ImmunoTargets and Therapy最新文献

{"title":"NLRP3 Inflammasome Upregulates PD-L1 in Ovarian Cancer and Contributes to an Immunosuppressive Microenvironment.","authors":"Wenjing Pan, Zhaoyang Jia, Jingtong Du, Kexin Chang, Yiming Liu, Wei Liu, Xibo Zhao, Wenhua Tan","doi":"10.2147/ITT.S495564","DOIUrl":"10.2147/ITT.S495564","url":null,"abstract":"<p><strong>Introduction: </strong>The NLRP3 inflammasome has been implicated in the initiation of inflammation and tumorigenesis; however, its role in epithelial ovarian cancer (EOC) remains unclear.</p><p><strong>Methods: </strong>This study employed high-throughput sequencing data, ELISA, clone formation assay, Western blot, and flow cytometric analysis to investigate the specific role of the NLRP3 inflammasome in EOC.</p><p><strong>Results: </strong>NLRP3 was highly expressed in human EOC tissues and correlated with an unfavorable prognosis. Activation of the NLRP3 inflammasome by LPS and ATP promoted EOC cell proliferation and increased IL-1 and PD-L1 levels. MCC950, a NLRP3 inflammasome blocker, reduced IL-1 and PD-L1 levels and diminished tumor-immune suppressive cells, such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and PD-1⁺ CD4⁺ T cells, in a murine model of ovarian cancer. This intervention also suppressed tumor growth.</p><p><strong>Conclusion: </strong>Our investigation revealed the pro-tumorigenic role of the NLRP3 inflammasome and its regulation of PD-L1 expression in EOC. Blockade of the NLRP3 inflammasome led to reduced PD-L1 expression, fewer immunosuppressive cells, and suppressed tumor growth. These findings suggest that targeting the NLRP3 inflammasome-PD-L1 axis could be a novel treatment approach for ovarian cancer.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"13 ","pages":"775-788"},"PeriodicalIF":6.2,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11656484/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbiome Differences in Colorectal Cancer Patients and Healthy Individuals: Implications for Vaccine Antigen Discovery.","authors":"Gordon C Ibeanu, Adekunle B Rowaiye, Joy C Okoli, Daniel U Eze","doi":"10.2147/ITT.S486731","DOIUrl":"10.2147/ITT.S486731","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) is the third most prevalent cancer worldwide, with numerous risk factors contributing to its development. Recent research has illuminated the significant role of the gut microbiota in CRC pathogenesis, identifying various microbial antigens as potential targets for vaccine development.</p><p><strong>Aim: </strong>This review aimed at exploring the potential sources of microbial antigens that could be harnessed to create effective CRC vaccines and understand the role of microbiome-CRC interactions in carcinogenesis.</p><p><strong>Methods: </strong>A comprehensive search of original research and review articles on the pathological links between key microbial candidates, particularly those more prevalent in CRC tissues, was conducted. This involved extensive use of the PubMed and Medline databases, as well as the Google Scholar search engine, utilizing pertinent keywords. A total of one hundred and forty-three relevant articles in English, mostly published between 2018 and 2024, were selected.</p><p><strong>Results: </strong>Numerous microbes, particularly bacteria and viruses, are significantly overrepresented in CRC tissues and have been shown to promote tumorigenesis by inducing inflammation and modulating the immune system. This makes them promising candidates for antigens in the development of CRC vaccines.</p><p><strong>Conclusion: </strong>The selection of microbial antigens focuses on their capacity to trigger a strong immune response and their link to tumor presence and progression. Identifying and validating these antigens through preclinical testing is essential in developing a CRC vaccine.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"13 ","pages":"749-774"},"PeriodicalIF":6.2,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11652712/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRPC6 is a Biomarker for Prognosis and Immunotherapy of Stomach Adenocarcinoma Based on Bioinformatic Analysis and Experimental Validation.","authors":"Xingchi Hu, Hongwei Wang, Haitao Sun, Jingxin Zhang, ZhenXiong Ye, Zhenhua Huang","doi":"10.2147/ITT.S488953","DOIUrl":"10.2147/ITT.S488953","url":null,"abstract":"<p><strong>Background: </strong>Transient receptor potential canonical 6 (TRPC6), a key member of the TRPC family, is involved in diverse physiological and pathological processes. Although previous studies have implicated TRPC6 in the progression of stomach adenocarcinoma (STAD), its precise functions and mechanisms remain unclear. Understanding TRPC6's role in STAD may provide insights into its prognostic and therapeutic potential.</p><p><strong>Methods: </strong>Using transcriptional and clinical data from The Cancer Genome Atlas (TCGA) database, we assessed the expression and prognostic value of TRPC6 in STAD through Kaplan-Meier survival curve analysis and correlation studies. Immune-related parameters, including immune cell infiltration and immune checkpoint gene expression, were also evaluated. Additionally, drug response analyses explored TRPC6's association with therapeutic agents. In vitro experiments were conducted to investigate TRPC6's role in STAD cell proliferation, migration, and invasion, focusing on its regulation of the PI3K-Akt signaling pathway.</p><p><strong>Results: </strong>TRPC6 was significantly overexpressed in STAD tissues compared to normal tissues, with high TRPC6 expression associated with poor overall survival. TRPC6 expression correlated strongly with immune cell infiltration, immune checkpoint genes, and sensitivity to therapies such as Lapatinib, anti-CTLA4, and anti-PD1 treatments. Functional assays confirmed that TRPC6 promotes STAD cell proliferation, migration, and invasion by activating the PI3K-Akt signaling pathway.</p><p><strong>Conclusion: </strong>This study highlights the prognostic significance of TRPC6 in STAD and its potential as a therapeutic target. TRPC6's involvement in immune regulation and cancer cell progression underscores its dual role in STAD pathogenesis and treatment, offering new avenues for targeted therapy development.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"13 ","pages":"735-748"},"PeriodicalIF":6.2,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11649498/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in B Cell Targeting for Treating Muscle-Specific Tyrosine Kinase-Associated Myasthenia Gravis.","authors":"Guanlian Hu, Xue Zhao, Yiren Wang, Xiaoyan Zhu, Zhan Sun, Xiaoxiao Yu, Jiahui Wang, Qian Liu, Jing Zhang, Yingna Zhang, Junhong Yang, Ting Chang, Zhe Ruan, Jie Lv, Feng Gao","doi":"10.2147/ITT.S492062","DOIUrl":"10.2147/ITT.S492062","url":null,"abstract":"<p><p>Myasthenia gravis (MG) is a typical autoimmune disease of the nervous system. It is characterized by skeletal muscle weakness and fatigue due to impaired neuromuscular junction transmission mediated by IgG autoantibodies. Muscle-specific receptor tyrosine kinase-associated MG (MuSK-MG), a rare and severe subtype of MG, is distinguished by the presence of anti-MuSK antibodies; it responds poorly to traditional therapies. Recent research on MuSK-MG treatment has focused on specific targeted therapies. Since B cells play a critical pathogenic role in producing autoantibodies and inflammatory mediators, they are often considered the preferred target for treating MuSK-MG. Currently, various B cell-targeted drugs have been developed to treat MuSK-MG; they have shown good therapeutic effects. This review explores the evolving landscape of B cell-targeted therapies in MuSK-MG, focusing on their mechanisms, efficacy, and safety, and the current limitations associated with their use. We discuss current B cell-targeted therapies aimed at depleting or modulating B cells via both direct and indirect approaches. Furthermore, we focus on novel and promising strategies such as Chimeric Autoantibody Receptor T cell therapy, which explicitly targets MuSK-specific B cells without compromising general humoral immunity. Finally, this review provides an outlook on the potential benefits and limitations of B cell-targeted therapy in developing new therapies for MuSK-MG. We conclude by discussing future research efforts needed to optimize these therapies, expand treatment options, and improve long-term outcomes in MuSK-MG management.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"13 ","pages":"707-720"},"PeriodicalIF":6.2,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11646387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated Analysis of Single-Cell and Bulk RNA-Sequencing Based on EcoTyper Machine Learning Framework Identifies Cell-State-Specific M2 Macrophage Markers Associated with Gastric Cancer Prognosis.","authors":"A-Kao Zhu, Guang-Yao Li, Fang-Ci Chen, Jia-Qi Shan, Yu-Qiang Shan, Chen-Xi Lv, Zhi-Qiang Zhu, Yi-Ren He, Lu-Lu Zhai","doi":"10.2147/ITT.S490075","DOIUrl":"10.2147/ITT.S490075","url":null,"abstract":"<p><strong>Background: </strong>Tumor is a complex and dynamic ecosystem formed by the interaction of numerous diverse cells types and the microenvironments they inhabit. Determining how cellular states change and develop distinct cellular communities in response to the tumor microenvironment is critical to understanding cancer progression. Tumour-associated macrophages (TAMs) are an important component of the tumour microenvironment and play a crucial role in cancer progression. This study was designed to identify cell-state-specific M2 macrophage markers associated with gastric cancer (GC) prognosis through integrative analysis of single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data using a machine learning framework named EcoTyper.</p><p><strong>Results: </strong>The results showed that TAMs were classified into M1 macrophages, M2 macrophages, monocytes, undefined macrophages and dendritic cells, with M2 macrophages predominating. EcoTyper assigned macrophages to different cell states and ecotypes. A total of 168 cell-state-specific M2 macrophage markers were obtained by integrative analysis of scRNA-seq and bulk RNA-seq data. These markers could categorize GC patients into two clusters (clusters A and B) with different survival and M2 macrophages infiltration abundance. Cell adhesion molecules, cytokine-cytokine receptor interaction, JAK/STAT pathway, MAPK pathway were significantly enriched in cluster A, which had worse survival and higher M2 macrophages infiltration.</p><p><strong>Conclusion: </strong>In conclusion, this study profiles a single-cell atlas of intratumor heterogeneity and defines the cell states and ecotypes of TAMs in GC. Furthermore, we have identified prognostically relevant cell-state-specific M2 macrophage markers. These findings provide novel insights into the tumor ecosystem and cancer progression.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"13 ","pages":"721-734"},"PeriodicalIF":6.2,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11646439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evolution of Hematobiochemical Profiles in Newly Diagnosed HIV Patients and HIV-TB Co-Infected Patients: Correlation with Immunological and Virological Status.","authors":"Nawaid Hussain Khan, Chaitenya Verma, Mirza Masroor Ali Beg, Shashi Nandar Kumar, Gaurav Kaushik, Hafiz Ahmad, Kudaibergen Osmonaliev, Vinay Kumar","doi":"10.2147/ITT.S495295","DOIUrl":"10.2147/ITT.S495295","url":null,"abstract":"<p><strong>Background: </strong>CD4+ cells, HIV-1 plasma viral load (PVL), and IFN-γ have been observed to enhance susceptibility in TB infection/reactivation among HIV-1 infected people, leading to unusual clinical manifestations. HIV-TB co-infection is significant for immunological and virological response, making it a great clinical challenge for patient management. The objective of this study was to explore the correlation among various hematological and biochemical profiles with CD4+ count and PVL in order to decipher mechanisms of TB development or reactivation in HIV-infected patients.</p><p><strong>Methods: </strong>In this cross-sectional study, we included 200 newly diagnosed treatment naïve HIV-1 infected patients, of which 118 were HIV-TB co-infected and 82 were HIV-alone. The CD4+ T count was determined using the BD FACS Count System, and the plasma HIV-1 viral load was estimated using the Abbott m2000 real-time platform. The hematobiochemical testing was performed on fully-automated analyzer ADVIA^® 560 and Cobas^® 501 Roche Diagnostics. Statistical software SPSS-2, Spearman correlation analysis was used for data analysis and a P-value less than 0.05 was considered statistically significant.</p><p><strong>Results: </strong>Declined hemoglobulin level positively correlated with CD4 counts (r = 0.229; p = 0.001), and a negative correlation was observed with HIV-1 plasma viral load (r = -0.171; p = 0.016). Moreover, the CD4+ count and HIV-1 plasma viral load (PVL) were also correlated to anomalies such as thrombocytopenia, leucopenia, eosinophils, neutrophils, ESR, potassium, Albumin, globulin, SGOT, uric acid. Studies also found significantly higher absolute neutrophil count, ESR, and serum fasting blood sugar, creatine, uric acid, total bilirubin, globulin, and alkaline phosphatase in HIV-TB co-infected patients.</p><p><strong>Conclusion and recommendation: </strong>The initial value of Hb, ESR, absolute neutrophil counts, serum calcium, uric acid, and potassium can be used as an early indicator for active tuberculosis (TB) and as a substitute marker for the course of HIV disease, especially in areas with low resources.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"13 ","pages":"691-705"},"PeriodicalIF":6.2,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11645950/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Potential Value of RPS27A in Prognosis and Immunotherapy: From Pan-Cancer Analysis to Hepatocellular Carcinoma Validation.","authors":"Xingwang Kuai, Chenyu Wei, Xiaoqian He, Fengli Wang, Chunbin Wang, Juling Ji","doi":"10.2147/ITT.S493217","DOIUrl":"10.2147/ITT.S493217","url":null,"abstract":"<p><strong>Purpose: </strong>Elucidation of the potential value of ribosomal protein S27a (RPS27A) for prognosis and immunotherapy in pan-cancer analysis, and exploration of the oncogenic function of RPS27A on hepatocellular carcinoma (HCC) and macrophage polarization.</p><p><strong>Methods: </strong>A systematic analysis of the function and mechanism of RPS27A was conducted with R software and multiple public platforms, including UALCAN, HPA, TISIDB, TIMER, cBioPortal, cancerSEA, TIDE, and TIMSO databases. The RPS27A expression in human and mouse liver was detected by immunohistochemistry. The biological behavior of HCC cells was detected in vitro after RPS27A overexpression. The influence of RPS27A on macrophage polarization was detected by the coculturing assay.</p><p><strong>Results: </strong>RPS27A dysregulation was found in multiple cancer types, and RPS27A level was associated with clinicopathologic features and prognosis in human cancers. RPS27A affected cancer statuses and multiple signaling pathways, such as DNA repair, invasion, IL10 synthesis, and MAPK activation. RPS27A took part in regulations of genomic alterations and heterogeneity and was associated with tumor mutation burden, microsatellite instability, neoantigen and so on. RPS27A expression was connected to the immune subtypes, tumor purity and immune cell infiltration and participated in regulation of the immunotherapy response. RPS27A was upregulated in HCC tissues compared to normal liver tissues. RPS27A overexpression in HCC cells promoted the proliferation, migration, and invasion of cancer cells, and accelerated M2 polarization of macrophage.</p><p><strong>Conclusion: </strong>RPS27A had the potential to be a biomarker for diagnosis, prognosis and immunotherapy response in pan-cancer, and targeting RPS27A may provide new ideas for cancer immunotherapy.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"13 ","pages":"673-690"},"PeriodicalIF":6.2,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11636265/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diminished Diversities and Clonally Expanded Sequences of T-Cell Receptors in Patients with Chronic Spontaneous Urticaria.","authors":"Xian He, Xueping Wen, Peng Ming He, Dan Liang, Lihong Yang, Yuping Ran, Zhixin Zhang","doi":"10.2147/ITT.S481361","DOIUrl":"10.2147/ITT.S481361","url":null,"abstract":"<p><strong>Objective: </strong>Studies establish a link between autoimmune factors and chronic spontaneous urticaria (CSU). T cells are crucial in immune-mediated diseases like CSU, and T-cell receptor (TCR) diversity could be pivotal in autoimmune responses. The clinical relevance of TCR variations in CSU is unknown, but understanding them may offer insights into CSU's pathogenesis and treatment.</p><p><strong>Methods: </strong>This cross-sectional study included 132 chronic urticaria (CU) patients versus 100 age-matched healthy donors (HD), with subgroup analyses on CU type, angioedema, allergic comorbidities, and anti-IgE therapy efficacy. Peripheral TCRβ repertoires were analyzed by high-throughput sequencing.</p><p><strong>Results: </strong>CSU patients showed reduced TCR diversity (lower D50) and increased large clone proportions than HD. Moreover, TCR diversity in CSU patients was significantly lower than in those with Chronic Inducible Urticaria (ClndU). There were also differences in variable (V) and joining (J) gene usage between CU and HD groups as well as CSU and ClndU groups. However, in subgroup analyses regarding angioedema, allergic comorbidities, and the efficacy of anti-IgE treatment, no significant differences were found in TCR diversity or large TCRβ clones. Notably, patients with treatment relapse or poor response to anti-IgE therapy had a higher proportion of positively charged CDR3. Additionally, age affected TCR diversity, but TIgE value, EOS counts, CU duration, and UAS7 score did not associate significantly with D50.</p><p><strong>Conclusion: </strong>CSU patients exhibit reduced TCR diversity and increased large clone proportions, indicating abnormal T cell activation. The TCR diversity differences and distinct V and J gene usage between CSU and ClndU may indicate different mechanisms in T lymphocyte-associated immune responses for these two subtypes of CU. The higher positive charge in CDR3 of relapsed or poorly responsive patients to anti-IGE treatment may indicate more antigen charge involvement. These findings provide new insights into the pathogenesis of CSU and potential future treatments.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"13 ","pages":"661-671"},"PeriodicalIF":6.2,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11628316/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142808098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circ_0001944 Targets the miR-1292-5p/FBLN2 Axis to Facilitate Sorafenib Resistance in Hepatocellular Carcinoma by Impeding Ferroptosis.","authors":"FanJing Jing, YunYan Shi, Dong Jiang, Xiao Li, JiaLin Sun, Qie Guo","doi":"10.2147/ITT.S463556","DOIUrl":"https://doi.org/10.2147/ITT.S463556","url":null,"abstract":"<p><strong>Background: </strong>Sorafenib, an orally active potent tyrosine kinase inhibitor (TKI), represented a primary treatment in patients with advanced hepatocellular carcinoma (HCC). Unfortunately, sorafenib resistance was regarded as a huge obstacle for HCC treatment.</p><p><strong>Methods: </strong>RNA-sequencing including circRNA Sequencing (circRNA-Seq) for circular RNAs (circRNAs), miRNA Sequencing (miRNA-Seq) for microRNAs (miRNAs), as well as mRNA Sequencing (mRNA-Seq) for mRNAs in <i>sorafenib-resistant HCC cells vs sorafenib-sensitive HCC cells</i>, were performed. Then, interaction correlation analysis between differentially expressed circRNAs and miRNAs and their target genes in Huh7/SOR and SMMC7721/SOR cells was exhibited. The \"circRNA-miRNA-mRNA\" network was constructed through <i>the Cytoscape software application, Circular RNA Interactome</i> and <i>Targetscan prediction, RNA binding protein immunoprecipitation (RIP), RNA pull-down, and Dual luciferase reporter assay</i>. Furthermore, <i>mRNA-Seq, Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis</i> for the downstream genes involved in the \"circRNA-miRNA-mRNA\" network was implemented. <i>Iron detection assay, Lipid peroxidation quantification assay, ROS measurement assay, CCK-8 assay,</i> and <i>tumor challenge</i> in vivo were used to determine the mechanisms promoting sorafenib resistance in HCC, where the \"circRNA-miRNA-mRNA\" network is clearly involved in.</p><p><strong>Results: </strong>circ_0001944 and circ_0078607 with upregulation and 2 downregulated expressed circRNAs (circ_0002874 and circ_0069981), as well as 11 upregulated miRNAs including miR-193a-5p, miR-197-3p, miR-27a-5p, miR-551b-5p, miR-335-3p, miR-767-3p, miR-767-5p, miR-92a-1-5p, miR-92a-3p, miR-3940-3p, and miR-664b-3p and 3 downregulated expressed miRNAs (miR-1292-5p, let-7c-5p, and miR-99a-5p) in sorafenib-resistant HCC cells were determined. Among these non-coding RNAs (ncRNAs), circ_0001944 and miR-1292-5p should not be drop out of sight; circ_0001944 has been proved to target miR-1292-5p to inhibit its expression in HCC. Subsequent findings also raise that miR-1292-5p directly targeted the 3'-noncoding region (3'-UTR) of <i>Fibulin 2 (FBLN2)</i> mRNA. Furthermore, circ_0001944 targets the miR-1292-5p/FBLN2 axis to inhibit cell ferroptosis in which the indicated regulators associated with iron overload and lipid peroxidation were \"rearranged\". Most importantly, circ_0001944 advanced sorafenib resistance in HCC through mitigating ferroptosis, where the miR-1292-5p/FBLN2 axis cannot be left unrecognized.</p><p><strong>Conclusion: </strong>Circ_0001944 is a putative target for reversing sorafenib resistance in HCC. Our findings are expected to provide new targets and new directions for sorafenib sensitization in the treatment of HCC.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"13 ","pages":"643-659"},"PeriodicalIF":6.2,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11611519/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142772964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Insights into Causal Effects of Lipid and Lipid-Lowering Targets with Autoimmune Thyroid Disease: A Mendelian Randomization Study.","authors":"Chang Su, Juan Tian, Xueqing He, Xiaona Chang, Guang Wang, Jia Liu","doi":"10.2147/ITT.S487319","DOIUrl":"10.2147/ITT.S487319","url":null,"abstract":"<p><strong>Background: </strong>Dyslipidemia has been implicated in the pathogenesis of several diseases, including thyroid dysfunction and immune disorders. However, whether circulating lipids and long-term use of lipid-lowering drugs influence the development of autoimmune thyroid disease (AITD) remains unclear. This study aims to evaluate the effects of lipid-lowering drugs on AITD and explore their potential mechanisms.</p><p><strong>Methods: </strong>Two-sample and two-step Mendelian randomization (MR) studies were performed to assess the causal relationships between circulating lipids (LDL-C, TC, TG, and ApoB) and seven lipid-lowering drug targets (<i>ApoB, CETP, HMGCR, LDLR, NPC1L1, PCSK9</i>, and <i>PPARα</i>) with AITD. Mediation analyses were conducted to explore potential mediating factors.</p><p><strong>Results: </strong>There was no clear causality between circulating lipids (ApoB, LDL-C, TC, and TG) and AITD (<i>p</i> > 0.05). <i>ApoB</i> inhibition is related to a reduced risk of autoimmune thyroiditis (AT) (OR = 0.462, <i>p</i>= 0.046), while <i>PCSK9</i> inhibition is related to reduced Graves' disease (GD) risk (OR = 0. 551, <i>p</i> = 0.033). Moreover, <i>PCSK9</i> inhibition (OR = 0.735, <i>p</i> = 0.003), <i>LDLR</i> inhibition (OR = 0.779, <i>p</i> = 0.027), and <i>NPC1L1</i> inhibition (OR = 0.599, <i>p</i> = 0.016) reduced the risk of autoimmune hypothyroidism (AIH). Mediation analysis showed that <i>NPC1L1</i> inhibition and <i>PCSK9</i> inhibition exerted effects on AIH through IL-4 and FGF-19 levels. And the effect of <i>PCSK9</i> inhibition on GD through TNF-β levels.</p><p><strong>Conclusion: </strong>There was no clear causality between circulating lipids (ApoB, LDL-C, TC, and TG) and AITD. Lipid-lowering drug target gene inhibitors reduced the AITD risk by modulating inflammatory factors.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"13 ","pages":"631-641"},"PeriodicalIF":6.2,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11600951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}