Pub Date : 2023-08-12DOI: 10.1038/s41435-023-00218-7
Francesca Sposito, Sarah Northey, Amandine Charras, Paul S. McNamara, Christian M. Hedrich
Nebulized hypertonic saline (3–7%) is commonly used to increase mucociliary clearance in patients with chronic airway disease and/or virus infections. However, altered salt concentrations may contribute to inflammatory responses. The aim of this study was to investigate whether 500 mM NaCl (3%) triggers inflammation in human macrophages and identify the molecular mechanisms involved. NaCl-induced pyroptosis, IL-1β, IL-18 and ASC speck release were measured in primary human monocyte-derived macrophages. Treatment with the recombinant IL-1 receptor antagonist anakinra or the NLRP3 inhibitor MCC950 did not affect NaCl-mediated inflammasome assembly. Knock-down of NLRP1 expression, but not of NLRP3 and NLRC4, reduced NaCl-induced pyroptosis, pro-inflammatory cytokine and ASC speck release from human THP-1-derived macrophages. Data from this study suggest that 3% NaCl-induced inflammatory responses in human macrophages depend on NLRP1 and inflammasome assembly. Targeting inflammation in addition to inhalation with hypertonic saline may benefit patients with inflammatory airway disease.
雾化高渗盐水（3-7%）通常用于增加慢性呼吸道疾病和/或病毒感染患者的粘液纤毛清除率。然而，盐浓度的改变可能会导致炎症反应。本研究的目的是调查500 mM NaCl（3%）触发人类巨噬细胞的炎症并确定所涉及的分子机制。在原代人单核细胞衍生的巨噬细胞中测量NaCl诱导的焦下垂、IL-1β、IL-18和ASC斑点释放。用重组IL-1受体拮抗剂anakinra或NLRP3抑制剂MCC950处理不影响NaCl介导的炎症小体组装。NLRP1表达的下调，而不是NLRP3和NLRC4的下调，减少了NaCl诱导的焦下垂、促炎细胞因子和人类THP-1衍生巨噬细胞的ASC斑点释放。这项研究的数据表明，3%NaCl诱导的人类巨噬细胞炎症反应依赖于NLRP1和炎症小体组装。除了吸入高渗盐水外，靶向炎症可能对炎症性气道疾病患者有益。
{"title":"Hypertonic saline induces inflammation in human macrophages through the NLRP1 inflammasome","authors":"Francesca Sposito, Sarah Northey, Amandine Charras, Paul S. McNamara, Christian M. Hedrich","doi":"10.1038/s41435-023-00218-7","DOIUrl":"10.1038/s41435-023-00218-7","url":null,"abstract":"Nebulized hypertonic saline (3–7%) is commonly used to increase mucociliary clearance in patients with chronic airway disease and/or virus infections. However, altered salt concentrations may contribute to inflammatory responses. The aim of this study was to investigate whether 500 mM NaCl (3%) triggers inflammation in human macrophages and identify the molecular mechanisms involved. NaCl-induced pyroptosis, IL-1β, IL-18 and ASC speck release were measured in primary human monocyte-derived macrophages. Treatment with the recombinant IL-1 receptor antagonist anakinra or the NLRP3 inhibitor MCC950 did not affect NaCl-mediated inflammasome assembly. Knock-down of NLRP1 expression, but not of NLRP3 and NLRC4, reduced NaCl-induced pyroptosis, pro-inflammatory cytokine and ASC speck release from human THP-1-derived macrophages. Data from this study suggest that 3% NaCl-induced inflammatory responses in human macrophages depend on NLRP1 and inflammasome assembly. Targeting inflammation in addition to inhalation with hypertonic saline may benefit patients with inflammatory airway disease.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10575766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9972859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-08-07DOI: 10.1038/s41435-023-00216-9
Xueli Yang, Xianliang Hou, Junning Zhang, Zhenyu Liu, Guangyu Wang
Autoimmune diseases (AIDs) are caused by immune tolerance deficiency or abnormal immune regulation, leading to damage to host organs. The complicated pathogenesis and varied clinical symptoms of AIDs pose great challenges in diagnosing and monitoring this disease. Regrettably, the etiological factors and pathogenesis of AIDs are still not completely understood. It is noteworthy that the development of single-cell RNA sequencing (scRNA-seq) technology provides a new tool for analyzing the transcriptome of AIDs. In this essay, we have summarized the development of scRNA-seq technology, and made a relatively systematic review of the current research progress of scRNA-seq technology in the field of AIDs, providing a reference to preferably understand the pathogenesis, diagnosis, and treatment of AIDs.
{"title":"Research progress on the application of single-cell sequencing in autoimmune diseases","authors":"Xueli Yang, Xianliang Hou, Junning Zhang, Zhenyu Liu, Guangyu Wang","doi":"10.1038/s41435-023-00216-9","DOIUrl":"10.1038/s41435-023-00216-9","url":null,"abstract":"Autoimmune diseases (AIDs) are caused by immune tolerance deficiency or abnormal immune regulation, leading to damage to host organs. The complicated pathogenesis and varied clinical symptoms of AIDs pose great challenges in diagnosing and monitoring this disease. Regrettably, the etiological factors and pathogenesis of AIDs are still not completely understood. It is noteworthy that the development of single-cell RNA sequencing (scRNA-seq) technology provides a new tool for analyzing the transcriptome of AIDs. In this essay, we have summarized the development of scRNA-seq technology, and made a relatively systematic review of the current research progress of scRNA-seq technology in the field of AIDs, providing a reference to preferably understand the pathogenesis, diagnosis, and treatment of AIDs.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9954390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-29DOI: 10.1038/s41435-023-00215-w
Zahra Alizadeh, Mohammad Reza Fazlollahi, Marzieh Mazinani, Mohsen Badalzadeh, Hanieh Heydarlou, Raphael Carapito, Anne Molitor, Andrés Caballero Garcia de Oteyza, Michele Proietti, Maryam Soleimani Bavani, Mansoureh Shariat, Morteza Fallahpour, Masoud Movahedi, Leila Moradi, Bodo Grimbacher, Seiamak Bahram, Zahra Pourpak
Severe combined immunodeficiency (SCID) is one of the severe inborn errors of the immune system associated with life-threatening infections. Variations in SCID phenotypes, especially atypical SCID, may cause a significant delay in diagnosis. Therefore, SCID patients need to receive an early diagnosis. Here, we describe the clinical manifestations and genetic results of four SCID and atypical SCID patients. All patients (4 males and 4 females) in early infancy presented with SCID phenotypes within 6 months of birth. The mutations include RAG2 (p.I273T,p.G44X), IL7R (p.F361WfsTer17), ADA (c.780+1G>A), JAK3 (p.Q228Ter), LIG4 (p.G428R), and LAT (p.Y207fsTer33), as well as a previously reported missense mutation in RAG1 (p.A444V). The second report of LAT deficiency in SCID patients is presented in this study. Moreover, all variants were confirmed in patients and their parents as a heterozygous state by Sanger sequencing. The results of our study expand the clinical and molecular spectrum associated with SCID and leaky SCID phenotypes and provide valuable information for the clinical management of the patients.
{"title":"Clinical, immunological and molecular findings of 8 patients with typical and atypical severe combined immunodeficiency: identification of 7 novel mutations by whole exome sequencing","authors":"Zahra Alizadeh, Mohammad Reza Fazlollahi, Marzieh Mazinani, Mohsen Badalzadeh, Hanieh Heydarlou, Raphael Carapito, Anne Molitor, Andrés Caballero Garcia de Oteyza, Michele Proietti, Maryam Soleimani Bavani, Mansoureh Shariat, Morteza Fallahpour, Masoud Movahedi, Leila Moradi, Bodo Grimbacher, Seiamak Bahram, Zahra Pourpak","doi":"10.1038/s41435-023-00215-w","DOIUrl":"10.1038/s41435-023-00215-w","url":null,"abstract":"Severe combined immunodeficiency (SCID) is one of the severe inborn errors of the immune system associated with life-threatening infections. Variations in SCID phenotypes, especially atypical SCID, may cause a significant delay in diagnosis. Therefore, SCID patients need to receive an early diagnosis. Here, we describe the clinical manifestations and genetic results of four SCID and atypical SCID patients. All patients (4 males and 4 females) in early infancy presented with SCID phenotypes within 6 months of birth. The mutations include RAG2 (p.I273T,p.G44X), IL7R (p.F361WfsTer17), ADA (c.780+1G>A), JAK3 (p.Q228Ter), LIG4 (p.G428R), and LAT (p.Y207fsTer33), as well as a previously reported missense mutation in RAG1 (p.A444V). The second report of LAT deficiency in SCID patients is presented in this study. Moreover, all variants were confirmed in patients and their parents as a heterozygous state by Sanger sequencing. The results of our study expand the clinical and molecular spectrum associated with SCID and leaky SCID phenotypes and provide valuable information for the clinical management of the patients.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10030776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-24DOI: 10.1038/s41435-023-00214-x
Kathleen M. Vazzana, Anthony M. Musolf, Joan E. Bailey-Wilson, Linda T. Hiraki, Earl D. Silverman, Christiaan Scott, Clifton L. Dalgard, Sarfaraz Hasni, Zuoming Deng, Mariana J. Kaplan, Laura B. Lewandowski
Childhood-onset systemic lupus erythematosus (cSLE) patients are unique, with hallmarks of Mendelian disorders (early-onset and severe disease) and thus are an ideal population for genetic investigation of SLE. In this study, we use the transmission disequilibrium test (TDT), a family-based genetic association analysis that employs robust methodology, to analyze whole genome sequencing data. We aim to identify novel genetic associations in an ancestrally diverse, international cSLE cohort. Forty-two cSLE patients and 84 unaffected parents from 3 countries underwent whole genome sequencing. First, we performed TDT with single nucleotide variant (SNV)-based (common variants) using PLINK 1.9, and gene-based (rare variants) analyses using Efficient and Parallelizable Association Container Toolbox (EPACTS) and rare variant TDT (rvTDT), which applies multiple gene-based burden tests adapted for TDT, including the burden of rare variants test. Applying the GWAS standard threshold (5.0 × 10−8) to common variants, our SNV-based analysis did not return any genome-wide significant SNVs. The rare variant gene-based TDT analysis identified many novel genes significantly enriched in cSLE patients, including HNRNPUL2, a DNA repair protein, and DNAH11, a ciliary movement protein, among others. Our approach identifies several novel SLE susceptibility genes in an ancestrally diverse childhood-onset lupus cohort.
{"title":"Transmission disequilibrium analysis of whole genome data in childhood-onset systemic lupus erythematosus","authors":"Kathleen M. Vazzana, Anthony M. Musolf, Joan E. Bailey-Wilson, Linda T. Hiraki, Earl D. Silverman, Christiaan Scott, Clifton L. Dalgard, Sarfaraz Hasni, Zuoming Deng, Mariana J. Kaplan, Laura B. Lewandowski","doi":"10.1038/s41435-023-00214-x","DOIUrl":"10.1038/s41435-023-00214-x","url":null,"abstract":"Childhood-onset systemic lupus erythematosus (cSLE) patients are unique, with hallmarks of Mendelian disorders (early-onset and severe disease) and thus are an ideal population for genetic investigation of SLE. In this study, we use the transmission disequilibrium test (TDT), a family-based genetic association analysis that employs robust methodology, to analyze whole genome sequencing data. We aim to identify novel genetic associations in an ancestrally diverse, international cSLE cohort. Forty-two cSLE patients and 84 unaffected parents from 3 countries underwent whole genome sequencing. First, we performed TDT with single nucleotide variant (SNV)-based (common variants) using PLINK 1.9, and gene-based (rare variants) analyses using Efficient and Parallelizable Association Container Toolbox (EPACTS) and rare variant TDT (rvTDT), which applies multiple gene-based burden tests adapted for TDT, including the burden of rare variants test. Applying the GWAS standard threshold (5.0 × 10−8) to common variants, our SNV-based analysis did not return any genome-wide significant SNVs. The rare variant gene-based TDT analysis identified many novel genes significantly enriched in cSLE patients, including HNRNPUL2, a DNA repair protein, and DNAH11, a ciliary movement protein, among others. Our approach identifies several novel SLE susceptibility genes in an ancestrally diverse childhood-onset lupus cohort.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10027890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-18DOI: 10.1038/s41435-023-00213-y
Abhishek D. Garg
Understanding the genetic basis of immunological processes and their overall dynamics under the influence of population immunogenetics and host-microbe interactions has been at the core of health and disease research. Our understanding of these dynamics has recently undergone a paradigm shift with the application of high-resolution single cell or spatial omics technologies that have facilitated a deeper understanding of healthy or diseased immune milieu. At Genes & Immunity, we wish to revamp the journal to cater to these trends and bring together researchers working at these multidisciplinary interfaces of immunology and genetics, with the aim of advancing fundamental and translational knowledge while revealing new immunotherapy or biomarker modalities.
{"title":"The dynamic interface of genetics and immunity: toward future horizons in health & disease","authors":"Abhishek D. Garg","doi":"10.1038/s41435-023-00213-y","DOIUrl":"10.1038/s41435-023-00213-y","url":null,"abstract":"Understanding the genetic basis of immunological processes and their overall dynamics under the influence of population immunogenetics and host-microbe interactions has been at the core of health and disease research. Our understanding of these dynamics has recently undergone a paradigm shift with the application of high-resolution single cell or spatial omics technologies that have facilitated a deeper understanding of healthy or diseased immune milieu. At Genes & Immunity, we wish to revamp the journal to cater to these trends and bring together researchers working at these multidisciplinary interfaces of immunology and genetics, with the aim of advancing fundamental and translational knowledge while revealing new immunotherapy or biomarker modalities.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41435-023-00213-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10405173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-13DOI: 10.1038/s41435-023-00212-z
Hope J. Wolmarans, Vayda R. Barker, Andrea Chobrutskiy, Boris I. Chobrutskiy, Taha I. Huda, George Blanck
With the improvement of treatment options, multiple myeloma related life expectancy has been prolonged, but the disease remains largely incurable. Immunotherapy is a growing field that shows promise in advancements for treatment, and recent work has demonstrated an opportunity to use immune receptor, complementarity determining region-3 (CDR3)-candidate antigen chemical complementarity scores to identify survival distinctions among subgroups of patients. Here, we have applied the complementarity scoring algorithm to identify multiple myeloma related, CDR3-cancer testis antigen (CTA) relationships associated with survival distinctions. Furthermore, we have overlapped these immune receptor features with a previous study that showed a dramatic survival distinction based on T-cell receptor, V- and J-gene segment usage, HLA allele combinations, whereby 100% of the patients in certain combination groups had no mortality related to multiple myeloma, during the study period. This overlap evaluation was consistent with the idea that there are likely considerable constraints on productive TRB-antigen-HLA combinations but more flexibility, and unpredictability, for the TRA-antigen-HLA combinations. Also, the approaches in this reported indicated the potential importance of the CTA, IGSF11, as a multiple myeloma antigen, an antigen previously, independently considered as a vaccine candidate in other settings.
{"title":"Exploiting big data survival information to unify risk-stratification related, adaptive immune receptor parameters for multiple myeloma","authors":"Hope J. Wolmarans, Vayda R. Barker, Andrea Chobrutskiy, Boris I. Chobrutskiy, Taha I. Huda, George Blanck","doi":"10.1038/s41435-023-00212-z","DOIUrl":"10.1038/s41435-023-00212-z","url":null,"abstract":"With the improvement of treatment options, multiple myeloma related life expectancy has been prolonged, but the disease remains largely incurable. Immunotherapy is a growing field that shows promise in advancements for treatment, and recent work has demonstrated an opportunity to use immune receptor, complementarity determining region-3 (CDR3)-candidate antigen chemical complementarity scores to identify survival distinctions among subgroups of patients. Here, we have applied the complementarity scoring algorithm to identify multiple myeloma related, CDR3-cancer testis antigen (CTA) relationships associated with survival distinctions. Furthermore, we have overlapped these immune receptor features with a previous study that showed a dramatic survival distinction based on T-cell receptor, V- and J-gene segment usage, HLA allele combinations, whereby 100% of the patients in certain combination groups had no mortality related to multiple myeloma, during the study period. This overlap evaluation was consistent with the idea that there are likely considerable constraints on productive TRB-antigen-HLA combinations but more flexibility, and unpredictability, for the TRA-antigen-HLA combinations. Also, the approaches in this reported indicated the potential importance of the CTA, IGSF11, as a multiple myeloma antigen, an antigen previously, independently considered as a vaccine candidate in other settings.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10405148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Host immune response to COVID-19 plays a significant role in regulating disease severity. Although big data analysis has provided significant insights into the host biology of COVID-19 across the world, very few such studies have been performed in the Indian population. This study utilizes a transcriptome-integrated network analysis approach to compare the immune responses between asymptomatic or mild and moderate-severe COVID-19 patients in an Indian cohort. An immune suppression phenotype is observed in the early stages of moderate-severe COVID-19 manifestation. A number of pathways are identified that play crucial roles in the host control of the disease such as the type I interferon response and classical complement pathway which show different activity levels across the severity spectrum. This study also identifies two transcription factors, IRF7 and ESR1, to be important in regulating the severity of COVID-19. Overall this study provides a deep understanding of the peripheral immune landscape in the COVID-19 severity spectrum in the Indian genetic background and opens up future research avenues to compare immune responses across global populations.
{"title":"Systems-level profiling of early peripheral host-response landscape variations across COVID-19 severity states in an Indian cohort","authors":"Ushashi Banerjee, Sneha Chunchanur, Ambica R, Kithiganahalli Narayanaswamy Balaji, Amit Singh, Dipshikha Chakravortty, Nagasuma Chandra","doi":"10.1038/s41435-023-00210-1","DOIUrl":"10.1038/s41435-023-00210-1","url":null,"abstract":"Host immune response to COVID-19 plays a significant role in regulating disease severity. Although big data analysis has provided significant insights into the host biology of COVID-19 across the world, very few such studies have been performed in the Indian population. This study utilizes a transcriptome-integrated network analysis approach to compare the immune responses between asymptomatic or mild and moderate-severe COVID-19 patients in an Indian cohort. An immune suppression phenotype is observed in the early stages of moderate-severe COVID-19 manifestation. A number of pathways are identified that play crucial roles in the host control of the disease such as the type I interferon response and classical complement pathway which show different activity levels across the severity spectrum. This study also identifies two transcription factors, IRF7 and ESR1, to be important in regulating the severity of COVID-19. Overall this study provides a deep understanding of the peripheral immune landscape in the COVID-19 severity spectrum in the Indian genetic background and opens up future research avenues to compare immune responses across global populations.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10032423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-10DOI: 10.1038/s41435-023-00211-0
Yi Wang, Xinyu Zhang, Guihua Chen, Qianwei Xing, Bingye Zhu, Xiang Wang
The ferredoxin 1 (FDX1) gene had been recently reported as a critical mediator of cuproptosis, and without doubt, its roles in KIRC would be of importance. Hence, this paper was to explore the roles of FDX1 in kidney renal clear cell carcinoma (KIRC) and its potential molecular mechanisms via scRNA-sequencing and bulk RNA-sequencing analyses. FDX1 was lowly expressed in KIRC and validated both at the protein and mRNA levels (all p < 0.05). Moreover, its elevated expression was linked with a better overall survival (OS) prognosis in KIRC (p < 0.01). The independent impact of FDX1 on KIRC prognosis was demonstrated by univariate/multivariate regression analysis (p < 0.01). Gene set enrichment analysis (GSEA) identified seven pathways strongly associated with FDX1 in KIRC. Furthermore, FDX1 was also revealed to be significantly related with immunity (p < 0.05). In addition, patients with low expression of FDX1 might be more sensitive to immunotherapies. ScRNA-seq analysis found that FDX1 could be expressed in immune cells and was mainly differently expressed in Mono/Macro cells. Ultimately, we also identified several LncRNA/RBP/FDX1 mRNA networks to reveal its underlying mechanisms in KIRC. Taken together, FDX1 was closely related to prognosis and immunity in KIRC, and its RBP-involved mechanisms of LncRNA/RBP/FDX1 networks were also revealed by us.
{"title":"Integrated analyses reveal the prognostic, immunological features and mechanisms of cuproptosis critical mediator gene FDX1 in KIRC","authors":"Yi Wang, Xinyu Zhang, Guihua Chen, Qianwei Xing, Bingye Zhu, Xiang Wang","doi":"10.1038/s41435-023-00211-0","DOIUrl":"10.1038/s41435-023-00211-0","url":null,"abstract":"The ferredoxin 1 (FDX1) gene had been recently reported as a critical mediator of cuproptosis, and without doubt, its roles in KIRC would be of importance. Hence, this paper was to explore the roles of FDX1 in kidney renal clear cell carcinoma (KIRC) and its potential molecular mechanisms via scRNA-sequencing and bulk RNA-sequencing analyses. FDX1 was lowly expressed in KIRC and validated both at the protein and mRNA levels (all p < 0.05). Moreover, its elevated expression was linked with a better overall survival (OS) prognosis in KIRC (p < 0.01). The independent impact of FDX1 on KIRC prognosis was demonstrated by univariate/multivariate regression analysis (p < 0.01). Gene set enrichment analysis (GSEA) identified seven pathways strongly associated with FDX1 in KIRC. Furthermore, FDX1 was also revealed to be significantly related with immunity (p < 0.05). In addition, patients with low expression of FDX1 might be more sensitive to immunotherapies. ScRNA-seq analysis found that FDX1 could be expressed in immune cells and was mainly differently expressed in Mono/Macro cells. Ultimately, we also identified several LncRNA/RBP/FDX1 mRNA networks to reveal its underlying mechanisms in KIRC. Taken together, FDX1 was closely related to prognosis and immunity in KIRC, and its RBP-involved mechanisms of LncRNA/RBP/FDX1 networks were also revealed by us.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10114656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-08DOI: 10.1038/s41435-023-00209-8
Mengdan Miao, Shanhu Cao, Yifei Tian, Da Liu, Lixia Chen, Qiaoying Chai, Mei Wei, Shaoguang Sun, Le Wang, Shuanli Xin, Gang Liu, Mingqi Zheng
The current diagnostic biomarkers of acute myocardial infarction (AMI), troponins, lack specificity and exist as false positives in other non-cardiac diseases. Previous studies revealed that cuproptosis, ferroptosis, and immune infiltration are all involved in the development of AMI. We hypothesize that combining the analysis of cuproptosis, ferroptosis, and immune infiltration in AMI will help identify more precise diagnostic biomarkers. The results showed that a total of 19 cuproptosis- and ferroptosis-related genes (CFRGs) were differentially expressed between the healthy and AMI groups. Functional enrichment analysis showed that the differential CFRGs were mostly enriched in biological processes related to oxidative stress and the inflammatory response. The immune infiltration status analyzed by ssGSEA found elevated levels of macrophages, neutrophils, and CCR in AMI. Then, we screened 6 immune-related CFRGs (CXCL2, DDIT3, DUSP1, CDKN1A, TLR4, STAT3) to construct a nomogram for predicting AMI and validated it in the GSE109048 dataset. Moreover, we also identified 5 pivotal miRNAs and 10 candidate drugs that target the 6 feature genes. Finally, RT-qPCR analysis verified that all 6 feature genes were upregulated in both animals and patients. In conclusion, our study reveals the significance of immune-related CFRGs in AMI and provides new insights for AMI diagnosis and treatment.
目前诊断急性心肌梗死（AMI）的生物标志物肌钙蛋白缺乏特异性，在其他非心脏疾病中存在假阳性。以前的研究表明，杯突、铁突和免疫浸润都与急性心肌梗死的发生有关。我们假设，结合分析 AMI 中的铜氧化酶、铁氧化酶和免疫浸润，将有助于确定更精确的诊断生物标志物。结果显示，共有 19 个杯突症和铁突症相关基因（CFRGs）在健康组和 AMI 组之间存在差异表达。功能富集分析表明，不同的CFRGs大多富集在与氧化应激和炎症反应相关的生物过程中。通过ssGSEA分析免疫浸润状态，发现AMI患者的巨噬细胞、中性粒细胞和CCR水平升高。然后，我们筛选了 6 个与免疫相关的 CFRGs（CXCL2、DDIT3、DUSP1、CDKN1A、TLR4、STAT3），构建了预测 AMI 的提名图，并在 GSE109048 数据集中进行了验证。此外，我们还发现了针对这 6 个特征基因的 5 个关键 miRNA 和 10 个候选药物。最后，RT-qPCR 分析验证了所有 6 个特征基因在动物和患者体内均上调。总之，我们的研究揭示了免疫相关 CFRGs 在 AMI 中的重要性，并为 AMI 的诊断和治疗提供了新的见解。
{"title":"Potential diagnostic biomarkers: 6 cuproptosis- and ferroptosis-related genes linking immune infiltration in acute myocardial infarction","authors":"Mengdan Miao, Shanhu Cao, Yifei Tian, Da Liu, Lixia Chen, Qiaoying Chai, Mei Wei, Shaoguang Sun, Le Wang, Shuanli Xin, Gang Liu, Mingqi Zheng","doi":"10.1038/s41435-023-00209-8","DOIUrl":"10.1038/s41435-023-00209-8","url":null,"abstract":"The current diagnostic biomarkers of acute myocardial infarction (AMI), troponins, lack specificity and exist as false positives in other non-cardiac diseases. Previous studies revealed that cuproptosis, ferroptosis, and immune infiltration are all involved in the development of AMI. We hypothesize that combining the analysis of cuproptosis, ferroptosis, and immune infiltration in AMI will help identify more precise diagnostic biomarkers. The results showed that a total of 19 cuproptosis- and ferroptosis-related genes (CFRGs) were differentially expressed between the healthy and AMI groups. Functional enrichment analysis showed that the differential CFRGs were mostly enriched in biological processes related to oxidative stress and the inflammatory response. The immune infiltration status analyzed by ssGSEA found elevated levels of macrophages, neutrophils, and CCR in AMI. Then, we screened 6 immune-related CFRGs (CXCL2, DDIT3, DUSP1, CDKN1A, TLR4, STAT3) to construct a nomogram for predicting AMI and validated it in the GSE109048 dataset. Moreover, we also identified 5 pivotal miRNAs and 10 candidate drugs that target the 6 feature genes. Finally, RT-qPCR analysis verified that all 6 feature genes were upregulated in both animals and patients. In conclusion, our study reveals the significance of immune-related CFRGs in AMI and provides new insights for AMI diagnosis and treatment.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10435388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10107865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-06-27DOI: 10.1038/s41435-023-00208-9
Yiqin Wang, Murad Alahdal, Jia Ye, Liangliang Jing, Xiaoxin Liu, Huan Chen, Liang Jin, Rongyue Cao
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