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Xing Z, Cui L, Feng Y, Yang Y, He X. Exploring the prognostic implications of cuproptosis-associated alterations in clear cell renal cell carcinoma via in vitro experiments. Sci Rep 2024; 14:16935. [PMID: 39043799 PMCID: PMC11266406 DOI: 10.1038/s41598-024-67756-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 07/15/2024] [Indexed: 07/25/2024] Open
Abstract
This study investigated the impact of novel copper ionophores on the prognosis of clear cell renal cell carcinoma (ccRCC) and the tumor microenvironment (TME). The differential expression of 10 cuproptosis and 40 TME-pathway-related genes were measured in 531 tumor samples and 71 adjacent kidney samples in The Cancer Genome Atlas database. A risk score model was constructed with LASSO cox to predict the prognosis of ccRCC patients. Forest plot and function enrichment were used to study the biological function of the key genes in depth. The study found that the risk score model accurately predicted the prognosis of ccRCC patients. Patients with high scores had higher immune responses with a higher proportion of anti-tumor lymphocytes and a lower proportion of immunosuppressive M2-like macrophages. However, the high-score group also exhibited a higher proportion of T follicular helper cells and regulatory T cells. These results suggest that cuproptosis-based therapy may be worth further investigation for the treatment of ccRCC and TME. Subsequently, by using RNAi, we established the stable depletion models of FDX1 and PDHB in ccRCC cell lines 786-O and ACHN. Through CCK8, colony formation, and Transwell assays, we observed that the knockdown of FDX1 and PDHB could significantly reduce the capabilities of proliferation and migration in ccRCC cells. In conclusion, this study illuminates the potential effectiveness of copper ionophores in the treatment of ccRCC, with higher risk scores correlating with better TME immune responses. It sets the stage for future cuproptosis-based therapy research in ccRCC and other cancers, focusing on copper's role in TME.
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Affiliation(s)
- Zhaoyu Xing
- The Department of Urology, The Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu Province, China
| | - Li Cui
- The Department of Urology, The Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu Province, China
| | - Yuehua Feng
- The Department of Comprehensive Laboratory, The Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu Province, China
| | - Yang Yang
- The Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu Province, China
| | - Xiaozhou He
- The Department of Urology, The Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu Province, China.
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Wu T, Hou Y, Xin G, Niu J, Peng S, Xu F, Li Y, Chen Y, Yu Y, Zhang H, Kong X, Cao Y, Ning S, Wang L, Hao J. MSGD: a manually curated database of genomic, transcriptomic, proteomic and drug information for multiple sclerosis. Database (Oxford) 2024; 2024:baae037. [PMID: 38788333 PMCID: PMC11126313 DOI: 10.1093/database/baae037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 04/26/2024] [Accepted: 05/13/2024] [Indexed: 05/26/2024]
Abstract
Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system. 'Omics' technologies (genomics, transcriptomics, proteomics) and associated drug information have begun reshaping our understanding of multiple sclerosis. However, these data are scattered across numerous references, making them challenging to fully utilize. We manually mined and compiled these data within the Multiple Sclerosis Gene Database (MSGD) database, intending to continue updating it in the future. We screened 5485 publications and constructed the current version of MSGD. MSGD comprises 6255 entries, including 3274 variant entries, 1175 RNA entries, 418 protein entries, 313 knockout entries, 612 drug entries and 463 high-throughput entries. Each entry contains detailed information, such as species, disease type, detailed gene descriptions (such as official gene symbols), and original references. MSGD is freely accessible and provides a user-friendly web interface. Users can easily search for genes of interest, view their expression patterns and detailed information, manage gene sets and submit new MS-gene associations through the platform. The primary principle behind MSGD's design is to provide an exploratory platform, aiming to minimize filtration and interpretation barriers while ensuring highly accessible presentation of data. This initiative is expected to significantly assist researchers in deciphering gene mechanisms and improving the prevention, diagnosis and treatment of MS. Database URL: http://bio-bigdata.hrbmu.edu.cn/MSGD.
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Affiliation(s)
- Tao Wu
- Department of Neurology, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Xicheng District, Beijing 100053, China
- National Center for Neurological Disorders, No.45 Changchun Street, Xicheng District, Beijing 100053, China
| | - Yaopan Hou
- College of Bioinformatics Science and Technology, Harbin Medical University, Baojian Road, Nangang District, Harbin, Heilongjiang 150081, China
| | - Guanghao Xin
- Department of Neurology, The Second Affiliated Hospital, Harbin Medical University, Baojian Road, Nangang District, Harbin, Heilongjiang 150081, China
| | - Jingyan Niu
- Department of Neurology, The Second Affiliated Hospital, Harbin Medical University, Baojian Road, Nangang District, Harbin, Heilongjiang 150081, China
| | - Shanshan Peng
- Department of Neurology, The Second Affiliated Hospital, Harbin Medical University, Baojian Road, Nangang District, Harbin, Heilongjiang 150081, China
| | - Fanfan Xu
- Department of Neurology, The Second Affiliated Hospital, Harbin Medical University, Baojian Road, Nangang District, Harbin, Heilongjiang 150081, China
| | - Ying Li
- Department of Neurology, The Second Affiliated Hospital, Harbin Medical University, Baojian Road, Nangang District, Harbin, Heilongjiang 150081, China
| | - Yuling Chen
- College of Bioinformatics Science and Technology, Harbin Medical University, Baojian Road, Nangang District, Harbin, Heilongjiang 150081, China
| | - Yifangfei Yu
- College of Bioinformatics Science and Technology, Harbin Medical University, Baojian Road, Nangang District, Harbin, Heilongjiang 150081, China
| | - Huixue Zhang
- Department of Neurology, The Second Affiliated Hospital, Harbin Medical University, Baojian Road, Nangang District, Harbin, Heilongjiang 150081, China
| | - Xiaotong Kong
- Department of Neurology, The Second Affiliated Hospital, Harbin Medical University, Baojian Road, Nangang District, Harbin, Heilongjiang 150081, China
| | - Yuze Cao
- Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Dongcheng District, Beijing 100730, China
| | - Shangwei Ning
- College of Bioinformatics Science and Technology, Harbin Medical University, Baojian Road, Nangang District, Harbin, Heilongjiang 150081, China
| | - Lihua Wang
- Department of Neurology, The Second Affiliated Hospital, Harbin Medical University, Baojian Road, Nangang District, Harbin, Heilongjiang 150081, China
| | - Junwei Hao
- Department of Neurology, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Xicheng District, Beijing 100053, China
- National Center for Neurological Disorders, No.45 Changchun Street, Xicheng District, Beijing 100053, China
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Xu M, Wang H, Ren S, Wang B, Yang W, Lv L, Sha X, Li W, Wang Y. Identification of crucial inflammaging related risk factors in multiple sclerosis. Front Mol Neurosci 2024; 17:1398665. [PMID: 38836117 PMCID: PMC11148336 DOI: 10.3389/fnmol.2024.1398665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Accepted: 04/30/2024] [Indexed: 06/06/2024] Open
Abstract
Background Multiple sclerosis (MS) is an immune-mediated disease characterized by inflammatory demyelinating lesions in the central nervous system. Studies have shown that the inflammation is vital to both the onset and progression of MS, where aging plays a key role in it. However, the potential mechanisms on how aging-related inflammation (inflammaging) promotes MS have not been fully understood. Therefore, there is an urgent need to integrate the underlying mechanisms between inflammaging and MS, where meaningful prediction models are needed. Methods First, both aging and disease models were developed using machine learning methods, respectively. Then, an integrated inflammaging model was used to identify relative risk factors, by identifying essential "aging-inflammation-disease" triples. Finally, a series of bioinformatics analyses (including network analysis, enrichment analysis, sensitivity analysis, and pan-cancer analysis) were further used to explore the potential mechanisms between inflammaging and MS. Results A series of risk factors were identified, such as the protein homeostasis, cellular homeostasis, neurodevelopment and energy metabolism. The inflammaging indices were further validated in different cancer types. Therefore, various risk factors were integrated, and even both the theories of inflammaging and immunosenescence were further confirmed. Conclusion In conclusion, our study systematically investigated the potential relationships between inflammaging and MS through a series of computational approaches, and could present a novel thought for other aging-related diseases.
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Affiliation(s)
- Mengchu Xu
- Department of Biomedical Engineering, School of Intelligent Sciences, China Medical University, Shenyang, Liaoning, China
| | - Huize Wang
- Department of Nursing, First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Siwei Ren
- Department of Biomedical Engineering, School of Intelligent Sciences, China Medical University, Shenyang, Liaoning, China
| | - Bing Wang
- Department of Biomedical Engineering, School of Intelligent Sciences, China Medical University, Shenyang, Liaoning, China
| | - Wenyan Yang
- Department of Biomedical Engineering, School of Intelligent Sciences, China Medical University, Shenyang, Liaoning, China
| | - Ling Lv
- Department of Thorax, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xianzheng Sha
- Department of Biomedical Engineering, School of Intelligent Sciences, China Medical University, Shenyang, Liaoning, China
| | - Wenya Li
- Department of Thorax, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yin Wang
- Department of Biomedical Engineering, School of Intelligent Sciences, China Medical University, Shenyang, Liaoning, China
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
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Rafaqat S, Rafaqat S. Role of IL-2/IL-2 receptor in pathogenesis of autoimmune disorders: Genetic and therapeutic aspects. World J Med Genet 2023; 11:28-38. [DOI: 10.5496/wjmg.v11.i3.28] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 06/10/2023] [Accepted: 06/30/2023] [Indexed: 07/20/2023] Open
Abstract
Interleukin-2 (IL-2) is an important cytokine that plays a key role in the immune response. The IL-2 receptor (IL-2R) is composed of three subunits, alpha, beta, and gamma, with the alpha subunit having the highest affinity for IL-2. Several studies reported that immune dysregulation of IL-2 may cause tissue injury as well as damage leading to the pathogenesis of various autoimmune diseases such as acute necrotizing vasculitis in systemic lupus erythematosus (SLE), inflammatory synovitis in rheumatoid arthritis (RA), salivary and lacrimal gland dys-function in Sjogren syndrome (SS), obliterative vasculopathy fibrosis in systemic sclerosis (SSc), and inflammatory demyelination in multiple sclerosis (MS). The aim of this review paper was to examine the role of IL-2/IL-2R in various autoimmune disorders, taking into account recent advancements and discoveries, gaps in the current literature, ongoing debates, and potential avenues for future research. The focus of this review is on systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, sjogren syndrome, and multiple sclerosis, which are all linked to the malfunctioning of IL-2/IL-2R. In genetic studies, gene polymorphisms of IL-2 such as IL-2 330/T, IL-2 330/G, and rs2069763 are involved in increasing the risk of SLE. Furthermore, genetic associations of IL-2/IL-2R such as rs791588, rs2281089, rs2104286, rs11594656, and rs35285258 are significantly associated with RA susceptibility. The IL-2 polymorphism including rs2069762A, rs6822844T, rs6835457G, and rs907715T are significant connections with systemic sclerosis. In addition, rs2104286 (IL-2), rs11594656 (IL-2RA), rs35285258 (IL-2RB) gene polymorphism significant increases the risk of multiple sclerosis. In therapeutic approaches, low-dose IL-2 therapy could regulate Tfr and Tfh cells, resulting in a reduction in disease activity in the SLE patients. In addition, elevated sIL-2R levels in the peripheral blood of SLE patients could be linked to an immunoregulatory imbalance, which may contribute to the onset and progression of SLE. Consequently, sIL-2R could potentially be a target for future SLE therapy. Moreover, Low dose-IL2 was well-tolerated, and low levels of Treg and high levels of IL-21 were associated with positive responses to Ld-IL2 suggested to be a safe and effective treatment for RA. Additionally, low-dose IL-2 treatment improves the exocrine glands' ability to secrete saliva in SS-affected mice. Whereas, Basiliximab targets the alpha chain of the IL-2 receptor suggested as a potential treatment for SSc. Also, pre-and post-treatment with Tregs, MDSCs, and IL-2 may have the potential to prevent EAE induction in patients with MS. It is suggested that further studies should be conducted on IL-2 polymorphism in Sjogren syndrome.
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Affiliation(s)
- Sana Rafaqat
- Department of Biotechnology (Specialized in Human Genetics), Lahore College for Women University, Lahore 54000, Pakistan
| | - Saira Rafaqat
- Department of Zoology, Lahore College for Women University, Lahore 54000, Pakistan
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Manaig YJY, Mármol-Sánchez E, Castelló A, Esteve-Codina A, Sandrini S, Savoini G, Agazzi A, Sánchez A, Folch JM. Exon-intron split analysis reveals posttranscriptional regulatory signals induced by high and low n-6/n-3 polyunsaturated fatty acid ratio diets in piglets. J Anim Sci 2023; 101:skad271. [PMID: 37561402 PMCID: PMC10503648 DOI: 10.1093/jas/skad271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 08/08/2023] [Indexed: 08/11/2023] Open
Abstract
Polyunsaturated fatty acids (PUFA), such as omega-6 (n-6) and omega-3 (n-3), play a vital role in nutrient metabolism, inflammatory response, and gene regulation. microRNAs (miRNA), which can potentially degrade targeted messenger RNAs (mRNA) and/or inhibit their translation, might play a relevant role in PUFA-related changes in gene expression. Although differential expression analyses can provide a comprehensive picture of gene expression variation, they are unable to disentangle when in the mRNA life cycle the regulation of expression is taking place, including any putative functional miRNA-driven repression. To capture this, we used an exon-intron split analysis (EISA) approach to account for posttranscriptional changes in response to extreme values of n-6/n-3 PUFA ratio. Longissimus dorsi muscle samples of male and female piglets from sows fed with n-6/n-3 PUFA ratio of 13:1 (SOY) or 4:1 (LIN), were analyzed in a bidirectional contrast (LIN vs. SOY, SOY vs. LIN). Our results allowed the identification of genes showing strong posttranscriptional downregulation signals putatively targeted by significantly upregulated miRNA. Moreover, we identified genes primarily involved in the regulation of lipid-related metabolism and immune response, which may be associated with the pro- and anti-inflammatory functions of the n-6 and n-3 PUFA, respectively. EISA allowed us to uncover regulatory networks complementing canonical differential expression analyses, thus providing a more comprehensive view of muscle metabolic changes in response to PUFA concentration.
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Affiliation(s)
- Yron Joseph Yabut Manaig
- Departament de Ciència Animal i dels Aliments, Universitat Autònoma de Barcelona, Barcelona 08193, Spain
- Plant and Animal Genomics, Centre for Research in Agricultural Genomics (CRAG), CSIC-IRTA-UAB-UB, Campus Universitat Autònoma de Barcelona, Barcelona 08193, Spain
- Department of Veterinary Medicine and Animal Sciences, Università degli Studi di Milano, Lodi 26900, Italy
| | - Emilio Mármol-Sánchez
- Science for Life Laboratory, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm 11418, Sweden
- Centre for Palaeogenetics, Stockholm 10691, Sweden
| | - Anna Castelló
- Departament de Ciència Animal i dels Aliments, Universitat Autònoma de Barcelona, Barcelona 08193, Spain
- Plant and Animal Genomics, Centre for Research in Agricultural Genomics (CRAG), CSIC-IRTA-UAB-UB, Campus Universitat Autònoma de Barcelona, Barcelona 08193, Spain
| | - Anna Esteve-Codina
- Functional Genomics, CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain
| | - Silvia Sandrini
- Department of Veterinary Medicine and Animal Sciences, Università degli Studi di Milano, Lodi 26900, Italy
| | - Giovanni Savoini
- Department of Veterinary Medicine and Animal Sciences, Università degli Studi di Milano, Lodi 26900, Italy
| | - Alessandro Agazzi
- Department of Veterinary Medicine and Animal Sciences, Università degli Studi di Milano, Lodi 26900, Italy
| | - Armand Sánchez
- Departament de Ciència Animal i dels Aliments, Universitat Autònoma de Barcelona, Barcelona 08193, Spain
- Plant and Animal Genomics, Centre for Research in Agricultural Genomics (CRAG), CSIC-IRTA-UAB-UB, Campus Universitat Autònoma de Barcelona, Barcelona 08193, Spain
| | - Josep M Folch
- Departament de Ciència Animal i dels Aliments, Universitat Autònoma de Barcelona, Barcelona 08193, Spain
- Plant and Animal Genomics, Centre for Research in Agricultural Genomics (CRAG), CSIC-IRTA-UAB-UB, Campus Universitat Autònoma de Barcelona, Barcelona 08193, Spain
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KIAA0101 and IL2RA Were Identified as Core Genes in Hormone-Resistant Nephropathy. DISEASE MARKERS 2022; 2022:6545266. [PMID: 36164371 PMCID: PMC9509277 DOI: 10.1155/2022/6545266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 08/26/2022] [Indexed: 11/17/2022]
Abstract
Objectives To analyze the tissue heterogeneity of hormone-sensitive and drug-resistant nephrotic syndrome genes using a bioinformatics approach and to analyze gene-related functional pathways. Methods The limma package of R software was used to screen differential genes from the nephropathy datasets GSE145969 and GSE189734. The differential genes were analyzed for functional and pathway enrichment in terms of biological processes, cellular components, and molecular functions. The Metascape tool was used to construct protein networks for the differential genes, and the results were imported into Cytoscape software for visualization. The genes were identified as key modules and genes using the MCODE plug-in. Gene set enrichment analysis was performed for the HALLMARK analysis of the two microarray key genes to obtain the relevant pathways. Results GSE145969 screened 351 differential genes, 168 upregulated genes, and 183 downregulated genes. The differential genes were enriched in biological processes, cellular components, and molecular functions, such as myocardial contraction, intracellular nonmembrane organelles, and structural molecular activities. The protein-protein interaction (PPI) network contained 140 nodes, with the highest-scoring module containing seven genes, and the MCODE plug-in calculated the downseed. The key gene was KIAA0101, whose HALLMARK pathway was significantly enriched in the mTORC1 signaling pathway. A total of 263 differential genes were screened by GSE189734, and they were enriched in biological processes, molecular functions, and cellular components, such as immune system processes, signaling receptor binding, and the cytoplasmic matrix. The PPI network contained 253 nodes, with the highest-scoring module containing 37 genes. The seed gene obtained through the MCODE plug-in calculation was IL2RA, whose HALLMARK pathway was significantly enriched in the KRAS signaling pathway. Conclusion By analyzing the gene sets of different tissues in nephropathy, two key genes, namely KIAA0101 and IL2RA, were obtained. Their gene function enrichment is related to cell growth, development, and reproduction. Therefore, IL2RA and KIAA0101 can be used as diagnostic markers for hormone-resistant nephropathy.
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Li Y, Li X, Geng X, Zhao H. The IL-2A receptor pathway and its role in lymphocyte differentiation and function. Cytokine Growth Factor Rev 2022; 67:66-79. [DOI: 10.1016/j.cytogfr.2022.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 06/29/2022] [Accepted: 06/30/2022] [Indexed: 11/03/2022]
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