Journal of advanced research最新文献

{"title":"Inhibition of mitophagy via the EIF2S1-ATF4-PRKN pathway contributes to viral encephalitis.","authors":"Xiaowei Song, Yiliang Wang, Weixiangmin Zou, Zexu Wang, Wenyan Cao, Minting Liang, Feng Li, Qiongzhen Zeng, Zhe Ren, Yifei Wang, Kai Zheng","doi":"10.1016/j.jare.2024.08.003","DOIUrl":"10.1016/j.jare.2024.08.003","url":null,"abstract":"<p><strong>Introduction: </strong>Mitophagy, a selective form of autophagy responsible for maintaining mitochondrial homeostasis, regulates the antiviral immune response and acts as viral replication platforms to facilitate infection with various viruses. However, its precise role in herpes simplex virus 1 (HSV-1) infection and herpes simplex encephalitis (HSE) remains largely unknown.</p><p><strong>Objectives: </strong>We aimed to investigate the regulation of mitophagy by HSV-1 neurotropic infection and its role in viral encephalitis, and to identify small compounds that regulate mitophagy to affect HSV-1 infection.</p><p><strong>Methods: </strong>The antiviral effects of compounds were investigated by Western blot, RT-PCR and plaque assay. The changes of Parkin (PRKN)-mediated mitophagy and Nuclear Factor kappa B (NFKB)-mediated neuroinflammation were examined by TEM, RT-qPCR, Western blot and ELISA. The therapeutic effect of taurine or PRKN-overexpression was confirmed in the HSE mouse model by evaluating survival rate, eye damage, neurodegenerative symptoms, immunohistochemistry analysis and histopathology.</p><p><strong>Results: </strong>HSV-1 infection caused the accumulation of damaged mitochondria in neuronal cells and in the brain tissue of HSE mice. Early HSV-1 infection led to mitophagy activation, followed by inhibition in the later viral infection. The HSV-1 proteins ICP34.5 or US11 deregulated the EIF2S1-ATF4 axis to suppress PRKN/Parkin mRNA expression, thereby impeding PRKN-dependent mitophagy. Consequently, inhibition of mitophagy by specific inhibitor midiv-1 promoted HSV-1 infection, whereas mitophagy activation by PRKN overexpression or agonists (CCCP and rotenone) attenuated HSV-1 infection and reduced the NF-κB-mediated neuroinflammation. Moreover, PRKN-overexpressing mice showed enhanced resistance to HSV-1 infection and ameliorated HSE pathogenesis. Furthermore, taurine, a differentially regulated gut microbial metabolite upon HSV-1 infection, acted as a mitophagy activator that transcriptionally promotes PRKN expression to stimulate mitophagy and to limit HSV-1 infection both in vitro and in vivo.</p><p><strong>Conclusion: </strong>These results reveal the protective function of mitophagy in HSE pathogenesis and highlight mitophagy activation as a potential antiviral therapeutic strategy for HSV-1-related diseases.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141895077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ADAM8 deficiency in macrophages promotes cardiac repair after myocardial infarction via ANXA2-mTOR-autophagy pathway.","authors":"Zhenjun Ji, Jiaqi Guo, Rui Zhang, Wenjie Zuo, Yang Xu, Yangyang Qu, Zaixiao Tao, Xinxin Li, Yongjun Li, Yuyu Yao, Genshan Ma","doi":"10.1016/j.jare.2024.07.037","DOIUrl":"10.1016/j.jare.2024.07.037","url":null,"abstract":"<p><strong>Introduction: </strong>A disintegrin and metalloproteinase 8 (ADAM8), a crucial regulator in macrophages, is closely associated with cardiovascular disease progression.</p><p><strong>Objectives: </strong>This study aimed to explore how ADAM8 regulates macrophage function to inhibit cardiac repair after myocardial infarction (MI).</p><p><strong>Methods: </strong>Macrophage-specific ADAM8 knockout mice (ADAM8^{flox/flox, Lyz2-Cre}, KO) and corresponding control mice (ADAM8^flox/flox, Flox) were established using the CRISPR/Cas9 system. Bone marrow transplantation was performed, and macrophage-specific ADAM8-overexpressing adeno-associated virus (AAV6-CD68-Adam8) was produced. Finally, proteomics, RNA sequencing, and co-immunoprecipitation/mass spectrometry (COIP/MS) were used to explore the underlying mechanisms involved.</p><p><strong>Results: </strong>ADAM8 was highly expressed in the plasma of patients with acute myocardial infarction (AMI) and in cardiac macrophages derived from AMI mice. ADAM8 KO mice exhibited enhanced angiogenesis, suppressed inflammation, reduced cardiac fibrosis, and improved cardiac function during AMI, which were reversed by overexpressing macrophage-specific ADAM8 and intervention with the clinical anti-angiogenic biologic bevacizumab. Bone marrow transplantation experiments produced ADAM8 KO phenotypes. RNA sequencing showed that autophagy was activated in bone marrow-derived macrophages (BMDMs) with ADAM8 KO, which was confirmed via p-mTOR Ser2448/mTOR, p62, and LC3II/I detection. Autophagy inactivation suppressed angiogenic factor release and promoted inflammation in BMDMs with ADAM8 KO. Mechanistically, ADAM8 could bind to ANXA2 and promote phosphorylation of the ANXA2 Ser26 site. ADAM8 KO impeded ANXA2 phosphorylation, inhibited mTOR Ser2448 site phosphorylation, and activated autophagy, which were demonstrated using the activation or inactivation of ANXA2 phosphorylation.</p><p><strong>Conclusions: </strong>ADAM8 was increased in cardiac macrophages after AMI. The ADAM8-ANXA2-mTOR-autophagy axis in macrophages is responsible for regulating angiogenesis and inflammation following MI. Thus, ADAM8 may be a new target in MI treatment.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141891299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glutathione hybrid poly (beta-amino ester)-plasmid nanoparticles for enhancing gene delivery and biosafety.","authors":"Songwei Tan, Caiyan Yuan, Yuhe Zhu, Shuangyan Chang, Qianru Li, Jiahui Ding, Xueqin Gao, Rui Tian, Zhiqiang Han, Zheng Hu","doi":"10.1016/j.jare.2024.07.038","DOIUrl":"10.1016/j.jare.2024.07.038","url":null,"abstract":"<p><strong>Introduction: </strong>CRISPR/Cas9 gene editing technology has significantly advanced gene therapy, with gene vectors being one of the key factors for its success. Poly (beta-amino ester) (PBAE), a distinguished non-viral cationic gene vector, is known to elevate intracellular reactive oxygen species (ROS) levels, which may cause cytotoxicity and, consequently, impact gene transfection efficacy (T.E.).</p><p><strong>Objectives: </strong>To develop a simple but efficient strategy to improve the gene delivery ability and biosafety of PBAE both in vivo and in vitro.</p><p><strong>Methods: </strong>We used glutathione (GSH), a clinically utilized drug with capability to modulating intracellular ROS level, to prepare a hybrid system with PBAE-plasmid nanoparticles (NPs). This system was characterized by flow cytometry, RNA-seq, Polymerase Chain Reaction (PCR) and Sanger sequencing in vitro, and its safety and efficacy in vivo was evaluated by imaging, PCR, Sanger sequencing and histology analysis.</p><p><strong>Results: </strong>The particle size of GSH-PBAE-plasmid NPs were 168.31 nm with a ζ-potential of 15.21 mV. An enhancement in T.E. and gene editing efficiency, ranging from 10 % to 100 %, was observed compared to GSH-free PBAE-plasmid NPs in various cell lines. In vitro results proved that GSH-PBAE-plasmid NPs reduced intracellular ROS levels by 25 %-40 %, decreased the total number of upregulated/downregulated genes from 4,952 to 789, and significantly avoided the disturbance in gene expression related to cellular oxidative stress-response and cell growth regulation signaling pathway compared to PBAE-plasmid NPs. They also demonstrated lower impact on the cell cycle, slighter hemolysis, and higher cell viability after gene transfection. Furthermore, GSH hybrid PBAE-plasmid NPs exhibited superior safety and improved tumor suppression ability in an Epstein-Barr virus (EBV)-infected murine tumor model, via targeting cleavage the EBV related oncogene by delivering CRISPR/Cas9 gene editing system and down-regulating the expression levels. This simple but effective strategy is expected to promote clinical applications of non-viral vector gene delivery.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141891301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal association between ambient nitrogen dioxide exposure and all-cause mortality in Chinese adults","authors":"Yunquan Zhang, Jing Wei, Y. Zhan, Zhiming Yang, Riyang Liu, Yuanyuan Zhang, Linjiong Liu, Zongwei Ma","doi":"10.21203/rs.3.rs-634789/v2","DOIUrl":"https://doi.org/10.21203/rs.3.rs-634789/v2","url":null,"abstract":"\u0000 A number of population-based studies have investigated long-term effects of nitrogen dioxide (NO2) on mortality, while great heterogeneities exist between studies. In highly populated countries in Asia, cohort evidence for NO2-mortality association was extensively sparse. This study aimed to quantify longitudinal association of ambient NO2 exposure with all-cause mortality in Chinese adults. A national cohort of 30,843 adult men and women were drawn from 25 provincial regions across mainland China, and followed up from 2010 through 2018. Participants’ exposures to ambient air pollutants were assigned according to their residential counties at baseline, through deriving monthly estimates from high-quality gridded datasets developed by machine learning methods. Cox proportional hazards models with time-varying exposures were utilized to assess the association of all-cause mortality with long-term exposure to ambient NO2. An approximately linear NO2-mortality relation (p=0.273 for nonlinearity) was identified across a broad exposure range of 6.9–57.4 μg/m3. Per 10-µg/m3 increase in annual NO2 exposure was associated with an hazard ratio of 1.127 (95% confidence interval: 1.042–1.219, p<0.003) for all-cause mortality. Risk estimates remained robust after additionally adjusting for the confounding effects of co-pollutants (i.e., PM2.5 or O3). In 2018, 1.65 million deaths could be attributed to ambient NO2 exposure (national average 17.3 µg/m3) in China, representing a decrease of 4.3% compared with the estimate of 1.72 million in 2010 (20.5 µg/m3). This cohort study provided national evidence for elevated risk of all-cause mortality associated with long-term exposure to ambient NO2 in Chinese adults.","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46452730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WITHDRAWN: Surface response technique optimized green synthesis of polymeric nanocomposite for adsorptive uptake-sunlight/UV-visible irradiated mineralization of fuchsin basic","authors":"Priya, B. Kaith, U. Shanker, B. Gupta","doi":"10.1016/J.JARE.2019.03.010","DOIUrl":"https://doi.org/10.1016/J.JARE.2019.03.010","url":null,"abstract":"","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/J.JARE.2019.03.010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49531968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}