Alexander N. Orekhov, Volha I. Summerhill, V. Khotina, Mikhail A. Popov, Jamol K. Uzokov, V. Sukhorukov
Inflammation is a natural reaction of the innate immune system that evolved primarily to protect the human body from invading pathogens and to heal injuries. There are two different types of inflammation, acute and chronic inflammation, differing in duration, underlying causes, and characteristics. The acute-to-chronic transition can be determined by several pathomech-anisms, including dysregulation of immune response and failure to eliminate the underlying cause. Moreover, epigenetic changes that refer to modifications in gene expression that are heritable but do not involve changes to the underlying DNA sequence can also contribute to prolonged inflammation. Emerging evidence suggests that dysfunctional mitochondria can promote the development of chronic inflammation. In this respect, the mechanisms triggering defective mitophagy, a selective form of autophagy that exterminates dysfunctional mitochondria to maintain cellular homeostasis, attracted special attention. The hypothesis on the pivotal role of mutations in mitochondrial DNA causing defective mitophagy stimulated the area of the research that applies editing of the mitochondrial genome. The mitoCAS9 vector and two single guide RNAs to the G15059A mutation were used to eliminate the mutation from the macrophage-like cells. The normal activity of the initially defective mitophagy was restored in intact macrophage-like cells, confirming the causal role of the G15059A mutation in the disruption of the mitophagy process. The unraveling of the underlying mechanisms of chronic inflammation will help to develop targeted therapeutic approaches aimed at restoring mitochondrial health and alleviating chronic inflammation that can be used for the treatment of a wide range of chronic inflammatory diseases.
炎症是先天性免疫系统的一种自然反应，主要是为了保护人体免受病原体入侵和治愈创伤而进化而来。炎症有两种不同类型，即急性炎症和慢性炎症，其持续时间、潜在原因和特征各不相同。急性炎症向慢性炎症的转变可由多种病理机制决定，包括免疫反应失调和未能消除根本原因。此外，表观遗传变化（指基因表达的改变，可遗传但不涉及基本 DNA 序列的改变）也可能导致炎症持续时间延长。新的证据表明，线粒体功能失调可促进慢性炎症的发展。在这方面，引发线粒体吞噬缺陷的机制引起了人们的特别关注，线粒体吞噬是自噬的一种选择性形式，可消灭功能失调的线粒体以维持细胞平衡。关于线粒体 DNA 变异导致有丝分裂缺陷的关键作用的假说，刺激了线粒体基因组编辑的研究领域。研究人员利用 mitoCAS9 载体和两个针对 G15059A 突变的单导 RNA 来消除巨噬细胞样细胞中的突变。在完整的巨噬细胞样细胞中，最初有缺陷的有丝分裂活动恢复了正常，这证实了 G15059A 突变在有丝分裂过程的破坏中起到了因果作用。揭示慢性炎症的内在机制将有助于开发旨在恢复线粒体健康和缓解慢性炎症的靶向治疗方法，这些方法可用于治疗各种慢性炎症性疾病。
{"title":"Role of Mitochondria in the Chronification of Inflammation: Focus on Dysfunctional Mitophagy and Mitochondrial DNA Mutations","authors":"Alexander N. Orekhov, Volha I. Summerhill, V. Khotina, Mikhail A. Popov, Jamol K. Uzokov, V. Sukhorukov","doi":"10.14218/ge.2023.00061","DOIUrl":"https://doi.org/10.14218/ge.2023.00061","url":null,"abstract":"Inflammation is a natural reaction of the innate immune system that evolved primarily to protect the human body from invading pathogens and to heal injuries. There are two different types of inflammation, acute and chronic inflammation, differing in duration, underlying causes, and characteristics. The acute-to-chronic transition can be determined by several pathomech-anisms, including dysregulation of immune response and failure to eliminate the underlying cause. Moreover, epigenetic changes that refer to modifications in gene expression that are heritable but do not involve changes to the underlying DNA sequence can also contribute to prolonged inflammation. Emerging evidence suggests that dysfunctional mitochondria can promote the development of chronic inflammation. In this respect, the mechanisms triggering defective mitophagy, a selective form of autophagy that exterminates dysfunctional mitochondria to maintain cellular homeostasis, attracted special attention. The hypothesis on the pivotal role of mutations in mitochondrial DNA causing defective mitophagy stimulated the area of the research that applies editing of the mitochondrial genome. The mitoCAS9 vector and two single guide RNAs to the G15059A mutation were used to eliminate the mutation from the macrophage-like cells. The normal activity of the initially defective mitophagy was restored in intact macrophage-like cells, confirming the causal role of the G15059A mutation in the disruption of the mitophagy process. The unraveling of the underlying mechanisms of chronic inflammation will help to develop targeted therapeutic approaches aimed at restoring mitochondrial health and alleviating chronic inflammation that can be used for the treatment of a wide range of chronic inflammatory diseases.","PeriodicalId":502456,"journal":{"name":"Gene Expression","volume":"602 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139202927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"An Ensemble Learning-based Framework from Multicohort Reveals the Molecular Mechanism of GREM1 in Endometrial Cancer","authors":"Yihao Zhu, Hui Wang, Yao Zu","doi":"10.14218/ge.2023.00095","DOIUrl":"https://doi.org/10.14218/ge.2023.00095","url":null,"abstract":"","PeriodicalId":502456,"journal":{"name":"Gene Expression","volume":" 28","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139207072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Liacini, D. Olwi, Gaurav Tripathi, R. Faridi, Faisal Khan, A. Sar, Serdar Yilmaz, N. Berka
Background and objectives: Polymorphisms of the interleukin (IL)-17 proinflammatory cytokine family (IL17A and IL17F) have been associated with kidney chronic allograft failure (CAF). To date, the impact of heritable differences in IL17F genes and CAF among kidney transplant patients from North America has not been reported. The objective of the study was to assess the association of five distinct polymorphisms in the IL17F gene with histopathological changes in chronic kidney allograft failure. Methods: Two hundred eighteen kidney transplant recipients were enrolled. Surveillance biopsies were performed to evaluate 11 distinct histological markers and the combined grade of interstitial fibrosis and tubular atrophy, 6 to 12 months post-transplant. Using direct sequencing, the IL17F polymorphisms (-1507C/T rs1889570, -1165A/G rs1266828, -5046C/T rs7771511, -6328G/A rs766748, and -7488A/G rs763780) were genotyped in the 10 healthy volunteer samples followed by all kidney transplant recipients were genotyped for five IL17F gene polymorphisms using polymerase chain reaction and sequence-specific primers. The association was evaluated using both univariate and multivariate logistic regression analysis. Results: We observed weak associations of TC genotype of IL17F - 1165 (rs1266828) and allele of IL17F -1507C (rs1889570) with glomerular sclerosis and interstitial fibrosis and tubular atrophy ( p = 0.017 and p = 0.03) respectively. Allele C of IL-17 -1165C/T (rs1266828) was associated with better glomerular sclerosis ( p = 0.004, odds ratio = 0.39) score. Conclusions: Our findings demonstrate that IL17F SNPs were not associated with CAF and support our prior published results
{"title":"Interleukin 17F Gene Polymorphisms and Chronic Kidney Allograft Failure","authors":"A. Liacini, D. Olwi, Gaurav Tripathi, R. Faridi, Faisal Khan, A. Sar, Serdar Yilmaz, N. Berka","doi":"10.14218/ge.2023.00099","DOIUrl":"https://doi.org/10.14218/ge.2023.00099","url":null,"abstract":"Background and objectives: Polymorphisms of the interleukin (IL)-17 proinflammatory cytokine family (IL17A and IL17F) have been associated with kidney chronic allograft failure (CAF). To date, the impact of heritable differences in IL17F genes and CAF among kidney transplant patients from North America has not been reported. The objective of the study was to assess the association of five distinct polymorphisms in the IL17F gene with histopathological changes in chronic kidney allograft failure. Methods: Two hundred eighteen kidney transplant recipients were enrolled. Surveillance biopsies were performed to evaluate 11 distinct histological markers and the combined grade of interstitial fibrosis and tubular atrophy, 6 to 12 months post-transplant. Using direct sequencing, the IL17F polymorphisms (-1507C/T rs1889570, -1165A/G rs1266828, -5046C/T rs7771511, -6328G/A rs766748, and -7488A/G rs763780) were genotyped in the 10 healthy volunteer samples followed by all kidney transplant recipients were genotyped for five IL17F gene polymorphisms using polymerase chain reaction and sequence-specific primers. The association was evaluated using both univariate and multivariate logistic regression analysis. Results: We observed weak associations of TC genotype of IL17F - 1165 (rs1266828) and allele of IL17F -1507C (rs1889570) with glomerular sclerosis and interstitial fibrosis and tubular atrophy ( p = 0.017 and p = 0.03) respectively. Allele C of IL-17 -1165C/T (rs1266828) was associated with better glomerular sclerosis ( p = 0.004, odds ratio = 0.39) score. Conclusions: Our findings demonstrate that IL17F SNPs were not associated with CAF and support our prior published results","PeriodicalId":502456,"journal":{"name":"Gene Expression","volume":"127 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139197171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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