Cell and Bioscience最新文献

{"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}

{"title":"Dietary contributions in the genetic variation of liver fibrosis: a genome-wide association study of fibrosis-4 index in the liver fibrosis development.","authors":"Poppy Diah Palupi, Chun-Yu Wei, Wan-Hsuan Chou, Min-Rou Lin, Yu-Jui Yvonne Wan, Wei-Chiao Chang","doi":"10.1186/s13578-024-01321-6","DOIUrl":"10.1186/s13578-024-01321-6","url":null,"abstract":"<p><strong>Background: </strong>The fibrosis-4 (FIB-4) index is a non-invasive method to assess the severity of liver fibrosis. The development of liver fibrosis is influenced by genetic predisposition and dietary factors. However, the modulating effect of dietary factors on the genetic susceptibility of liver fibrosis remains unclear. The study aims to investigate the role of dietary factors in modulating the genetic susceptibility of liver fibrosis.</p><p><strong>Methods: </strong>Here, we conducted a genome-wide association study (GWAS) of FIB-4 index-directed liver fibrosis risk, adjusted with diet, lifestyle factors, and hepatitis serological markers. The high (N = 1,476) and low (N = 36,735) liver fibrosis risk groups were defined with a FIB-4 > 2.67 and < 1.3, respectively.</p><p><strong>Results: </strong>The age-related FIB-4 variation showed subjects with a FIB-4 > 2.67 (3.8%), indicating high fibrosis risk, occurred predominantly among individuals above 60 years old. The multivariable analysis showed that tea intake is significantly associated with a reduced risk of liver fibrosis. The GWAS adjusted for sex, age, age², dietary factors (tea and coffee consumption, vegetarian preference), lifestyle (alcohol consumption, physical activity), hepatitis serological markers (anti-HCV, HBsAg, HBeAg), and the top ten principal components indicated 25 genome-wide significant signals (p < 5 × 10^- 8). Two variants (rs56293029 and rs9389269) were previously associated with the FIB-4 index in alcohol-related cirrhosis, while the 23 SNPs remaining were novel. The rs9399136 (HBS1L) is a protective variant, and rs9274407 (HLA-DQB1) is a risk variant, both contributing to liver fibrosis development. Our results showed that genetic factors play a major role in liver fibrosis, while dietary factors have minor effects on disease progression. Pathway analysis suggested the potential of immune response and hematopoietic systems function in the pathogenesis of liver disease.</p><p><strong>Conclusions: </strong>The studies not only revealed the protective role of rs9399136 (HBS1L) and the risk effect of rs9274407 (HLA-DQB1) toward liver fibrosis in a Taiwanese population, but also demonstrated that individual consumption patterns, such as tea uptake, have a minor impact on liver fibrosis prevention. The pathway analysis from GWAS variants further indicated the importance of immune responses in the pathogenesis of liver fibrosis.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"14 1","pages":"141"},"PeriodicalIF":6.1,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11583755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693875","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":"CXCL11 reprograms M2-biased macrophage polarization to alleviate pulmonary fibrosis in mice.","authors":"Ji-Young Kim, Dong-Wook Cho, Jung-Yun Choi, Suji Jeong, Minje Kang, Woo Jin Kim, In-Sun Hong, Haengseok Song, Heesoon Chang, Se-Ran Yang, Seung-Joon Lee, Mira Park, Seok-Ho Hong","doi":"10.1186/s13578-024-01320-7","DOIUrl":"10.1186/s13578-024-01320-7","url":null,"abstract":"<p><strong>Background: </strong>In understanding the pathophysiology of pulmonary fibrosis (PF), macrophage plasticity has been implicated with a crucial role in the fibrogenic process. Growing evidence indicates that accumulation of M2 macrophages correlates with the progression of PF, suggesting that targeted modulation of molecules that influence M2 macrophage polarization could be a promising therapeutic approach for PF. Here, we demonstrated a decisive role of C-X-C motif chemokine ligand 11 (CXCL11) in driving M1 macrophage polarization to alleviate PF in the bleomycin-induced murine model.</p><p><strong>Results: </strong>We intravenously administered secretome derived from naïve (M0) and polarized macrophages (M1 and M2) into PF mice and found that lung fibrosis was effectively reversed in only the M1-treated group, with modulation of the M1/M2 ratio toward the ratio of the control group. These findings suggest that the factors secreted from M1 macrophages contribute to alleviating PF by targeting macrophages and reshaping the immunofibrotic environment in a paracrine manner. Secretome analysis of macrophages identified CXCL11 as an M1-specific chemokine, and administration of recombinant CXCL11 effectively improved fibrosis with the reduction of M2 macrophages in vivo. Furthermore, a mechanistic in vitro study revealed that CXCL11 reprogrammed macrophages from M2 to M1 through the activation of pERK, pAKT, and p65 signaling.</p><p><strong>Conclusions: </strong>Collectively, we demonstrate an unprecedented role for M1 macrophage-derived CXCL11 as an inducer of M1 macrophage polarization to revert the fibrogenic process in mice with PF, which may provide a clinically meaningful benefit.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"14 1","pages":"140"},"PeriodicalIF":6.1,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11566568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644733","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":"Stearoyl-CoA desaturase in CD4⁺ T cells suppresses tumor growth through activation of the CXCR3/CXCL11 axis in CD8⁺ T cells.","authors":"Sung-Hyun Hwang, Yeseul Yang, Jae-Ha Jung, Jin Won Kim, Yongbaek Kim","doi":"10.1186/s13578-024-01308-3","DOIUrl":"10.1186/s13578-024-01308-3","url":null,"abstract":"<p><strong>Background: </strong>Within the tumor microenvironment, altered lipid metabolism promotes cancer cell malignancy by activating oncogenic cascades; however, impact of lipid metabolism in CD4⁺ tumor-infiltrating lymphocytes (TILs) remains poorly understood. Here, we elucidated that role of stearoyl-CoA desaturase (SCD) increased by treatment with cancer-associated fibroblast (CAF) supernatant in CD4⁺ T cells on their subset differentiation and activity of CD8⁺ T cells.</p><p><strong>Results: </strong>In our study, we observed that CD4⁺ TILs had higher lipid droplet content than CD4⁺ splenic T cells. In tumor tissue, CAF-derived supernatant provided fatty acids to CD4⁺ TILs, which increased the expression of SCD and oleic acid (OA) content. Increased SCD expression by OA treatment enhanced the levels of Th1 cell markers TBX21, interleukin-2, and interferon-γ. However, SCD inhibition upregulated the expression of regulatory T (Treg) cell markers, FOXP3 and transforming growth factor-β. Comparative fatty acid analysis of genetically engineered Jurkat cells revealed that OA level was significantly higher in SCD-overexpressing cells. Overexpression of SCD increased expression of Th1 cell markers, while treatment with OA enhanced the transcriptional level of TBX21 in Jurkat cells. In contrast, palmitic acid which is higher in SCD-KO cells than other subclones enhanced the expression of Treg cell markers through upregulation of mitochondrial superoxide. Furthermore, SCD increased the secretion of the C-X-C motif chemokine ligand 11 (CXCL11) from CD4⁺ T cells. The binding of CXCL11 to CXCR3 on CD8⁺ T cells augmented their cytotoxic activity. In a mouse tumor model, the suppressive effect of CD8⁺ T cells on tumor growth was dependent on CXCR3 expression.</p><p><strong>Conclusion: </strong>These findings illustrate that SCD not only orchestrates the differentiation of T helper cells, but also promotes the antitumor activity of CD8⁺ T cells, suggesting its function in adverse tumor microenvironments.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"14 1","pages":"137"},"PeriodicalIF":6.1,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11566202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142630893","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":"A novel function for α-synuclein as a regulator of NCK2 in olfactory bulb: implications for its role in olfaction.","authors":"Jing Ren, Chao Wu, Mengxia Zeng, Mingqin Qu, Ge Gao, Ning Chen, Jingjing Yue, Yuwen Jiang, Tongfei Zhao, Na Xiang, Fangang Meng, Ling-Ling Lu","doi":"10.1186/s13578-024-01313-6","DOIUrl":"10.1186/s13578-024-01313-6","url":null,"abstract":"<p><p>To investigate physiological function of α-synuclein is important for understanding its pathophysiological mechanism in synucleinopathies including Parkinson's disease. Employing knockout mice, we found that Snac/α-synuclein deletion induced aberrant projection of olfactory sensory neurons and hyposmia. We identified 9 axon guidance associated differentially expressed proteins using iTRAQ based Liquid Chromatograph Mass Spectrometer. NCK2 is most significantly down-regulated protein among them. We further found that either α-synuclein deletion or NCK2 deficiency induced Eph A4 inactivation. Re-expressing Snac/α-synuclein in its knockout neurons reversed the down-regulation of NCK2, as well as the inactivation of EphA4. Overexpression of Snac/α-synuclein in α-synuclein deleted mice reversed the down-regulation of NCK2 and pEphA4, and improved the olfactory impairment of mice. Correlation analysis showed that there is a significant correlation between the protein level of α-synuclein, NCK2, and pEphA4, respectively. Nonetheless, immunoprecipitation analysis showed that NCK2 was associated with both EphA4 and Rho A, suggesting that NCK2 as a scaffolding protein to modulate Eph A4/Rho A pathway. Moreover, Rho A activity was significantly lower in α-synuclein deficient mice. Thus, α-synuclein regulates olfactory neurons projection through NCK2 dependent EphA4/Rho A pathway. Malfunction of α-synuclein because of deletion may cause aberrant olfactory neurons projection. This extended our knowledge of α-synuclein functions, which may explain why olfaction is usually impaired in some synucleinopathies.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"14 1","pages":"139"},"PeriodicalIF":6.1,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11566155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142630624","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}