020","url":null,"abstract":"<h3>Introduction</h3>Niemann-Pick C1 (NPC1), a lysosomal cholesterol transport protein, is required for efficient efferocytosis. Patients with <em>Npc1</em> mutation are frequently accompanied with hepatic symptoms, including hepatomegaly, elevated liver transaminases, or even acute liver failure, but the pathogenic mechanism remains unknown.<h3>Objectives</h3>Our work aims to characterize the functional role of myeloid NPC1 in liver injury and elucidate its underlying mechanism.<h3>Methods</h3>Analyses of injured livers from patients with liver diseases and mouse models were conducted to examine NPC1 expression. Myeloid cell-specific <em>Npc1</em> knockout mice were constructed to determine the functional role of macrophage NPC1 in liver injury. Isolated macrophages were subjected to <em>in vitro</em> mechanistical assays.<h3>Results</h3>We found that NPC1 is mainly expressed in hepatic macrophages. Its mRNA and protein expression are significantly elevated in injured livers from both patients and mouse models. Tissue-specific deletion of myeloid <em>Npc1</em> increased liver inflammation, levels of serum liver function enzymes, and liver fibrosis in mouse models of liver injury induced by carbon tetrachloride (CCl₄) injection and methionine-and-choline-deficient (MCD) diets. Further analyses indicate that <em>Npc1</em> deficiency in mouse models of liver injury resulted in increased levels of serum HMGB1 and mitochondrial DNA, promoted hepatic macrophage proinflammatory activation, M1 polarization, led to overproduction of hepatic inflammatory cytokines/chemokines, e.g. CCL2 and STING/NFκB pathway activation. In vitro mechanistical studies reveal that <em>Npc1</em>-deficient macrophages exhibited inefficient efferocytosis, partly due to impaired cargo degradation.<h3>Conclusions</h3>These findings indicate that elevated expression of myeloid NPC1 in liver diseases protects liver from injury by promoting macrophage efferocytosis of damaged cells. Dysfunction of NPC1 aggravates liver injury, suggesting that NPC1 may be a potential therapeutic target for treating liver diseases.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"45 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142609977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transformative applications of oculomics-based AI approaches in the management of systemic diseases: A systematic review","authors":"Zhongwen Li, Shiqi Yin, Shihong Wang, Yangyang Wang, Wei Qiang, Jiewei Jiang","doi":"10.1016/j.jare.2024.11.018","DOIUrl":"https://doi.org/10.1016/j.jare.2024.11.018","url":null,"abstract":"<h3>Background</h3>Systemic diseases, such as cardiovascular and cerebrovascular conditions, pose significant global health challenges due to their high mortality rates. Early identification and intervention in systemic diseases can substantially enhance their prognosis. However, diagnosing systemic diseases often necessitates complex, expensive, and invasive tests, posing challenges in their timely detection. Therefore, simple, cost-effective, and non-invasive methods for the management (such as screening, diagnosis, and monitoring) of systemic diseases are needed to reduce associated comorbidities and mortality rates.<h3>Aim of the review</h3>This systematic review examines the application of artificial intelligence (AI) algorithms in managing systemic diseases by analyzing ophthalmic features (oculomics) obtained from convenient, affordable, and non-invasive ophthalmic imaging.<h3>Key scientific concepts of review</h3>Our analysis demonstrates the promising accuracy of AI in predicting systemic diseases. Subgroup analysis reveals promising capabilities of oculomics-based AI for disease staging, while caution is warranted due to the possible overestimation of AI capabilities in low-quality studies. These systems are cost-effective and safe, with high rates of acceptance among patients and clinicians. This review underscores the potential of oculomics-based AI approaches in revolutionizing the management of systemic diseases.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"3 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Host genetic regulation of specific functional groups in the rumen microbiome of dairy cows: Implications for lactation trait","authors":"Hao Bai, Zheng Lai, Jiawei Zhang, Xinyi Zheng, Jiyou Zhang, Wei Jin, Limei Lin, Shengyong Mao","doi":"10.1016/j.jare.2024.11.012","DOIUrl":"https://doi.org/10.1016/j.jare.2024.11.012","url":null,"abstract":"<h3>Introduction</h3>Ruminants play a pivotal role in our society by transforming non-consumable substances from industrial by-products and plant fibers into valuable resources such as meat and milk. This remarkable conversion ability is primarily attributed to the rumen microbiota, which is influenced by various factors, including diet, climate, and geographical location. In recent years, increasing research has shown that host factors (breed, genetic variation, etc.) also play vital roles in shaping rumen microbial composition and function in cattle.<h3>Objective</h3>This study aims to provide a theoretical basis and an opportunity for further investigating the regulation of lactation traits in dairy cows through host genetics and the interaction with the rumen microbiota.<h3>Method</h3>To investigate the interactions between host genotype, rumen microbiota, and animal phenotype, we curated and analyzed the dairy herd improvement (DHI) data, single nucleotide polymorphisms (SNPs) genotypes, and 16S rumen microbiota data from 1,169 Holstein dairy cows. Heritability and microbiability estimation, along with genome-wide association studies (GWAS) were performed to identify candidate microorganisms and host genetic loci.<h3>Result</h3>We identified thirty-one heritable taxa, whose functions were predominantly enriched in carbohydrate metabolism and energy metabolism. The genome-wide association study revealed that nine heritable bacteria were significantly associated with forty-three SNPs. Functional genes located within or near these SNPs were primarily associated with rumen epithelial development. Additionally, these nine heritable bacteria were primarily annotated as complex polysaccharide degraders and butyrate producers, such as <em>Fibrobacter sp900143055</em> and <em>Pseudoruminococcus massiliensis</em>, which showed significant associations with milk yield and milk fat percentage. Compared to previous studies, we newly discovered the existence of a high heritability of <em>Olsenella umbonate</em>, <em>Butyrivibrio hungatei</em>, among others.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"6 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactate-mediated lactylation in human health and diseases: Progress and remaining challenges","authors":"","doi":"10.1016/j.jare.2024.11.010","DOIUrl":"https://doi.org/10.1016/j.jare.2024.11.010","url":null,"abstract":"Lactate was once considered as metabolic waste for a long time. In 2019, Professor Zhao Yingming’s team from the University of Chicago found that lact…","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"18 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain-targeted autoimmunity is strongly associated with Long COVID and its chronic fatigue syndrome as well as its affective symptoms","authors":"Abbas F. Almulla, Michael Maes, Bo Zhou, Hussein K. Al-Hakeim, Aristo Vojdani","doi":"10.1016/j.jare.2024.11.011","DOIUrl":"https://doi.org/10.1016/j.jare.2024.11.011","url":null,"abstract":"<h3>Introduction</h3>Autoimmune responses contribute to the pathophysiology of Long COVID, affective symptoms and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).<h3>Objectives</h3>To examine whether Long COVID, and its accompanying affective symptoms and CFS are associated with immunoglobulin (Ig)A/IgM/IgG directed at neuronal proteins including myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), synapsin, α + β-tubulin, neurofilament protein (NFP), cerebellar protein-2 (CP2), and the blood–brain-barrier-brain-damage (BBD) proteins claudin-5 and S100B.<h3>Methods</h3>IgA<strong>/</strong>IgM/IgG to the above neuronal proteins, human herpes virus-6 (HHV-6) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) were measured in 90 Long COVID patients and 90 healthy controls, while C-reactive protein (CRP), and advanced oxidation protein products (AOPP) in association with affective and CFS ratings were additionally assessed in a subgroup thereof.<h3>Results</h3>Long COVID is associated with significant increases in IgG directed at tubulin (IgG-tubulin), MBP, MOG and synapsin; IgM-MBP, MOG, CP2, synapsin and BBD; and IgA-CP2 and synapsin. IgM-SARS-CoV-2 and IgM-HHV-6 antibody titers were significantly correlated with IgA/IgG/IgM-tubulin and -CP2, IgG/IgM-BBD, IgM-MOG, IgA/IgM-NFP, and IgG/IgM-synapsin. Binary logistic regression analysis shows that IgM-MBP and IgG-MBP are the best predictors of Long COVID. Multiple regression analysis shows that IgG-MOG, CRP and AOPP explain together 41.7 % of the variance in the severity of CFS. Neural network analysis shows that IgM-synapsin, IgA-MBP, IgG-MOG, IgA-synapsin, IgA-CP2, IgG-MBP and CRP are the most important predictors of affective symptoms due to Long COVID with a predictive accuracy of r = 0.801.<h3>Conclusion</h3>Brain-targeted autoimmunity contributes significantly to the pathogenesis of Long COVID and the severity of its physio-affective phenome.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"13 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biological functions and pharmacological behaviors of bile acids in metabolic diseases","authors":"Tongxi Zhuang, Xunjiang Wang, Zixuan Wang, Lihua Gu, Dawei Yue, Zhengtao Wang, Xiaohua Li, Li Yang, Wendong Huang, Lili Ding","doi":"10.1016/j.jare.2024.11.003","DOIUrl":"https://doi.org/10.1016/j.jare.2024.11.003","url":null,"abstract":"<h3>Background</h3>Bile acids (BAs), synthesized endogenously from cholesterol, play a central role in metabolic regulation within the enterohepatic circulatory system. Traditionally known as emulsifying agents that facilitate the intestinal absorption of vitamins and lipids, recent research reveals their function as multifaceted signal modulators involved in various physiological processes. These molecules are now recognized as key regulators of chronic metabolic diseases and immune dysfunction. Despite progress in understanding their roles, their structural diversity and the specific functions of individual bile acids remain underexplored.<h3>Aim of review</h3>This study categorizes the bile acids based on their chemical structures and their roles as signaling molecules in physiological processes. It consolidates current knowledge and provides a comprehensive overview of the current research. The review also includes natural and semisynthetic variants that have demonstrated potential in regulating metabolic processes in animal models or clinical contexts.<h3>Key scientific concepts of review</h3>Bile acids circulate primarily within the enterohepatic circulation, where they help maintain a healthy digestive system. Disruptions in their balance are linked to metabolic disorders, hepatobiliary diseases and intestinal inflammation. Through receptor-mediated pathways, bile acids influence the progression of metabolic diseases by regulating glucose and lipid metabolism, immune function, and energy expenditure. This review aims to provide a comprehensive, systematic foundation to for understanding their physiological roles and supporting future therapeutic developments for metabolic and inflammatory diseases.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"34 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial NMMHC IIA dissociation from PAR1 activates the CREB3/ARF4 signaling in thrombin-mediated intracerebral hemorrhage","authors":"Yujie Dai, Liangying Bao, Juan Huang, Miling Zhang, Junhe Yu, Yuanyuan Zhang, Fang Li, Boyang Yu, Shuaishuai Gong, Junping Kou","doi":"10.1016/j.jare.2024.11.008","DOIUrl":"https://doi.org/10.1016/j.jare.2024.11.008","url":null,"abstract":"<h3>Introduction</h3>There is an urgent need for cerebroprotective interventions to improve the suboptimal outcomes with intracerebral hemorrhage (ICH). Despite the important role of nonmuscle myosin heavy chain IIA (NMMHC IIA) in the blood–brain barrier (BBB), its function in ICH remains unclear.<h3>Objectives</h3>The objective of this study is to explore how NMMHC IIA functions in ICH and to evaluate the effectiveness of targeting NMMHC IIA as a treatment for ICH.<h3>Methods</h3>We firstly examined the protein expression of NMMHC IIA in clinical patients and animal models with ICH. The function of NNMMHC IIA was then corroborated by using overexpress or knockdown NMMHC IIA specifically in ECs mice and pBMECs. In addition, we explored protein interacts with NMMHC IIA and signaling pathways after ICH by LC-MS/MS and transcriptomics analysis with an emphasis on the function of PAR1 and the CREB3/ARF4 signaling pathway, and validated them in three kind of animal models. To support the clinical translation of our results, we targeted NMMHC IIA to bicalutamide selected from a library of marketed drugs and examined to validate its ameliorative effect on ICH.<h3>Results</h3>We observed an upregulation of endothelial NMMHC IIA in the brain following the onset of ICH in both patients and mice, while inhibited NMMHC ⅡA improved ICH induced by thrombin, warfarin or tissue plasminogen activator (tPA) after ischemic stroke. Mechanistically, the head domain of NMMHC IIA interacted with protease-activated receptor 1 (PAR1) at the 380–430 aa region and subsequently dissociated and activated the CREB3/ARF4 signaling pathway. We found that bicalutamide and blebbistatin could bind to NMMHC IIA and effectively protect mice from thrombin-mediated ICH.<h3>Conclusion</h3>The findings indicated that NMMHC IIA dissociated from PAR1 and activated CREB3/ARF4 pathway, which aggravated BBB damage induced by thrombin. This suggested that NMMHC IIA was a novel potential therapeutic target for BBB-related diseases.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"147 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}