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Identifying the interactions conferring functional mechanical rigidity on rnase-resistant rna from Zika virus

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2025年第11期122卷 e2417234122页

作者： Zhaguparov, Daniiar Zhao, Meng Sekar, Rohith Vedhthaanth Woodside, Michael T. Univ Alberta Dept Phys Edmonton AB T6G 2E1 Canada Univ Alberta Ctr Prions & Prot Folding Dis Edmonton AB T6G 2E1 Canada Univ Alberta Li Ka Shing Inst Virol Edmonton AB T6G 2E1 Canada Chinese Acad Sci Hangzhou Inst Med Hangzhou 310022 Zhejiang Peoples R China

Some viruses counter host-cell efforts to digest invading viral rna by using special structures resistant to host rnases, known as exoribonuclease-resistant rnas (xrrnas). xrrnas typically form an unusual fold with the 5 '-end threaded through a ring consisting of a multihelix junction closed by a pseudoknot. By using single-molecule force spectroscopy (SMFS), we previously showed that a Zika virus xrrna is extremely rigid mechanically, withstanding very high forces, and that this mechanical resistance-not simply the knot-like fold topology-is essential for rnase resistance. Here, we have determined which interactions are most important for generating mechanical rigidity in the Zika virus xrrna, by systematically mutating tertiary contacts. We found that removing any of the tertiary contacts involving the threaded 5 ' end was sufficient to abrogate mechanical resistance. In contrast, breaking a single pseudoknot base pair was not sufficient to do so: Two broken pairs were needed. This hierarchy of interaction importance for mechanical rigidity was supported by simulations mapping how mechanical tension was distributed within the xrrna. For all mutants, rnase resistance varied in lock-step with mechanical resistance, confirming the primary role of mechanical rigidity in xrrna function. This work reveals which interactions are most important for Zika xrrna function, with implications for targeting the xrrna therapeutically.

关键词： noncoding rna Zika virus single-molecule force spectroscopy rnase resistance

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noncoding rnas regulating ferroptosis in cardiovascular diseases: novel roles and therapeutic strategies

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MOLECULAR AND CELLULAR BIOCHEMISTRY 2024年第11期479卷 2827-2841页

作者： Wu, Changyong Bao, Suli Sun, Huang Chen, Xiaocui Yang, Lu Li, Ruijie Peng, Yunzhu Kunming Med Univ Affiliated Hosp 1 Dept Cardiol Kunming Peoples R China Panzhihua Univ Affiliated Hosp Dept Gastroenterol Panzhihua Peoples R China

The morbidity and mortality rates of cardiovascular diseases (CVDs) are increasing;thus, they impose substantial health and economic burdens worldwide, and effective interventions are needed for immediate resolution of this issue. Recent studies have suggested that noncoding rnas (ncrnas) play critical roles in the occurrence and development of CVDs and are potential therapeutic targets and novel biomarkers for these diseases. Newly discovered modes of cell death, including necroptosis, pyroptosis, apoptosis, autophagy-dependent cell death and ferroptosis, also play key roles in CVD progression. However, ferroptosis, which differs from the other aforementioned forms of regulated cell death in terms of cell morphology, biochemistry and inhereditability, is a unique iron-dependent mode of nonapoptotic cell death induced by abnormal iron metabolism and excessive accumulation of iron-dependent lipid peroxides and reactive oxygen species (ROS). Increasing evidence has confirmed that ncrna-mediated ferroptosis is involved in regulating tissue homeostasis and CVD-related pathophysiological conditions, such as cardiac ischemia/reperfusion (I/R) injury, myocardial infarction (MI), atrial fibrillation (AF), cardiomyopathy and heart failure (HF). In this review, we summarize the underlying mechanism of ferroptosis, discuss the pathophysiological effects of ncrna-mediated ferroptosis in CVDs and provide ideas for effective therapeutic strategies.

关键词： noncoding rna Ferroptosis Cardiovascular diseases Iron metabolism Lipid peroxidation Molecular mechanism

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The Emerging Field of noncoding rnas and Their Importance in Pediatric Diseases

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JOUrnaL OF PEDIATRICS 2020年第Sup期221卷 S11-S19页

作者： Zhou, Rui Joshi, Piyush Katsushima, Keisuke Liang, Weihong Liu, Wei Goldenberg, Neil A. Dover, George Perera, Ranjan J. Johns Hopkins Univ Sch Med Dept Oncol Baltimore MD 21205 USA Johns Hopkins Univ Sch Med Dept Biol Chem Baltimore MD 21205 USA Johns Hopkins All Childrens Hosp Inst Fundamental Biomed Res St Petersburg FL USA Johns Hopkins Univ Sch Med Dept Pediat Baltimore MD 21205 USA Johns Hopkins All Childrens Inst Clin & Translat St Petersburg FL USA

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Identification of novel diagnostic and prognostic micrornas in sarcoma on TCGA dataset: bioinformatics and machine learning approach

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SCIENTIFIC REPORTS 2025年第1期15卷 1-14页

作者： Rahmati, Rahem Zarimeidani, Fatemeh Ahmadi, Farnaz Yousefi-Koma, Hannaneh Mohammadnia, Abdolreza Hajimoradi, Maryam Shafaghi, Shadi Nazari, Elham Shahrekord Univ Med Sci Students Res Comm Shahrekord Iran Shahid Beheshti Univ Med Sci Natl Res Inst TB & Lung Dis NRITLD Lung Transplantat Res Ctr Tehran Iran Shahid Beheshti Univ Med Sci Natl Res Inst TB & Lung Dis NRITLD Chron Resp Dis Res Ctr Tehran Iran Shahid Beheshti Univ Med Sci Fac Paramed Sci Prote Res Ctr Tehran Iran

The discovery of unique microrna (miR) patterns and their corresponding genes in sarcoma patients indicates their involvement in cancer development and suggests their potential use in medical management. MiRs were identified from The Cancer Genome Atlas (TCGA) dataset, with a Deep Neural Network (DNN) employed for novel miR identification. MiRDB facilitated target predictions. Functional enrichment analysis, identify critical pathways, protein-protein interaction network, and diseases/clinical data correlations were explored. COX regression, Kaplan-Meier analyses, and CombioROC was also utilized. The population consisted of 119 females and 142 males, and 1046 miRs were uncovered. Ten miRs was selected for further analysis using DNN. Upon analyzing for gene ontology, it was found that these genes showed enrichment in various activities. We identified a significant association between the overall survival rate of sarcoma patients and miRs levels. The combination of miR.3688 and miR.3936 achieved the greatest diagnostic standing. MiRs have the capability to screen sarcoma patients to identify undetected tumors, predict prognosis, and pinpoint prospective targets for treatment. Further large clinical trials are required to validate our findings.

关键词： Artificial intelligence Biomarker Cancer noncoding rna Prognosis

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Epigenetics in metabolic dysfunction-associated steatohepatitis

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CELLULAR SIGNALLING 2025年 130卷 111684页

作者： Zhang, Yanru Ding, Ruike Hu, Liangshuo Liu, Enqi Qu, Pengxiang Xi An Jiao Tong Univ Lab Anim Ctr Hlth Sci Ctr Xian 710061 Peoples R China Minist Educ China Key Lab Environm & Genes Related Dis Xian 710049 Peoples R China Xi An Jiao Tong Univ Affiliated Hosp 1 Dept Hepatobiliary Surg Xian Shaanxi Peoples R China

Metabolic dysfunction-associated steatohepatitis (MASH) is a complex disease involving genetics, environment, and lifestyle, with the potential to progress to liver fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC). Although the pathogenesis of MASH is not fully clear, increasing evidence has indicated that epigenetics plays an important role in the genesis and progression of MASH, during which, as drastic changes in metabolites, epigenetics undergo drastic changes. Roles of chromatin structure, chromatin accessibility, DNA methylation, histone modification, and non-coding rnas were considered as bridges of pathogenic factors and MASH. In this review, the research progress on the epigenetics of MASH was summarized, and indepth research and therapeutic strategies based on epigenetics is expected to bring new hope to MASH patients.

关键词： MASH Epigenetics Liver DNA methylation Histone modifications noncoding rna

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Metabolic and epigenetic regulation of macrophage polarization in atherosclerosis: Molecular mechanisms and targeted therapies

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PHARMACOLOGICAL RESEARCH 2025年 212卷 107588页

作者： Yang, Pinglian Rong, Xiaoling Gao, Zhechang Wang, Jiaojiao Liu, Zhiping Jinan Univ Coll Pharm Int Cooperat Lab Tradit Chinese Med Modernizat & I Chinese Minist Educ MOEState Key Lab Bioact Mol & Guangzhou 510632 Peoples R China Nanjing Univ Chinese Med Sch Pharm Nanjing 210023 Peoples R China Guangdong Med Univ Key Lab Big Data Min & Precis Drug Design Guangdon Key Lab Comp Aided Drug Design Dongguan City Key Lab Res & Dev Nat Drugs Guangdong ProvSch Pha Dongguan 523808 Peoples R China

Atherosclerosis, a multifactorial progressive inflammatory disease, is the common pathology underlying cardiovascular and cerebrovascular diseases. The macrophage plasticity is involved in the pathogenesis of atherosclerosis. With the advance of metabolomics and epigenetics, metabolites/metabolic and epigenetic modification such as DNA methylation, histone modification and noncoding rna, play a crucial role in macrophage polarization and the progression of atherosclerosis. Herein, we provide a comprehensive review of the essential role of metabolic and epigenetic regulation, as well as the crosstalk between the two in regulating macrophage polarization in atherosclerosis. We also highlight the potential therapeutic strategies of regulating macrophage polarization via epigenetic and metabolic modifications for atherosclerosis, and offer recommendations to advance our knowledge of the roles of metabolic-epigenetic crosstalk in macrophage polarization in the context of atherosclerosis. Fundamental studies that elucidate the mechanisms by which metabolic and epigenetic regulation of macrophage polarization influence atherosclerosis will pave the way for novel therapeutic approaches.

关键词： Macrophage polarization Atherosclerosis Epigenetic Metabolism noncoding rna Therapies

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Effect of epigenetic changes in hypoxia induced factor (HIF) gene across cancer types

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GENE 2025年 934卷 149047页

作者： Agarwal, Aditi P. Kumar, Maushmi S. Somaiya Vidyavihar Univ Somaiya Inst Res & Consultancy Near Madhuban GardenVidyavihar E Mumbai 400077 India

Cancer hypoxia, a crucial characteristic of malignancy, ranging from practically non-hypoxic to severe, impacts gene expression, metabolism and mechanisms associated with tumor formation serves as a key obstacle in cancer therapy. It triggers a complex network of cell signaling pathways, such as the NF-kappa B, PI3K, mTOR/AKT, MAPK, HIF and their associated genes regulating the effects of the same. The onset and advancement of cancer are attributed to genetic and epigenetic modifications which are intrinsically related. Off late, it has been observed that in disease progression, the epigenetic modifications lead to gene mutations that in turn alter the epigenome, presenting a major hurdle in fabricating treatment strategies. However, the progress in science and technology has led to the emergence of various surfacing omics and multi-view clustering algorithms, which offer unparalleled prospects for further subtyping cancers, enhancing the prognosis and treatment results of these subtypes, and comprehending crucial pathophysiological mechanisms across diverse molecular strata. Multi-omics has allowed scientists to gain a more comprehensive understanding of the various ways that cellular malfunction can lead to cancer. So, it becomes of utmost importance to firstly understand the epigenetic changes taking place in tumor hypoxia at gene level. This review sheds light on the role of HIF gene in hypoxic milieu and its relationship with mechanisms of cancer epigenetics. It further glances as to how omics approach can be used to study the oncogenic cellular changes and how bioinformatic tools aid in identification of complex gene networks involved in disease progression. Lastly, it glimpses through the benefits and shortcomings of the existing epi drug therapy and how it can be used in developing novel treatment options.

关键词： DNA methylation noncoding rna Immunotherapy Omics Breast cancer Melanoma

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Advances in rna therapy for the treatment of autoimmune diseases

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AUTOIMMUNITY REVIEWS 2025年第4期24卷 103753-103753页

作者： Zhang, Ying Zang, Chenyang Mao, Manyun Zhang, Mi Tang, Zhenwei Chen, Wangqing Zhu, Wu Cent South Univ Xiangya Hosp Dept Dermatol Changsha Hunan Peoples R China XiangYa Hosp Natl Clin Res Ctr Geriatr Disorders Changsha Hunan Peoples R China Xiangya Hosp Hunan Key Lab Skin Canc & Psoriasis Changsha Hunan Peoples R China Xiangya Hosp Hunan Engn Res Ctr Skin Hlth & Dis Changsha Hunan Peoples R China Zhejiang Univ Affiliated Hosp 2 Dept Dermatol Sch Med Hangzhou Peoples R China

Autoimmune diseases (ADs) are a group of complex, chronic conditions characterized by disturbance of immune tolerance, with examples including systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and psoriasis. These diseases have unclear pathogenesis, and traditional therapeutic approaches remain limited. However, advances in high-throughput histology technology and scientific discoveries have led to the identification of various pathogenic factors contributing to ADs. Coupled with improvements in rna nucleic acid-based drug synthesis, design, and delivery, rna-based therapies have been extensively investigated for their potential in treating ADs. This paper reviews the progress in the use of mirnas, lncrnas, circrnas, sirnas, antisense oligonucleotides (ASOs), aptamers, mrnas, and other rna-based therapies in ADs, focusing on their therapeutic potential and application prospects, providing insights for future research and clinical treatment of autoimmune diseases.

关键词： Autoimmune diseases rna therapy noncoding rna ASO mrna

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Novel approaches for efficient in vivo fermentation production of noncoding rnas

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APPLIED MICROBIOLOGY AND BIOTECHNOLOGY 2020年第5期104卷 1927-1937页

作者： Yu, Ai-Ming Batra, Neelu Tu, Mei-Juan Sweeney, Colleen Univ Calif Davis Sch Med Dept Biochem & Mol Med Sacramento CA 95817 USA

Genome-derived noncoding rnas (ncrnas), including micrornas (mirnas), small interfering rnas (sirnas), and long noncoding rnas (lncrnas), play an essential role in the control of target gene expression underlying various cellular processes, and dysregulation of ncrnas is involved in the pathogenesis and progression of various diseases in virtually all species including humans. Understanding ncrna biology has opened new avenues to develop novel rna-based therapeutics. Presently, ncrna research and drug development is dominated by the use of ncrna mimics that are synthesized chemically in vitro and supplemented with extensive and various types of artificial modifications and thus may not necessarily recapitulate the properties of natural rnas generated and folded in living cells in vivo. Therefore, there are growing interests in developing novel technologies for in vivo production of rna molecules. The two most recent major breakthroughs in achieving an efficient, large-scale, and cost-effective fermentation production of recombinant or bioengineered rnas (e.g., tens of milligrams from 1 L of bacterial culture) are (1) using stable rna carriers and (2) direct overexpression in rnase III-deficient bacteria, while other approaches offer a low yield (e.g., nano- to microgram scales per liter). In this article, we highlight these novel microbial fermentation-based technologies that have shifted the paradigm to the production of true biological ncrna molecules for research and development.

关键词： noncoding rna Microrna sirna Bioengineering Biotechnology

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The dichotomy of p53 regulation by noncoding rnas

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Journal of Molecular Cell Biology 2014年第3期8卷 198-205页

作者： Qipan Deng Lindsey Becker Xiaodong Ma Xiaoming Zhong Ken Young Kenneth Ramos and Yong Li Department of Biochemistry and Molecular Biology School of Medicine University of Louisville 319 Abraham Flexner Way Louisville KY 40202 USA Department of Cardiology Huaihe Hospital of Henan University Kaifeng 475000 China Department of Hematopathology The University of Texas MD AndersonCancer Center Houston TX 77030 USA School of Life Science and Technology ShanghaiTech University Shanghai 200031 Cl~ina

The p53 tumor suppressor gene is the most frequently mutated gene in cancer. Significant progress has been made to discern the im- portance of p53 in coordinating cellular responses to DNA damage, oncogene activation, and other stresses. noncoding rnas are rna molecules functioning without being translated into proteins. In this work, we discuss the dichotomy of p53 regulation by noncoding rnas with four unconventional questions. First, is overexpression of micrornas responsible for p53 inactivation in the absence of p53 mutation？ Second, are there somatic mutations in the noncoding regions of the p53 gene？ Third, is there a germline mutant in the non- coding regions of the p53 gene that predisposes carriers to cancer？ Fourth, can p53 activation mediated by a noncoding rna mutation cause cancer？ This work highUghts the prominence of noncoding rnas in p53 dysregutation and tumorigenesis.

关键词： noncoding rna p53 activation mutation 3'UTR poiymorphism ribosomopathies

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