Cell and Bioscience最新文献

{"title":"Impact of c-JUN deficiency on thalamus development in mice and human neural models.","authors":"Jiantao Shi, Qing Chen, Jianheng Lai, Jieying Zhu, Ran Zhang, Md Abdul Mazid, Dongwei Li, Huanxing Su, Dajiang Qin","doi":"10.1186/s13578-024-01303-8","DOIUrl":"10.1186/s13578-024-01303-8","url":null,"abstract":"<p><strong>Background: </strong>c-Jun is a key regulator of gene expression. Through the formation of homo- or heterodimers, c-JUN binds to DNA and regulates gene transcription. While c-Jun plays a crucial role in embryonic development, its impact on nervous system development in higher mammals, especially for some deep structures, for example, thalamus in diencephalon, remains unclear.</p><p><strong>Methods: </strong>To investigate the influence of c-JUN on early nervous system development, c-Jun knockout (KO) mice and c-JUN KO H1 embryonic stem cells (ESCs)-derived neural progenitor cells (NPCs), cerebral organoids (COs), and thalamus organoids (ThOs) models were used. We detected the dysplasia via histological examination and immunofluorescence staining, omics analysis, and loss/gain of function analysis.</p><p><strong>Results: </strong>At embryonic day 14.5, c-Jun knockout (KO) mice exhibited sparseness of fibers in the brain ventricular parenchyma and malformation of the thalamus in the diencephalon. The absence of c-JUN accelerated the induction of NPCs but impaired the extension of fibers in human neuronal cultures. COs lacking c-JUN displayed a robust PAX6⁺/NESTIN⁺ exterior layer but lacked a fibers-connected core. Moreover, the subcortex-like areas exhibited defective thalamus characteristics with transcription factor 7 like 2-positive cells. Notably, in guided ThOs, c-JUN KO led to inadequate thalamus patterning with sparse internal nerve fibers. Chromatin accessibility analysis confirmed a less accessible chromatin state in genes related to the thalamus. Overexpression of c-JUN rescued these defects. RNA-seq identified 18 significantly down-regulated genes including RSPO2, WNT8B, MXRA5, HSPG2 and PLAGL1 while 24 genes including MSX1, CYP1B1, LMX1B, NQO1 and COL2A1 were significantly up-regulated.</p><p><strong>Conclusion: </strong>Our findings from in vivo and in vitro experiments indicate that c-JUN depletion impedes the extension of nerve fibers and renders the thalamus susceptible to dysplasia during early mouse embryonic development and human ThO patterning. Our work provides evidence for the first time that c-JUN is a key transcription regulator that play important roles in the thalamus/diencephalon development.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"14 1","pages":"149"},"PeriodicalIF":6.1,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662577/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The inactivation of the Niemann Pick C1 cholesterol transporter restricts SARS-CoV-2 entry into host cells by decreasing ACE2 abundance at the plasma membrane.","authors":"Piergiorgio La Rosa, Jessica Tiberi, Enrico Palermo, Roberta Stefanelli, Sofia Maria Luigia Tiano, Sonia Canterini, Mirko Cortese, John Hiscott, Maria Teresa Fiorenza","doi":"10.1186/s13578-024-01331-4","DOIUrl":"10.1186/s13578-024-01331-4","url":null,"abstract":"<p><strong>Background: </strong>The Niemann Pick C1 (NPC1) protein is an intracellular cholesterol transporter located in the late endosome/lysosome (LE/Ly) that is involved in the mobilization of endocytosed cholesterol. Loss-of-function mutations in the NPC1 gene lead to the accumulation of cholesterol and sphingolipids in LE/Ly, resulting in severe fatal NPC1 disease. Cellular alterations associated with NPC1 inactivation affect both the integrity of lipid rafts and the endocytic pathway. Because the angiotensin-converting enzyme 2 (ACE2) and type 2 serine transmembrane protease (TMPRSS2), interactors of the SARS-CoV-2 Spike protein also localize to lipid rafts, we sought to investigate the hypothesis that NPC1 inactivation would generate an intrinsically unfavorable barrier to SARS-CoV-2 entry.</p><p><strong>Results: </strong>In this study, we show that inhibition of the cholesterol transporter activity of NPC1 in cells that express both ACE2 and TMPRSS2, considerably reduces SARS-CoV-2 infectivity, evaluated as early as 4 h post-infection. Mechanistically, treatment with NPC1 specific inhibitor U18666A relocalizes ACE2 from the plasma membrane to the autophagosomal/lysosomal compartment, thereby reducing SARS-CoV-2 entry into treated cells. Reduction of viral entry was observed for both fully infectious SARS-CoV-2 virus and with a pseudotyped VSV-Spike-GFP virus. For instance, U18666A-treated Caco-2 cells infected with the pseudotyped VSV-Spike-GFP showed a > threefold and > 40-fold reduction in virus titer when infectivity was measured at 4 h or 24 h post-infection, respectively. A similar effect was observed in CRISP/R-Cas9-edited Caco-2 cells, which were even more resistant to SARS-CoV-2 infection as indicated by a 97% reduction of viral titers.</p><p><strong>Conclusion: </strong>Overall, this study provides compelling evidence that the inhibition of NPC1 cholesterol transporter activity generates a cellular environment that hinders SARS-CoV-2 entry. ACE2 depletion from the plasma membrane appears to play a major role as limiting factor for viral entry.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"14 1","pages":"148"},"PeriodicalIF":6.1,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662611/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Signal regulatory protein α dynamically mediates macrophage polarization facilitated alleviation of ischemic diseases.","authors":"Haiyi Liu, Yonghui Yuan, Takerra K Johnson-Stephenson, Chenyang Jing, Mingchao Zhang, Jun Huang, Ke Zen, Limin Li, Dihan Zhu","doi":"10.1186/s13578-024-01325-2","DOIUrl":"10.1186/s13578-024-01325-2","url":null,"abstract":"<p><strong>Background: </strong>macrophage-targeting therapy of ischemic disease has made progress in clinic trial. However, the role and underlying mechanism of pro-inflammatory or anti-inflammatory polarized macrophages in modulating ischemic diseases remain incompletely understood.</p><p><strong>Results: </strong>here we examine the effect of pro-inflammatory (LPS) and anti-inflammatory (IL-4) macrophage on ischemic diseases in a mouse ischemic hindlimb and heart model, and identify that signal regulatory protein α (Sirpα) modulates macrophage polarization induced angiogenesis via promoting phagocytosis or activating HIF1α nucleus relocation in macrophages, respectively. More importantly, the therapeutic effect of polarized macrophages is controlled by Sirpα in a time-dependent manner. Downregulation of macrophage Sirpα at the early-stage or upregulation of macrophage Sirpα at the late-stage of ischemic disease enhances the therapeutic effect. In contrast, increasing Sirpα at the early-stage or decreasing it at the late-stage leads to failure of inducing ischemic disease resilience. Mechanistically, we find that signal transducer and activator of transcription 3 and 6 (Stat3 and Stat6) mediate downregulation (pro-inflammatory polarization) or upregulation (anti-inflammatory polarization) of Sirpα, respectively.</p><p><strong>Conclusion: </strong>Our results reveal that dynamic regulation of macrophage by Sirpα plays a critical role in alleviating ischemic diseases.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"14 1","pages":"150"},"PeriodicalIF":6.1,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell multi-omics analysis reveals candidate therapeutic drugs and key transcription factor specifically for the mesenchymal subtype of glioblastoma.","authors":"Yufan Yang, Ziyuan Liu, Yerong Wei, Shuai He, Ancheng Gu, Zhiyong Li, Jianlong Li, Zhongyuan Xu, Bohong Cen","doi":"10.1186/s13578-024-01332-3","DOIUrl":"10.1186/s13578-024-01332-3","url":null,"abstract":"<p><p>The inherent heterogeneity of tumor cells impedes the development of targeted therapies for specific glioblastoma (GBM) subtypes. This study aims to investigate the mesenchymal subtype of GBM to uncover detailed characteristics, potential therapeutic strategies, and improve precision treatment for GBM patients. We integrated single-cell RNA sequencing (scRNA-seq), single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq), and bulk RNA sequencing datasets to identify core gene modules, candidate therapeutic drugs, and key transcription factors specific to mesenchymal subtype GBM tumor cells which we validated in vitro and human samples. Our analysis encompassed a heterogeneous single-cell landscape of 55,845 cells from tumor and adjacent normal tissues, focusing on the mesenchymal subtype's adverse prognosis and its association with hypoxia. We identified a core gene module composed of 38 genes and, through pharmacogenomic analysis, found that Trametinib and Dasatinib exhibit increased effectiveness against mesenchymal subtype GBM cells. Furthermore, by incorporating snATAC-seq data, we delineated a crucial regulatory network and pinpointed the key transcription factor CEBPG. Our research has highlighted the strong link between the mesenchymal-like (MES-like) properties of GBM and hypoxia, providing valuable insights into candidate drugs and pivotal targets for precision treatment of the mesenchymal subtype.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"14 1","pages":"151"},"PeriodicalIF":6.1,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662595/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of potential drug targets for diabetic polyneuropathy through Mendelian randomization analysis.","authors":"Xiaokun Chen, Guohua Jiang, Tianjing Zhao, Nian Sun, Shanshan Liu, Hao Guo, Canjun Zeng, Yijun Liu","doi":"10.1186/s13578-024-01323-4","DOIUrl":"10.1186/s13578-024-01323-4","url":null,"abstract":"<p><strong>Background: </strong>Diabetic polyneuropathy (DPN) is a common diabetes complication with limited treatment options. We aimed to identify circulating plasma proteins as potential therapeutic targets for DPN using Mendelian Randomization (MR).</p><p><strong>Methods: </strong>The protein quantitative trait loci (pQTLs) utilized in this study were derived from seven previously published genome-wide association studies (GWASs) on plasma proteomics. The DPN data were obtained from the IEU OpenGWAS project. This study employed two-sample MR using MR-Egger and inverse-variance weighted methods to evaluate the causal relationship between plasma proteins and DPN risk, with Cochran's Q test, and I² statistics, among other methods, used to validate the robustness of the results.</p><p><strong>Results: </strong>Using cis-pQTLs as genetic instruments, we identified 62 proteins associated with DPN, with 33 increasing the risk and 29 decreasing the risk of DPN. Using cis-pQTLs + trans-pQTLs, we identified 116 proteins associated with DPN, with 44 increasing the risk and 72 decreasing the risk of DPN. Steiger directionality tests indicated that the causal relationships between circulating plasma proteins and DPN were consistent with expected directions.</p><p><strong>Conclusion: </strong>This study identified 96 circulating plasma proteins with genetically determined levels that affect the risk of DPN, providing new potential targets for DPN drug development, particularly ITM2B, CREG1, CD14, and PLXNA4.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"14 1","pages":"147"},"PeriodicalIF":6.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142787263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing striatal acetylcholine facilitates dopamine release and striatal output in parkinsonian mice.","authors":"Hongxia Li, Ziluo Chen, Yuyan Tan, Huoqing Luo, Chen Lu, Chao Gao, Xin Shen, Fang Cai, Ji Hu, Shengdi Chen","doi":"10.1186/s13578-024-01328-z","DOIUrl":"10.1186/s13578-024-01328-z","url":null,"abstract":"<p><strong>Background: </strong>L-DOPA has been considered the first-line therapy for treating Parkinson's disease (PD) via restoring striatal dopamine (DA) to normalize the activity of local spiny projection neurons (SPNs) in the direct (dSPNs) pathway and the indirect (iSPNs) pathway. While the changes in striatal acetylcholine (ACh) induced by increasing DA have been extensively discussed, their validity remains controversial. Inhibition of striatal cholinergic signaling attenuates PD motor deficits. Interestingly, enhancing striatal ACh triggers local DA release, suggesting the pro-kinetic effects of ACh in movement control. Here, we investigated the in-vivo dynamics of ACh in the dorsolateral striatum (DLS) of the 6-OHDA-lesioned mouse model after L-DOPA administration, as well as its underlying mechanism, and to explore its modulatory role and mechanism in parkinsonian symptoms.</p><p><strong>Results: </strong>Using in vivo fiber photometry recordings with genetically encoded fluorescent DA or ACh indicator, we found L-DOPA selectively decreased DLS ACh levels in parkinsonian conditions. DA inhibited ACh release via dopamine D2 receptors and dSPNs-mediated activation of type-A γ-aminobutyric acid receptors on cholinergic interneurons. Restoring DLS ACh levels during L-DOPA treatment induced additional DA release by activating nicotinic acetylcholine receptors, thereby promoting the activity of dSPNs and iSPNs. Enhancing DLS ACh facilitated L-DOPA-induced turning behavior but not dyskinesia in parkinsonian mice.</p><p><strong>Conclusions: </strong>Our results demonstrated that enhancing striatal ACh facilitated the effect of L-DOPA by modulating DA tone. It may challenge the classical hypothesis of a purely competitive interaction between dopaminergic and cholinergic neuromodulation in improving PD motor deficits. Modulating ACh levels within the dopaminergic system may improve striatal DA availability in PD patients.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"14 1","pages":"146"},"PeriodicalIF":6.1,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11616140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics landscape of childhood simple obesity: novel insights into pathogenesis and biomarkers discovery.","authors":"Yi Ren, Peng Huang, Lu Zhang, Yufen Tang, Siyi He, HaiDan Li, XiaoYan Huang, Yan Ding, Lingjuan Liu, Liqun Liu, Xiaojie He","doi":"10.1186/s13578-024-01322-5","DOIUrl":"10.1186/s13578-024-01322-5","url":null,"abstract":"<p><strong>Background: </strong>The increasing incidence of childhood obesity annually has led to a surge in physical and mental health risks, making it a significant global public health concern. This study aimed to discover novel biomarkers of childhood simple obesity through integrative multi-omics analysis, uncovering their potential connections and providing fresh research directions for the complex pathogenesis and treatment strategies.</p><p><strong>Methods: </strong>Transcriptome, untargeted metabolome, and 16 S rDNA sequencing were conducted on subjects to examine transcripts, metabolites in blood, and gut microflora in stool.</p><p><strong>Results: </strong>Transcriptomic analysis identified 599 differentially expressed genes (DEGs), of which 25 were immune-related genes, and participated in immune pathways such as antimicrobial peptides, neutrophil degranulation, and interferons. The optimal random forest model based on these genes exhibited an AUC of 0.844. The metabolomic analysis examined 71 differentially expressed metabolites (DEMs), including 12 immune-related metabolites. Notably, lauric acid showed an extremely strong positive correlation with BMI and showed a good discriminative power for obesity (AUC = 0.82). DEMs were found to be significantly enriched in four metabolic pathways, namely \"Aminoacyl-tRNA biosynthesis\", \"Valine leucine and isoleucine biosynthesis, and Glycine\", \"Serine and threonine metabolism\", and \"Biosynthesis of unsaturated fatty acids\". Microbiome analysis revealed 12 differential gut microbiotas (DGMs) at the phylum and genus levels, with p_Firmicutes dominating in the obese group and g_Escherichia-Shigella in the normal group. Subsequently, a Random Forest model was developed based on the DEMs, immune-related DEGs, and metabolites with an AUC value of 0.912. The 14 indicators identified by this model could potentially serve as a set of biomarkers for obesity. The analysis of the inter-omics correlation network found 233 pairs of significant correlations. DEGs BPIFA1, BPI, and SAA1, DEMs Dimethy(tetradecyl)amine, Deoxycholic acid, Pathalic anhydride, and DL-Alanine, and DGMs g_Intestinimonas and g_Turicibacter showed strong connectivity within the network, constituting a large proportion of interactions.</p><p><strong>Conclusion: </strong>This study presents the first comprehensive description of the multi-omics characteristics of childhood simple obesity, recognizing promising biomarkers. Immune-related markers offer a new perspective for researching the immunological mechanisms underlying obesity and its associated complications. The revealed interactions among these biomarkers contribute to a deeper understanding the intricate biological regulatory networks associated with obesity.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"14 1","pages":"145"},"PeriodicalIF":6.1,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11606102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142752056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CAFs-derived lactate enhances the cancer stemness through inhibiting the MST1 ubiquitination degradation in OSCC.","authors":"Shuzhen Zhang, Jingjing Wang, Yang Chen, Weilian Liang, Hanzhe Liu, Ruixue Du, Yunqing Sun, Chuanyu Hu, Zhengjun Shang","doi":"10.1186/s13578-024-01329-y","DOIUrl":"10.1186/s13578-024-01329-y","url":null,"abstract":"<p><strong>Background: </strong>Cancer-associated fibroblasts (CAFs), a predominant stromal cell type in the tumor microenvironment, significantly affect the progression of oral squamous cell carcinoma (OSCC).</p><p><strong>Results: </strong>The specific mechanisms through which CAFs influence the cancer stem cell phenotype in OSCC are not fully understood. This study explored the effects of lactic acid produced by CAFs on the cancer stem cells (CSCs) phenotype of OSCC cells. Our results demonstrated that CAFs exhibit increased glycolysis and lactic acid production. Lactic acid treatment enhances CSCs-related markers expression, sphere formation, and clonogenic ability of OSCC cells. RNA sequencing revealed that lactic acid treatment elevates Discs Large Homolog 5 (DLG5) expression and markedly affects the Hippo pathway. Further investigation revealed that DLG5 mediates the effects of lactic acid on the CSCs phenotype. DLG5 knockdown results in elevated expression of E3 ubiquitin ligase Cullin 3, which can promote the ubiquitination and degradation of MST1, but the expression of phosphorylated MST1 remains unchanged. This leads to enhanced binding of phosphorylated MST1 to YAP1, increasing YAP1 phosphorylation and activating the Hippo pathway.</p><p><strong>Conclusion: </strong>Collectively, our findings suggest that lactic acid from CAFs promotes the CSCs phenotype in OSCC through the DLG5/CUL3/MST1 axis. Therefore, targeting lactic acid exchange between CAFs and tumor cells may provide a novel therapeutic approach to suppress the CSCs phenotype in OSCC.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"14 1","pages":"144"},"PeriodicalIF":6.1,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11603751/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142741077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bromodomain proteins as potential therapeutic targets for B-cell non-Hodgkin lymphoma.","authors":"Dan Zou, Sitong Feng, Bowen Hu, Mengya Guo, Yan Lv, Rong Ma, Yuxin Du, Jifeng Feng","doi":"10.1186/s13578-024-01326-1","DOIUrl":"10.1186/s13578-024-01326-1","url":null,"abstract":"<p><strong>Background: </strong>B-cell non-Hodgkin lymphoma (B-NHL) is the most common type of lymphoma and is significantly heterogeneous among various subtypes. Despite of considerable advancements in treatment strategies for B-NHL, the prognosis of relapsed/refractory patients remains poor.</p><p><strong>Main text: </strong>It has been indicated that epigenetic dysregulation is critically associated with the pathogenesis of most hematological malignancies, resulting in the clinical targeting of epigenetic modifications. Bromodomain (BRD) proteins are essential epigenetic regulators which contain eight subfamilies, including BRD and extra-terminal domain (BET) family, histone acetyltransferases (HATs) and HAT-related proteins, transcriptional coactivators, transcriptional mediators, methyltransferases, helicases, ATP-dependent chromatin-remodeling complexes, and nuclear-scaffolding proteins. Most pre-clinical and clinical studies on B-NHL have focused predominantly on the BET family and the use of BET inhibitors as mono-treatment or co-treatment with other anti-tumor drugs. Furthermore, preclinical models of B-NHL have revealed that BET degraders are more active than BET inhibitors. Moreover, with the development of BET inhibitors and degraders, non-BET BRD protein inhibitors have also been designed and have shown antitumor activities in B-NHL preclinical models. This review summarized the mechanism of BRD proteins and the recent progress of BRD protein-related drugs in B-NHL. This study aimed to collect the most recent evidences and summarize possibility on whether BRD proteins can serve as therapeutic targets for B-NHL.</p><p><strong>Conclusion: </strong>In summary, BRD proteins are critical epigenetic regulatory factors and may be potential therapeutic targets for B-NHL.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"14 1","pages":"143"},"PeriodicalIF":6.1,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11585172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Splicing factor SRSF1 attenuates cardiomyocytes apoptosis via regulating alternative splicing of Bcl2L12.","authors":"Yilin Xie, Zhenbo Yang, Wenxian Chen, Changsheng Zhong, Mengyang Li, Lei Zhang, Ting Cheng, Qin Deng, Huifang Wang, Jin Ju, Zhimin Du, Haihai Liang","doi":"10.1186/s13578-024-01324-3","DOIUrl":"10.1186/s13578-024-01324-3","url":null,"abstract":"<p><strong>Background: </strong>Aberrant alternative splicing (AS) events, triggered by the alterations in serine/arginine splicing factor 1 (SRSF1), a member of the SR protein family, have been implicated in various pathological processes. However, the function and mechanism of SRSF1 in cardiovascular diseases remain unclear.</p><p><strong>Results: </strong>In this study, we found that the expression of SRSF1 was significantly down-regulated in the hearts of mice with acute myocardial infarction (AMI) and H9C2 cells exposed to H₂O₂. Moreover, in vivo experiments utilizing adeno-associated virus serotype 9-mediated SRSF1 overexpression improved cardiac function and reduced infarct size in AMI mice. Mechanistically, we employed RNA-seq assay to identify AS aberrations associated with altered SRSF1 level in cardiomyocytes, and found that SRSF1 regulates the splice switching of Bcl2L12. Further study showed that silencing SRSF1 inhibits the inclusion of exon7 in Bcl2L12. Importantly, the truncated Bcl2L12 lacked the necessary structural elements and failed to interact with p53, thus compromising its ability to suppress apoptosis.</p><p><strong>Conclusions: </strong>Our study unraveled the role of SRSF1 as a splicing factor involved in the regulation of Bcl2L12 splice switching, thereby exerting an anti-apoptotic effect through the p53 pathway, which provides new insights into potential approaches targeting cardiomyocyte apoptosis in cardiovascular diseases.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"14 1","pages":"142"},"PeriodicalIF":6.1,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11585136/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}