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noncoding rna as potential therapeutics to rescue mitochondrial dysfunction in cardiovascular diseases

American Journal of Physiology - Heart and Circulatory Physiology 2025年第4期328卷 H846-H864页

作者： Alabere, Hafsat O. Taylor, Andrew D. Miller, Brianna R. Nohoesu, Remi Nicoletti, Roxy Mogus, Joshua Meadows, Ethan M. Hollander, John M. Division of Exercise Physiology West Virginia University School of Medicine Morgantown WV United States Mitochondria Metabolism & Bioenergetics Working Group West Virginia University School of Medicine Morgantown WV United States Department of Biochemistry and Molecular Medicine West Virginia University School of Medicine Morgantown WV United States Department of Physiology Pharmacology and Toxicology West Virginia University School of Medicine Morgantown WV United States

noncoding rnas (ncrnas) are critical regulators of mitochondrial function in cardiovascular diseases. Several studies have explored the manipulation of ncrnas in mitochondrial dysfunction in different cardiovascular disease contexts, however, there is a dearth of information on the exploration of these noncoding rnas as actual therapeutics to ameliorate cardiovascular diseases. This systematic review examines the roles of various ncrnas in modulating mitochondrial dysfunction across major cardiovascular diseases and how they can be targeted to the mitochondria. A comprehensive literature search was conducted using Web of Science and Scopus databases, following the PRISMA guidelines. Original research articles in the English language, focusing on ncrnas and mitochondrial dysfunction in specific cardiovascular diseases, were eligible for inclusion. A total of 76 studies were included in the systematic review with up to 100 ncrnas identified as therapeutic biomarkers. The identified ncrnas participate in regulating mitochondrial processes including oxidative phosphorylation (OXPHOS), fission/fusion dynamics, apoptosis, and calcium handling in cardiovascular diseases. Mitochondrial targeting moieties including mitochondrial targeting cell-penetrating peptides, mitochondrial targeting liposomes, and aptamers can be conjugated to ncrnas and delivered to the heart via various injection routes including the pericardium or the myocardium. However, significant challenges remain in developing effective delivery methods to modulate these ncrnas in vivo. Copyright © 2025 The Authors.

关键词： cardiovascular disease mitochondria noncoding rna rna therapeutics systematic review

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Long noncoding rna IDI2-AS1 modulates the expression of interleukin 5 in human cells

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2025年 761卷 151733页

作者： Endo, Ryuki Kurisu, Miyu Tani, Hidenori Yokohama Univ Pharm Dept Hlth Pharm 601 Matano Totsuka Yokohama 2450066 Japan

Long noncoding rnas (lncrnas) have emerged as critical regulators of gene expression, influencing a wide range of biological processes. In this study, we investigate the regulatory role of the lncrna IDI2-AS1 in the immune response. Our previous observations demonstrated that IDI2-AS1 expression is downregulated in A549 cells upon exposure to lipopolysaccharide (LPS) and poly I:C, which mimic bacterial and viral infections, respectively. Here, we analyzed the expression changes of 13 immune response genes following sirna-mediated knockdown of IDI2-AS1 in A549 cells. Notably, our results revealed a significant and selective upregulation of interleukin 5 (IL5) mrna expression, which increased approximately 60-fold, along with a corresponding similar to 70-fold increase in IL5 protein levels. These findings suggest a novel regulatory mechanism in which IDI2-AS1 functions as a suppressor of IL5 expression under normal conditions. During simulated bacterial or viral infections, the downregulation of IDI2-AS1 appears to initiate a rapid and robust increase in IL5 expression. Given the pivotal role of IL5 in allergic inflammation and eosinophil regulation, the IDI2-AS1-IL5 axis may represent an important pathway in the immune response to pathogenic challenges. This study provides new insights into the intricate interplay between lncrnas and cytokine gene regulation in innate immunity, potentially offering novel therapeutic targets for immune-related disorders.

关键词： noncoding rna Lncrna IDI2-AS1 Interleukin 5

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Genome-wide cataloging and orthology analysis of long noncoding rna expression in three species of Anopheles mosquito

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BMC Genomics 2025年第1期26卷 1-14页

作者： Malla, Waseem Akram Singh, Kuldeep Ayman, Niha Boro, Chandini Devi, Naorem Chaoba Mech, Priyanka Siddiqui, Nida Anvikar, Anupkumar R. Bharti, Praveen Kumar ICMR-National Institute of Malaria Research Field Unit Guwahati Assam Guwahati 781036 India ICMR-National Institute of Malaria Research New Delhi 110077 India Faculty of Biological Sciences Academy of Scientific and Innovative Research (AcSIR) Uttar Pradesh Ghaziabad 201002 India Faculty of Veterinary Sciences and Animal Husbandry SKUAST-K Srinagar Jammu and Kashmir Shuhama 190006 India

Background: Long noncoding rnas (lncrnas) are versatile regulatory molecules that affect cellular phenotypes through context-specific expression. While their role in controlling cellular pathways is well-established in insects, investigating lncrna expression in Anopheles in a tissue- and species-specific manner could add to our understanding of malaria transmission by this important vector. Methodology: We performed de novo transcriptome assembly of Anopheles minimus, Anopheles albimanus, and Anopheles arabiensis utilising publicly available rna-Seq datasets of male reproductive tissues, male carcasses, female reproductive tissues, and female carcasses. Various bioinformatics tools were subsequently used for lncrna identification, conservation analysis, and differential expression analysis across sexes and tissues. Results: We identified 9331, 5372, and 5256 lncrna transcripts in An. albimanus, An. arabiensis, and An. minimus, respectively. Compared with An. albimanus lncrnas, conservation analysis revealed that a total of 1964 and 1400 lncrnas were conserved in An. arabiensis and An. minimus;however, only 283 and 253 lncrnas presented sequence-level conservation. Differential expression (DE) analysis revealed that the carcasses presented the lowest difference in lncrna expression, whereas in each comparison, the reproductive tissues (whether male or female) presented relatively high levels of differential expression. Additionally, 69 lncrnas were found to be conserved at the sequence level in all 3 species. These lncrnas were almost exclusively upregulated in males (reproductive tissue as well as carcasses) and exclusively downregulated in female carcasses. Conclusions: The genes in the vicinity of differentially expressed, conserved lncrnas were found to be involved in critical pathways such as nuclear structure, chromatin remodelling, protein and rna metabolism, and cell cycle in each of these species. Future studies on these lncrnas can provide useful insights

关键词： Anopheles Anopheles albimanus Anopheles arabiensis Anopheles minimus Lncrna noncoding rna

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The human-specific noncoding rna RP11-424G14.1 functions at the intersection of sexually dimorphic pathways in inflammation, senescence, and metabolism

FASEB BIOADVANCES

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FASEB BIOADVANCES 2025年第2期7卷 e1479页

作者： Kennicott, Kameron Liang, Yun Michigan State Univ Dept Physiol & Pharmacol & Toxicol E Lansing MI USA Michigan State Univ Dept Pharmacol & Toxicol E Lansing MI 48824 USA

Sexual dimorphism is a fundamental characteristic of various physiological and pathological processes in humans, including immune responses, senescence, and metabolism. Most studies on the sex bias have focused on sex hormones or female-biased genes, whereas male-biased genetic factors remain understudied. Here, we show that the Y-linked noncoding rna, RP11-424G14.1, is expressed in human male keratinocytes. Microarray study suggests the NF-kappa B pathway as the top biological pathway affected by RP11-424G14.1 knockdown, consistent with known sex differences in inflammation. Additionally, IGFBP3 is identified as the top gene supported by RP11-424G14.1 in male keratinocytes. Conversely, in female keratinocytes, IGFBP3 is the top gene repressed by the X-linked long noncoding rna XIST, suggesting a central role of IGFBP3 in mediating sexual dimorphism. Knockdown of RP11-424G14.1 or IGFBP3 in male keratinocytes inhibits cellular senescence, consistent with increased longevity in females. IGFBP3 expression is dependent on insulin, and metabolomics analysis suggests that RP11-424G14.1 and IGFBP3 regulate acrylcarnitine metabolism. Our study identifies the role of the RP11-424G14.1-IGFBP3 pathway in coordinating sex differences in immunity, senescence, and metabolism. With RP11-424G14.1 being a human-specific genetic element, our study suggests the evolving feature of sexual dimorphisms in biological processes.

关键词： inflammation metabolism noncoding rna senescence sexual dimorphism

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noncoding rna transcription at enhancers and genome folding in cancer

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CANCER SCIENCE 2019年第8期110卷 2328-2336页

作者： Isoda, Takeshi Morio, Tomohiro Takagi, Masatoshi Tokyo Med & Dent Univ Dept Pediat & Dev Biol Tokyo Japan

Changes of nuclear localization of lineage-specific genes from a transcriptionally inert to permissive environment are a crucial step in establishing the identity of a cell. noncoding rna transcription-mediated genome folding and activation of target gene expression have been found in a variety of cell types. noncoding rna ThymoD (thymocyte differentiation factor) transcription at superenhancers is essential for mouse T-cell lineage commitment. The cessation of ThymoD transcription abolishes transcription-mediated demethylation, recruiting looping factors such as the cohesin complex, CCCTC-binding factor (CTCF), ultimately leading to the phenotype of severe combined immunodeficiency and T-cell leukemia/lymphoma. In this review, we describe the functional role of rna polymerase II-mediated transcription at enhancers and in genome folding. We also highlight the involvement of faulty activation or suppression of enhancer transcription and enhancer-promoter interaction in cancer development.

关键词： cancer genome folding noncoding rna ThymoD transcription

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noncoding rna for personalized prostate cancer treatment: utilizing the 'dark matters' of the genome

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PERSONALIZED MEDICINE 2017年第2期14卷 159-169页

作者： Hua, Junjie Lu, Jennifer Isaev, Keren Soares, Fraser Guo, Haiyang Ahmed, Musaddeque He, Housheng Hansen Univ Hlth Network Princess Margaret Canc Ctr Toronto ON Canada Univ Toronto Dept Med Biophys Toronto ON Canada Univ Toronto Dept Lab Med & Pathobiol Toronto ON Canada

Prostate cancer is the most commonly diagnosed cancer in men in western countries, with significant health impact. Clinically, it is complicated with the lack of biomarkers and effective treatments for aggressive disease, particularly castration-resistant prostate cancer. Although we have gained much insight into the biology of prostate cancer through studying protein-coding genes, they represent only a small fraction of our genome. Therefore, it is essential for us to investigate noncoding rnas, which comprise the majority of our transcriptome, in order to achieve a better understanding of prostate cancer and move toward personalized medicine. In this article, we will address recent advancements in our knowledge of noncoding rnas, and discuss the clinical potentials and challenges of different types of noncoding rnas in prostate cancer.

关键词： biomarker noncoding rna personalized medicine prostate cancer therapy

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Epigenetic modulations of noncoding rna: a novel dimension of Cancer biology

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MOLECULAR CANCER 2020年第1期19卷 1-12页

作者： Yang, Xiao Liu, Ming Li, Mengmeng Zhang, Sen Hiju, Hong Sun, Jing Mao, Zhihai Zheng, Minhua Feng, Bo Shanghai Jiao Tong Univ Sch Med Ruijin Hosp Dept Gen SurgDiv Gastrointestinal & Colorectal S Shanghai 200205 Peoples R China Shanghai Jiao Tong Univ Sch Med Tongren Hosp Dept Genecol & Obstet Shanghai 200205 Peoples R China Tongji Univ Sch Med Shanghai Peoples Hosp 10 Shanghai 200205 Peoples R China

Empowered by recent advances of sequencing techniques, transcriptome-wide studies have characterized over 150 different types of post-transcriptional chemical modifications of rna, ranging from methylations of single base to complex installing reactions catalyzed by coordinated actions of multiple modification enzymes. These modifications have been shown to regulate the function and fate of rnas and further affecting various cellular events. However, the current understanding of their biological functions in human diseases, especially in cancers, is still limited. Once regarded as "junk" or "noise" of the transcriptome, noncoding rna (ncrna) has been proved to be involved in a plethora of cellular signaling pathways especially those regulating cancer initiation and progression. Accumulating evidence has demonstrated that ncrnas manipulate multiple phenotypes of cancer cells including proliferation, metastasis and chemoresistance and may become promising biomarkers and targets for diagnosis and treatment of cancer. Importantly, recent studies have mapped plenty of modified residues in ncrna transcripts, indicating the existence of epigenetic modulation of ncrnas and the potential effects of rna modulation on cancer progression. In this review, we briefly introduced the characteristics of several main epigenetic marks on ncrnas and summarized their consecutive effects on cancer cells. We found that ncrnas could act both as regulators and targets of epigenetic enzymes, which indicated a cross-regulating network in cancer cells and unveil a novel dimension of cancer biology. Moreover, by epitomizing the knowledge of rna epigenetics, our work may pave the way for the design of patient-tailored therapeutics of cancers.

关键词： rna epigenetics noncoding rna Cancer progression Cancer treatment

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noncoding rna as Therapeutic Targets for Hepatocellular Carcinoma

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SEMINARS IN LIVER DISEASE 2015年第1期35卷 63-74页

作者： George, Joseph Patel, Tushar Mayo Clin Dept Canc Biol Jacksonville FL 32224 USA Mayo Clin Dept Transplantat Jacksonville FL 32224 USA

Recent studies have suggested that noncoding rnas (ncrnas) contribute to the pathogenesis and progression of hepatocellular carcinoma (HCC). These rna genes may be involved in various pathobiological processes such as cell proliferation, apoptosis, angiogenesis, invasion, and metastasis. Aberrant expression of ncrna resulting from deregulated epigenetic, transcriptional, or posttranscriptional activity has been described in several studies. ncrnas are comprised of a highly diverse group of transcripts that include micrornas (mirnas) and long noncoding rnas (lncrnas) as well as several other types of rna genes. Understanding the molecular mechanisms by which ncrna contribute to hepatocarcinogenesis may enable the design of ncrna-based therapeutics for HCC. In this review, the authors provide a perspective on therapeutic applications based on the emerging evidence of a contributory role of mirnas and lncrnas to the pathogenesis and progression of HCC. In addition, ncrnas that are deregulated in expression in HCC may have utility as potential prognostic or diagnostic markers.

关键词： hepatocellular carcinoma noncoding rna microrna long noncoding rna biomarker

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noncoding rna for CR20, a cytokinin-repressed gene of cucumber

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PLANT MOLECULAR BIOLOGY 1996年第5期32卷 797-808页

作者： Teramoto, H Toyama, T Takeba, G Tsuji, H KYOTO UNIV FAC SCIDEPT BOTKYOTO 60601JAPAN KOBE WOMENS UNIV DEPT BIOLSUMA KUKOBE 654JAPAN

The CR20 gene was identified as a cytokinin-repressed gene in excised cotyledons of cucumber. We determined the sequences of some CR20 cDNAs with different structures and sequenced genomic clones for CR20. This gene consisted of three exons, and there were at least three types of transcript, which seemed to be generated by alternative splicing of the second intron. None of the CR20 transcripts included a long open reading frame (ORF). We isolated a cDNA of Arabidopsis thaliana with cucumber CR20 cDNA as a probe. This cDNA for a gene designated AtCR20-1 also lacked a long ORE A region of 180 nucleotides was conserved in the CR20 rna of cucumber and the AtCR20-1 rna of Arabidopsis, although the homology was relatively low when the entire sequences were compared. Each conserved region consisted of seven elements, and seems to form stable secondary structure. These suggest that CR20 rna may function as an rna that is not translated into a protein.

关键词： Arabidopsis Cucumis cytokinin noncoding rna

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The noncoding rna linc-ADAMTS5 cooperates with RREB1 to protect from intervertebral disc degeneration through inhibiting ADAMTS5 expression

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CLINICAL SCIENCE 2017年第10期131卷 965-979页

作者： Wang, Kun Song, Yu Liu, Wei Wu, Xinghuo Zhang, Yukun Li, Shuai Kang, Liang Tu, Ji Zhao, Kangcheng Hua, Wenbin Yang, Cao Huazhong Univ Sci & Technol Union Hosp Dept Orthoped Tongji Med Coll Wuhan Peoples R China First Hosp Wuhan Dept Orthoped Wuhan Peoples R China

Previous studies have indicated the important roles of ADAMTS5 in intervertebral disc degeneration (IDD). However, the mechanisms that regulate ADAMTS5 expression in nuclear pulposus (NP) cells remain largely unknown. Evidence suggests that intergenic transcription may be associated with genes that encode transcriptional regulators. Here, we identified a long intergenic noncoding rna, linc-ADAMTS5, which was transcribed in the opposite direction to ADAMTS5. In the present study, through mining computational algorithm programs, and publicly available data sets, we identified Ras-responsive element-binding protein 1 (RREB1) as a crucial transcription factor regulating the expression of ADAMTS5 in NP cells. rna pull-down, rna immunoprecipitation (RIP), in vitro binding assays, and gain and loss-of-function studies indicated that a physical interaction between linc-ADAMTS5 and splicing factor proline/glutamine-rich (SFPQ) facilitated the recruitment of RREB1 to binding sites within the ADAMTS5 promoter to induce chromatin remodeling. This resulted in subdued ADAMTS5 levels in cultured NP cells involving histone deacetylases (HDACs). In clinical NP tissues, linc-ADAMTS5 and RREB1 were correlated negatively with ADAMTS5 expression. Taken together, these results demonstrate that RREB1 cooperates with noncoding rna linc-ADAMTS5 to inhibit ADAMTS5 expression, thereby affecting degeneration of the extracellular matrix (ECM) of the intervertebral disc (IVD).

关键词： ADAMTS5 intervertebral disc degeneration noncoding rna

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