Journal of Advanced Research最新文献

{"title":"Tailoring obeticholic acid activity by iridium(III) complex conjugation to develop a farnesoid X receptor probe","authors":"Dou Niu, Xiaolei Wu, Yuxin Zhang, Xueliang Wang, Daniel Shiu-Hin Chan, Shaozhen Jing, Chun-Yuen Wong, Wanhe Wang, Chung-Hang Leung","doi":"10.1016/j.jare.2024.10.028","DOIUrl":"https://doi.org/10.1016/j.jare.2024.10.028","url":null,"abstract":"<h3>Introduction</h3>The farnesoid X receptor (FXR) is a crucial regulator in the intestine, maintaining bile acid homeostasis. Inhibiting intestinal FXR shows promise in managing inflammatory bowel and liver diseases by reducing bile acid accumulation. Additionally, changes in FXR expression could serve as a potential biomarker for intestinal diseases. Therefore, developing an imaging probe for FXR holds significant potential for the early detection, simultaneous treatment, and monitoring of FXR-related diseases.<h3>Objectives</h3>The study aimed to develop a bioimaging probe for FXR by conjugating obeticholic acid (OCA), an FXR agonist, to an iridium(III) complex, and to investigate its application for targeting FXR in intestinal cells.<h3>Methods</h3>OCA was conjugated to an iridium(III) complex to generate the novel complex <strong>1</strong>. The effect of complex <strong>1</strong> on FXR activity, nuclear translocation, and downstream targets was investigated in intestinal epithelial cells using various biochemical and cellular assays. Additionally, the photophysical properties of complex <strong>1</strong> were assessed for FXR imaging.<h3>Results</h3>Complex <strong>1</strong> retained the desirable photophysical properties for monitoring FXR in intestinal cells while reversing OCA’s activity from agonistic to antagonistic. It disrupted FXR-RXR heterodimerization, inhibited FXR nuclear translocation, and downregulated downstream targets responsible for bile acid absorption, transport, and metabolism in intestinal epithelial cells.<h3>Conclusion</h3>The study successfully developed an imaging probe and modulator of FXR by conjugating OCA to an iridium(III) complex. Complex <strong>1</strong> retained the favorable photophysical properties of the iridium(III) complex, while reversing OCA’s activity from agonistic to antagonistic. The findings highlight the exciting application of using metals to tailor the activity of nuclear receptor modulators in living systems.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"3 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520223","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":"Impaired stemness in aging periodontal ligament stem cells is mediated by the progerin/endoplasmic reticulum stress/p53 axis","authors":"Xige Zhang, Yazheng Wang, Jinjin Wang, Yang Zhang, Rui Li, Xiaoyu Wang, Xiaotong Ge, Qingyuan Ye, Jiyun Ji, Dongdong Fei, Qintao Wang","doi":"10.1016/j.jare.2024.10.029","DOIUrl":"https://doi.org/10.1016/j.jare.2024.10.029","url":null,"abstract":"<h3>Introduction</h3>Decreased periodontal ligament stem cells (PDLSCs) stemness is a key factor in age-related alveolar bone loss. Endoplasmic reticulum (ER) stress is closely related to age-related diseases and the mesenchymal stem cell (MSC) stemness. However, the role of ER stress in regulating the stemness of senescent PDLSCs and its potential mechanism remain unclear.<h3>Objectives</h3>To investigate the detailed effect and mechanism of ER stress on impaired stemness in old periodontal ligament stem cells (OPDLSCs).<h3>Methods</h3>The level of ER stress of Young PDLSCs (YPDLSCs) and OPDLSCs were detected, and ER stress was regulated to observe its effect on PDLSCs stemness. The expression levels of ER stress sensors (protein kinase R-like ER kinase (PERK), activating transcription factor 6 (ATF6), inositol requiring enzyme 1 (IRE1)) were upregulated in YPDLSCs and downregulated in OPDLSCs by transfection experiments to verify the detailed unfolded protein response (UPR) pathway. Mechanismly, the regulatory effect of UPR pathway on p53/p21 pathway was explored. Further study was performed to investigated the important role of progerin accumulation during aging process on ER stress, UPR and p53/p21 pathway.<h3>Results</h3>Decreased stemness and ER stress activation were found in OPDLSCs. ER stress activation resulted in decreased stemness of YPDLSCs, while ER stress inhibition rescued compromised stemness of OPDLSCs. Mechanismly, ATF6 pathway regulated the OPDLSC stemness via the p53/p21 signaling as confirmed by transfection assay. Further study showed that progerin was accumulated in PDLSCs and progerin overexpression could resulted in ER stress activation, activating the ATF6/p53/p21 axis, leading to decreased stemness of aging PDLSCs.<h3>Conclusions</h3>Progerin accumulation during the aging process can lead to ER stress activation, which can suppress OPDLSC stemness via the ATF6/p53/p21 axis.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"12 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142519536","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":"Dihydrokoumine, a dual-target analgesic with reduced side effects isolated from a traditional Chinese medicine","authors":"Dian Liu, Jixia Wang, Tao Hou, Yan Zhang, Han Zhou, Yaopeng Zhao, Liangliang Zhou, Cuiyan Cao, Yanfang Liu, Xinmiao Liang","doi":"10.1016/j.jare.2024.10.011","DOIUrl":"https://doi.org/10.1016/j.jare.2024.10.011","url":null,"abstract":"<h3>Introduction</h3>Opioids are the most common antinociceptive drugs, but long-term administration causes serious adverse side effects. <em>Gelsemium elegans</em> Benth. is traditionally used as an analgesic agent and mainly contains indole alkaloids with structures different from those in common opioids, indicating distinct pharmacological properties. This work aims to find a new analgesic from <em>Gelsemium elegans</em> Benth. and evaluate it <em>in vitro</em> and <em>in vivo</em>.<h3>Methods</h3>Dihydrokoumine was purified from <em>Gelsemium elegans</em> Benth. Binding to mu opioid receptor (MOR), M3 receptor (M3R) and other 15 G protein-coupled receptors were evaluated <em>in vitro</em> combined with molecular docking analysis. Analgesic efficacy and side effects were measured <em>in vivo</em> using hot-plate, formalin paw, and rotarod tests in mice. Cytotoxicity, acute toxicity in mice and pharmacokinetics were assessed.<h3>Results</h3>A MOR agonist, dihydrokoumine, was first identified from <em>Gelsemium elegans</em> Benth. Further investigations showed that dihydrokoumine exhibited selective partial agonist action on the MOR and antagonist action on the M3R among other 15 GPCRs. In <em>in vivo</em> mouse models, dihydrokoumine could relieve acute pain and chronic inflammatory pain without drug tolerance and sedative side effects. Additionally, we observed a good safety profile and favorable pharmacokinetic properties.<h3>Conclusion</h3>A MOR partial agonist/M3R antagonist analgesic with reduced side effects was isolated from a traditional Chinese medicine. This study bestows dihydrokoumine as a new dual-target analgesic and as a potential lead compound in pain management.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"1 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489284","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":"Neural and molecular investigation into the paraventricular thalamus for chronic restraint stress induced depressive-like behaviors","authors":"Yong He, Yikun Ren, Xiangyu Chen, Yue Wang, Heming Yu, Junchao Cai, Peng Wang, Yi Ren, Peng Xie","doi":"10.1016/j.jare.2024.10.025","DOIUrl":"https://doi.org/10.1016/j.jare.2024.10.025","url":null,"abstract":"<h3>Introduction</h3>Disturbance of neural circuits and chronic stress contribute to depression onset. Given the crucial role of paraventricular nucleus of thalamus (PVT) in emotional behaviors, however, the specific neural and molecular mechanism of PVT in depression still unclear.<h3>Objective</h3>Our study aim to explore the neural and molecular mechanism of PVT in depression.<h3>Methods</h3>In the present study, we utilize behavioral tests,chemogenetics, RNA-sequence, molecular profiling and pharmacological approaches to investigate the role of PVT in depression.<h3>Results</h3>We observed that CamkIIα neurons in PVT were inactivated by chronic restraint stress (CRS) with reduced c-Fos positive neurons. Activation of PVT^CamkIIα neurons displayed antidepressant-like effect in both naive and CRS mice, whereas inhibition or ablation of these neurons is sufficient to trigger depressive-like behaviors. Moreover, we found that activating PVT → Nucleus accumbens (NAc) circuit attenuated depressive-like behaviors induced by CRS, while inhibiting this circuit directly caused behavioral deficits in mice. Intriguingly, artificially enhancing PVT → Central amygdala (CeA) pathway failed to alleviate depressive-like behaviors. Importantly, increased expression of neuropeptide Y (NPY) and depressive-like behaviors induced by CRS could be ameliorated via antidepressant treatment, manipulation of PVT^CamkIIα neurons (or PVT → NAc circuit) and NPY inhibitor.<h3>Conclusion</h3>Taken together, our study uncovered that PVT regulated depressive-like behaviors via PVT → NAc circuit together with NPY, thus shedding light on potential target for preventing depression and promoting clinical translation.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"17 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487540","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":"Roles of oral and gut microbiota in acute myocardial infarction","authors":"Yu-Lin Li, Bo-Yan Chen, Ze-Hao Feng, Lu-Jun Zhou, Ting Liu, Wen-Zhen Lin, Hong Zhu, Shuo Xu, Xue-Bing Bai, Xiao-Qian Meng, Jun Zhang, Yan Liu, Jun Pu, Meng Jiang, Sheng-Zhong Duan","doi":"10.1016/j.jare.2024.10.009","DOIUrl":"https://doi.org/10.1016/j.jare.2024.10.009","url":null,"abstract":"<h3>Introduction</h3>The significance of oral/gut microbiota in acute myocardial infarction (AMI) has been increasingly appreciated. However, correlations between oral/gut microbiota and AMI parameter, as well as the key microbiota that may have a crucial function in this process, remain unclear.<h3>Objectives</h3>To investigate the composition and structure of oral and gut microbiota associated with AMI and explore the roles of specific bacterial species in the progression of AMI.<h3>Methods</h3>We conducted a case-control study with 37 AMI patients and 36 controls. Oral and gut sample were collected and sequenced. Using correlation analysis, we combined bioinformatics data with AMI clinical parameters and obtained heatmaps of correlation coefficients. Additionally, we used antibiotics to eliminate the gut microbiota of C57BL/6J mice, followed by the transplantation of selected bacteria to verify the gut colonization of oral bacteria and their impact on AMI.<h3>Results</h3>The component of oral and gut microbiota of AMI group showed significant alterations when compared to the control group. 17 salivary genera, 21 subgingival genera, and 8 gut genera in AMI group substantially differed from those in control group. Additionally, 19 genera from saliva, 19 genera from subgingival plaque, and 11 genera from feces substantially correlated with AMI clinical parameters. Orally administrated S.o (<em>Streptococcus oralis</em> subsp. <em>dentisani</em>), S.p (<em>Streptococcus parasanguinis</em>), and S.s (<em>Streptococcus salivarius</em>) were able to colonize in the gut and exacerbate myocardial infarction.<h3>Conclusion</h3>There is a strong correlation between oral/gut microbiota and AMI. <em>Streptococcus</em> spp. is capable to transmit from oral to gut and exacerbate myocardial infarction in mice. Monitoring and control of specific oral microbiota may be an effective new strategy for improving the therapy of AMI.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"67 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487108","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":"Regulatory balance between ear rot resistance and grain yield and their breeding applications in maize and other crops","authors":"Zechao Yin, Xun Wei, Yanyong Cao, Zhenying Dong, Yan Long, Xiangyuan Wan","doi":"10.1016/j.jare.2024.10.024","DOIUrl":"https://doi.org/10.1016/j.jare.2024.10.024","url":null,"abstract":"<h3>Background</h3>Fungi are prevalent pathogens that cause substantial yield losses of major crops. Ear rot (ER), which is primarily induced by <em>Fusarium</em> or <em>Aspergillus</em> species, poses a significant challenge to maize production worldwide. ER resistance is regulated by several small effect quantitative trait loci (QTLs). To date, only a few ER-related genes have been identified that impede molecular breeding efforts to breed ER-resistant maize varieties.<h3>Aim</h3><strong><em>of review:</em></strong> Our aim here is to explore the research progress and mine genic resources related to ER resistance, and to propose a regulatory model elucidating the ER-resistant mechanism in maize as well as a trade-off model illustrating how crops balance fungal resistance and grain yield.<strong><em>Key Scientific Concepts of Review:</em></strong> This review presents a comprehensive bibliometric analysis of the research history and current trends in the genetic and molecular regulation underlying ER resistance in maize. Moreover, we analyzed and discovered the genic resources by identifying 162 environmentally stable loci (ESLs) from various independent forward genetics studies as well as 1391 conservatively differentially expressed genes (DEGs) that respond to <em>Fusarium</em> or <em>Aspergillus</em> infection through multi-omics data analysis. Additionally, this review discusses the syntenies found among maize ER, wheat <em>Fusarium</em> <!-- -->head blight (FHB), and rice Bakanae<!-- --> <!-- -->disease (RBD) resistance-related loci, along with the significant overlap between fungal resistance loci and reported yield-related loci, thus providing valuable insights into the regulatory mechanisms underlying the trade-offs between yield and defense in crops.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"25 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487105","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":"Achilles tendinopathy treatment via circadian rhythm regulation","authors":"Yibo Zhang, Yizhang Wu, Yong Wang, Jun Lu, Yang Lu, Peng Wang, Lan Li, Wenjin Yan, Hongling Cai, Weisbecker Hannah Leigh, Lin Zhang, Wubin Bai, Qing Jiang, Xingquan Xu","doi":"10.1016/j.jare.2024.10.022","DOIUrl":"https://doi.org/10.1016/j.jare.2024.10.022","url":null,"abstract":"<h3>Introduction</h3>Achilles tendinopathy (AT) is a prevalent musculoskeletal disorder closely linked to oxidative stress. Existing evidence suggests a potential link between circadian clock rhythms and oxidative stress. However, the precise role of the circadian clock in the progression and treatment of AT remains unclear.<h3>Objective</h3>The purpose of this study was to investigate the role of the Achilles tendon circadian clock in AT pathology and explore the potential use of biomaterials for modulating the circadian clock in the treatment of AT.<h3>Methods</h3>We utilized in vivo and in vitro models to investigate the alterations of the circadian clock within the Achilles tendon during the progression of AT, as well as its impact on disease development. Additionally, we fabricated Nb₂C@CeO₂ composites featuring a Schottky heterojunction for regulating the circadian rhythm and validated its therapeutic efficacy and molecular mechanism of AT through both in vivo and in vitro experiments.<h3>Results</h3>The Achilles tendon functioned as a peripheral oscillator with an independent and self-sustained time-keeping system. The rhythm of the Achilles tendon clock was disrupted during the development of AT, as indicated by the decreased amplitude of <em>Bmal1</em> and <em>Nrf2</em> rhythm expression. Mechanistically, the knockdown of <em>Bmal1</em> disrupted the Achilles tendon clock, thereby destroying the <em>Bmal1</em>-<em>Nrf2</em> axis dependent molecular defense mechanism, and exacerbating the inflammatory response, whereas overexpression of <em>Bmal1</em> had a protective effect. Nb₂C@CeO₂ composites with Schottky heterojunctions enhance intercellular electrical signaling, boosting <em>Bmal1</em> expression and mitigating AT’s pathological changes. Importantly, enhancing <em>Bmal1</em> expression during its peak, rather than its trough, was more effective.<h3>Conclusion</h3>This study identified the protective role of the circadian clock against oxidative stress and inflammation in the Achilles tendon. Achilles tendon circadian clock-targeted therapy represents a promising strategy for AT treatment.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"51 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451665","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":"Intra species dissection of phytophthora capsici resistance in black pepper","authors":"Yupeng Hao, Rui Fan, Yongyan Zhao, Ke Nie, Luyao Wang, Ting Zhao, Zhiyuan Zhang, Xiaoyuan Tao, Hongyu Wu, Jiaying Pan, Chaoyun Hao, Xueying Guan","doi":"10.1016/j.jare.2024.10.015","DOIUrl":"https://doi.org/10.1016/j.jare.2024.10.015","url":null,"abstract":"<h3>Introduction</h3>Black pepper, a financially significant tropical crop, assumes a pivotal role in global agriculture for the major source of specie flavor. Nonetheless, the growth and productivity of black pepper face severe impediments due to the destructive pathogen <em>Phytophthora capsici</em>, ultimately resulting in black pepper blight. The dissecting for the genetic source of pathogen resistance for black pepper is beneficial for its global production. The genetic sources include the variations on gene coding sequences, transcription capabilities and epigenetic modifications, which exerts hierarchy of influences on plant defense against pathogen. However, the understanding of genetic source of disease resistance in black pepper remains limited.<h3>Methods</h3>The wild species <em>Piper flaviflorum</em> (<em>P. flaviflorum</em>, <em>Pf</em>) is known for blight resistance, while the cultivated species <em>P. nigrum</em> is susceptible. To dissecting the genetic sources of pathogen resistance for black pepper, the chromatin modification on H3K4me3 and transcriptome of black pepper species were profiled for genome wide comparative studies, applied with CUT&amp;Tag and RNA sequencing technologies.<h3>Results</h3>The intraspecies difference between <em>P. flaviflorum</em> and <em>P. nigrum</em> on gene body region led to coding variations on 5137 genes, including 359 gene with biotic stress responses and regulation. <em>P. flaviflorum</em> exhibited a more comprehensive resistance response to <em>Phytophthora capsica</em> in terms of transcriptome features. The pathogen responsive transcribing was significant associated with histone modification mark of H3K4me3 in black pepper. The collective data on variations of sequence, transcription activity and chromatin structure lead to an exclusive jasmonic acid-responsive pathway for disease resistance in <em>P. flaviflorum</em> was revealed. This research provides a comprehensive frame work to identify the fine genetic source for pathogen resistance from wild species of black pepper.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"67 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451664","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":"Pleiotropic role of CCR9/CCL25 signaling in adriamycin-induced cardiomyopathy","authors":"Xue Wu, Zheng Wang, Zhenxiang Liang, Ning Li, Junmin Chen, Qiong Liu, Wangrui Lei, Xiaopeng Wu, Chenxi Lu, Chao Deng, Ying Chen, Xue Wang, Jinhong Wei, Yang Yang","doi":"10.1016/j.jare.2024.10.018","DOIUrl":"https://doi.org/10.1016/j.jare.2024.10.018","url":null,"abstract":"<h3>Introduction</h3>Adriamycin (ADR)-induced cardiomyopathy is a common problem in many cancer survivors. Recently, specific chemokine receptors have garnered interest as therapeutic targets in cardiovascular diseases.<h3>Objectives</h3>This study aim to report the role of the C–C chemokine receptor 9 (CCR9)/C–C chemokine ligand 25 (CCL25) and its therapeutic potential in ADR-induced cardiomyopathy.<h3>Methods</h3>Functional gene knockout and overexpression mouse models were utilized to investigate the role of CCR9 against ADR-induced cardiomyopathy. Transcriptome sequencing was also performed to identify the downstream molecular mechanisms of CCR9.<h3>Results</h3>This study revealed that CCR9 and CCL25 levels were increased in mice and HL-1 cells injured by ADR, consistent with the results of patients with heart failure. Both <em>in vivo</em> and <em>in vitro,</em> CCR9 overexpression overtly aggravated cardiac dysfunction, accompanied by decreased AMPK activity and increased mitochondrial dysfunction, fibrosis, oxidative stress, and apoptosis. However, the cardiac harmful effects were reserved by CCR9 knockdown or AMPK agonist GSK621. By constructing different domain-missing CCR9 mutants, we suspected that the △4 region of CCR9 is important for AMPK activity. Furthermore, RNA-seq illustrated the CCR9-controlled transcriptome and genome in detail, pinpointing that CCR9 overexpression aggravated ADR-induced cardiotoxicity was associated with CYP1A1. Finally, lithospermic acid (LA) was screened and alleviated ADR-induced cardiotoxicity through regulation of CCR9/CCL25-AMPK signaling, bolstering CCR9-targeted potential clinical application.<h3>Conclusion</h3>These findings present a promising target and drug for treating chemotherapy-induced cardiotoxicity.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"8 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451667","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":"The gut microbiotas with metabolites regulate the protective role of miR-30a-5p in myocardial infarction","authors":"Ruiying Wang, Ruo-Lan Chen, Chan Wu, Xiao-Cheng Zhang, Wei-Yin Wu, Cuilian Dai, Yan Wang, Gang Li","doi":"10.1016/j.jare.2024.10.017","DOIUrl":"https://doi.org/10.1016/j.jare.2024.10.017","url":null,"abstract":"<h3>Introduction</h3>Gut microbial homeostasis is closely associated with myocardial infarction (MI). However, little is known about how gut microbiota influences miRNAs-regulated MI.<h3>Objectives</h3>This study aims to elucidate the connections between miR-30a-5p, MI, gut microbiota, and gut microbial metabolite-related pathways, to explore potential strategy for preventing and treating MI.<h3>Methods</h3>We evaluated the effects of knocking out (KO) or overexpressing (OE) miR-30a-5p on MI by assessing cardiac structure and function, myocardial enzyme levels, and apoptosis. Then, we applied 16S rDNA sequencing and metabolomics to explore how intestinal microecology and its microorganisms affect miR-30a-5p-regulated MI.<h3>Results</h3>The results showed that KO exacerbated MI, whereas OE improved MI damage, compared to the wild-type (WT) mice. KO exacerbated intestinal barrier structure deterioration and further downregulated the expression of Cloudin-1, Occludin, and ZO-1 in MI mice. 16S rDNA sequencing-analyzed gut microbiome of KO and WT mice found that KO mainly reduced g_Lactobacillus. Transplanting fecal microorganisms from KO mice aggravated MI damage in WT mice. However, administering probiotics (mainly containing lactobacilli) helped neutralize these damages. Intriguingly, fecal microbiota transplantation from OE mice reduced MI damage. Analysis of intestinal microbial metabolites in KO and WT mice found that KO may mainly affect ABC transporters. ABCC1 was identified as the target of KO-aggravated MI. Furthermore, fecal transplantation microorganisms of MI patients aggravated MI injury in mice and miR-30a-5p and ABCC1 were involved in the process.<h3>Conclusions</h3>Our findings demonstrate that miR-30a-5p regulates MI by affecting intestinal microbiota homeostasis and targeting ABCC1. This highlights the critical importance of maintaining a healthy gut microbiota homeostasis in MI management.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"2 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486533","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}