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Vilkaite A, Nguyen XP, Güzel CT, Gottschlich L, Bender U, Dietrich JE, Hinderhofer K, Strowitzki T, Rehnitz J. Beyond Repetition: The Role of Gray Zone Alleles in the Upregulation of FMR1-Binding miR-323a-3p and the Modification of BMP/SMAD-Pathway Gene Expression in Human Granulosa Cells. Int J Mol Sci 2025; 26:3192. [PMID: 40244008 PMCID: PMC11989689 DOI: 10.3390/ijms26073192] [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: 02/05/2025] [Revised: 03/17/2025] [Accepted: 03/27/2025] [Indexed: 04/18/2025] Open
Abstract
The Fragile X mental retardation type 1 gene (FMR1) contains a CGG triplet cluster of varied length (30 repeats on average) located in its 5' UTR. In its premutated state (54-200 repeats), FMR1 contributes to the pathogenesis of premature ovarian insufficiency (POI). Its gray zone alleles (41-54 repeats) are supposed to impair the ovarian function as well. In the case of a CGG repeat length > 200, Fragile X syndrome occurs. Post-transcriptional expression of FMR1 is regulated by microRNAs. Although miR-323a-3p overexpression suppresses FMR1 in various tissues, this relationship has not been evaluated in the human ovary. Additionally, this microRNA targets SMADs, which are suggested regulators of ovarian cell proliferation, growth, and function. This study investigated how FMR1 allele lengths with CGG repeat numbers n < 55 (normal and gray zone genotypes) relate to miR-323a-3p expression and how they may impact associated SMAD expression in human granulosa cells. COV434 cells and patient-derived GCs were used to evaluate FMR1, miR-323a-3p, and BMP/SMAD-pathway member expression levels. Briefly, miR-323a-3p was significantly upregulated in GCs of the gray zone group compared to the normal allele group (p < 0.0001), while the FMR1 level did not vary. Furthermore, the gray zone group showed a significant upregulation of BMPR2, SMAD1, SMAD4, and SMAD9. In contrast, the miR-323a-3p transfection of COV434 cells significantly downregulated SMAD3, SMAD4, SMAD5, and SMAD9, while the FMR1 and SMAD1 levels remained stable. Our findings highlight a CGG repeat number-dependent upregulation of miR-323a-3p and an alteration of the BMP/SMAD pathway, suggesting that these changes happen and contribute to impaired ovarian function independently.
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Affiliation(s)
- Adriana Vilkaite
- Department of Gynecological Endocrinology and Fertility Disorders, University Women’s Hospital, 69120 Heidelberg, Germany; (A.V.); (X.P.N.); (C.T.G.); (L.G.); (U.B.); (J.E.D.); (T.S.)
| | - Xuan Phuoc Nguyen
- Department of Gynecological Endocrinology and Fertility Disorders, University Women’s Hospital, 69120 Heidelberg, Germany; (A.V.); (X.P.N.); (C.T.G.); (L.G.); (U.B.); (J.E.D.); (T.S.)
| | - Cansu Türkan Güzel
- Department of Gynecological Endocrinology and Fertility Disorders, University Women’s Hospital, 69120 Heidelberg, Germany; (A.V.); (X.P.N.); (C.T.G.); (L.G.); (U.B.); (J.E.D.); (T.S.)
| | - Lucas Gottschlich
- Department of Gynecological Endocrinology and Fertility Disorders, University Women’s Hospital, 69120 Heidelberg, Germany; (A.V.); (X.P.N.); (C.T.G.); (L.G.); (U.B.); (J.E.D.); (T.S.)
| | - Ulrike Bender
- Department of Gynecological Endocrinology and Fertility Disorders, University Women’s Hospital, 69120 Heidelberg, Germany; (A.V.); (X.P.N.); (C.T.G.); (L.G.); (U.B.); (J.E.D.); (T.S.)
| | - Jens E. Dietrich
- Department of Gynecological Endocrinology and Fertility Disorders, University Women’s Hospital, 69120 Heidelberg, Germany; (A.V.); (X.P.N.); (C.T.G.); (L.G.); (U.B.); (J.E.D.); (T.S.)
| | - Katrin Hinderhofer
- Institute of Human Genetics, University Heidelberg, 69120 Heidelberg, Germany;
| | - Thomas Strowitzki
- Department of Gynecological Endocrinology and Fertility Disorders, University Women’s Hospital, 69120 Heidelberg, Germany; (A.V.); (X.P.N.); (C.T.G.); (L.G.); (U.B.); (J.E.D.); (T.S.)
| | - Julia Rehnitz
- Department of Gynecological Endocrinology and Fertility Disorders, University Women’s Hospital, 69120 Heidelberg, Germany; (A.V.); (X.P.N.); (C.T.G.); (L.G.); (U.B.); (J.E.D.); (T.S.)
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Gao XD, Ding JE, Xie JX, Xu HM. Epigenetic regulation of iron metabolism and ferroptosis in Parkinson's disease: Identifying novel epigenetic targets. Acta Pharmacol Sin 2025:10.1038/s41401-025-01499-6. [PMID: 40069488 DOI: 10.1038/s41401-025-01499-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 01/28/2025] [Indexed: 03/17/2025]
Abstract
Parkinson's disease (PD) is a neurodegenerative disease, and emerging evidence has shown that iron deposition, ferroptosis and epigenetic modifications are implicated in the pathogenesis of PD. However, the interplay among these factors in PD has not been fully understood. In this review, we provide an overview of the current research progress on iron metabolism, ferroptosis and epigenetic alterations associated with PD. Furthermore, we present new frontiers concerning various epigenetic modifications related to iron metabolism and ferroptosis that might contribute to the pathology of PD. Notably, epigenetic modifications of iron metabolism and ferroptosis as both diagnostic and therapeutic targets in PD have been discussed. This opens new avenues for the regulation of iron homeostasis and ferroptosis in PD from epigenetic perspectives, and provides evidence for their potential implications in the diagnosis and treatment of PD.
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Affiliation(s)
- Xiao-Die Gao
- Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Brain Diseases and State Key Disciplines: Physiology, Department of Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Jian-E Ding
- Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Brain Diseases and State Key Disciplines: Physiology, Department of Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Jun-Xia Xie
- Institute of Brain Science and Disease, Qingdao University, Qingdao, 266071, China.
| | - Hua-Min Xu
- Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Brain Diseases and State Key Disciplines: Physiology, Department of Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China.
- Institute of Brain Science and Disease, Qingdao University, Qingdao, 266071, China.
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Deng Q, Yao X, Fang S, Sun Y, Liu L, Li C, Li G, Guo Y, Liu J. Mast cell-mediated microRNA functioning in immune regulation and disease pathophysiology. Clin Exp Med 2025; 25:38. [PMID: 39812911 PMCID: PMC11735496 DOI: 10.1007/s10238-024-01554-2] [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: 11/08/2024] [Accepted: 12/28/2024] [Indexed: 01/16/2025]
Abstract
Upon stimulation and activation, mast cells (MCs) release soluble mediators, including histamine, proteases, and cytokines. These mediators are often stored within cytoplasmic granules in MCs and may be released in a granulated form. The secretion of cytokines and chemokines occurs within hours following activation, with the potential to result in chronic inflammation. In addition to their role in allergic inflammation, MCs are components of the tumor microenvironment (TME). MicroRNAs (miRNAs) are small RNA molecules that do not encode proteins, but regulate post-transcriptional gene expression by binding to the 3' non-coding regions of mRNAs. This plays a crucial role in the function of MC, including the key processes of MC proliferation, maturation, apoptosis, and activation. It has been demonstrated that miRNAs are also present in extracellular vesicles (EVs) secreted by MCs. EVs derived from MCs mediate intercellular communication by carrying miRNAs, affecting various diseases including allergic diseases, intestinal disorders, neuroinflammation, and tumors. These findings provide important insights into the therapeutic mechanisms and targets of miRNAs in MCs that affect diseases. This review discusses the relevance of miRNA production by MCs in regulating their own activity and the effect of miRNAs putatively produced by other cells in the control of MC activity and their participation in selected pathologies.
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Affiliation(s)
- Qiuping Deng
- Department of Clinical Laboratory, Chengdu Jinjiang Hospital for Women's and Children's Health, Chengdu, 610016, Sichuan, China
| | - Xiuju Yao
- Department of Clinical Laboratory, 363 Hospital, Chengdu, 610016, Sichuan, China
| | - Siyun Fang
- Department of Clinical Laboratory, Chengdu Jinjiang Hospital for Women's and Children's Health, Chengdu, 610016, Sichuan, China
| | - Yueshan Sun
- Medical Research Center, The Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu, 610031, China
| | - Lei Liu
- Medical Research Center, The Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu, 610031, China
| | - Chao Li
- Department of Clinical Laboratory, Chengdu Jinjiang Hospital for Women's and Children's Health, Chengdu, 610016, Sichuan, China
| | - Guangquan Li
- Department of Clinical Laboratory, 363 Hospital, Chengdu, 610016, Sichuan, China
| | - Yuanbiao Guo
- Medical Research Center, The Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu, 610031, China.
| | - Jinbo Liu
- The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China.
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He K, Zhou X, Zhao J, Du H, Guo J, Deng R, Wang J. Identification and Functional Mechanism Verification of Novel MicroRNAs Associated with the Fibrosis Progression in Chronic Kidney Disease. Biochem Genet 2024; 62:4472-4493. [PMID: 38316653 PMCID: PMC11604686 DOI: 10.1007/s10528-024-10688-7] [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: 10/17/2023] [Accepted: 01/04/2024] [Indexed: 02/07/2024]
Abstract
Chronic kidney disease (CKD) is a serious threat to human health worldwide, and its incidence is increasing annually. A growing amount of information is emerging about the role of micoRNAs (miRNAs) in the regulation of renal fibrosis, which has aroused interest in the development of drugs that block pathogenic miRNAs or restore protective miRNAs levels. To clarify the role of miRNAs in CKD, we selected patients with significant renal fibrotic disease (diabetic nephropathy (DN) and focal segmental glomerulosclerosis (FSGS)) as the disease group, and patients with little or no renal fibrotic disease (minimal change disease (MCD) and renal carcinoma adjacent to normal kidney) as controls. Significantly differentially expressed miRNAs were obtained by human kidney tissue sequencing, subsequently verified in mice models of DN and FSGS, and subsequently inhibited or overexpressed in human renal tubular epithelial cells (HK-2) stimulated by high glucose (HG) and TGF-β1 in vitro. Therefore, the mechanism of its action in renal fibrosis was further elaborated. Finally, the downstream target genes of the corresponding miRNAs were verified by bioinformatics analysis, qRT-PCR, western blot and double luciferase report analysis. Two novel miRNAs, hsa-miR-1470-3p (miR-1470) and hsa-miR-4483-3p (miR-4483), were detected by renal tissue sequencing in the disease group with significant renal fibrosis (DN and FSGS) and the control group with little or no renal fibrosis (MCD and normal renal tissue adjacent to renal carcinoma). Subsequent human renal tissue qRT-PCR verified that the expression of miR-1470 was significantly increased, while the expression of miR-4483 was markedly decreased in the disease group (p < 0.05). Moreover, in vivo DN and FSGS mice models, the expression levels of miR-1470 and miR-4483 were consistent with the results of human kidney tissue. In vitro, miR-4483 was suppressed, whereas miR-1470 was induced by treatment with TGF-β1 or HG. Inhibition of miR-1470 or overexpression of miR-4483 promoted HG or TGF-β1-induced fibrosis in HK-2 cells. Further study revealed that MMP-13 and TIMP1 were the target genes ofmiR-1470 and miR-4483, respectively. Our study identifies newly dysregulated miRNA profiles related to fibrosis kidneys. miR-1470 and miR-4483 are demonstrated to participate in kidney fibrosis by regulation of MMP-13, TIMP1 respectively. Our results may represent a promising research direction for renal disorders and help identify new biomarkers and therapeutic targets for CKD.
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Affiliation(s)
- Kaiying He
- Lanzhou University, Lanzhou, Gansu, China
- Department of Nephrology, The Second Hospital & Clinical Medical School, Lanzhou University, No. 82 Cuiyingmen, Lanzhou, Gansu, China
| | - Xiaochun Zhou
- Department of Nephrology, The Second Hospital & Clinical Medical School, Lanzhou University, No. 82 Cuiyingmen, Lanzhou, Gansu, China
| | - Jing Zhao
- Lanzhou University, Lanzhou, Gansu, China
- Department of Nephrology, The Second Hospital & Clinical Medical School, Lanzhou University, No. 82 Cuiyingmen, Lanzhou, Gansu, China
| | - Hongxuan Du
- Lanzhou University, Lanzhou, Gansu, China
- Department of Nephrology, The Second Hospital & Clinical Medical School, Lanzhou University, No. 82 Cuiyingmen, Lanzhou, Gansu, China
| | - Juan Guo
- Xi'an Huyi District Hospital Of Traditional Chinese Medicine, Xi'an, Shaanxi, China
| | - Rongrong Deng
- Lanzhou University, Lanzhou, Gansu, China
- Department of Nephrology, The Second Hospital & Clinical Medical School, Lanzhou University, No. 82 Cuiyingmen, Lanzhou, Gansu, China
| | - Jianqin Wang
- Department of Nephrology, The Second Hospital & Clinical Medical School, Lanzhou University, No. 82 Cuiyingmen, Lanzhou, Gansu, China.
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Liu F, Ma M, Li L, Zhang Y, Shang Y, Yuan Q, Ju B, Wang Z. A Study of Sperm DNA Damage Mechanism Based on miRNA Sequencing. Am J Mens Health 2024; 18:15579883241286672. [PMID: 39462893 PMCID: PMC11528732 DOI: 10.1177/15579883241286672] [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: 05/27/2024] [Revised: 08/07/2024] [Accepted: 08/23/2024] [Indexed: 10/29/2024] Open
Abstract
To analyze the differential expression profiles of microRNAs (miRNAs) in spermatozoa of patients with sperm DNA damage and to investigate the role of miRNAs in sperm DNA damage. Male infertility patients with sperm DNA damage who attended the First Affiliated Hospital of Henan University of Chinese Medicine from October 2023 to December 2023 were selected and included in this study as a case group. Fertile healthy men who were seen at the health check-up center during the same period and diagnosed by examination were also included as a control group. Sperm miRNA expression was detected in patients with sperm DNA damage (case group, n = 5) and healthy medical check-ups (control group, n = 5) using high-throughput sequencing technology. The differentially expressed miRNAs between the two groups were bioinformatically analyzed to explore the main biological functions of the target genes. We found that 63 miRNAs were significantly changed in the spermatozoa of patients with sperm DNA damage,|log2 (foldchange)| ≥ 1, p < .05. Gene Ontology (GO) enrichment analysis indicated that these differential miRNAs might be involved in developmental process, anatomical structure development, cellular macromolecule metabolic process, multicellular organism development, system development, and so on. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that that they mainly affect the PI3K-AKT signaling pathway. The present study suggests that the altered expression of miR-1255a, miR-921, and miR-3156-5p may play an important role in the sperm DNA damage process, and the mechanism may involve the phosphatidylinositol-3'-kinase-AKT (PI3K-AKT) signaling pathway.
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Affiliation(s)
- Feng Liu
- Henan University of Chinese Medicine, Zhengzhou, China
| | - Miaomiao Ma
- Henan University of Chinese Medicine, Zhengzhou, China
| | - Luyu Li
- Henan University of Chinese Medicine, Zhengzhou, China
| | - Yongtao Zhang
- Henan University of Chinese Medicine, Zhengzhou, China
| | - Yihan Shang
- Henan University of Chinese Medicine, Zhengzhou, China
| | - Quan Yuan
- Henan University of Chinese Medicine, Zhengzhou, China
| | - Baojun Ju
- Department of Andrology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Zulong Wang
- Department of Andrology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
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Zhuravskaya A, Yap K, Hamid F, Makeyev EV. Alternative splicing coupled to nonsense-mediated decay coordinates downregulation of non-neuronal genes in developing mouse neurons. Genome Biol 2024; 25:162. [PMID: 38902825 PMCID: PMC11188260 DOI: 10.1186/s13059-024-03305-8] [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: 07/08/2023] [Accepted: 06/07/2024] [Indexed: 06/22/2024] Open
Abstract
BACKGROUND The functional coupling between alternative pre-mRNA splicing (AS) and the mRNA quality control mechanism called nonsense-mediated decay (NMD) can modulate transcript abundance. Previous studies have identified several examples of such a regulation in developing neurons. However, the systems-level effects of AS-NMD in this context are poorly understood. RESULTS We developed an R package, factR2, which offers a comprehensive suite of AS-NMD analysis functions. Using this tool, we conducted a longitudinal analysis of gene expression in pluripotent stem cells undergoing induced neuronal differentiation. Our analysis uncovers hundreds of AS-NMD events with significant potential to regulate gene expression. Notably, this regulation is significantly overrepresented in specific functional groups of developmentally downregulated genes. Particularly strong association with gene downregulation is detected for alternative cassette exons stimulating NMD upon their inclusion into mature mRNA. By combining bioinformatic analyses with CRISPR/Cas9 genome editing and other experimental approaches we show that NMD-stimulating cassette exons regulated by the RNA-binding protein PTBP1 dampen the expression of their genes in developing neurons. We also provided evidence that the inclusion of NMD-stimulating cassette exons into mature mRNAs is temporally coordinated with NMD-independent gene repression mechanisms. CONCLUSIONS Our study provides an accessible workflow for the discovery and prioritization of AS-NMD targets. It further argues that the AS-NMD pathway plays a widespread role in developing neurons by facilitating the downregulation of functionally related non-neuronal genes.
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Affiliation(s)
- Anna Zhuravskaya
- Centre for Developmental Neurobiology, King's College London, London, SE1 1UL, UK
| | - Karen Yap
- Centre for Developmental Neurobiology, King's College London, London, SE1 1UL, UK
| | - Fursham Hamid
- Centre for Developmental Neurobiology, King's College London, London, SE1 1UL, UK.
| | - Eugene V Makeyev
- Centre for Developmental Neurobiology, King's College London, London, SE1 1UL, UK.
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Kotewitsch M, Heimer M, Schmitz B, Mooren FC. Non-coding RNAs in exercise immunology: A systematic review. JOURNAL OF SPORT AND HEALTH SCIENCE 2024; 13:311-338. [PMID: 37925072 PMCID: PMC11116971 DOI: 10.1016/j.jshs.2023.11.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 09/01/2023] [Accepted: 09/19/2023] [Indexed: 11/06/2023]
Abstract
Regular physical exercise has been recognized as a potent modulator of immune function, with its effects including enhanced immune surveillance, reduced inflammation, and improved overall health. While strong evidence exists that physical exercise affects the specific expression and activity of non-coding RNAs (ncRNAs) also involved in immune system regulation, heterogeneity in individual study designs and analyzed exercise protocols exists, and a condensed list of functional, exercise-dependent ncRNAs with known targets in the immune system is missing from the literature. A systematic review and qualitative analysis was used to identify and categorize ncRNAs participating in immune modulation by physical exercise. Two combined approaches were used: (a) a systematic literature search for "ncRNA and exercise immunology", (b) and a database search for microRNAs (miRNAs) (miRTarBase and DIANA-Tarbase v8) aligned with known target genes in the immune system based on the Reactome database, combined with a systematic literature search for "ncRNA and exercise". Literature searches were based on PubMed, Web of Science, and SPORTDiscus; and miRNA databases were filtered for targets validated by in vitro experimental data. Studies were eligible if they reported on exercise-based interventions in healthy humans. After duplicate removal, 95 studies were included reporting on 164 miRNAs, which were used for the qualitative synthesis. Six studies reporting on long-noncoding RNAs (lncRNAs) or circular RNAs were also identified. Results were analyzed using ordering tables that included exercise modality (endurance/resistance exercise), acute or chronic interventions, as well as the consistency in reported change between studies. Evaluation criteria were defined as "validated" with 100% of ≥3 independent studies showing identical direction of regulation, "plausible" (≥80%), or "suggestive" (≥70%). For resistance exercise, upregulation of miR-206 was validated while downregulation of miR-133a appeared plausible. For endurance exercise, 15 miRNAs were categorized as validated, with 12 miRNAs being consistently elevated and 3 miRNAs being downregulated, most of them after acute exercise training. In conclusion, our approach provides evidence that miRNAs play a major role in exercise-induced effects on the innate and adaptive immune system by targeting different pathways affecting immune cell distribution, function, and trafficking as well as production of (anti-)inflammatory cytokines. miRNAs miR-15, miR-29c, miR-30a, miR-142/3, miR-181a, and miR-338 emerged as key players in mediating the immunomodulatory effects of exercise predominantly after acute bouts of endurance exercise.
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Affiliation(s)
- Mona Kotewitsch
- Department of Rehabilitation Sciences, Faculty of Health, University of Witten/Herdecke, Witten 58455, Germany; DRV Clinic Königsfeld, Center for Medical Rehabilitation, Ennepetal 58256, Germany
| | - Melina Heimer
- Department of Rehabilitation Sciences, Faculty of Health, University of Witten/Herdecke, Witten 58455, Germany; DRV Clinic Königsfeld, Center for Medical Rehabilitation, Ennepetal 58256, Germany
| | - Boris Schmitz
- Department of Rehabilitation Sciences, Faculty of Health, University of Witten/Herdecke, Witten 58455, Germany; DRV Clinic Königsfeld, Center for Medical Rehabilitation, Ennepetal 58256, Germany.
| | - Frank C Mooren
- Department of Rehabilitation Sciences, Faculty of Health, University of Witten/Herdecke, Witten 58455, Germany; DRV Clinic Königsfeld, Center for Medical Rehabilitation, Ennepetal 58256, Germany
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Yu KQ, Li CF, Ye L, Song Y, Wang YH, Lin YR, Liao ST, Mei ZC, Lv L. Long Non-Coding RNA ANRIL Regulates Inflammatory Factor Expression in Ulcerative Colitis Via the miR-191-5p/SATB1 Axis. Inflammation 2024; 47:513-529. [PMID: 37985573 DOI: 10.1007/s10753-023-01925-z] [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: 09/21/2023] [Revised: 10/14/2023] [Accepted: 10/20/2023] [Indexed: 11/22/2023]
Abstract
Ulcerative colitis, an inflammatory bowel disease, manifests with symptoms such as abdominal pain, diarrhea, and mucopurulent feces. The long non-coding RNA (lncRNA) ANRIL exhibits significantly reduced expression in UC, yet its specific mechanism is unknown. This study revealed that ANRIL is involved in the progression of UC by inhibiting IL-6 and TNF-α via miR-191-5P/SATB1 axis. We found that in patients with UC, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were significantly overexpressed in inflamed colon sites, whereas ANRIL was significantly under-expressed and associated with disease severity. The downregulation of ANRIL resulted in the increased expression of IL-6 and TNF-α in LPS-treated FHCs. ANRIL directly targeted miR-191-5p, thereby inhibiting its expression and augmenting SATB1 expression. Moreover, overexpression of miR-191-5p abolished ANRIL-mediated inhibition of IL-6 and TNF-α production. Dual luciferase reporter assays revealed the specific binding of miR-191-5p to ANRIL and SATB1. Furthermore, the downregulation of ANRIL promoted DSS-induced colitis in mice. Together, we provide evidence that ANRIL plays a critical role in regulating IL-6 and TNF-α expression in UC by modulating the miR-191-5p/SATB1 axis. Our study provides novel insights into progression and molecular therapeutic strategies in UC.
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Affiliation(s)
- Ke-Qi Yu
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong, Chongqing, 400010, China
| | - Chuan-Fei Li
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong, Chongqing, 400010, China
| | - Lu Ye
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong, Chongqing, 400010, China
| | - Ya Song
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong, Chongqing, 400010, China
| | - Yan-Hui Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong, Chongqing, 400010, China
| | - Yu-Ru Lin
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong, Chongqing, 400010, China
| | - Sheng-Tao Liao
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong, Chongqing, 400010, China.
| | - Zhe-Chuan Mei
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong, Chongqing, 400010, China.
| | - Lin Lv
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong, Chongqing, 400010, China.
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Fromm B, Sorger T. Rapid adaptation of cellular metabolic rate to the MicroRNA complements of mammals and its relevance to the evolution of endothermy. iScience 2024; 27:108740. [PMID: 38327773 PMCID: PMC10847693 DOI: 10.1016/j.isci.2023.108740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 09/13/2023] [Accepted: 12/12/2023] [Indexed: 02/09/2024] Open
Abstract
The metabolic efficiency of mammalian cells depends on the attenuation of intrinsic translation noise by microRNAs. We devised a metric of cellular metabolic rate (cMR), rMR/Mexp optimally fit to the number of microRNA families (mirFam), that is robust to variation in mass and sensitive to body temperature (Tb), consistent with the heat dissipation limit theory of Speakman and Król (2010). Using mirFam as predictor, an Ornstein-Uhlenbeck process of stabilizing selection, with an adaptive shift at the divergence of Boreoeutheria, accounted for 95% of the variation in cMR across mammals. Branchwise rates of evolution of cMR, mirFam and Tb concurrently increased 6- to 7-fold at the divergence of Boreoeutheria, independent of mass. Cellular MR variation across placental mammals was also predicted by the sum of model conserved microRNA-target interactions, revealing an unexpected degree of integration of the microRNA-target apparatus into the energy economy of the mammalian cell.
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Affiliation(s)
- Bastian Fromm
- The Arctic University Museum of Norway, UiT- The Arctic University of Norway, Tromsø, Norway
| | - Thomas Sorger
- Department of Biology, Roger Williams University, Bristol, RI 02809, USA
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Shaheen N, Shaheen A, Diab RA, Desouki MT. MicroRNAs (miRNAs) role in hypertension: pathogenesis and promising therapeutics. Ann Med Surg (Lond) 2024; 86:319-328. [PMID: 38222760 PMCID: PMC10783350 DOI: 10.1097/ms9.0000000000001498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 11/02/2023] [Indexed: 01/16/2024] Open
Abstract
Background MicroRNAs (miRNAs) are small, non-coding RNA molecules that play a crucial role in regulating various cellular processes, including cell proliferation, differentiation, apoptosis, and disease development. Recent studies have highlighted the importance of miRNAs in the development and progression of essential hypertension, a common form of high blood pressure that affects millions of individuals worldwide. The molecular mechanisms by which miRNAs regulate hypertension are complex and multifaceted. MiRNAs target the 3' untranslated regions of mRNA molecules, thereby regulating the synthesis of specific proteins involved in cardiovascular function. For instance, miRNAs are known to regulate the expression of genes involved in blood vessel tone, cardiac function, and inflammation. The growing body of research on miRNAs in hypertension has highlighted their potential as therapeutic targets for managing this condition. Studies have shown that miRNA-based therapies can modulate the expression of key genes involved in hypertension, leading to improvements in blood pressure and cardiovascular function. However, more research is needed to fully understand the mechanisms of miRNA-mediated hypertension and to develop effective therapeutic strategies. Conclusions In summary, this review highlights the current understanding of the role of miRNAs in essential hypertension, including their molecular mechanisms and potential therapeutic applications. Further research is needed to fully understand the impact of miRNAs on hypertension and to develop new treatments for this common and debilitating condition.
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Affiliation(s)
- Nour Shaheen
- Faculty of Medicine, Alexandria University, Alexandria
| | - Ahmed Shaheen
- Faculty of Medicine, Alexandria University, Alexandria
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11
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Hao S, DelliPizzi A, Lasaracina AP, Ferreri NR. TNF inhibits AQP2 expression via a miR137-dependent pathway. Am J Physiol Renal Physiol 2024; 326:F152-F164. [PMID: 37969102 PMCID: PMC11198993 DOI: 10.1152/ajprenal.00210.2023] [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: 07/20/2023] [Revised: 10/23/2023] [Accepted: 11/08/2023] [Indexed: 11/17/2023] Open
Abstract
As miR-137 is a regulator of aquaporin (AQP)2 expression and tumor necrosis factor (TNF) inhibits the expression of several extrarenal AQPs, we tested the hypothesis that TNF inhibits AQP2 in the kidney via a miR-137-dependent mechanism. AQP2 mRNA and protein expression decreased ∼70% and 53%, respectively, in primary renal inner medullary collecting duct (IMCD) cells transfected with a miRNA mimic of mmu-miR-137, suggesting that miR-137 directly targets AQP2 mRNA in these cells. Exposure of IMCD cells for 2 h to 400 mosmol/kgH2O medium increased mmu-miR-137 mRNA expression about twofold, conditions that also increased TNF production approximately fourfold. To determine if the increase in mmu-miR-137 mRNA expression was related to the concomitant increase in TNF, IMCD cells were transfected with a lentivirus construct to silence TNF. This construct decreased mmu-miR-137 mRNA expression by ∼63%, suggesting that TNF upregulates the expression of miR-137. Levels of miR-137 also increased approximately twofold in IMCD tubules isolated from male mice given 1% NaCl in the drinking water for 3 days. Intrarenal lentivirus silencing of TNF increased AQP2 mRNA levels and protein expression concomitant with a decrease in miR-137 levels in tubules isolated from mice given NaCl. The changes in AQP2 expression levels affected the diluting ability of the kidney, which was assessed by measuring urine osmolality and urine volume, as the decrease in these parameters after renal silencing of TNF was prevented on intrarenal administration of miR-137. The study reveals a novel TNF function via a miR-137-dependent mechanism that regulates AQP2 expression and function.NEW & NOTEWORTHY An emerging intratubular tumor necrosis factor system, functioning during normotensive noninflammatory conditions, acts as a breaking mechanism that attenuates both the increases in Na+-K+-2Cl- cotransporter and aquaporin-2 induced by arginine vasopressin, thereby contributing to the regulation of electrolyte balance and blood pressure. A greater appreciation for the role of cytokines as mediators of immunophysiological responses may help reveal the relationship between the immune system and other physiological systems.
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Affiliation(s)
- Shoujin Hao
- Department of Pharmacology, New York Medical College, Valhalla, New York, United States
| | - AnnMarie DelliPizzi
- Department of Biology, Dominican University New York, Orangeburg, New York, United States
| | - Anna Pia Lasaracina
- Department of Pharmacology, New York Medical College, Valhalla, New York, United States
| | - Nicholas R Ferreri
- Department of Pharmacology, New York Medical College, Valhalla, New York, United States
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12
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Tariq M, Richard V, Kerin MJ. MicroRNAs as Molecular Biomarkers for the Characterization of Basal-like Breast Tumor Subtype. Biomedicines 2023; 11:3007. [PMID: 38002007 PMCID: PMC10669494 DOI: 10.3390/biomedicines11113007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 11/03/2023] [Accepted: 11/07/2023] [Indexed: 11/26/2023] Open
Abstract
Breast cancer is a heterogeneous disease highlighted by the presence of multiple tumor variants and the basal-like breast cancer (BLBC) is considered to be the most aggressive variant with limited therapeutics and a poor prognosis. Though the absence of detectable protein and hormonal receptors as biomarkers hinders early detection, the integration of genomic and transcriptomic profiling led to the identification of additional variants in BLBC. The high-throughput analysis of tissue-specific micro-ribonucleic acids (microRNAs/miRNAs) that are deemed to have a significant role in the development of breast cancer also displayed distinct expression profiles in each subtype of breast cancer and thus emerged to be a robust approach for the precise characterization of the BLBC subtypes. The classification schematic of breast cancer is still a fluid entity that continues to evolve alongside technological advancement, and the transcriptomic profiling of tissue-specific microRNAs is projected to aid in the substratification and diagnosis of the BLBC tumor subtype. In this review, we summarize the current knowledge on breast tumor classification, aim to collect comprehensive evidence based on the microRNA expression profiles, and explore their potential as prospective biomarkers of BLBC.
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Affiliation(s)
| | - Vinitha Richard
- Discipline of Surgery, Lambe Institute for Translational Research, H91 TK33 Galway, Ireland;
| | - Michael J. Kerin
- Discipline of Surgery, Lambe Institute for Translational Research, H91 TK33 Galway, Ireland;
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13
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Gupta R, Kadhim MM, Turki Jalil A, Obayes AM, Aminov Z, Alsaikhan F, Ramírez-Coronel AA, Ramaiah P, Tayyib NA, Luo X. Multifaceted role of NF-κB in hepatocellular carcinoma therapy: Molecular landscape, therapeutic compounds and nanomaterial approaches. ENVIRONMENTAL RESEARCH 2023; 228:115767. [PMID: 36966991 DOI: 10.1016/j.envres.2023.115767] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 03/20/2023] [Accepted: 03/22/2023] [Indexed: 05/16/2023]
Abstract
The predominant kind of liver cancer is hepatocellular carcinoma (HCC) that its treatment have been troublesome difficulties for physicians due to aggressive behavior of tumor cells in proliferation and metastasis. Moreover, stemness of HCC cells can result in tumor recurrence and angiogenesis occurs. Another problem is development of resistance to chemotherapy and radiotherapy in HCC cells. Genomic mutations participate in malignant behavior of HCC and nuclear factor-kappaB (NF-κB) has been one of the oncogenic factors in different human cancers that after nuclear translocation, it binds to promoter of genes in regulating their expression. Overexpression of NF-κB has been well-documented in increasing proliferation and invasion of tumor cells and notably, when its expression enhances, it induces chemoresistance and radio-resistance. Highlighting function of NF-κB in HCC can shed some light on the pathways regulating progression of tumor cells. The first aspect is proliferation acceleration and apoptosis inhibition in HCC cells mediated by enhancement in expression level of NF-κB. Moreover, NF-κB is able to enhance invasion of HCC cells via upregulation of MMPs and EMT, and it triggers angiogenesis as another step for increasing spread of tumor cells in tissues and organs. When NF-κB expression enhances, it stimulates chemoresistance and radio-resistance in HCC cells and by increasing stemness and population of cancer-stem cells, it can provide the way for recurrence of tumor. Overexpression of NF-κB mediates therapy resistance in HCC cells and it can be regulated by non-coding RNAs in HCC. Moreover, inhibition of NF-κB by anti-cancer and epigenetic drugs suppresses HCC tumorigenesis. More importantly, nanoparticles are considered for suppressing NF-κB axis in cancer and their prospectives and results can also be utilized for treatment of HCC. Nanomaterials are promising factors in treatment of HCC and by delivery of genes and drugs, they suppress HCC progression. Furthermore, nanomaterials provide phototherapy in HCC ablation.
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Affiliation(s)
- Reena Gupta
- Institute of Pharmaceutical Research, GLA University, District-Mathura, U. P., India
| | - Mustafa M Kadhim
- Department of Dentistry, Kut University College, Kut, Wasit, 52001, Iraq; Medical Laboratory Techniques Department, Al-Farahidi University, Baghdad, 10022, Iraq
| | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla, 51001, Iraq.
| | | | - Zafar Aminov
- Department of Public Health and Healthcare Management, Samarkand State Medical University, 18 Amir Temur Street, Samarkand, Uzbekistan; Department of Scientific Affairs, Tashkent State Dental Institute, 103 Makhtumkuli Str., Tashkent, Uzbekistan
| | - Fahad Alsaikhan
- College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia.
| | - Andrés Alexis Ramírez-Coronel
- Azogues Campus Nursing Career, Health and Behavior Research Group (HBR), Psychometry and Ethology Laboratory, Catholic University of Cuenca, Ecuador; Epidemiology and Biostatistics Research Group, CES University, Colombia; Educational Statistics Research Group (GIEE), National University of Education, Ecuador
| | | | - Nahla A Tayyib
- Faculty of Nursing, Umm al- Qura University, Makkah, Saudi Arabia
| | - Xuanming Luo
- Department of General Surgery, Shanghai Xuhui Central Hospital, Fudan University, Shanghai, 200031, China.
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Bratu D, Boda D, Caruntu C. Genomic, Epigenomic, Transcriptomic, Proteomic and Metabolomic Approaches in Atopic Dermatitis. Curr Issues Mol Biol 2023; 45:5215-5231. [PMID: 37367080 PMCID: PMC10297041 DOI: 10.3390/cimb45060331] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/03/2023] [Accepted: 06/07/2023] [Indexed: 06/28/2023] Open
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease with a high prevalence in the developed countries. It is associated with atopic and non-atopic diseases, and its close correlation with atopic comorbidities has been genetically demonstrated. One of the main roles of genetic studies is to comprehend the defects of the cutaneous barrier due to filaggrin deficit and epidermal spongiosis. Recently, epigenetic studies started to analyze the influence of the environmental factors on gene expression. The epigenome is considered to be a superior second code that controls the genome, which includes alterations of the chromatin. The epigenetic changes do not alter the genetic code, however, changes in the chromatin structure could activate or inhibit the transcription process of certain genes and consequently, the translation process of the new mRNA into a polypeptide chain. In-depth analysis of the transcriptomic, metabolomic and proteomic studies allow to unravel detailed mechanisms that cause AD. The extracellular space and lipid metabolism are associated with AD that is independent of the filaggrin expression. On the other hand, around 45 proteins are considered as the principal components in the atopic skin. Moreover, genetic studies based on the disrupted cutaneous barrier can lead to the development of new treatments targeting the cutaneous barrier or cutaneous inflammation. Unfortunately, at present, there are no target therapies that focus on the epigenetic process of AD. However, in the future, miR-143 could be an important objective for new therapies, as it targets the miR-335:SOX axis, thereby restoring the miR-335 expression, and repairing the cutaneous barrier defects.
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Affiliation(s)
- Dalia Bratu
- Department of Dermatology, ‘Colentina’ Clinical Hospital, 020125 Bucharest, Romania;
- Department of Dermatology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Daniel Boda
- Department of Dermatology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania;
- Department of Dermatology, ‘Ponderas’ Academic Hospital, 014142 Bucharest, Romania
- Department of Dermatology, “Prof. N.C. Paulescu” National Institute of Diabetes, Nutrition and Metabolic Diseases, 011233 Bucharest, Romania
| | - Constantin Caruntu
- Department of Dermatology, “Prof. N.C. Paulescu” National Institute of Diabetes, Nutrition and Metabolic Diseases, 011233 Bucharest, Romania
- Department of Physiology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
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15
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Jenike AE, Jenike KM, Peterson KJ, Fromm B, Halushka MK. Direct observation of the evolution of cell-type-specific microRNA expression signatures supports the hematopoietic origin model of endothelial cells. Evol Dev 2023; 25:226-239. [PMID: 37157156 PMCID: PMC10302300 DOI: 10.1111/ede.12438] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 03/22/2023] [Accepted: 04/26/2023] [Indexed: 05/10/2023]
Abstract
The evolution of specialized cell-types is a long-standing interest of biologists, but given the deep time-scales very difficult to reconstruct or observe. microRNAs have been linked to the evolution of cellular complexity and may inform on specialization. The endothelium is a vertebrate-specific specialization of the circulatory system that enabled a critical new level of vasoregulation. The evolutionary origin of these endothelial cells is unclear. We hypothesized that Mir-126, an endothelial cell-specific microRNA may be informative. We here reconstruct the evolutionary history of Mir-126. Mir-126 likely appeared in the last common ancestor of vertebrates and tunicates, which was a species without an endothelium, within an intron of the evolutionary much older EGF Like Domain Multiple (Egfl) locus. Mir-126 has a complex evolutionary history due to duplications and losses of both the host gene and the microRNA. Taking advantage of the strong evolutionary conservation of the microRNA among Olfactores, and using RNA in situ hybridization, we localized Mir-126 in the tunicate Ciona robusta. We found exclusive expression of the mature Mir-126 in granular amebocytes, supporting a long-proposed scenario that endothelial cells arose from hemoblasts, a type of proto-endothelial amoebocyte found throughout invertebrates. This observed change of expression of Mir-126 from proto-endothelial amoebocytes in the tunicate to endothelial cells in vertebrates is the first direct observation of the evolution of a cell-type in relation to microRNA expression indicating that microRNAs can be a prerequisite of cell-type evolution.
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Affiliation(s)
- Ana E. Jenike
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205 USA
| | - Katharine M. Jenike
- Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205 USA
| | - Kevin J. Peterson
- Department of Biological Sciences, Dartmouth College, Hanover NH, USA
| | - Bastian Fromm
- The Arctic University Museum of Norway, UiT-The Arctic University of Norway, 9006 Tromsø, Norway
| | - Marc K. Halushka
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205 USA
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16
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Elucidation of the Landscape of Alternatively Spliced Genes and Features in the Dorsal Striatum of Aggressive/Aggression-Deprived Mice in the Model of Chronic Social Conflicts. Genes (Basel) 2023; 14:genes14030599. [PMID: 36980872 PMCID: PMC10048575 DOI: 10.3390/genes14030599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 02/20/2023] [Accepted: 02/21/2023] [Indexed: 03/03/2023] Open
Abstract
Both aggressive and aggression-deprived (AD) individuals represent pathological cases extensively studied in psychiatry and substance abuse disciplines. We employed the animal model of chronic social conflicts curated in our laboratory for over 30 years. In the study, we pursued the task of evaluation of the key events in the dorsal striatum transcriptomes of aggression-experienced mice and AD species, as compared with the controls, using RNA-seq profiling. We evaluated the alternative splicing-mediated transcriptome dynamics based on the RNA-seq data. We confined our attention to the exon skipping (ES) events as the major AS type for animals. We report the concurrent posttranscriptional and posttranslational regulation of the ES events observed in the phosphorylation cycles (in phosphoproteins and their targets) in the neuron-specific genes of the striatum. Strikingly, we found that major neurospecific splicing factors (Nova1, Ptbp1, 2, Mbnl1, 2, and Sam68) related to the alternative splicing regulation of cAMP genes (Darpp-32, Grin1, Ptpn5, Ppp3ca, Pde10a, Prkaca, Psd95, and Adora1) are upregulated specifically in aggressive individuals as compared with the controls and specifically AD animals, assuming intense switching between isoforms in the cAMP-mediated (de)phosphorylation signaling cascade. We found that the coding alternative splicing events were mostly attributed to synaptic plasticity and neural development-related proteins, while the nonsense-mediated decay-associated splicing events are mostly attributed to the mRNA processing of genes, including the spliceosome and splicing factors. In addition, considering the gene families, the transporter (Slc) gene family manifested most of the ES events. We found out that the major molecular systems employing AS for their plasticity are the ‘spliceosome’, ‘chromatin rearrangement complex’, ‘synapse’, and ‘neural development/axonogenesis’ GO categories. Finally, we state that approximately 35% of the exon skipping variants in gene coding regions manifest the noncoding variants subject to nonsense-mediated decay, employed as a homeostasis-mediated expression regulation layer and often associated with the corresponding gene expression alteration.
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17
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Hao S, Zhao H, Hao DH, Ferreri NR. MicroRNA-195a-5p Regulates Blood Pressure by Inhibiting NKCC2A. Hypertension 2023; 80:426-439. [PMID: 36448465 PMCID: PMC9852070 DOI: 10.1161/hypertensionaha.122.19794] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 11/15/2022] [Indexed: 12/05/2022]
Abstract
BACKGROUND Previous studies showed that miR-195a-5p was among the most abundant microRNAs (miRNAs) expressed in the kidney. METHODS Lentivirus silencing of tumor necrosis factor-α (TNF) was performed in vivo and in vitro. Luciferase reporter assays confirmed that bumetanide-sensitive Na+-K+-2Cl- cotransporter isoform A (NKCC2A) mRNA is targeted and repressed by miR-195a-5p. Radiotelemetry was used to measure mean arterial pressure. RESULTS TNF upregulates mmu-miR-195a-5p, and -203 and downregulates mmu-miR-30c and -100 in the medullary thick ascending limb of male mice. miR-195a-5p was >3-fold higher in the renal outer medulla of mice given an intrarenal injection of murine recombinant TNF, whereas silencing TNF inhibited miR-195a-5p expression by ≈51%. Transient transfection of a miR-195a-5p mimic into medullary thick ascending limb cells suppressed NKCC2A mRNA by ≈83%, whereas transfection with Anti-miR-195a-5p increased NKCC2A mRNA. Silencing TNF in medullary thick ascending limb cells prevented increases in miR-195 induced by 400 mosmol/kg H2O medium, an effect reversed by transfection with a miR-195a-5p mimic. Expression of phosphorylated NKCC2 increased 1.5-fold in medullary thick ascending limb cells transfected with Anti-miR-195a-5p and a miR-195a-5p mimic prevented the increase, which was induced by silencing TNF in cells exposed to 400 mosmol/kg H2O medium after osmolality was increased by adding NaCl. Intrarenal injection of TNF suppressed NKCC2A mRNA, whereas injection of miR-195a-5p prevented the increase of NKCC2A mRNA abundance and phosphorylated NKCC2 expression when TNF was silenced. Intrarenal injection with miR-195a-5p markedly attenuated MAP after renal silencing of TNF in mice given 1% NaCl. CONCLUSIONS The study identifies miR-195a-5p as a salt-sensitive and TNF-inducible miRNA that attenuates NaCl-mediated increases in blood pressure by inhibiting NKCC2A.
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Affiliation(s)
- Shoujin Hao
- Department of Pharmacology, New York Medical College, Valhalla
| | - Hong Zhao
- Department of Pharmacology, New York Medical College, Valhalla
| | - David H Hao
- Department of Pharmacology, New York Medical College, Valhalla
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18
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Bratu D, Boda D, Caruntu C. Reflectance Confocal Microscopy in Monitoring Atopic Dermatitis Treated with Topical Calcineurin Inhibitors. Healthcare (Basel) 2023; 11:healthcare11020152. [PMID: 36673521 PMCID: PMC9859267 DOI: 10.3390/healthcare11020152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 12/27/2022] [Accepted: 01/01/2023] [Indexed: 01/05/2023] Open
Abstract
Atopic dermatitis is a chronic inflammatory skin disease associated with multiple allergies in the atopic march. It has a complex pathogenesis, related to genetic, immune, and environmental factors. Its incidence and prevalence are increasing in the last decades, especially in developed countries. It affects the quality of life due to the recurrent lesions and the associated pruritus. Thus, it is very important to use non-invasive techniques to manage and follow-up the patients with such a heterogenous disease that can have a high impact on some of them. The reflectance confocal microscope is a modern device for in vivo visualization of the epidermis and the upper dermis which could replace in some cases the cutaneous biopsy. We report a case of a patient with atopic dermatitis investigated with the confocal reflectance microscope at the beginning of the topical treatment with calcineurin inhibitors and three weeks after, with favorable evolution. Reflectance confocal microscopy allows the assessment of the dynamic changes in the skin during treatment. Moreover, it can be useful for highlighting discrete changes even in the subclinical stages of the inflammatory process. Future developments, which will lead to the definition and validation of reflectance confocal microscopy criteria for the diagnosis and staging of atopic dermatitis, could help to improve the treatment and prevention strategies of the disease.
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Affiliation(s)
- Dalia Bratu
- Department of Dermatology, ‘Colentina’ Clinical Hospital, 020125 Bucharest, Romania
- Department of Dermatology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Correspondence: (D.B.); (D.B.); Tel.: +40-726-309-744 (D.B.); +40-799-929-250 (D.B.)
| | - Daniel Boda
- Department of Dermatology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Dermatology, ‘Ponderas’ Academic Hospital, 014142 Bucharest, Romania
- Department of Dermatology, “Prof. N.C. Paulescu” National Institute of Diabetes, Nutrition and Metabolic Diseases, 011233 Bucharest, Romania
- Correspondence: (D.B.); (D.B.); Tel.: +40-726-309-744 (D.B.); +40-799-929-250 (D.B.)
| | - Constantin Caruntu
- Department of Dermatology, “Prof. N.C. Paulescu” National Institute of Diabetes, Nutrition and Metabolic Diseases, 011233 Bucharest, Romania
- Department of Physiology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
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Gai C, Xing X, Song Y, Zhao Y, Jiang Z, Cheng Y, Xiao Y, Wang Z. Up-Regulation of miR-9-5p Inhibits Hypoxia-Ischemia Brain Damage Through the DDIT4-Mediated Autophagy Pathways in Neonatal Mice. Drug Des Devel Ther 2023; 17:1175-1189. [PMID: 37113470 PMCID: PMC10128084 DOI: 10.2147/dddt.s393362] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 03/29/2023] [Indexed: 04/29/2023] Open
Abstract
Introduction Hypoxia-ischemia (HI) remains the leading cause of cerebral palsy and long-term neurological sequelae in infants. Despite intensive research and many therapeutic approaches, there are limited neuroprotective strategies against HI insults. Herein, we reported that HI insult significantly down-regulated microRNA-9-5p (miR-9-5p) level in the ipsilateral cortex of neonatal mice. Methods The biological function and expression patterns of protein in the ischemic hemispheres were evaluated by qRT-PCR, Western Blotting analysis, Immunofluorescence and Immunohistochemistry. Open field test and Y-maze test were applied to detect locomotor activity and exploratory behavior and working memory. Results Overexpression of miR-9-5p effectively alleviated brain injury and improved neurological behaviors following HI insult, accompanying with suppressed neuroinflammation and apoptosis. MiR-9-5p directly bound to the 3' untranslated region of DNA damage-inducible transcript 4 (DDIT4) and negatively regulated its expression. Furthermore, miR-9-5p mimics treatment down-regulated light chain 3 II/light chain 3 I (LC3 II/LC3 I) ratio and Beclin-1 expression and decreased LC3B accumulation in the ipsilateral cortex. Further analysis showed that DDIT4 knockdown conspicuously inhibited the HI-up-regulated LC3 II/ LC3 I ratio and Beclin-1 expression, associating with attenuated brain damage. Conclusion The study indicates that miR-9-5p-mediated HI injury is regulated by DDIT4-mediated autophagy pathway and up-regulation of miR-9-5p level may provide a potential therapeutic effect on HI brain damage.
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Affiliation(s)
- Chengcheng Gai
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China
| | - Xiaohui Xing
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China
- Department of Neurosurgery, Liaocheng People’s Hospital, Liaocheng, Shandong, 252000, People’s Republic of China
| | - Yan Song
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China
| | - Yijing Zhao
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China
| | - Zige Jiang
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China
| | - Yahong Cheng
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China
| | - Yilei Xiao
- Department of Neurosurgery, Liaocheng People’s Hospital, Liaocheng, Shandong, 252000, People’s Republic of China
- Liaocheng Neuroscience Laboratory, Liaocheng People’s Hospital, Liaocheng, Shandong, 252000, People’s Republic of China
- Correspondence: Yilei Xiao, Department of Neurosurgery, Liaocheng People’s Hospital, Liaocheng, Shandong, 252000, People’s Republic of China, Email
| | - Zhen Wang
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China
- Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Maternal and Child Health Care Hospital of Shandong Province Affiliated to Qingdao University, Jinan, 250014, People’s Republic of China
- Zhen Wang, Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, 250012, Shandong, People’s Republic of China, Email
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Pagano AD, Barreto BF, Domingues WB, Silveira TLR, Nunes LS, Blodorn EB, Dellagostin EN, Remião MH, Robaldo RB, Campos VF. Modulation of miR-429 during osmotic stress in the silverside Odontesthes humensis. Front Genet 2022; 13:903201. [PMID: 36159973 PMCID: PMC9490309 DOI: 10.3389/fgene.2022.903201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/26/2022] [Indexed: 11/13/2022] Open
Abstract
Silverside fish inhabit marine coastal waters, coastal lagoons, and estuarine regions in southern South America. Although silversides are not fully adapted to freshwater, they can tolerate a wide range of salinity variations. MicroRNAs (miRNAs) are a class of ∼22 nucleotide noncoding RNAs, which are crucial regulators of gene expression at post-transcriptional level. Current data indicate that miRNAs biogenesis is altered by situations of environmental stress, thereby altering the expression of target mRNAs. Foremost, the silversides were acutely exposed to 30 g.L−1 of salt to reveal in which tissue miR-429 could be differentially expressed. Thus, fish were acclimated to freshwater (0 g.L−1) and to brackish water (10 g.L−1), and then exposed to opposite salinity treatment. Here, we reveal that miR-429, a gill-enriched miRNA, emerges as a prime osmoregulator in silversides. Taken together, our findings suggest that miR-429 is an endogenous regulator of osmotic stress, which may be developed as a biomarker to assist silverside aquaculture.
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Affiliation(s)
- Antônio D. Pagano
- Laboratório de Genômica Estrutural, Programa de Pós-Graduação em Biotecnologia, Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Bruna F. Barreto
- Laboratório de Genômica Estrutural, Programa de Pós-Graduação em Biotecnologia, Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - William B. Domingues
- Laboratório de Genômica Estrutural, Programa de Pós-Graduação em Biotecnologia, Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Tony L. R. Silveira
- Instituto de Ciências Biológicas, Universidade Federal do Rio Grande, Rio Grande, Rio Grande do Sul, Brazil
| | - Leandro S. Nunes
- Laboratório de Genômica Estrutural, Programa de Pós-Graduação em Biotecnologia, Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Eduardo B. Blodorn
- Laboratório de Genômica Estrutural, Programa de Pós-Graduação em Biotecnologia, Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Eduardo N. Dellagostin
- Laboratório de Genômica Estrutural, Programa de Pós-Graduação em Biotecnologia, Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Mariana H. Remião
- Laboratório de Genômica Estrutural, Programa de Pós-Graduação em Biotecnologia, Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Ricardo B. Robaldo
- Instituto de Biologia, Universidade Federal de Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Vinicius F. Campos
- Laboratório de Genômica Estrutural, Programa de Pós-Graduação em Biotecnologia, Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, Rio Grande do Sul, Brazil
- *Correspondence: Vinicius F. Campos,
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21
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Coradduzza D, Solinas T, Balzano F, Culeddu N, Rossi N, Cruciani S, Azara E, Maioli M, Zinellu A, De Miglio MR, Madonia M, Falchi M, Carru C. miRNAs as molecular biomarkers for prostate cancer. J Mol Diagn 2022; 24:1171-1180. [PMID: 35835374 DOI: 10.1016/j.jmoldx.2022.05.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 04/05/2022] [Accepted: 05/23/2022] [Indexed: 01/10/2023] Open
Abstract
MicroRNAs (miRNAs) are short noncoding RNA able to regulate specific mRNA stability, thus influencing target gene expression. Disrupted levels of several miRNA have been associated with prostate cancer, the leading cause of cancer death among men and the fifth leading cause of death worldwide. Here, we investigated whether miR-145, miR-148, and miR-185 circulating levels in plasma could be used as molecular biomarkers, to allow distinguishing between individuals with benign prostatic hyperplasia, precancerous lesion, and prostate cancer. In this study, we recruited 170 urological clinic patients with suspected prostate cancer who underwent prostate biopsy. Total RNA was isolated from plasma, and TaqMan MicroRNA assays were used to analyze miR-145, miR-185, and miR-148 expression. First, differential miRNA expression among patient groups was evaluated. Then, miRNA levels were combined with clinical assessment outcomes, including results from invasive tests, using multivariate analysis to examine their ability in discriminating among the three patient groups. Our results suggest that miRNA is a promising molecular tool for clinical management of at-risk patients.
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Affiliation(s)
| | - Tatiana Solinas
- Urologic Clinic, Dep. of Clinical and Experimental Medicine, University of Sassari
| | - Francesca Balzano
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Nicola Culeddu
- Institute of Biomolecular Chemistry, National Research Council, Sassari, Italy
| | - Niccolò Rossi
- Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
| | - Sara Cruciani
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Emanuela Azara
- Institute of Biomolecular Chemistry, National Research Council, Sassari, Italy
| | - Margherita Maioli
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Angelo Zinellu
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | | | - Massimo Madonia
- Urologic Clinic, Dep. of Clinical and Experimental Medicine, University of Sassari
| | - Mario Falchi
- Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
| | - Ciriaco Carru
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy; University Hospital of Sassari (AOU), Sassari, Italy.
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22
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Perkins ML, Gandara L, Crocker J. A synthetic synthesis to explore animal evolution and development. Philos Trans R Soc Lond B Biol Sci 2022; 377:20200517. [PMID: 35634925 PMCID: PMC9149795 DOI: 10.1098/rstb.2020.0517] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Identifying the general principles by which genotypes are converted into phenotypes remains a challenge in the post-genomic era. We still lack a predictive understanding of how genes shape interactions among cells and tissues in response to signalling and environmental cues, and hence how regulatory networks generate the phenotypic variation required for adaptive evolution. Here, we discuss how techniques borrowed from synthetic biology may facilitate a systematic exploration of evolvability across biological scales. Synthetic approaches permit controlled manipulation of both endogenous and fully engineered systems, providing a flexible platform for investigating causal mechanisms in vivo. Combining synthetic approaches with multi-level phenotyping (phenomics) will supply a detailed, quantitative characterization of how internal and external stimuli shape the morphology and behaviour of living organisms. We advocate integrating high-throughput experimental data with mathematical and computational techniques from a variety of disciplines in order to pursue a comprehensive theory of evolution. This article is part of the theme issue ‘Genetic basis of adaptation and speciation: from loci to causative mutations’.
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Affiliation(s)
- Mindy Liu Perkins
- Developmental Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany
| | - Lautaro Gandara
- Developmental Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany
| | - Justin Crocker
- Developmental Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany
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23
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Mohammed Z, McHale C, Kubinak JL, Dryer S, Gomez G. miR-155 Is a Positive Regulator of FcεRI-Induced Cyclooxygenase-2 Expression and Cytokine Production in Mast Cells. FRONTIERS IN ALLERGY 2022; 3:835776. [PMID: 36211602 PMCID: PMC9543708 DOI: 10.3389/falgy.2022.835776] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 03/15/2022] [Indexed: 12/02/2022] Open
Abstract
MicroRNA-155 (miR-155) has been implicated in IgE-dependent allergic disease including asthma and atopic dermatitis. A few roles for miR-155 have been described in mast cells and some specifically related to IgE receptor signaling, but it is not completely understood. Here, we demonstrate by miRNA seq profiling and quantitative RT-PCR that miR-155 expression is significantly increased in human skin-derived mast cells (SMCs) and mouse bone marrow-derived mast cells (BMMCs) following FcεRI crosslinking with antigen. We demonstrate that FcεRI-induced expression of cyclooxygenase-2 (COX-2) was significantly inhibited in miR-155 knockout (KO) BMMCs whereas arachidonate-5-lipoxygenase (ALOX-5) expression and leukotriene C4 (LTC4) biosynthesis, and degranulation were unaffected. FcεRI-induced cytokine production (TNF, IL-6, and IL-13) from miR-155 KO BMMCs was also significantly diminished. Correspondingly, Akt phosphorylation, but not protein expression, was inhibited in the absence of miR-155 whereas p38 and p42/44 were unaffected. Interesting, lipopolysaccharide (LPS)-induced cytokine production was increased in miR-155 KO BMMCs. Together, these data demonstrate that miR-155 specifically targets the FcεRI-induced prostaglandin and cytokine pathways, but not the leukotriene or degranulation pathways, in mast cells. The data further suggest that miR-155 acts indirectly by targeting a repressor of COX-2 expression and a phosphatase that normally blocks Akt phosphorylation. Overall, this study reveals the role of miR-155 as a positive regulator of mast cell function.
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Affiliation(s)
- Zahraa Mohammed
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, United States
| | - Cody McHale
- Molecular Targeted Therapeutics Laboratory, Levine Cancer Institute, Charlotte, NC, United States
| | - Jason L. Kubinak
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, United States
| | - Stuart Dryer
- Department of Biology and Biochemistry, College of Natural Sciences and Mathematics, University of Houston, Houston, TX, United States
| | - Gregorio Gomez
- Department of Biomedical Sciences, College of Medicine, University of Houston, Houston, TX, United States
- *Correspondence: Gregorio Gomez
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Men Y, Zhai Y, Wu L, Liu L, Zhang W, Jiang W, Bi N, Song Y, Hui Z, Wang L. MiR-323a-3p acts as a tumor suppressor by suppressing FMR1 and predicts better esophageal squamous cell carcinoma outcome. Cancer Cell Int 2022; 22:140. [PMID: 35351128 PMCID: PMC8966287 DOI: 10.1186/s12935-022-02541-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 03/05/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC) has unfavorable outcomes with the highest incidence seen in China. Accordingly, exploring effective molecular biomarkers is of great value. MicroRNAs (miRNAs) are posttranscriptional regulators of gene expression and modulate numerous biological processes in tumors. Our study aimed to identify prognostic miRNAs and investigate their role in ESCC. METHODS Prognosis-related plasma miRNAs were detected by miRNA microarray and qRT-PCR. Functional assays and molecular mechanism studies were used to investigate the role of miRNA in ESCC. RESULTS Over-expression of miR-323a-3p was associated with a favorable prognosis. MiR-323a-3p negatively regulated proliferation, migration, and invasion. Through biological predictions, the fragile X mental retardation 1 (FMR1) was found to be a potential target of miR-323a-3p. Further investigation revealed that miR-323a-3p directly targeted and suppressed FMR1. MiR-323a-3p and FMR1 mRNA, as well as miR-323a-3p and the FMR1-encoded protein FMRP, showed negative correlations. Luciferase activity of FMR1-3'-UTR, but not mutant counterparts, was decreased by mimic compared with that of the control. The compromised cell proliferation, migration, and invasion induced by transfection with miR-323a-3p mimic were rescued by transfection with a FMR1 expression plasmid. Tumors induced by miR-323a-3p overexpressed ESCC cells grew significantly slower in vivo and resulted in smaller tumor masses. Metastatic lung colonization was also inhibited by miR-323a-3p overexpression. CONCLUSIONS MiR-323a-3p was significantly associated with survival and acted as a tumor suppressor by inhibiting proliferation, migration, and invasion via the regulation of FMR1. MiR-323a-3p is a promising biomarker and may be a potential therapeutic target.
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Affiliation(s)
- Yu Men
- Department of VIP Medical Services & Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yirui Zhai
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lihong Wu
- Genecast Precision Medicine Technology Institute, Beijing, China
| | - Lipin Liu
- Department of Radiation Oncology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Wenjue Zhang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Guangdong, China
| | - Wei Jiang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Guangdong, China
| | - Nan Bi
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yongmei Song
- The State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhouguang Hui
- Department of VIP Medical Services & Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Luhua Wang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Guangdong, China.
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25
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Kos MZ, Puppala S, Cruz D, Neary JL, Kumar A, Dalan E, Li C, Nathanielsz P, Carless MA. Blood-Based miRNA Biomarkers as Correlates of Brain-Based miRNA Expression. Front Mol Neurosci 2022; 15:817290. [PMID: 35392269 PMCID: PMC8981579 DOI: 10.3389/fnmol.2022.817290] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 02/18/2022] [Indexed: 01/08/2023] Open
Abstract
The use of easily accessible peripheral samples, such as blood or saliva, to investigate neurological and neuropsychiatric disorders is well-established in genetic and epigenetic research, but the pathological implications of such biomarkers are not easily discerned. To better understand the relationship between peripheral blood- and brain-based epigenetic activity, we conducted a pilot study on captive baboons (Papio hamadryas) to investigate correlations between miRNA expression in peripheral blood mononuclear cells (PBMCs) and 14 different cortical and subcortical brain regions, represented by two study groups comprised of 4 and 6 animals. Using next-generation sequencing, we identified 362 miRNAs expressed at ≥ 10 read counts in 80% or more of the brain samples analyzed. Nominally significant pairwise correlations (one-sided P < 0.05) between peripheral blood and mean brain expression levels of individual miRNAs were observed for 39 and 44 miRNAs in each group. When miRNA expression levels were averaged for tissue type across animals within the groups, Spearman's rank correlations between PBMCs and the brain regions are all highly significant (r s = 0.47-0.57; P < 2.2 × 10-16), although pairwise correlations among the brain regions are markedly stronger (r s = 0.86-0.99). Principal component analysis revealed differentiation in miRNA expression between peripheral blood and the brain regions for the first component (accounting for ∼75% of variance). Linear mixed effects modeling attributed most of the variance in expression to differences between miRNAs (>70%), with non-significant 7.5% and 13.1% assigned to differences between blood and brain-based samples in the two study groups. Hierarchical UPGMA clustering revealed a major co-expression branch in both study groups, comprised of miRNAs globally upregulated in blood relative to the brain samples, exhibiting an enrichment of miRNAs expressed in immune cells (CD14+, CD15+, CD19+, CD3+, and CD56 + leukocytes) among the top blood-brain correlates, with the gene MYC, encoding a master transcription factor that regulates angiogenesis and neural stem cell activation, representing the most prevalent miRNA target. Although some differentiation was observed between tissue types, these preliminary findings reveal wider correlated patterns between blood- and brain-expressed miRNAs, suggesting the potential utility of blood-based miRNA profiling for investigating by proxy certain miRNA activity in the brain, with implications for neuroinflammatory and c-Myc-mediated processes.
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Affiliation(s)
- Mark Z. Kos
- Department of Human Genetics, South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Edinburg, TX, United States
| | - Sobha Puppala
- Department of Internal Medicine-Section of Molecular Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States
| | - Dianne Cruz
- Duke University School of Medicine, Durham, NC, United States
| | - Jennifer L. Neary
- Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, United States
| | - Ashish Kumar
- Department of Internal Medicine-Section of Molecular Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States
| | - Emma Dalan
- Department of Biology, University of Texas at San Antonio, San Antonio, TX, United States
| | - Cun Li
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX, United States,Department of Animal Science, University of Wyoming, Laramie, WY, United States
| | - Peter Nathanielsz
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX, United States,Department of Animal Science, University of Wyoming, Laramie, WY, United States
| | - Melanie A. Carless
- Department of Biology, University of Texas at San Antonio, San Antonio, TX, United States,Population Health, Texas Biomedical Research Institute, San Antonio, TX, United States,*Correspondence: Melanie A. Carless,
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Spatiotemporal expression pattern of miR-205, miR-26a-5p, miR-17-5p, let-7b-5p, and their target genes during different stages of corpus luteum in Egyptian buffaloes. J Genet Eng Biotechnol 2022; 20:37. [PMID: 35212793 PMCID: PMC8881532 DOI: 10.1186/s43141-022-00320-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 02/17/2022] [Indexed: 12/22/2022]
Abstract
Background No doubt that the corpus luteum (CL) plays a vital role in the regulation of female cyclicity in mammals. The scenarios among microRNAs (miRNAs) and their target genes and steroid hormones {estradiol (E2) and progesterone (P4)} are required for better understanding the molecular regulation of CL during its formation, maturation, and regression. We aimed to (I) study the changes in the relative abundance of miR-205, miR-26a-5p, miR-17-5p, and let-7b-5p and their target genes: LHCGR, CASP3, PCNA, AMH, and PLA2G3, during different stages of corpus luteum in Egyptian buffaloes, and (II) and to address different scenarios between steroid concentrations in the serum and the expression pattern of selected miRNAs and their targets. Methods The paired ovaries and blood samples were collected from apparently healthy 50 buffalo cows at a private abattoir. The ovaries bearing CL were macroscopically divided according to their morphological structure and color into hemorrhagic (CLH), developing (CLD), mature (CLM), regressed (CLR), and albicans (CLA). Small pieces from different stages of CL (CLH, CLD, CLM, CLR, and CLA) were cut and immediately kept at − 80 °C for total RNA isolation and qRT-PCR. The serum was separated for steroid level estimation. Results The LHCGR was expressed during different stages of CL, and the peak of expression was at the mid-luteal stage. The CASP3 revealed a stage-specific response at different stages of CL. The PCNA has an essential role in cellular proliferation in buffaloes CL. Both expression patterns of PLA2G3 and AMH were found over the various developmental and regression stages. It was noticed that miR-205 is conserved to target LHCGR and CASP3 transcripts. Moreover, CASP3 and AMH were targeted via miR-26a-5p. Additionally, the CASP3 and PLA2G3 were targeted via let-7b-5p. The P4 level reached its peak during CLM. There were positive and negative strong correlations between miRNAs (miR-26a-5p and miR-205), target genes (LHCGR and CASP3) during different stages of CL, and steroid hormones in the serum. Conclusions Taken together, the orchestrated pattern among miRNAs, target genes, and steroid hormones is essential for maintaining the proper development and function of CL in buffalo cows. Supplementary Information The online version contains supplementary material available at 10.1186/s43141-022-00320-9.
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Yoon J, Shin M, Lee JY, Lee SN, Choi JH, Choi JW. RNA interference (RNAi)-based plasmonic nanomaterials for cancer diagnosis and therapy. J Control Release 2022; 342:228-240. [PMID: 35016917 DOI: 10.1016/j.jconrel.2022.01.012] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 01/04/2022] [Accepted: 01/06/2022] [Indexed: 01/15/2023]
Abstract
RNA interference (RNAi) is being extensively investigated as a potential therapeutic strategy for cancer treatment. However, RNAi-based therapeutics have not yet been used to treat cancer because of their instability and the difficulty of microRNA (miRNA) delivery. Plasmonic nanoparticle-based RNAi nanotherapeutics have been developed for accurate and sensitive diagnosis and a strong therapeutic effect on cancers by leveraging their ease-of-use and specific properties such as photothermal conversion. In this review, recent strategies and advances in plasmonic nanoparticle-based miRNA delivery are briefly presented to facilitate the detection and treatment of several cancers. The challenges and potential opportunities afforded by the RNAi-based theragnosis field are discussed. We expect that the RNAi-integrated plasmonic nanotherapeutics discussed in this review can provide insights for the early diagnosis and effective treatment of cancer.
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Affiliation(s)
- Jinho Yoon
- Department of Chemical & Biomolecular Engineering, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul 04107, Republic of Korea; Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey,123 Bevier Road, Piscataway, NJ 08854, USA
| | - Minkyu Shin
- Department of Chemical & Biomolecular Engineering, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul 04107, Republic of Korea
| | - Ji-Young Lee
- Department of Chemical & Biomolecular Engineering, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul 04107, Republic of Korea
| | - Sang-Nam Lee
- Uniance Gene Inc., 1107 Teilhard Hall, 35 Baekbeom-Ro, Mapo-Gu, Seoul 04107, Republic of Korea
| | - Jin-Ha Choi
- School of Chemical Engineering, Jeonbuk National University, 567 Baekje-daero, Deokjin-gu, Jeonju-si, Jeollabuk-do 54896, Republic of Korea.
| | - Jeong-Woo Choi
- Department of Chemical & Biomolecular Engineering, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul 04107, Republic of Korea.
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Li L, Ren J, Pan C, Li Y, Xu J, Dong H, Chen Y, Liu W. Serum miR-214 Serves as a Biomarker for Prodromal Parkinson's Disease. Front Aging Neurosci 2021; 13:700959. [PMID: 34776924 PMCID: PMC8581655 DOI: 10.3389/fnagi.2021.700959] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 10/06/2021] [Indexed: 12/23/2022] Open
Abstract
Circulating microRNAs (miRNAs) have been proposed to be accessible biomarkers for Parkinson’s disease (PD). However, there is a lack of known miRNAs that can serve as biomarkers for prodromal PD (pPD). We previously identified that miR-31 and miR-214 were dysregulated in PD. The aim of this study was to explore the roles of miR-31 and miR-214 in pPD. We recruited 25 pPD patients, 20 patients with de novo PD (dnPD), 24 advanced PD (aPD) patients and 21 controls. Next, we investigated the expression of miR-31 and miR-214. Compared to controls, miR-214 was found to be significantly upregulated in pPD patients while miR-31 was significantly upregulated in aPD patients. In addition, the expression of miR-214 was lower in aPD patients compared to both dnPD or pPD patients, while the expression of miR-31 was higher in aPD patients compared to dnPD patients. In order to predict pPD via miRNA expression, the receiver operating characteristic curve was constructed and the area under curve (AUC) was calculated. For pPD prediction by miR-214, the AUC was 0.756. The optimal cut-off value of miR-214 was 0.1962, and the sensitivity and specificity were 72.0% and 76.2%, respectively. On the other hand, the AUC for aPD detection by miR-31 was 0.744. The optimal cut-off value for miR-31 was 0.0148, with a sensitivity of 87.5% and a specificity of 71.4%. In conclusion, miR-214 can distinguish pPD patients from controls and may be used as a potential biomarker for pPD diagnosis.
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Affiliation(s)
- Lanting Li
- Department of Neurology, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China
| | - Jingru Ren
- Department of Neurology, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China
| | - Chenxi Pan
- Department of Neurology, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China
| | - Yuqian Li
- Department of Neurology, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China
| | - Jianxia Xu
- Department of Neurology, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China
| | - Hui Dong
- Department of Medical Genetics and Cell Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yong Chen
- Department of Laboratory, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China
| | - Weiguo Liu
- Department of Neurology, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China
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29
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Kinsella S, Evandy CA, Cooper K, Iovino L, deRoos PC, Hopwo KS, Granadier DW, Smith CW, Rafii S, Dudakov JA. Attenuation of apoptotic cell detection triggers thymic regeneration after damage. Cell Rep 2021; 37:109789. [PMID: 34610317 PMCID: PMC8627669 DOI: 10.1016/j.celrep.2021.109789] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 07/02/2021] [Accepted: 09/10/2021] [Indexed: 01/21/2023] Open
Abstract
The thymus, which is the primary site of T cell development, is particularly sensitive to insult but also has a remarkable capacity for repair. However, the mechanisms orchestrating regeneration are poorly understood, and delayed repair is common after cytoreductive therapies. Here, we demonstrate a trigger of thymic regeneration, centered on detecting the loss of dying thymocytes that are abundant during steady-state T cell development. Specifically, apoptotic thymocytes suppressed production of the regenerative factors IL-23 and BMP4 via TAM receptor signaling and activation of the Rho-GTPase Rac1, the intracellular pattern recognition receptor NOD2, and micro-RNA-29c. However, after damage, when profound thymocyte depletion occurs, this TAM-Rac1-NOD2-miR29c pathway is attenuated, increasing production of IL-23 and BMP4. Notably, pharmacological inhibition of Rac1-GTPase enhanced thymic function after acute damage. These findings identify a complex trigger of tissue regeneration and offer a regenerative strategy for restoring immune competence in patients whose thymic function has been compromised.
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Affiliation(s)
- Sinéad Kinsella
- Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
| | - Cindy A Evandy
- Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Kirsten Cooper
- Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Lorenzo Iovino
- Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Paul C deRoos
- Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Kayla S Hopwo
- Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - David W Granadier
- Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Colton W Smith
- Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Shahin Rafii
- Department of Genetic Medicine and Ansary Stem Cell Institute, Weill Cornell Medical College, New York, NY 10021, USA
| | - Jarrod A Dudakov
- Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Immunology, University of Washington, Seattle, WA 98109, USA.
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Estradiol ameliorates metformin-inhibited Sertoli cell proliferation via AMPK/TSC2/mTOR signaling pathway. Theriogenology 2021; 175:7-22. [PMID: 34481229 DOI: 10.1016/j.theriogenology.2021.08.030] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 07/31/2021] [Accepted: 08/25/2021] [Indexed: 12/15/2022]
Abstract
Metformin is a commonly used for treating type 2 diabetes and it acts on a variety of organs including the male reproductive system. 17β-estradiol plays an important role in Sertoli cell (SC) proliferation which determines the germ cell development and spermatogenesis. The aim of this study is to investigate the effect of metformin on immature chicken SC proliferation and the potential mechanisms by which 17β-estradiol regulate this process. Results showed that metformin significantly inhibited SC proliferation, whereas 17β-estradiol weakened the inhibitory effects of metformin on SC viability, cell growth, and cell cycle progression. SC proliferation-inhibiting effect of metformin exposure was regulated by decreasing adenosine triphosphate level and respiratory enzyme activity in the mitochondria; this process was possibly mediated by the adenosine monophosphate-activated protein kinase (AMPK)/tuberous sclerosis complex 2 (TSC2)/mammalian target of rapamycin (mTOR) signaling pathway, which was regulated by the down-expressed miR-1764 and by the decreased antioxidant enzyme activity and excessive reactive oxygen species generation. In addition, SCs transfected with the miR-1764 agomir led to an improvement of proliferation capacity through down-regulating AMPKα2 level, which further decreased TSC2 expression and induced mTOR activation. However, the anti-proliferative effect of miR-1764 antagomir can be alleviated by 17β-estradiol treatment via the up-expression of miR-1764 in transfected SCs. Our findings suggest appropriate dose of exogenous 17β-estradiol treatment can ameliorate the inhibitory effect of metformin on SC proliferation via the regulation of AMPK/TSC2/mTOR signaling pathway, this might reduce the risk of poor male fertility caused by the abuse of anti-diabetic agents.
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31
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Karami S, Sarabandi S, Pourzand P, Tabasi F, Hashemi M, Bahari G. Lack of association between 4-base pair insertion/deletion (rs3783553) polymorphism within the 3′UTR of IL1A and breast cancer: A preliminary report. GENE REPORTS 2021. [DOI: 10.1016/j.genrep.2021.101067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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32
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Meng CL, Zhao W, Zhong DN. Epigenetics and microRNAs in UGT1As. Hum Genomics 2021; 15:30. [PMID: 34034810 PMCID: PMC8147421 DOI: 10.1186/s40246-021-00331-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 05/10/2021] [Indexed: 11/10/2022] Open
Abstract
UDP-glucuronosyltransferases (UGTs) are the main phase II drug-metabolizing enzymes mediating the most extensive glucuronidation-binding reaction in the human body. The UGT1A family is involved in more than half of glucuronidation reactions. However, significant differences exist in the distribution of UGT1As in vivo and the expression of UGT1As among individuals, and these differences are related to the occurrence of disease and differences in metabolism. In addition to genetic polymorphisms, there is now interest in the contribution of epigenetics and noncoding RNAs (especially miRNAs) to this differential change. Epigenetics regulates UGT1As pretranscriptionally through DNA methylation and histone modification, and miRNAs are considered the key mechanism of posttranscriptional regulation of UGT1As. Both epigenetic inheritance and miRNAs are involved in the differences in sex expression and in vivo distribution of UGT1As. Moreover, epigenetic changes early in life have been shown to affect gene expression throughout life. Here, we review and summarize the current regulatory role of epigenetics in the UGT1A family and discuss the relationship among epigenetics and UGT1A-related diseases and treatment, with references for future research.
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Affiliation(s)
- Cui-Lan Meng
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning City, Guangxi, China
| | - Wei Zhao
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning City, Guangxi, China
| | - Dan-Ni Zhong
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning City, Guangxi, China.
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The miR-378c-Samd1 circuit promotes phenotypic modulation of vascular smooth muscle cells and foam cells formation in atherosclerosis lesions. Sci Rep 2021; 11:10548. [PMID: 34006929 PMCID: PMC8131603 DOI: 10.1038/s41598-021-89981-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 05/05/2021] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs have emerged as key regulators in vascular diseases and are involved in the formation of atherosclerotic lesions. However, the atherosclerotic-specific MicroRNAs and their functional roles in atherosclerosis are unclear. Here, we report that miR-378c protects against atherosclerosis by directly targeting Sterile Alpha Motif Domain Containing 1 (Samd1), a predicted transcriptional repressor. miR-378c was strikingly reduced in atherosclerotic plaques and blood of acute coronary syndrome (ACS) patients relative to healthy controls. Suppression of miR-378c promoted vascular smooth muscle cells (VSMCs) phenotypic transition during atherosclerosis. We also reported for the first time that Samd1 prolonged immobilization of LDL on the VSMCs, thus facilitated LDL oxidation and subsequently foam cell formation. Further, we found that Samd1 contains predicted DNA binding domain and directly binds to DNA regions as a transcriptional repressor. Together, we uncovered a novel mechanism whereby miR-378c-Samd1 circuit participates in two key elements of atherosclerosis, VSMCs phenotypic transition and LDL oxidation. Our results provided a better understanding of atherosclerosis pathophysiology and potential therapeutic management by targeting miR-378c-Samd1 circuit.
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Zhang B, Chen G, Yang X, Fan T, Chen X, Chen Z. Dysregulation of MicroRNAs in Hypertrophy and Ossification of Ligamentum Flavum: New Advances, Challenges, and Potential Directions. Front Genet 2021; 12:641575. [PMID: 33912216 PMCID: PMC8075056 DOI: 10.3389/fgene.2021.641575] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 03/03/2021] [Indexed: 12/13/2022] Open
Abstract
Pathological changes in the ligamentum flavum (LF) can be defined as a process of chronic progressive aberrations in the nature and structure of ligamentous tissues characterized by increased thickness, reduced elasticity, local calcification, or aggravated ossification, which may cause severe myelopathy, radiculopathy, or both. Hypertrophy of ligamentum flavum (HLF) and ossification of ligamentum flavum (OLF) are clinically common entities. Though accumulated evidence has indicated both genetic and environmental factors could contribute to the initiation and progression of HLF/OLF, the definite pathogenesis remains fully unclear. MicroRNAs (miRNAs), one of the important epigenetic modifications, are short single-stranded RNA molecules that regulate protein-coding gene expression at posttranscriptional level, which can disclose the mechanism underlying diseases, identify valuable biomarkers, and explore potential therapeutic targets. Considering that miRNAs play a central role in regulating gene expression, we summarized current studies from the point of view of miRNA-related molecular regulation networks in HLF/OLF. Exploratory studies revealed a variety of miRNA expression profiles and identified a battery of upregulated and downregulated miRNAs in OLF/HLF patients through microarray datasets or transcriptome sequencing. Experimental studies validated the roles of specific miRNAs (e.g., miR-132-3p, miR-199b-5p in OLF, miR-155, and miR-21 in HLF) in regulating fibrosis or osteogenesis differentiation of LF cells and related target genes or molecular signaling pathways. Finally, we discussed the perspectives and challenges of miRNA-based molecular mechanism, diagnostic biomarkers, and therapeutic targets of HLF/OLF.
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Affiliation(s)
- Baoliang Zhang
- Orthopaedic Department, Peking University Third Hospital, Beijing, China
| | - Guanghui Chen
- Orthopaedic Department, Peking University Third Hospital, Beijing, China
| | - Xiaoxi Yang
- Orthopaedic Department, Peking University Third Hospital, Beijing, China
| | - Tianqi Fan
- Orthopaedic Department, Peking University Third Hospital, Beijing, China
| | - Xi Chen
- Orthopaedic Department, Peking University Third Hospital, Beijing, China
| | - Zhongqiang Chen
- Orthopaedic Department, Peking University Third Hospital, Beijing, China
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Abstract
The Ediacara Biota preserves the oldest fossil evidence of abundant, complex metazoans. Despite their significance, assigning individual taxa to specific phylogenetic groups has proved problematic. To better understand these forms, we identify developmentally controlled characters in representative taxa from the Ediacaran White Sea assemblage and compare them with the regulatory tools underlying similar traits in modern organisms. This analysis demonstrates that the genetic pathways for multicellularity, axial polarity, musculature, and a nervous system were likely present in some of these early animals. Equally meaningful is the absence of evidence for major differentiation of macroscopic body units, including distinct organs, localized sensory machinery or appendages. Together these traits help to better constrain the phylogenetic position of several key Ediacara taxa and inform our views of early metazoan evolution. An apparent lack of heads with concentrated sensory machinery or ventral nerve cords in such taxa supports the hypothesis that these evolved independently in disparate bilaterian clades.
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Affiliation(s)
- Scott D Evans
- Department of Paleobiology MRC-121, National Museum of Natural History, Washington, DC 20013-7012, USA
| | - Mary L Droser
- Department of Earth and Planetary Sciences, University of California, Riverside, CA 92521, USA
| | - Douglas H Erwin
- Department of Paleobiology MRC-121, National Museum of Natural History, Washington, DC 20013-7012, USA
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Cheng N, Wang MY, Wu YB, Cui HM, Wei SX, Liu B, Wang R. Circular RNA POSTN Promotes Myocardial Infarction-Induced Myocardial Injury and Cardiac Remodeling by Regulating miR-96-5p/BNIP3 Axis. Front Cell Dev Biol 2021; 8:618574. [PMID: 33681183 PMCID: PMC7930329 DOI: 10.3389/fcell.2020.618574] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Accepted: 12/30/2020] [Indexed: 12/23/2022] Open
Abstract
Myocardial infarction (MI) is the most prevalent cardiac disease with high mortality, leading to severe heart injury. Circular RNAs (circRNAs) are a new type of regulatory RNAs and participate in multiple pathological cardiac progressions. However, the role of circRNAs Postn (circPostn) in MI modulation remains unclear. Here, we aimed to explore the effect of circPostn on MI-induced myocardial injury and cardiac remodeling. We identified that the expression of circPostn was elevated in the plasma of MI patients, MI mouse model, and hypoxia and reoxygenation (H/R)-treated human cardiomyocytes. The depletion of circPostn significantly attenuated MI-related myocardium injury and reduced the infarct size in MI mouse model. The circPostn knockdown obviously enhanced left ventricular ejection fraction (LVEF) and left ventricular fraction shortening (LVFS) and inhibited left ventricular anterior wall thickness at diastole (LVAWd) and left ventricular posterior wall thickness at diastole (LVPWd). The depletion of circPostn was able to decrease MI-induced expression of collagen 1α1 and collagen 3α1 in the ventricular tissues of mice. The protein expression of collagen and α-smooth muscle actin (SMA) was up-regulated in MI mice and was inhibited by circPostn knockdown. Meanwhile, the expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) was repressed by circPostn depletion in the ventricular tissues of MI mice. Besides, the circPostn depletion attenuated cardiomyocyte apoptosis in mice. Mechanically, circPostn served as a miR-96-5p sponge and miR-96-5p-targeted BNIP3 in human cardiomyocytes, in which circPostn up-regulated BNIP3 expression by targeting miR-96-5p. circPostn promoted H/R-induced cardiomyocyte injury by modulating miR-96-5p/BNIP3 axis. Thus, we conclude that circPostn contributes to MI-induced myocardial injury and cardiac remodeling by regulating miR-96-5p/BNIP3 axis. Our finding provides new insight into the mechanism by which circPostn regulates MI-related cardiac dysfunction. circPostn, miR-96-5p, and BNIP3 are potential targets for the treatment of MI-caused heart injury.
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Affiliation(s)
| | | | | | | | | | | | - Rong Wang
- Department of Cardiovascular Surgery, PLA General Hospital, Beijing, China
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Ning J, Ye Y, Bu D, Zhao G, Song T, Liu P, Yu W, Wang H, Li H, Ren X, Ying G, Zhao Y, Yu J. Imbalance of TGF-β1/BMP-7 pathways induced by M2-polarized macrophages promotes hepatocellular carcinoma aggressiveness. Mol Ther 2021; 29:2067-2087. [PMID: 33601054 DOI: 10.1016/j.ymthe.2021.02.016] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 01/27/2021] [Accepted: 02/10/2021] [Indexed: 12/27/2022] Open
Abstract
The transforming growth factor-beta (TGF-β) signaling pathway is the predominant cytokine signaling pathway in the development and progression of hepatocellular carcinoma (HCC). Bone morphogenetic protein (BMP), another member of the TGF-β superfamily, has been frequently found to participate in crosstalk with the TGF-β pathway. However, the complex interaction between the TGF-β and BMP pathways has not been fully elucidated in HCC. We found that the imbalance of TGF-β1/BMP-7 pathways was associated with aggressive pathological features and poor clinical outcomes in HCC. The induction of the imbalance of TGF-β1/BMP-7 pathways in HCC cells could significantly promote HCC cell invasion and stemness by increasing inhibitor of differentiation 1 (ID1) expression. We also found that the microRNA (miR)-17-92 cluster, originating from the extracellular vesicles (EVs) of M2-polarized tumor-associated macrophages (M2-TAMs), stimulated the imbalance of TGF-β1/BMP-7 pathways in HCC cells by inducing TGF-β type II receptor (TGFBR2) post-transcriptional silencing and inhibiting activin A receptor type 1 (ACVR1) post-translational ubiquitylation by targeting Smad ubiquitylation regulatory factor 1 (Smurf1). In vivo, short hairpin (sh)-MIR17HG and ACVR1 inhibitors profoundly attenuated HCC cell growth and metastasis by rectifying the imbalance of TGF-β1/BMP-7 pathways. Therefore, we proposed that the imbalance of TGF-β1/BMP-7 pathways is a feasible prognostic biomarker and recovering the imbalance of TGF-β1/BMP-7 pathways might be a potential therapeutic strategy for HCC.
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Affiliation(s)
- Junya Ning
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China; Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Yingnan Ye
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Dechao Bu
- Key Laboratory of Intelligent Information Processing, Advanced Computer Research Center, Institute of Computing Technology, Chinese Academy of Sciences, Beijing 100190, China
| | - Gang Zhao
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Tianqiang Song
- Department of Liver Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Pengpeng Liu
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Wenwen Yu
- Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Hailong Wang
- Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Hui Li
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Xiubao Ren
- Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Guoguang Ying
- Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Yi Zhao
- Key Laboratory of Intelligent Information Processing, Advanced Computer Research Center, Institute of Computing Technology, Chinese Academy of Sciences, Beijing 100190, China; Ningbo Institute of Life and Health Industry, University of China Academy of Sciences, Zhejiang 315000, China.
| | - Jinpu Yu
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China; Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.
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Li S, Zeng H, Huang J, Lu J, Chen J, Zhou Y, Mi L, Zhao X, Lei L, Zeng Q. Identification of the Competing Endogenous RNA Networks in Oxidative Stress Injury of Melanocytes. DNA Cell Biol 2021; 40:192-208. [PMID: 33471583 DOI: 10.1089/dna.2020.5455] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Competing endogenous RNAs (ceRNAs), including long noncoding RNA (lncRNA), circular RNA (circRNA), pseudogenes, synthetic miRNA inhibitors, etc. are classes of RNAs that can compete and interact with each other within an organism. There are regions in these RNAs that can be bound by messenger-RNA-interfering complementary RNA (microRNA), called microRNA response elements (MREs). These RNAs compete with each other to combine complementary microRNAs and MREs to form ceRNA regulatory mechanisms and participate in the regulation of many biological processes. The oxidative stress injury of melanocytes is one of the crucial mechanisms of vitiligo. However, it is unclear whether the ceRNA regulation mechanism is involved in the oxidative stress injury of melanocytes. The purpose of this study is to explore the changes of messenger RNA (mRNA), lncRNAs, and circRNAs in melanocytes under oxidative stress and to identify the key ceRNA regulatory networks. Compared with the normal cells, the chip detection of ceRNA expression profile showed that the expression of 491 mRNAs, 865 lncRNAs, and 1161 circRNAs were altered more than fivefold during the oxidative stress injury of melanocytes. The oxidative stress-related genes (SOD2, PTGS2, DHFR, HMOX1, FOSL1, and PARP1), cell cycle-related genes (CDK1, CCNB1, CCNA2, OIP5, and MK167), and apoptosis-related gene (BIRC5) were identified in the formation of ceRNA regulation networks with lncRNAs and circRNAs, which shares the common MREs. Further verification found that LNCV6_120941_PI430048170 or hsa_circ_0048910 might regulate the expression of SOD2 by sponging hsa-miR-4755-3p, LNCV6_119109_PI430048170, or hsa_circ_0048909 might regulate the expression of HMOX1 by sponging hsa-miR-6721-5p in the oxidative stress injury of melanocytes. In conclusion, complex changes of the ceRNA regulatory network in the oxidative stress response of melanocytes are evident. Oxidative stress may mediate melanocyte injury through the ceRNA regulation mechanism and induce the pathogenesis of vitiligo.
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Affiliation(s)
- Si Li
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Hongliang Zeng
- Institute of Chinese Materia Medica, Hunan Academy of Chinese Medicine, Changsha, China
| | - Jinhua Huang
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Jianyun Lu
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Jing Chen
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Ying Zhou
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Lan Mi
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Xiaojiao Zhao
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Li Lei
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Qinghai Zeng
- Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, China
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Toyoshima S, Sakamoto-Sasaki T, Kurosawa Y, Hayama K, Matsuda A, Watanabe Y, Terui T, Gon Y, Matsumoto K, Okayama Y. miR103a-3p in extracellular vesicles from FcεRI-aggregated human mast cells enhances IL-5 production by group 2 innate lymphoid cells. J Allergy Clin Immunol 2021; 147:1878-1891. [PMID: 33465368 DOI: 10.1016/j.jaci.2021.01.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 12/27/2020] [Accepted: 01/05/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND Mast cells (MCs) are key regulators of IgE-mediated allergic inflammation. Cell-derived extracellular vesicles (EVs) contain bioactive compounds such as microRNAs. EVs can transfer signals to recipient cells, thus using a novel mechanism of cell-to-cell communication. However, whether MC-derived EVs are involved in FcεRI-mediated allergic inflammation is unclear. OBJECTIVE We sought to investigate the effect of EVs derived from FcεRI-aggregated human MCs on the function of human group 2 innate lymphoid cells (ILC2s). METHODS Human cultured MCs were sensitized with and without IgE for 1 hour and then incubated with anti-IgE antibody, IL-33, or medium alone for 24 hours. EVs in the MC supernatant were isolated by using ExoQuick-TC. RESULTS Coculture of ILC2s with EVs derived from the FcεRI-aggregated MCs significantly enhanced IL-5 production and sustained upregulation of IL-5 mRNA expression in IL-33-stimulated ILC2s, but IL-13 production and IL-13 mRNA expression were unchanged. miR103a-3p expression was upregulated in IL-33-stimulated ILC2s that had been cocultured with EVs derived from anti-IgE antibody-stimulated MCs. Transduction of an miR103a-3p mimic to ILC2s significantly enhanced IL-5 production by IL-33-stimulated ILC2s. miR103a-3p promoted demethylation of an arginine residue of GATA3 by downregulating protein arginine methyltransferase 5 (PRMT5) mRNA. Reduction of protein arginine methyltransferase 5 expression in ILC2s by using a small interfering RNA technique resulted in upregulation of IL-5 production by IL-33-stimulated ILC2s. Furthermore, the level of miR103a-3p expression was significantly higher in EVs from sera of patients with atopic dermatitis than in EVs from nonatopic healthy control subjects. CONCLUSION Eosinophilic allergic inflammation may be exacerbated owing to ILC2 activation by MC-derived miR103a-3p.
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Affiliation(s)
- Shota Toyoshima
- Allergy and Immunology Research Project Team, Research Institute of Medical Science, Nihon University School of Medicine, Tokyo, Japan; Center for Allergy, Nihon University Itabashi Hospital, Tokyo, Japan; Center for Medical Education, Nihon University School of Medicine, Tokyo, Japan
| | - Tomomi Sakamoto-Sasaki
- Allergy and Immunology Research Project Team, Research Institute of Medical Science, Nihon University School of Medicine, Tokyo, Japan; Center for Allergy, Nihon University Itabashi Hospital, Tokyo, Japan; Center for Medical Education, Nihon University School of Medicine, Tokyo, Japan
| | - Yusuke Kurosawa
- Allergy and Immunology Research Project Team, Research Institute of Medical Science, Nihon University School of Medicine, Tokyo, Japan; Center for Allergy, Nihon University Itabashi Hospital, Tokyo, Japan; Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Koremasa Hayama
- Center for Allergy, Nihon University Itabashi Hospital, Tokyo, Japan; Divison of Cutaneous Science, Department of Dermatology, Nihon University School of Medicine, Tokyo, Japan
| | - Akira Matsuda
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yasuo Watanabe
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Tadashi Terui
- Center for Allergy, Nihon University Itabashi Hospital, Tokyo, Japan; Divison of Cutaneous Science, Department of Dermatology, Nihon University School of Medicine, Tokyo, Japan
| | - Yasuhiro Gon
- Center for Allergy, Nihon University Itabashi Hospital, Tokyo, Japan; Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Kenji Matsumoto
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Yoshimichi Okayama
- Allergy and Immunology Research Project Team, Research Institute of Medical Science, Nihon University School of Medicine, Tokyo, Japan; Center for Allergy, Nihon University Itabashi Hospital, Tokyo, Japan; Center for Medical Education, Nihon University School of Medicine, Tokyo, Japan.
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Wang JY, Dong X, Yu Z, Ge L, Lu L, Ding L, Gan W. Borneol inhibits CD4 + T cells proliferation by down-regulating miR-26a and miR-142-3p to attenuate asthma. Int Immunopharmacol 2021; 90:107223. [PMID: 33272847 DOI: 10.1016/j.intimp.2020.107223] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 11/12/2020] [Accepted: 11/16/2020] [Indexed: 01/14/2023]
Abstract
BACKGROUND Asthma is a chronic airway inflammatory disease caused by a variety of cytokines and signaling pathways closely related to immunoregulation. Corticosteroids are the most widely used drug in the asthma treatment. However, the use of corticosteroids could cause topical side effects. So, it's important to find new drugs for asthma treatment. Our study aims to explore the pharmacological effect of borneol on asthma and its underlying mechanism. METHODS We constructed the OVA-induced asthma model to investigate the effect of borneol on asthma in mice. HE and PAS staining was used to detect the effect of borneol on pathological change of mice with asthma. Inflammatory cytokines were measured by ELISA. qRT-PCR was used to explore the effect of borneol on microRNAs expression. Cell proliferation of CD4 + T cells was detected by CCK-8 assay and flow cytometry. Western blot was used to detect pten expression and Akt activation. RESULTS We found that borneol significantly alleviated asthma progression in mice. Borneol inhibited CD4 + T cells infiltration in vivo and proliferation in vitro by downregulating miR-26a and miR-142-3p. miR-26a and miR-142-3p promoted CD4 + T cells proliferation in vitro through targeting Pten. Overexpression of miR-26a and miR-142-3p abolished the effect of borneol in vivo. CONCLUSION In a word, these findings suggested that borneol attenuated asthma in mice by decreasing the CD4 + T cells infiltration. The molecular mechanism of borneol was dependent on the downregulation of miR-26a and miR-142-3p to upregulate the Pten expression.
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Affiliation(s)
- Jin-Ya Wang
- Department of Pediatrics, The Second Affiliated Hospital of Nanjing Medical University, 262 Zhongshan North Road, Nanjing, Jiangsu 210003, China.
| | - Xiaoyan Dong
- Department of Pulmonary, Shanghai Children's Hospital, Shanghai Jiaotong University Shanghai, China
| | - Zhiwei Yu
- Department of Pediatrics, The Second Affiliated Hospital of Nanjing Medical University, 262 Zhongshan North Road, Nanjing, Jiangsu 210003, China; Department of Pediatrics, The Affiliated Wuxi Children's Hospital of Nanjing Medical University, Wuxi 214023, Jiangsu, China
| | - Lei Ge
- Department of Pediatrics, The Second Affiliated Hospital of Nanjing Medical University, 262 Zhongshan North Road, Nanjing, Jiangsu 210003, China
| | - Lu Lu
- Department of Pediatrics, The Second Affiliated Hospital of Nanjing Medical University, 262 Zhongshan North Road, Nanjing, Jiangsu 210003, China
| | - Ling Ding
- Department of Pediatrics, The Second Affiliated Hospital of Nanjing Medical University, 262 Zhongshan North Road, Nanjing, Jiangsu 210003, China
| | - Weihua Gan
- Department of Pediatrics, The Second Affiliated Hospital of Nanjing Medical University, 262 Zhongshan North Road, Nanjing, Jiangsu 210003, China.
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41
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Oladejo AO, Li Y, Wu X, Imam BH, Shen W, Ding XZ, Wang S, Yan Z. MicroRNAome: Potential and Veritable Immunomolecular Therapeutic and Diagnostic Baseline for Lingering Bovine Endometritis. Front Vet Sci 2020; 7:614054. [PMID: 33426032 PMCID: PMC7785807 DOI: 10.3389/fvets.2020.614054] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 11/18/2020] [Indexed: 12/28/2022] Open
Abstract
The bovine endometrium is a natural pathogen invasion barrier of the uterine tissues' endometrial epithelial cells that can resist foreign pathogen invasion by controlling the inflammatory immune response. Some pathogens suppress the innate immune system of the endometrium, leading to prolonged systemic inflammatory response through the blood circulation or cellular degradation resulting in bovine endometritis by bacterial endotoxins. The microRNA (miRNA) typically involves gene expression in multicellular organisms in post-transcription regulation by affecting both the stability and the translation of messenger RNA. Accumulated evidence suggests that miRNAs are important regulators of genes in several cellular processes. They are a class of endogenous non-coding RNAs, which play pivotal roles in the inflammatory response of reproductive diseases. Studies confirmed that miRNAs play a key regulatory role in various inflammatory diseases by mediating the molecular mechanism of inflammatory cytokines via signal pathways. It implicates some miRNAs in the occurrence of bovine endometritis, resorting to regulating the activities of some inflammatory cytokines, chemokine, differentially expressed genes, and protein through modulating of specific cellular signal pathways functions. This review dwells on improving the knowledge of the role of miRNAs involvement in inflammatory response as to early diagnosis, control, and prevention of bovine endometritis and consequently enlighten on the molecular improvement of the genes coded by various differentially expressed miRNA through the need to adopt recent genetic technologies and the development of new pharmaceutical preparations.
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Affiliation(s)
- Ayodele Olaolu Oladejo
- Key Laboratory of Veterinary Pharmaceutical Development of Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Science, Lanzhou, China.,Department of Animal Health Technology, Oyo State College of Agriculture and Technology, Igbo-Ora, Nigeria
| | - Yajuan Li
- Key Laboratory of Veterinary Pharmaceutical Development of Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Science, Lanzhou, China
| | - Xiaohu Wu
- Key Laboratory of Veterinary Pharmaceutical Development of Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Science, Lanzhou, China
| | - Bereket Habte Imam
- Key Laboratory of Veterinary Pharmaceutical Development of Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Science, Lanzhou, China
| | - Wenxiang Shen
- Key Laboratory of Veterinary Pharmaceutical Development of Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Science, Lanzhou, China
| | - Xue Zhi Ding
- Key Laboratory of Veterinary Pharmaceutical Development of Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Science, Lanzhou, China
| | - Shengyi Wang
- Key Laboratory of Veterinary Pharmaceutical Development of Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Science, Lanzhou, China
| | - Zuoting Yan
- Key Laboratory of Veterinary Pharmaceutical Development of Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Science, Lanzhou, China
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Xu HK, Chen LJ, Zhou SN, Li YF, Xiang C. Multifunctional role of microRNAs in mesenchymal stem cell-derived exosomes in treatment of diseases. World J Stem Cells 2020; 12:1276-1294. [PMID: 33312398 PMCID: PMC7705472 DOI: 10.4252/wjsc.v12.i11.1276] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 08/23/2020] [Accepted: 09/18/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells can be replaced by exosomes for the treatment of inflammatory diseases, injury repair, degenerative diseases, and tumors. Exosomes are small vesicles rich in a variety of nucleic acids [including messenger RNA, Long non-coding RNA, microRNA (miRNA), and circular RNA], proteins, and lipids. Exosomes can be secreted by most cells in the human body and are known to play a key role in the communication of information and material transport between cells. Like exosomes, miRNAs were neglected before their role in various activities of organisms was discovered. Several studies have confirmed that miRNAs play a vital role within exosomes. This review focuses on the specific role of miRNAs in MSC-derived exosomes (MSC-exosomes) and the methods commonly used by researchers to study miRNAs in exosomes. Taken together, miRNAs from MSC-exosomes display immense potential and practical value, both in basic medicine and future clinical applications, in treating several diseases.
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Affiliation(s)
- Hui-Kang Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Li-Jun Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Si-Ning Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Yi-Fei Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Charlie Xiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China.
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Zhong D, Lyu X, Fu X, Xie P, Liu M, He F, Huang G. Upregulation of miR-124-3p by Liver X Receptor Inhibits the Growth of Hepatocellular Carcinoma Cells Via Suppressing Cyclin D1 and CDK6. Technol Cancer Res Treat 2020; 19:1533033820967473. [PMID: 33073697 PMCID: PMC7592319 DOI: 10.1177/1533033820967473] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
MiR-124-3p has been identified as a novel tumor suppressor and a potential therapeutic target in hepatocellular carcinoma (HCC) through regulating its target genes. However, the upstream regulatory mechanisms of mir-124-3p in HCC has not been fully understood. The transcription factor liver X receptor (LXR) plays a critical role in suppressing the proliferation of HCC cells, but it is unclear whether LXR is involved in the regulation of mir-124-3p. In the present study, we demonstrated that the expression of mir-124-3p was positively correlated with that of LXR in HCC, and the cell growth of HCC was significantly inhibited by LXR agonists. Moreover, activation of LXR with the agonists up-regulated the expression of mir-124-3p, and in turn down-regulated cyclin D1 and cyclin-dependent kinase 6 (CDK6) expression, which are the target genes of mir-124-3p. Mechanistically, miR-124-3p mediates LXR induced inhibition of HCC cell growth and down-regulation of cyclin D1 and CDK6 expression. In vivo experiments also confirmed that LXR induced miR-124-3p expression inhibited the growth of HCC xenograft tumors, as well as cyclin D1 and CDK6 expression. Our findings revealed that miR-124-3p is a novel target gene of LXR, and regulation of the miR-124-3p-cyclin D1/CDK6 pathway by LXR plays a crucial role in the proliferation of HCC cells. LXR-miR-124-3p-cyclin D1/CDK6 pathway may be a novel potential therapeutic target for HCC treatment.
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Affiliation(s)
- Dan Zhong
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, 12525Army Medical University (Third Military Medical University), Chongqing, China
| | - Xilin Lyu
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, 12525Army Medical University (Third Military Medical University), Chongqing, China
| | - Xiaohong Fu
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, 12525Army Medical University (Third Military Medical University), Chongqing, China
| | - Peng Xie
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, 12525Army Medical University (Third Military Medical University), Chongqing, China
| | - Menggang Liu
- Department of Hepatobiliary Surgery, Daping Hospital (Army Medical Center), 12525Army Medical University (Third Military Medical University), Chongqing, China
| | - Fengtian He
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, 12525Army Medical University (Third Military Medical University), Chongqing, China
| | - Gang Huang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, 12525Army Medical University (Third Military Medical University), Chongqing, China
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Zhao X, Li J, Ma J, Jiao C, Qiu X, Cui X, Wang D, Zhang H. MiR-124a Mediates the Impairment of Intestinal Epithelial Integrity by Targeting Aryl Hydrocarbon Receptor in Crohn's Disease. Inflammation 2020; 43:1862-1875. [PMID: 32607693 DOI: 10.1007/s10753-020-01259-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Growing evidence suggested that microRNAs (miRNAs) contributed to the progression of Crohn's disease (CD), but the exact physiological functions of many miRNAs in CD patients still remain illusive. In this study, we explore the potent pathogenicity of miRNAs in CD. Expressions of miRNAs and aryl hydrocarbon receptor (AHR) protein were determined in the colitic colon of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis mice and CD patients. Colitis was induced in wild-type (WT), miR-124a overexpression (miR-124a-Nju), and AHR knockout (AHR-/-) mice. Intestinal barrier function was evaluated in colitis mice and Caco2 monolayers. There was a negative relationship between miR-124a and AHR protein in inflamed colons from CD patients. MiR-124a-Nju and AHR-/- mice treated with TNBS had more severe intestinal inflammation than WT mice. Both miR-124a-Nju mice and AHR-/- mice underwent evident intestinal barrier destruction, and anti-miR-124a administration could reverse this dysfunction in miR-124a-Nju mice but not in AHR-/- mice. In vitro studies revealed that miR-124a mimics downregulated the expression of AHR and tight junction proteins and induced hyperpermeability by increasing miR-124a expression, which was abrogated by miR-124a inhibitor and AHR antagonist FICZ. This study suggests that miR-124a can induce intestinal inflammation and cause intestinal barrier dysfunction by supressing AHR.
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Affiliation(s)
- Xiaojing Zhao
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Jiajia Li
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Jingjing Ma
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Chunhua Jiao
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Xinyun Qiu
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Xiufang Cui
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Di Wang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Hongjie Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
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Genetic and Epigenetic Aspects of Atopic Dermatitis. Int J Mol Sci 2020; 21:ijms21186484. [PMID: 32899887 PMCID: PMC7554821 DOI: 10.3390/ijms21186484] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/02/2020] [Accepted: 09/02/2020] [Indexed: 12/21/2022] Open
Abstract
Atopic dermatitis is a heterogeneous disease, in which the pathogenesis is associated with mutations in genes encoding epidermal structural proteins, barrier enzymes, and their inhibitors; the role of genes regulating innate and adaptive immune responses and environmental factors inducing the disease is also noted. Recent studies point to the key role of epigenetic changes in the development of the disease. Epigenetic modifications are mainly mediated by DNA methylation, histone acetylation, and the action of specific non-coding RNAs. It has been documented that the profile of epigenetic changes in patients with atopic dermatitis (AD) differs from that observed in healthy people. This applies to the genes affecting the regulation of immune response and inflammatory processes, e.g., both affecting Th1 bias and promoting Th2 responses and the genes of innate immunity, as well as those encoding the structural proteins of the epidermis. Understanding of the epigenetic alterations is therefore pivotal to both create new molecular classifications of atopic dermatitis and to enable the development of personalized treatment strategies.
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46
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Ghafouri-Fard S, Eghtedarian R, Taheri M. The crucial role of non-coding RNAs in the pathophysiology of inflammatory bowel disease. Biomed Pharmacother 2020; 129:110507. [DOI: 10.1016/j.biopha.2020.110507] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 06/25/2020] [Accepted: 07/02/2020] [Indexed: 02/07/2023] Open
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Fields C, Levin M. Scale-Free Biology: Integrating Evolutionary and Developmental Thinking. Bioessays 2020; 42:e1900228. [PMID: 32537770 DOI: 10.1002/bies.201900228] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 04/24/2020] [Indexed: 12/16/2022]
Abstract
When the history of life on earth is viewed as a history of cell division, all of life becomes a single cell lineage. The growth and differentiation of this lineage in reciprocal interaction with its environment can be viewed as a developmental process; hence the evolution of life on earth can also be seen as the development of life on earth. Here, in reviewing this field, some potentially fruitful research directions suggested by this change in perspective are highlighted. Variation and selection become, for example, bidirectional information flows between scales, while the notions of "cooperation" and "competition" become scale relative. The language of communication, inference, and information processing becomes more useful than the language of causation to describe the interactions of both homogeneous and heterogeneous living systems at any scale. Emerging scale-free theoretical frameworks such as predictive coding and active inference provide conceptual tools for reconceptualizing biology as the study of a unified, multiscale dynamical system.
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Affiliation(s)
- Chris Fields
- 23 Rue des Lavandieres, 11160 Caunes Minervois, France
| | - Michael Levin
- Allen Discovery Center at Tufts University, Medford, MA, 02155, USA
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48
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Sumathipala M, Weiss ST. Predicting miRNA-based disease-disease relationships through network diffusion on multi-omics biological data. Sci Rep 2020; 10:8705. [PMID: 32457435 PMCID: PMC7251138 DOI: 10.1038/s41598-020-65633-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 05/07/2020] [Indexed: 12/18/2022] Open
Abstract
With critical roles in regulating gene expression, miRNAs are strongly implicated in the pathophysiology of many complex diseases. Experimental methods to determine disease related miRNAs are time consuming and costly. Computationally predicting miRNA-disease associations has potential applications in finding miRNA therapeutic pathways and in understanding the role of miRNAs in disease-disease relationships. In this study, we propose the MiRNA-disease Association Prediction (MAP) method, an in-silico method to predict and prioritize miRNA-disease associations. The MAP method applies a network diffusion approach, starting from the known disease genes in a heterogenous network constructed from miRNA-gene associations, protein-protein interactions, and gene-disease associations. Validation using experimental data on miRNA-disease associations demonstrated superior performance to two current state-of-the-art methods, with areas under the ROC curve all over 0.8 for four types of cancer. MAP is successfully applied to predict differential miRNA expression in four cancer types. Most strikingly, disease-disease relationships in terms of shared miRNAs revealed hidden disease subtyping comparable to that of previous work on shared genes between diseases, with applications for multi-omics characterization of disease relationships.
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Affiliation(s)
- Marissa Sumathipala
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
- Harvard College, Cambridge, MA, USA.
| | - Scott T Weiss
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
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Yuan F, Zhang S, Xie W, Yang S, Lin T, Chen X. Effect and mechanism of miR-146a on malignant biological behaviors of lung adenocarcinoma cell line. Oncol Lett 2020; 19:3643-3652. [PMID: 32382320 PMCID: PMC7202298 DOI: 10.3892/ol.2020.11474] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Accepted: 06/28/2019] [Indexed: 12/28/2022] Open
Abstract
The aim of the present study was to assess the expression of microRNA-146a (miR-146a) in human lung adenocarcinoma cells, its effect on cellular behaviors, and the underlying molecular mechanisms. Reverse transcription-quantitative PCR (RT-qPCR) was used to measure miR-146a expression in the human normal lung epithelial cell line, BEAS-2B, and human lung adenocarcinoma cell lines, A549, PC-9 and H1299, to determine whether miR-146a acts as an oncogene or anti-oncogene. miR-146a mimics were transfected into target cells to observe the proliferation, apoptosis, invasion and migration of human lung adenocarcinoma cells. The target genes of miR-146a were predicted using bioinformatics analysis, and binding sites were validated by dual-luciferase reporter assay. Target gene expression at the mRNA and protein levels was measured by RT-qPCR and western blot analysis, respectively. The expression levels of miR-146a in human lung adenocarcinoma cell lines were lower than its expression in BEAS-2B (P<0.01). A549 cell line is a EGFR wild-type lung adenocarcinoma cell line, which is also the most widely studied in NSCLC, and therefore this was chosen as the target cell line for further investigation. Overexpression of miR-146a in A549 cells can inhibit cell proliferation (P<0.05), promote apoptosis (P<0.05), and reduce the cells' migratory ability (P<0.01). Bioinformatics prediction indicated that interleukin-1 receptor-associated kinase 1 (IRAK1) and TNF receptor associated factor 6 (TRAF6) are the target genes of miR-146a. Dual-luciferase reporter assay showed that miR-146a could specifically bind to 3′-untranslated regions of IRAK1 and TRAF6. The protein and mRNA levels of IRAK1 and TRAF6 were significantly downregulated after miR-146a overexpression in A549 cells (P<0.01). The results of this study demonstrated that the expression of miR-146a in human lung adenocarcinoma cells was significantly lower than in normal lung epithelial cells, indicating that miR-146a acts as an anti-oncogene. miR-146a suppresses the proliferation and migration of human lung adenocarcinoma cells by downregulating the expression of IRAK1 and TRAF6.
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Affiliation(s)
- Fang Yuan
- Department of Respiratory Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China.,Department of Respiratory, The First Hospital of Jiujiang City, Jiujiang, Jiangxi 332000, P.R. China
| | - Suyun Zhang
- Department of Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Wenying Xie
- Department of Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Sheng Yang
- Department of Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Tingyan Lin
- Department of Respiratory Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Xiangqi Chen
- Department of Respiratory Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
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50
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Yu X, Wang M, Li L, Zhang L, Chan MTV, Wu WKK. MicroRNAs in atopic dermatitis: A systematic review. J Cell Mol Med 2020; 24:5966-5972. [PMID: 32351034 PMCID: PMC7294122 DOI: 10.1111/jcmm.15208] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 02/03/2020] [Accepted: 02/15/2020] [Indexed: 12/22/2022] Open
Abstract
Atopic dermatitis (AD) is a chronic and recurrent inflammatory skin disease, affecting up to 10% to 20% of children and 3% of adults. Although allergen sensitization, skin barrier abnormalities and type 2 immune responses are involved, the exact molecular pathogenesis of AD remains unclear. MicroRNAs (miRNAs) are short (19‐25 nucleotides) single‐stranded RNA molecules that regulate gene expression at post‐transcriptional level and are implicated in the pathogenesis of many inflammatory and immunological skin disorders. This systematic review sought to summarize our current understanding regarding the role of miRNAs in AD development. We searched articles indexed in PubMed (MEDLINE) and Web of Science databases using Medical Subject Heading (MeSH) or Title/Abstract words (‘microRNA/miRNA’ and ‘atopic dermatitis/eczema’) from inception through January 2020. Observational studies revealed dysregulation of miRNAs, including miR‐143, miR‐146a, miR‐151a, miR‐155 and miR‐223, in AD patients. Experimental studies confirmed their functions in regulating keratinocyte proliferation/apoptosis, cytokine signalling and nuclear factor‐κB‐dependent inflammatory responses, together with T helper 17 and regulatory T cell activities. Altogether, this systematic review brings together contemporary findings on how deregulation of miRNAs contributes to AD.
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Affiliation(s)
- Xin Yu
- Department of Dermatology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Meifang Wang
- Department of Dermatology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Linfeng Li
- Department of Dermatology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Lin Zhang
- Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong.,State Key Laboratory of Digestive Diseases and LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Matthew Tak Vai Chan
- Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - William Ka Kei Wu
- Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong.,State Key Laboratory of Digestive Diseases and LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong
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