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1
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Gheitasi I, Akbari G, Savari F. Physiological and cellular mechanisms of ischemic preconditioning microRNAs-mediated in underlying of ischemia/reperfusion injury in different organs. Mol Cell Biochem 2025; 480:855-868. [PMID: 39001984 DOI: 10.1007/s11010-024-05052-7] [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: 03/28/2024] [Accepted: 06/10/2024] [Indexed: 07/15/2024]
Abstract
Ischemia-reperfusion (I/R) injury, as a pathological phenomenon, takes place when blood supply to an organ is disrupted and then aggravated during restoration of blood flow. Ischemic preconditioning (IPC) is a potent method for attenuating subsequent events of IR damage in numerous organs. IPC protocol is determined by a brief and sequential time periods of I/R before the main ischemia. MicroRNAs are endogenous non-coding RNAs that regulate post-transcriptionally target mRNA translation via degrading it and/or suppressing protein synthesis. This review introduces the physiological and cellular mechanisms of ischemic preconditioning microRNAs-mediated after I/R insult in different organs such as the liver, kidney, heart, brain, and intestine. Data of this review have been collected from the scientific articles published in databases such as Science Direct, Scopus, PubMed, Web of Science, and Scientific Information Database from 2000 to 2023. Based on these literature studies, IPC/IR intervention can affect cellular mechanisms including oxidative stress, apoptosis, angiogenesis, and inflammation through up-regulation or down-regulation of multiple microRNAs and their target genes.
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Affiliation(s)
- Izadpanah Gheitasi
- Department of Physiology, Faculty of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Ghaidafeh Akbari
- Department of Physiology, Faculty of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran.
| | - Feryal Savari
- Department of Medical Basic Sciences, Shoushtar Faculty of Medical Sciences, Shoushtar, Iran.
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2
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Peppicelli S, Calorini L, Bianchini F, Papucci L, Magnelli L, Andreucci E. Acidity and hypoxia of tumor microenvironment, a positive interplay in extracellular vesicle release by tumor cells. Cell Oncol (Dordr) 2025; 48:27-41. [PMID: 39023664 PMCID: PMC11850579 DOI: 10.1007/s13402-024-00969-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] [Accepted: 06/28/2024] [Indexed: 07/20/2024] Open
Abstract
The complex and continuously evolving features of the tumor microenvironment, varying between tumor histotypes, are characterized by the presence of host cells and tumor cells embedded in a milieu shaped by hypoxia and low pH, resulting from the frequent imbalance between vascularity and tumor cell proliferation. These microenvironmental metabolic stressors play a crucial role in remodeling host cells and tumor cells, contributing to the stimulation of cancer cell heterogeneity, clonal evolution, and multidrug resistance, ultimately leading to progression and metastasis. The extracellular vesicles (EVs), membrane-enclosed structures released into the extracellular milieu by tumor/host cells, are now recognized as critical drivers in the complex intercellular communication between tumor cells and the local cellular components in a hypoxic/acidic microenvironment. Understanding the intricate molecular mechanisms governing the interactions between tumor and host cells within a hypoxic and acidic microenvironment, triggered by the release of EVs, could pave the way for innovative strategies to disrupt the complex interplay of cancer cells with their microenvironment. This approach may contribute to the development of an efficient and safe therapeutic strategy to combat cancer progression. Therefore, we review the major findings on the release of EVs in a hypoxic/acidic tumor microenvironment to appreciate their role in tumor progression toward metastatic disease.
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Affiliation(s)
- Silvia Peppicelli
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, 50134, Italy.
| | - Lido Calorini
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, 50134, Italy
| | - Francesca Bianchini
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, 50134, Italy
| | - Laura Papucci
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, 50134, Italy
| | - Lucia Magnelli
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, 50134, Italy
| | - Elena Andreucci
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, 50134, Italy
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3
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Shen Z, Yu N, Zhang Y, Jia M, Sun Y, Li Y, Zhao L. The potential roles of HIF-1α in epithelial-mesenchymal transition and ferroptosis in tumor cells. Cell Signal 2024; 122:111345. [PMID: 39134249 DOI: 10.1016/j.cellsig.2024.111345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 08/03/2024] [Accepted: 08/09/2024] [Indexed: 08/15/2024]
Abstract
In tumors, the rapid proliferation of cells and the imperfect blood supply system lead to hypoxia, which can regulate the adaptation of tumor cells to the hypoxic environment through hypoxia-inducible factor-1α (HIF-1α) and promote tumor development in multiple ways. Recent studies have found that epithelial-mesenchymal transition (EMT) and ferroptosis play important roles in the progression of tumor cells. The activation of HIF-1α is considered a key factor in inducing EMT in tumor cells. When HIF-1α is activated, it can regulate EMT-related genes, causing tumor cells to gradually lose their epithelial characteristics and acquire more invasive mesenchymal traits. The occurrence of EMT allows tumor cells to better adapt to changes in the surrounding tissue, enhancing their migratory and invasive capabilities, thus promoting tumor progression. At the same time, HIF-1α also plays a crucial regulatory role in ferroptosis in tumor cells. In a hypoxic environment, HIF-1α may affect processes such as iron metabolism and oxidative stress responses, inducing ferroptosis in tumor cells. This article briefly reviews the dual role of HIF-1α in EMT and ferroptosis in tumor cells, helping to gain a deeper understanding of the regulatory pathways of HIF-1α in the development of tumor cells, providing a new perspective for understanding the pathogenesis of tumors. The regulation of HIF-1α may become an important strategy for future tumor therapy.
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Affiliation(s)
- Zhongjun Shen
- Department of Blood Transfusion, Second Hospital of Jilin University, Changchun, 130041 Jilin, China
| | - Na Yu
- Department of Blood Transfusion, Second Hospital of Jilin University, Changchun, 130041 Jilin, China
| | - Yanfeng Zhang
- Department of Blood Transfusion, Second Hospital of Jilin University, Changchun, 130041 Jilin, China
| | - Mingbo Jia
- Department of Blood Transfusion, Second Hospital of Jilin University, Changchun, 130041 Jilin, China
| | - Ying Sun
- Department of Blood Transfusion, Second Hospital of Jilin University, Changchun, 130041 Jilin, China
| | - Yao Li
- Department of Blood Transfusion, Second Hospital of Jilin University, Changchun, 130041 Jilin, China
| | - Liyan Zhao
- Department of Blood Transfusion, Second Hospital of Jilin University, Changchun, 130041 Jilin, China.
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4
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Slawski J, Jaśkiewicz M, Barton A, Kozioł S, Collawn JF, Bartoszewski R. Regulation of the HIF switch in human endothelial and cancer cells. Eur J Cell Biol 2024; 103:151386. [PMID: 38262137 DOI: 10.1016/j.ejcb.2024.151386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 01/17/2024] [Accepted: 01/17/2024] [Indexed: 01/25/2024] Open
Abstract
Hypoxia-inducible factors (HIFs) are transcription factors that reprogram the transcriptome for cells to survive hypoxic insults and oxidative stress. They are important during embryonic development and reprogram the cells to utilize glycolysis when the oxygen levels are extremely low. This metabolic change facilitates normal cell survival as well as cancer cell survival. The key feature in survival is the transition between acute hypoxia and chronic hypoxia, and this is regulated by the transition between HIF-1 expression and HIF-2/HIF-3 expression. This transition is observed in many human cancers and endothelial cells and referred to as the HIF Switch. Here we discuss the mechanisms involved in the HIF Switch in human endothelial and cancer cells which include mRNA and protein levels of the alpha chains of the HIFs. A major continuing effort in this field is directed towards determining the differences between normal and tumor cell utilization of this important pathway, and how this could lead to potential therapeutic approaches.
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Affiliation(s)
- Jakub Slawski
- Department of Biophysics, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
| | - Maciej Jaśkiewicz
- International Research Agenda 3P, Medicine Laboratory, Medical University of Gdansk, Gdansk, Poland
| | - Anna Barton
- Department of Biophysics, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
| | - Sylwia Kozioł
- Department of Biophysics, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
| | - James F Collawn
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, USA
| | - Rafał Bartoszewski
- Department of Biophysics, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland.
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5
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Zhuang X, Gallo G, Sharma P, Ha J, Magri A, Borrmann H, Harris JM, Tsukuda S, Bentley E, Kirby A, de Neck S, Yang H, Balfe P, Wing PA, Matthews D, Harris AL, Kipar A, Stewart JP, Bailey D, McKeating JA. Hypoxia inducible factors inhibit respiratory syncytial virus infection by modulation of nucleolin expression. iScience 2024; 27:108763. [PMID: 38261926 PMCID: PMC10797196 DOI: 10.1016/j.isci.2023.108763] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 10/13/2023] [Accepted: 12/15/2023] [Indexed: 01/25/2024] Open
Abstract
Respiratory syncytial virus (RSV) is a global healthcare problem, causing respiratory illness in young children and elderly individuals. Our knowledge of the host pathways that define susceptibility to infection and disease severity are limited. Hypoxia inducible factors (HIFs) define metabolic responses to low oxygen and regulate inflammatory responses in the lower respiratory tract. We demonstrate a role for HIFs to suppress RSV entry and RNA replication. We show that hypoxia and HIF prolyl-hydroxylase inhibitors reduce the expression of the RSV entry receptor nucleolin and inhibit viral cell-cell fusion. We identify a HIF regulated microRNA, miR-494, that regulates nucleolin expression. In RSV-infected mice, treatment with the clinically approved HIF prolyl-hydroxylase inhibitor, Daprodustat, reduced the level of infectious virus and infiltrating monocytes and neutrophils in the lung. This study highlights a role for HIF-signalling to limit multiple aspects of RSV infection and associated inflammation and informs future therapeutic approaches for this respiratory pathogen.
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Affiliation(s)
- Xiaodong Zhuang
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | | | - Parul Sharma
- Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
| | - Jiyeon Ha
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Andrea Magri
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Helene Borrmann
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - James M. Harris
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Senko Tsukuda
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Eleanor Bentley
- Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
| | - Adam Kirby
- Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
| | - Simon de Neck
- Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 268, 8057 Zurich, Switzerland
| | - Hongbing Yang
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Peter Balfe
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Peter A.C. Wing
- Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, UK
| | - David Matthews
- School of Cellular and Molecular Medicine, Faculty of Life Sciences, University of Bristol, Bristol, UK
| | | | - Anja Kipar
- Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
- Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 268, 8057 Zurich, Switzerland
| | - James P. Stewart
- Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
| | | | - Jane A. McKeating
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, UK
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6
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Zeng B, Liu Y, Xu J, Niu L, Wu Y, Zhang D, Tang X, Zhu Z, Chen Y, Hu L, Yu S, Yu P, Zhang J, Wang W. Future Directions in Optimizing Anesthesia to Reduce Perioperative Acute Kidney Injury. Am J Nephrol 2023; 54:434-450. [PMID: 37742618 DOI: 10.1159/000533534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 08/01/2023] [Indexed: 09/26/2023]
Abstract
BACKGROUND Perioperative acute kidney injury (AKI) is common in surgical patients and is associated with high morbidity and mortality. There are currently few options for AKI prevention and treatment. Due to its complex pathophysiology, there is no efficient medication therapy to stop the onset of the injury or repair the damage already done. Certain anesthetics, however, have been demonstrated to affect the risk of perioperative AKI in some studies. The impact of anesthetics on renal function is particularly important as it is closely related to the prognosis of patients. Some anesthetics can induce anti-inflammatory, anti-necrotic, and anti-apoptotic effects. Propofol, sevoflurane, and dexmedetomidine are a few examples of anesthetics that have protective association with AKI in the perioperative period. SUMMARY In this study, we reviewed the clinical characteristics, risk factors, and pathogenesis of AKI. Subsequently, the protective effects of various anesthetic agents against perioperative AKI and the latest research are introduced. KEY MESSAGE This work demonstrates that a thorough understanding of the reciprocal effects of anesthetic drugs and AKI is crucial for safe perioperative care and prognosis of patients. However, more complete mechanisms and pathophysiological processes still need to be further studied.
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Affiliation(s)
- Bin Zeng
- Department of Gastroenterology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Yinuo Liu
- Department of Metabolism and Endocrinology, The Second Affiliated Hospital of Nanchang University, Nanchang, China,
- The Second Clinical Medical College of Nanchang University, Nanchang, China,
| | - Jiawei Xu
- Department of Metabolism and Endocrinology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- The Second Clinical Medical College of Nanchang University, Nanchang, China
| | - Liyan Niu
- Department of Metabolism and Endocrinology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- The Second Clinical Medical College of Nanchang University, Nanchang, China
- Huan Kui College, Nanchang University, Nanchang, China
| | - Yuting Wu
- Huan Kui College, Nanchang University, Nanchang, China
- Department of Metabolism and Endocrinology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Deju Zhang
- Huan Kui College, Nanchang University, Nanchang, China
- Food and Nutritional Sciences, School of Biological Sciences, The University of Hong Kong, Hong Kong, Hong Kong, China
| | - Xiaoyi Tang
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zicheng Zhu
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yixuan Chen
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Leilei Hu
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Shuchun Yu
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Peng Yu
- Department of Metabolism and Endocrinology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jing Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Wenting Wang
- Department of Anesthesiology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
- Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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7
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Shao JL, Wang LJ, Xiao J, Yang JF. Non-coding RNAs: The potential biomarker or therapeutic target in hepatic ischemia-reperfusion injury. World J Gastroenterol 2023; 29:4927-4941. [PMID: 37731999 PMCID: PMC10507504 DOI: 10.3748/wjg.v29.i33.4927] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 07/22/2023] [Accepted: 08/18/2023] [Indexed: 09/01/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (HIRI) is the major complication of liver surgery and liver transplantation, that may increase the postoperative morbidity, mortality, tumor progression, and metastasis. The underlying mechanisms have been extensively investigated in recent years. Among these, oxidative stress, inflammatory responses, immunoreactions, and cell death are the most studied. Non-coding RNAs (ncRNAs) are defined as the RNAs that do not encode proteins, but can regulate gene expressions. In recent years, ncRNAs have emerged as research hotspots for various diseases. During the progression of HIRI, ncRNAs are differentially expressed, while these dysregulations of ncRNAs, in turn, have been verified to be related to the above pathological processes involved in HIRI. ncRNAs mainly contain microRNAs, long ncRNAs, and circular RNAs, some of which have been reported as biomarkers for early diagnosis or assessment of liver damage severity, and as therapeutic targets to attenuate HIRI. Here, we briefly summarize the common pathophysiology of HIRI, describe the current knowledge of ncRNAs involved in HIRI in animal and human studies, and discuss the potential of ncRNA-targeted therapeutic strategies. Given the scarcity of clinical trials, there is still a long way to go from pre-clinical to clinical application, and further studies are needed to uncover their potential as therapeutic targets.
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Affiliation(s)
- Jia-Li Shao
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Li-Juan Wang
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Ji Xiao
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Jin-Feng Yang
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
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8
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You J, Liu M, Li M, Zhai S, Quni S, Zhang L, Liu X, Jia K, Zhang Y, Zhou Y. The Role of HIF-1α in Bone Regeneration: A New Direction and Challenge in Bone Tissue Engineering. Int J Mol Sci 2023; 24:ijms24098029. [PMID: 37175732 PMCID: PMC10179302 DOI: 10.3390/ijms24098029] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 04/22/2023] [Accepted: 04/25/2023] [Indexed: 05/15/2023] Open
Abstract
The process of repairing significant bone defects requires the recruitment of a considerable number of cells for osteogenesis-related activities, which implies the consumption of a substantial amount of oxygen and nutrients. Therefore, the limited supply of nutrients and oxygen at the defect site is a vital constraint that affects the regenerative effect, which is closely related to the degree of a well-established vascular network. Hypoxia-inducible factor (HIF-1α), which is an essential transcription factor activated in hypoxic environments, plays a vital role in vascular network construction. HIF-1α, which plays a central role in regulating cartilage and bone formation, induces vascular invasion and differentiation of osteoprogenitor cells to promote and maintain extracellular matrix production by mediating the adaptive response of cells to changes in oxygen levels. However, the application of HIF-1α in bone tissue engineering is still controversial. As such, clarifying the function of HIF-1α in regulating the bone regeneration process is one of the urgent issues that need to be addressed. This review provides insight into the mechanisms of HIF-1α action in bone regeneration and related recent advances. It also describes current strategies for applying hypoxia induction and hypoxia mimicry in bone tissue engineering, providing theoretical support for the use of HIF-1α in establishing a novel and feasible bone repair strategy in clinical settings.
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Affiliation(s)
- Jiaqian You
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun 130021, China
- School of Stomatology, Jilin University, Changchun 130021, China
| | - Manxuan Liu
- School of Stomatology, Jilin University, Changchun 130021, China
| | - Minghui Li
- School of Stomatology, Jilin University, Changchun 130021, China
| | - Shaobo Zhai
- School of Stomatology, Jilin University, Changchun 130021, China
| | - Sezhen Quni
- School of Stomatology, Jilin University, Changchun 130021, China
| | - Lu Zhang
- School of Stomatology, Jilin University, Changchun 130021, China
| | - Xiuyu Liu
- School of Stomatology, Jilin University, Changchun 130021, China
| | - Kewen Jia
- School of Stomatology, Jilin University, Changchun 130021, China
| | - Yidi Zhang
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun 130021, China
- School of Stomatology, Jilin University, Changchun 130021, China
| | - Yanmin Zhou
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun 130021, China
- School of Stomatology, Jilin University, Changchun 130021, China
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9
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miR-494-5p mediates the antioxidant activity of EPA by targeting the mitochondrial elongation factor 1 gene MIEF1 in HepG2 cells. J Nutr Biochem 2023; 115:109279. [PMID: 36739098 DOI: 10.1016/j.jnutbio.2023.109279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 01/20/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023]
Abstract
Eicosapentaenoic acid (EPA) shows antioxidant activity, which may be attributed to its regulatory effect on microRNA expression. Our preliminary study indicated that EPA upregulated miR-494-5p, which was possibly involved in the regulation of cellular stress responses. The current study aimed to address whether miR-494-5p was targeted by EPA to regulate cellular oxidative stress and its possible functional mechanism. The results showed that miR-494-5p mediated the antioxidant effect of EPA and miR-494-5p reduction deteriorated EPA-induced increase in the cellular antioxidant capacity of HepG2 cells. Moreover, the mitochondrial elongation factor 1 (MIEF1) gene was a target gene of miR-494-5p. Both miR-494-5p overexpression and MIEF1 knockdown significantly enhanced cellular antioxidant capacity, as indicated by a reduction in the reactive oxygen species level and an increase in the total cellular antioxidant capacity, along with enhancing antioxidant enzymes. Thus, miR-494-5p and MIEF1 had opposite effects on cellular antioxidant capacity. Furthermore, their regulatory effects on oxidative stress may have been attributed to modulation of mitochondrial function, biogenesis and homeostasis. Taken together, the findings indicated that miR-494-5p mediated EPA activity and promoted cellular antioxidant capacity by inhibiting the expression of MIEF1, which further modulated mitochondrial structure and activity. This study may provide novel insights into the post-translational regulation of antioxidation reactions, which involves the coordinated control of mitochondria.
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10
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Zhu SF, Yuan W, Du YL, Wang BL. Research progress of lncRNA and miRNA in hepatic ischemia-reperfusion injury. Hepatobiliary Pancreat Dis Int 2023; 22:45-53. [PMID: 35934611 DOI: 10.1016/j.hbpd.2022.07.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 07/18/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatic ischemia-reperfusion injury (HIRI) is a common complication of liver surgeries, such as hepatectomy and liver transplantation. In recent years, several non-coding RNAs (ncRNAs) including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been identified as factors involved in the pathological progression of HIRI. In this review, we summarized the latest research on lncRNAs, miRNAs and the lncRNA-miRNA regulatory networks in HIRI. DATA SOURCES The PubMed and Web of Science databases were searched for articles published up to December 2021 using the following keywords: "hepatic ischemia-reperfusion injury", "lncRNA", "long non-coding RNA", "miRNA" and "microRNA". The bibliography of the selected articles was manually screened to identify additional studies. RESULTS The mechanism of HIRI is complex, and involves multiple lncRNAs and miRNAs. The roles of lncRNAs such as AK139328, CCAT1, MALAT1, TUG1 and NEAT1 have been established in HIRI. In addition, numerous miRNAs are associated with apoptosis, autophagy, oxidative stress and cellular inflammation that accompany HIRI pathogenesis. Based on the literature, we conclude that four lncRNA-miRNA regulatory networks mediate the pathological progression of HIRI. Furthermore, the expression levels of some lncRNAs and miRNAs undergo significant changes during the progression of HIRI, and thus are potential prognostic markers and therapeutic targets. CONCLUSIONS Complex lncRNA-miRNA-mRNA networks regulate HIRI progression through mutual activation and antagonism. It is necessary to screen for more HIRI-associated lncRNAs and miRNAs in order to identify novel therapeutic targets.
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Affiliation(s)
- Shan-Fei Zhu
- Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou 510220, China
| | - Wei Yuan
- Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou 510220, China
| | - Yong-Liang Du
- Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou 510220, China
| | - Bai-Lin Wang
- Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou 510220, China.
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11
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Ren W, Zhao F, Han Y, Liu Z, Zhai J, Jia K. Muscone improves hypoxia/reoxygenation (H/R)-induced neuronal injury by blocking HMGB1/TLR4/NF-κB pathway via modulating microRNA-142. PeerJ 2022; 10:e13523. [PMID: 35860039 PMCID: PMC9290999 DOI: 10.7717/peerj.13523] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 05/10/2022] [Indexed: 01/25/2023] Open
Abstract
Previous reports have indicated that natural muscone has neuroprotective effects against cerebral hypoxia injury; however, little is known in regards to its pharmacological mechanism. In this study, we tried to evaluate the neuroprotective effects and mechanisms of muscone against cerebral hypoxia injury using an in vitro model. The cerebral hypoxia injury cell model was produced by hypoxia/reoxygenation (H/R). The cell viability and apoptosis were measured using the cell counting Kit-8 and the Annexin V-FITC/PI Apoptosis Detection kit, respectively. To screen microRNAs regulated by muscone, we analyzed the gene expression datasets of GSE84216 retrieved from gene expression omnibus (GEO). Here, it was demonstrated that muscone treatment significantly alleviated the cell apoptosis, oxidative stress and inflammation in H/R-exposed neurons. Subsequently, through analyzing GSE84216 from the GEO database, miR-142-5p was markedly upregulated by treatment of muscone in this cell model of cerebral hypoxia injury. Further experiments revealed that downregulation of miR-142-5p eliminated the neuroprotective effects of muscone against H/R induced neuronal injury. Additionally, high mobility group box 1 (HMGB1), an important inflammatory factor, was identified as a direct target of miR-142-5p in neurons. Meanwhile, we further demonstrated that muscone could reduce the expression of HMGB1 by upregulating miR-142-5p expression, which subsequently resulted in the inactivation of TLR4/NF-κB pathway, finally leading to the improvement of cell injury in H/R-exposed neurons. Overall, we demonstrate for the first time that muscone treatment alleviates cerebral hypoxia injury in in vitro experiments through blocking activation of the TLR4/NF-κB signaling pathway by targeting HMGB1, suggesting that muscone may serve as a potential therapeutic drug for treating cerebral hypoxia injury.
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12
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Wu Y, Qiu G, Zhang H, Zhu L, Cheng G, Wang Y, Li Y, Wu W. Dexmedetomidine alleviates hepatic ischaemia-reperfusion injury via the PI3K/AKT/Nrf2-NLRP3 pathway. J Cell Mol Med 2021; 25:9983-9994. [PMID: 34664412 PMCID: PMC8572787 DOI: 10.1111/jcmm.16871] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 08/02/2021] [Accepted: 08/10/2021] [Indexed: 12/22/2022] Open
Abstract
Hepatic ischaemia-reperfusion (I/R) injury constitutes a tough difficulty in liver surgery. Dexmedetomidine (Dex) plays a protective role in I/R injury. This study investigated protective mechanism of Dex in hepatic I/R injury. The human hepatocyte line L02 received hypoxia/reoxygenation (H/R) treatment to stimulate cell model of hepatic I/R. The levels of pyroptosis proteins and inflammatory factors were detected. Functional rescue experiments were performed to confirm the effects of miR-494 and JUND on hepatic I/R injury. The levels of JUND, PI3K/p-PI3K, AKT/p-AKT, Nrf2, and NLRP3 activation were detected. The rat model of hepatic I/R injury was established to confirm the effect of Dex in vivo. Dex reduced pyroptosis and inflammation in H/R cells. Dex increased miR-494 expression, and miR-494 targeted JUND. miR-494 inhibition or JUND upregulation reversed the protective effect of Dex. Dex repressed NLRP3 inflammasome by activating the PI3K/AKT/Nrf2 pathway. In vivo experiments confirmed the protective effect of Dex on hepatic I/R injury. Overall, Dex repressed NLRP3 inflammasome and alleviated hepatic I/R injury via the miR-494/JUND/PI3K/AKT/Nrf2 axis.
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Affiliation(s)
- Yan Wu
- Department of AnesthesiologyThe First Affiliated Hospital of Anhui University of Chinese MedicineHefeiChina
| | - Gaolin Qiu
- Department of AnesthesiologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiChina
| | - Hainie Zhang
- Department of AnesthesiologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiChina
| | - Leilei Zhu
- Department of AnesthesiologyThe Fourth Affiliated Hospital of Anhui Medical UniversityHefeiChina
| | - Gao Cheng
- Department of AnesthesiologyThe Fourth Affiliated Hospital of Anhui Medical UniversityHefeiChina
| | - Yiqiao Wang
- Department of AnesthesiologyAnhui NO.2 Provincial People's HospitalHefeiChina
| | - Yuanhai Li
- Department of AnesthesiologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiChina
| | - Weiwei Wu
- Department of AnesthesiologyThe Fourth Affiliated Hospital of Anhui Medical UniversityHefeiChina
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13
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Targeted Sequencing Identifies the Genetic Variants Associated with High-altitude Polycythemia in the Tibetan Population. Indian J Hematol Blood Transfus 2021; 38:556-565. [PMID: 35747576 PMCID: PMC9209555 DOI: 10.1007/s12288-021-01474-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 07/12/2021] [Indexed: 12/01/2022] Open
Abstract
High-altitude polycythemia (HAPC) is characterized by excessive proliferation of erythrocytes, resulting from the hypobaric hypoxia condition in high altitude. The genetic variants and molecular mechanisms of HAPC remain unclear in highlanders. We recruited 141 Tibetan dwellers, including 70 HAPC patients and 71 healthy controls, to detect the possible genetic variants associated with the disease; and performed targeted sequencing on 529 genes associated with the oxygen metabolism and erythrocyte regulation, utilized unconditional logistic regression analysis and GO (gene ontology) analysis to investigate the genetic variations of HAPC. We identified 12 single nucleotide variants, harbored in 12 genes, associated with the risk of HAPC (4.7 ≤ odd ratios ≤ 13.6; 7.6E − 08 ≤ p-value ≤ 1E − 04). The pathway enrichment study of these genes indicated the three pathways, the PI3K-AKT pathway, JAK-STAT pathway, and HIF-1 pathway, are essential, which p-values as 3.70E − 08, 1.28 E − 07, and 3.98 E − 06, respectively. We are hopeful that our results will provide a reference for the etiology research of HAPC. However, additional genetic risk factors and functional investigations are necessary to confirm our results further.
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14
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Brewster LM, Bain AR, Garcia VP, Fandl HK, Stone R, DeSouza NM, Greiner JJ, Tymko MM, Vizcardo-Galindo GA, Figueroa-Mujica RJ, Villafuerte FC, Ainslie PN, DeSouza CA. Global REACH 2018: dysfunctional extracellular microvesicles in Andean highlander males with excessive erythrocytosis. Am J Physiol Heart Circ Physiol 2021; 320:H1851-H1861. [PMID: 33710927 DOI: 10.1152/ajpheart.00016.2021] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
High altitude-related excessive erythrocytosis (EE) is associated with increased cardiovascular risk. The experimental aim of this study was to determine the effects of microvesicles isolated from Andean highlanders with EE on endothelial cell inflammation, oxidative stress, apoptosis, and nitric oxide (NO) production. Twenty-six male residents of Cerro de Pasco, Peru (4,340 m), were studied: 12 highlanders without EE (age: 40 ± 4 yr; BMI: 26.4 ± 1.7; Hb: 17.4 ± 0.5 g/dL, Spo2: 86.9 ± 1.0%) and 14 highlanders with EE (43 ± 4 yr; 26.2 ± 0.9; 24.4 ± 0.4 g/dL; 79.7 ± 1.6%). Microvesicles were isolated, enumerated, and collected from plasma by flow cytometry. Human umbilical vein endothelial cells were cultured and treated with microvesicles from highlanders without and with EE. Microvesicles from highlanders with EE induced significantly higher release of interleukin (IL)-6 (89.8 ± 2.7 vs. 77.1 ± 1.9 pg/mL) and IL-8 (62.0 ± 2.7 vs. 53.3 ± 2.2 pg/mL) compared with microvesicles from healthy highlanders. Although intracellular expression of total NF-κB p65 (65.3 ± 6.0 vs. 74.9 ± 7.8.9 AU) was not significantly affected in cells treated with microvesicles from highlanders without versus with EE, microvesicles from highlanders with EE resulted in an ∼25% higher (P < 0.05) expression of p-NF-κB p65 (173.6 ± 14.3 vs. 132.8 ± 12.2 AU). Cell reactive oxygen species production was significantly higher (76.4.7 ± 5.4 vs. 56.7 ± 1.7% of control) and endothelial nitric oxide synthase (p-eNOS) activation (231.3 ± 15.5 vs. 286.6 ± 23.0 AU) and NO production (8.3 ± 0.6 vs. 10.7 ± 0.7 μM/L) were significantly lower in cells treated with microvesicles from highlanders with versus without EE. Cell apoptotic susceptibility was not significantly affected by EE-related microvesicles. Circulating microvesicles from Andean highlanders with EE increased endothelial cell inflammation and oxidative stress and reduced NO production.NEW & NOTEWORTHY In this study, we determined the effects of microvesicles isolated from Andean highlanders with excessive erythrocytosis (EE) on endothelial cell inflammation, oxidative stress, apoptosis, and NO production. Microvesicles from highlanders with EE induced a dysfunctional response from endothelial cells characterized by increased cytokine release and expression of active nuclear factor-κB and reduced nitric oxide production. Andean highlanders with EE exhibit dysfunctional circulating extracellular microvesicles that induce a proinflammatory, proatherogenic endothelial phenotype.
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Affiliation(s)
- L Madden Brewster
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder, Colorado
| | - Anthony R Bain
- Department of Kinesiology, University of Windsor, Windsor, Ontario, Canada
| | - Vinicius P Garcia
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder, Colorado
| | - Hannah K Fandl
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder, Colorado
| | - Rachel Stone
- Department of Kinesiology, University of Windsor, Windsor, Ontario, Canada
| | - Noah M DeSouza
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder, Colorado.,Faculty of Health and Social Development, Centre for Heart, Lung and Vascular Health, University of British Columbia Okanagan, Kelowna, British Columbia, Canada
| | - Jared J Greiner
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder, Colorado
| | | | | | | | | | - Philip N Ainslie
- Faculty of Health and Social Development, Centre for Heart, Lung and Vascular Health, University of British Columbia Okanagan, Kelowna, British Columbia, Canada
| | - Christopher A DeSouza
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder, Colorado
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Ning S, Li Z, Ji Z, Fan D, Wang K, Wang Q, Hua L, Zhang J, Meng X, Yuan Y. MicroRNA‑494 suppresses hypoxia/reoxygenation‑induced cardiomyocyte apoptosis and autophagy via the PI3K/AKT/mTOR signaling pathway by targeting SIRT1. Mol Med Rep 2020; 22:5231-5242. [PMID: 33174056 PMCID: PMC7646990 DOI: 10.3892/mmr.2020.11636] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 10/02/2020] [Indexed: 12/18/2022] Open
Abstract
Acute myocardial infarction can be caused by ischemia/reperfusion (I/R) injury; however, the mechanism underlying I/R is not completely understood. The present study investigated the functions and mechanisms underlying microRNA (miR)-494 in I/R-induced cardiomyocyte apoptosis and autophagy. Hypoxia/reoxygenation (H/R)-treated H9c2 rat myocardial cells were used as an in vitro I/R injury model. Apoptosis and autophagy were analyzed by Cell Counting Kit-8 assay, Lactic dehydrogenase and superoxide dismutase assay, flow cytometry, TUNEL staining and western blotting. Reverse transcription-quantitative PCR demonstrated that, H9c2 cells treated with 12 h hypoxia and 3 h reoxygenation displayed significantly downregulated miR-494 expression levels compared with control cells. Compared with the corresponding negative control (NC) groups, miR-494 mimic reduced H/R-induced cell apoptosis and autophagy, whereas miR-494 inhibitor displayed the opposite effects. Silent information regulator 1 (SIRT1) was identified as a target gene of miR-494. Furthermore, miR-494 inhibitor-mediated effects on H/R-induced cardiomyocyte apoptosis and autophagy were partially reversed by SIRT1 knockdown. Moreover, compared with si-NC, SIRT1 knockdown significantly increased the phosphorylation levels of PI3K, AKT and mTOR in H/R-treated and miR-494 inhibitor-transfected H9c2 cells. Collectively, the results indicated that miR-494 served a protective role against H/R-induced cardiomyocyte apoptosis and autophagy by directly targeting SIRT1, suggesting that miR-494 may serve as a novel therapeutic target for myocardial I/R injury.
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Affiliation(s)
- Shuwei Ning
- Laboratory of Cardiovascular Disease and Drug Research, Zhengzhou No. 7 People's Hospital, Zhengzhou, Henan 450016, P.R. China
| | - Zhiying Li
- Laboratory of Cardiovascular Disease and Drug Research, Zhengzhou No. 7 People's Hospital, Zhengzhou, Henan 450016, P.R. China
| | - Zhenyu Ji
- Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Dandan Fan
- Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Keke Wang
- Laboratory of Cardiovascular Disease and Drug Research, Zhengzhou No. 7 People's Hospital, Zhengzhou, Henan 450016, P.R. China
| | - Qian Wang
- Laboratory of Cardiovascular Disease and Drug Research, Zhengzhou No. 7 People's Hospital, Zhengzhou, Henan 450016, P.R. China
| | - Lei Hua
- Laboratory of Cardiovascular Disease and Drug Research, Zhengzhou No. 7 People's Hospital, Zhengzhou, Henan 450016, P.R. China
| | - Junyue Zhang
- Laboratory of Cardiovascular Disease and Drug Research, Zhengzhou No. 7 People's Hospital, Zhengzhou, Henan 450016, P.R. China
| | - Xiangguang Meng
- Laboratory of Cardiovascular Disease and Drug Research, Zhengzhou No. 7 People's Hospital, Zhengzhou, Henan 450016, P.R. China
| | - Yiqiang Yuan
- Department of Cardiovascular Internal Medicine, Henan Provincial Chest Hospital, Zhengzhou, Henan 450003, P.R. China
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Chemically Induced Hypoxia Enhances miRNA Functions in Breast Cancer. Cancers (Basel) 2020; 12:cancers12082008. [PMID: 32707933 PMCID: PMC7465874 DOI: 10.3390/cancers12082008] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/19/2020] [Accepted: 07/19/2020] [Indexed: 12/11/2022] Open
Abstract
In aggressively growing tumors, hypoxia induces HIF-1α expression promoting angiogenesis. Previously, we have shown that overexpression of oncogenic microRNAs (miRNAs, miRs) miR526b/miR655 in poorly metastatic breast cancer cell lines promotes aggressive cancer phenotypes in vitro and in vivo. Additionally, miR526b/miR655 expression is significantly higher in human breast tumors, and high miR526b/miR655 expression is associated with poor prognosis. However, the roles of miR526b/miR655 in hypoxia are unknown. To test the relationship between miR526b/miR655 and hypoxia, we used various in vitro, in silico, and in situ assays. In normoxia, miRNA-high aggressive breast cancer cell lines show higher HIF-1α expression than miRNA-low poorly metastatic breast cancer cell lines. To test direct involvement of miR526b/miR655 in hypoxia, we analyzed miRNA-high cell lines (MCF7-miR526b, MCF7-miR655, MCF7-COX2, and SKBR3-miR526b) compared to controls (MCF7 and SKBR3). CoCl2-induced hypoxia in breast cancer further promotes HIF-1α mRNA and protein expression while reducing VHL expression (a negative HIF-1α regulator), especially in miRNA-high cell lines. Hypoxia enhances oxidative stress, epithelial to mesenchymal transition, cell migration, and vascular mimicry more prominently in MCF7-miR526b/MCF7-miR655 cell lines compared to MCF7 cells. Hypoxia promotes inflammatory and angiogenesis marker (COX-2, EP4, NFκB1, VEGFA) expression in all miRNA-high cells. Hypoxia upregulates miR526b/miR655 expression in MCF7 cells, thus observed enhancement of hypoxia-induced functions in MCF7 could be attributed to miR526b/miR655 upregulation. In silico bioinformatics analysis shows miR526b/miR655 regulate PTEN (a negative regulator of HIF-1α) and NFκB1 (positive regulator of COX-2 and EP4) expression by downregulation of transcription factors NR2C2, SALL4, and ZNF207. Hypoxia-enhanced functions in miRNA-high cells are inhibited by COX-2 inhibitor (Celecoxib), EP4 antagonist (ONO-AE3-208), and irreversible PI3K/Akt inhibitor (Wortmannin). This establishes that hypoxia enhances miRNA functions following the COX-2/EP4/PI3K/Akt pathways and this pathway can serve as a therapeutic target to abrogate hypoxia and miRNA induced functions in breast cancer. In situ, HIF-1α expression is significantly higher in human breast tumors (n = 96) compared to non-cancerous control tissues (n = 20) and is positively correlated with miR526b/miR655 expression. In stratified tumor samples, HIF-1α expression was significantly higher in ER-positive, PR-positive, and HER2-negative breast tumors. Data extracted from the TCGA database also show a strong correlation between HIF-1α and miRNA-cluster expression in breast tumors. This study, for the first time, establishes the dynamic roles of miR526b/miR655 in hypoxia.
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17
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Orr WC, Fass R, Sundaram SS, Scheimann AO. The effect of sleep on gastrointestinal functioning in common digestive diseases. Lancet Gastroenterol Hepatol 2020; 5:616-624. [DOI: 10.1016/s2468-1253(19)30412-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 09/25/2019] [Accepted: 11/12/2019] [Indexed: 02/07/2023]
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Al Bawab AQ, Zihlif M, Jarrar Y, Sharab A. Continuous Hypoxia and Glucose Metabolism: The Effects on Gene Expression in Mcf7 Breast Cancer Cell Line. Endocr Metab Immune Disord Drug Targets 2020; 21:511-519. [PMID: 32370732 DOI: 10.2174/1871530320666200506082020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 03/23/2020] [Accepted: 03/26/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Hypoxia (deprived oxygen in tissues) may induce molecular and genetic changes in cancer cells. OBJECTIVE To Investigate the genetic changes of glucose metabolism in breast cancer cell line (MCF7) after exposure to continuous hypoxia (10 and 20 cycles exposure of 72 hours continuously on a weekly basis). METHODS Gene expression of MCF7 cells was evaluated using real-time polymerase chain reactionarray method. Furthermore, cell migration and wound healing assays were also applied. RESULTS It was found that 10 episodes of continuous hypoxia activated the Warburg effect in MCF7 cells, via the significant up-regulation of genes involved in glycolysis (ANOVA, p value < 0.05). The molecular changes were associated with the ability of MCF7 cells to divide and migrate. Interestingly, after 20 episodes of continuous hypoxia, the expression glycolysis mediated genes dropped significantly (from 30 to 9 folds). This could be attributed to the adaptive ability of cancer cells. CONCLUSION It is concluded that 10 hypoxic episodes increased the survival rate and aggressiveness of MCF7 cells and induced the Warburg effect by the up-regulation of the glycolysis mediating gene expression.
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Affiliation(s)
- Abdel Q Al Bawab
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman, Jordan
| | - Malek Zihlif
- Department of Pharmacology, Faculty of Medicine, University of Jordan, Amman, Jordan
| | - Yazan Jarrar
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman, Jordan
| | - Ahmad Sharab
- Department of Biology and Biotechnology, Faculty of Science, American University of Madaba, Madaba, Jordan
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19
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Taheem DK, Jell G, Gentleman E. Hypoxia Inducible Factor-1α in Osteochondral Tissue Engineering. TISSUE ENGINEERING. PART B, REVIEWS 2020; 26:105-115. [PMID: 31774026 PMCID: PMC7166133 DOI: 10.1089/ten.teb.2019.0283] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 11/19/2019] [Indexed: 12/19/2022]
Abstract
Damage to osteochondral (OC) tissues can lead to pain, loss of motility, and progress to osteoarthritis. Tissue engineering approaches offer the possibility of replacing damaged tissues and restoring joint function; however, replicating the spatial and functional heterogeneity of native OC tissue remains a pressing challenge. Chondrocytes in healthy cartilage exist in relatively low-oxygen conditions, while osteoblasts in the underlying bone experience higher oxygen pressures. Such oxygen gradients also exist in the limb bud, where they influence OC tissue development. The cellular response to these spatial variations in oxygen pressure, which is mediated by the hypoxia inducible factor (HIF) pathway, plays a central role in regulating osteo- and chondrogenesis by directing progenitor cell differentiation and promoting and maintaining appropriate extracellular matrix production. Understanding the role of the HIF pathway in OC tissue development may enable new approaches to engineer OC tissue. In this review, we discuss strategies to spatially and temporarily regulate the HIF pathway in progenitor cells to create functional OC tissue for regenerative therapies. Impact statement Strategies to engineer osteochondral (OC) tissue are limited by the complex and varying microenvironmental conditions in native bone and cartilage. Indeed, native cartilage experiences low-oxygen conditions, while the underlying bone is relatively normoxic. The cellular response to these low-oxygen conditions, which is mediated through the hypoxia inducible factor (HIF) pathway, is known to promote and maintain the chondrocyte phenotype. By using tissue engineering scaffolds to spatially and temporally harness the HIF pathway, it may be possible to improve OC tissue engineering strategies for the regeneration of damaged cartilage and its underlying subchondral bone.
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Affiliation(s)
- Dheraj K. Taheem
- Centre for Craniofacial and Regenerative Biology, King's College London, London, United Kingdom
| | - Gavin Jell
- Division of Surgery and Interventional Sciences, University College London, London, United Kingdom
| | - Eileen Gentleman
- Centre for Craniofacial and Regenerative Biology, King's College London, London, United Kingdom
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20
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Extracellular Vesicle lincRNA-p21 Expression in Tumor-Draining Pulmonary Vein Defines Prognosis in NSCLC and Modulates Endothelial Cell Behavior. Cancers (Basel) 2020; 12:cancers12030734. [PMID: 32244977 PMCID: PMC7140053 DOI: 10.3390/cancers12030734] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 03/12/2020] [Accepted: 03/18/2020] [Indexed: 12/21/2022] Open
Abstract
Hypoxia-induced upregulation of lincRNA-p21 in tumor tissue was previously shown by our group to be related to poor prognosis in resected non-small cell lung cancer (NSCLC) patients. In the present study, we have evaluated the presence of lincRNA-p21 in extracellular vesicles (EVs) from NSCLC patients and assessed its potential as a prognostic biomarker. High EV lincRNA-p21 levels in blood from the tumor-draining vein were associated with shorter time to relapse and shorter overall survival. Moreover, the multivariate analysis identified high lincRNA-p21 levels as an independent prognostic marker. In addition, lincRNA-p21 was overexpressed in H23 and HCC44 NSCLC cell lines and their derived EVs under hypoxic conditions. Functional assays using human umbilical vein endothelial cells (HUVECs) showed that tumor-derived EVs enriched in lincRNA-p21 affected endothelial cells by promoting tube formation and enhancing tumor cell adhesion to endothelial cells. Additionally, the analysis of selected EV microRNAs related to angiogenesis and metastasis showed that the microRNAs correlated with EV lincRNA-p21 levels in both patients and cell lines. Finally, EV co-culture with HUVEC cells increased the expression of microRNAs and genes related to endothelial cell activation. In conclusion, EV lincRNA-p21 acts as a novel prognosis marker in resected NSCLC patients, promoting angiogenesis and metastasis.
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21
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Hummitzsch L, Albrecht M, Zitta K, Hess K, Parczany K, Rusch R, Cremer J, Steinfath M, Haneya A, Faendrich F, Berndt R. Human monocytes subjected to ischaemia/reperfusion inhibit angiogenesis and wound healing in vitro. Cell Prolif 2020; 53:e12753. [PMID: 31957193 PMCID: PMC7048205 DOI: 10.1111/cpr.12753] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 11/15/2019] [Accepted: 12/13/2019] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVES The sequence of initial tissue ischaemia and consecutive blood flow restoration leads to ischaemia/reperfusion (I/R) injury, which is typically characterized by a specific inflammatory response. Migrating monocytes seem to mediate the immune response in ischaemic tissues and influence detrimental as well as regenerative effects during I/R injury. MATERIALS AND METHODS To clarify the role of classical monocytes in I/R injury, isolated human monocytes were subjected to I/R in vitro (3 hours ischaemia followed by 24 hours of reperfusion). Cellular resilience, monocyte differentiation, cytokine secretion, as well as influence on endothelial tube formation, migration and cell recovery were investigated. RESULTS We show that I/R supported an enhanced resilience of monocytes and induced intracellular phosphorylation of the prosurvival molecules Erk1/2 and Akt. FACS analysis showed no major alteration in monocyte subtype differentiation and surface marker expression under I/R. Further, our experiments revealed that I/R changes the cytokine secretion pattern, release of angiogenesis associated proteins and MMP-9 activity in supernatants of monocytes exposed to I/R. Supernatants from monocytes subjected to I/R attenuated endothelial tube formation as indicator for angiogenesis as well as endothelial cell migration and recovery. CONCLUSION In summary, monocytes showed no significant change in cellular integrity and monocyte subtype after I/R. Functionally, monocytes might have a rather detrimental influence during the initial phase of I/R, suppressing endothelial cell migration and neoangiogenesis.
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Affiliation(s)
- Lars Hummitzsch
- Department of Anesthesiology and Intensive Care MedicineUniversity Hospital of Schleswig‐HolsteinKielGermany
| | - Martin Albrecht
- Department of Anesthesiology and Intensive Care MedicineUniversity Hospital of Schleswig‐HolsteinKielGermany
| | - Karina Zitta
- Department of Anesthesiology and Intensive Care MedicineUniversity Hospital of Schleswig‐HolsteinKielGermany
| | - Katharina Hess
- Institute of NeuropathologyUniversity Hospital MuensterMuensterGermany
| | - Kerstin Parczany
- Department of Anesthesiology and Intensive Care MedicineUniversity Hospital of Schleswig‐HolsteinKielGermany
| | - René Rusch
- Department of Cardiovascular SurgeryUniversity Hospital of Schleswig‐HolsteinKielGermany
| | - Jochen Cremer
- Department of Cardiovascular SurgeryUniversity Hospital of Schleswig‐HolsteinKielGermany
| | - Markus Steinfath
- Department of Anesthesiology and Intensive Care MedicineUniversity Hospital of Schleswig‐HolsteinKielGermany
| | - Assad Haneya
- Department of Cardiovascular SurgeryUniversity Hospital of Schleswig‐HolsteinKielGermany
| | - Fred Faendrich
- Department of Applied Cell TherapyUniversity Hospital of Schleswig‐HolsteinKielGermany
| | - Rouven Berndt
- Department of Cardiovascular SurgeryUniversity Hospital of Schleswig‐HolsteinKielGermany
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22
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Yamamoto M, Morita T, Ishikawa M, Sakamoto A. Specific microRNAs are involved in the reno‑protective effects of sevoflurane preconditioning and ischemic preconditioning against ischemia reperfusion injury in rats. Int J Mol Med 2020; 45:1141-1149. [PMID: 31985019 PMCID: PMC7053861 DOI: 10.3892/ijmm.2020.4477] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 01/08/2020] [Indexed: 01/14/2023] Open
Abstract
The kidneys are prone to developing ischemia reperfusion injury (IRI) following certain renal surgeries and cardiovascular surgeries requiring cardiac arrest. Sevoflurane and ischemic preconditioning reportedly alleviate IRI, which is mediated via microRNAs. The present study compared anesthetic preconditioning (APC) and ischemic preconditioning (IPC) on microRNAs, which promote cell‑survival pathways in rats in a randomized controlled study. After undergoing right nephrectomy under general anesthesia, male Wistar rats (336±24 g) and were divided into four groups (IRI, APC, IPC and sham; n=7 each). The IRI group underwent 45 min clamping of the left renal vasculature, followed by 4 h of reperfusion. APC involved exposure to one minimum alveolar concentration sevoflurane for 15 min. IPC included three cycles of two‑min clamping and five‑min reperfusion. Blood and renal biopsy samples were assessed postoperatively to measure serum creatinine and to analyze renal microRNA (miR) expression using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) testing and their target pathways with Ingenuity Pathway Analysis™. The present study found that serum creatinine values in APC (0.71±0.08 mg/dl) and IPC (0.73±0.1 mg/dl) groups were lower than in the IRI group (0.96±0.13 mg/dl; P<0.05), indicating amelioration of IRI by APC and IPC. RT‑qPCR followed by pathway analysis indicated that APC and IPC affect 'protein kinase B (Akt)'. APC promoted miR‑17‑3p and suppressed miR‑27a. IPC promoted miR‑19a. All the miRs were predicted to regulate phosphorylated Akt, which promotes cell‑protection. Western blot analysis showed that expression of phosphorylated Akt increased and phosphatase and tensin homologue deleted from chromosome 10 (PTEN) decreased following APC and IPC. The present study concluded that APC and IPC affect different miRs, although they are estimated to similarly promote the PTEN/phosphoinositide 3‑kinase/Akt signaling pathway, resulting in reno‑protection.
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Affiliation(s)
- Makiko Yamamoto
- Department of Anesthesiology and Pain Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo 1138602, Japan
| | - Tomonori Morita
- Department of Anesthesiology and Pain Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo 1138602, Japan
| | - Masashi Ishikawa
- Department of Anesthesiology and Pain Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo 1138602, Japan
| | - Atsuhiro Sakamoto
- Department of Anesthesiology and Pain Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo 1138602, Japan
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Ouyang Y, Li C, Du X, Liu C. Effect of Endothelial Growth Factor on Flap Surgical Delay. Plast Reconstr Surg 2019; 144:1116e-1117e. [PMID: 31764691 DOI: 10.1097/prs.0000000000006219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- Yiye Ouyang
- Plastic Surgery Hospital (Institute), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People's Republic of China
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24
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Protective Role of mTOR in Liver Ischemia/Reperfusion Injury: Involvement of Inflammation and Autophagy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:7861290. [PMID: 31827701 PMCID: PMC6885218 DOI: 10.1155/2019/7861290] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 08/24/2019] [Accepted: 10/14/2019] [Indexed: 02/06/2023]
Abstract
Liver ischemia/reperfusion (IR) injury is a common phenomenon after liver resection and transplantation, which often results in liver graft dysfunction such as delayed graft function and primary nonfunction. The mammalian target of rapamycin (mTOR) is an evolutionarily highly conserved serine/threonine protein kinase, which coordinates cell growth and metabolism through sensing environmental inputs under physiological or pathological conditions, involved in the pathophysiological process of IR injury. In this review, we mainly present current evidence of the beneficial role of mTOR in modulating inflammation and autophagy under liver IR to provide some evidence for the potential therapies for liver IR injury.
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Cui R, Ye S, Zhong J, Liu L, Li S, Lin X, Yuan L, Yi L. MicroRNA‑494 inhibits apoptosis of murine vascular smooth muscle cells in vitro. Mol Med Rep 2019; 19:4457-4467. [PMID: 30942414 DOI: 10.3892/mmr.2019.10085] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 01/21/2019] [Indexed: 11/05/2022] Open
Abstract
Apoptosis of vascular smooth muscle cells (VSMCs) is a process that regulates vessel remodeling in various cardiovascular diseases. The specific mechanisms that control VSMC apoptosis remain unclear. The present study aimed to investigate whether microRNA‑494 (miR‑494) is involved in regulating VSMC apoptosis and its underlying mechanisms. Cell death ELISA and terminal deoxynucleotidyl‑transferase‑mediated dUTP nick end labeling assays were used to detect apoptosis of murine VSMCs following stimulation with tumor necrosis factor‑α (TNF‑α). The results indicated that TNF‑α upregulated VSMC apoptosis in a dose‑dependent manner. Microarray analysis was used to evaluate the expression profile of microRNAs following TNF‑α stimulation in murine VSMCs. The expression of miR‑494 was downregulated, whereas B‑cell lymphoma-2‑like 11 (BCL2L11) protein expression levels were upregulated in VSMCs following treatment with TNF‑α. Luciferase reporter assays confirmed that BCL2L11 was a direct target of miR‑494. Transfection with miR‑494 mimics decreased VSMC apoptosis and downregulated BCL2L11 protein levels. Conversely, transfection with miR‑494 inhibitors increased cell apoptosis and upregulated BCL2L11 protein levels, suggesting that miR‑494 may function as an essential regulator of BCL2L11. The increase in apoptosis caused by miR‑494 inhibitors was abolished in cells co‑transfected with BCL2L11‑targeting small interfering RNA. The findings of the present study revealed that miR‑494 inhibited TNF‑α‑induced VSMC apoptosis by downregulating the expression of BCL2L11.
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Affiliation(s)
- Rongrong Cui
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Senlin Ye
- Department of Urologic Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Jiayu Zhong
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Lingjuan Liu
- Department of Pediatrics, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Shijun Li
- Department of Pediatrics, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Xiao Lin
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Lingqing Yuan
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Lu Yi
- Department of Urologic Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
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26
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Zonneveld MI, Keulers TGH, Rouschop KMA. Extracellular Vesicles as Transmitters of Hypoxia Tolerance in Solid Cancers. Cancers (Basel) 2019; 11:cancers11020154. [PMID: 30699970 PMCID: PMC6406242 DOI: 10.3390/cancers11020154] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 01/23/2019] [Accepted: 01/24/2019] [Indexed: 02/07/2023] Open
Abstract
Tumour hypoxia is a common feature of solid tumours that contributes to poor prognosis after treatment. This is mainly due to increased resistance of hypoxic cells to radio- and chemotherapy and the association of hypoxic cells with increased metastasis development. It is therefore not surprising that an increased hypoxic tumour fraction is associated with poor patient survival. The extent of hypoxia within a tumour is influenced by the tolerance of individual tumor cells to hypoxia, a feature that differs considerably between tumors. High numbers of hypoxic cells may, therefore, be a direct consequence of enhanced cellular capability inactivation of hypoxia tolerance mechanisms. These include HIF-1α signaling, the unfolded protein response (UPR) and autophagy to prevent hypoxia-induced cell death. Recent evidence shows hypoxia tolerance can be modulated by distant cells that have experienced episodes of hypoxia and is mediated by the systemic release of factors, such as extracellular vesicles (EV). In this review, the evidence for transfer of a hypoxia tolerance phenotype between tumour cells via EV is discussed. In particular, proteins, mRNA and microRNA enriched in EV, derived from hypoxic cells, that impact HIF-1α-, UPR-, angiogenesis- and autophagy signalling cascades are listed.
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Affiliation(s)
- Marijke I Zonneveld
- Maastricht Radiation Oncology (MaastRO) lab, GROW⁻School for Oncology and Developmental Biology, Maastricht University, 6200 MD Maastricht, The Netherlands.
| | - Tom G H Keulers
- Maastricht Radiation Oncology (MaastRO) lab, GROW⁻School for Oncology and Developmental Biology, Maastricht University, 6200 MD Maastricht, The Netherlands.
| | - Kasper M A Rouschop
- Maastricht Radiation Oncology (MaastRO) lab, GROW⁻School for Oncology and Developmental Biology, Maastricht University, 6200 MD Maastricht, The Netherlands.
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Zhang C, Su C, Song Q, Dong F, Yu S, Huo J. LncRNA PICART1 suppressed non-small cell lung cancer cells proliferation and invasion by targeting AKT1 signaling pathway. Am J Transl Res 2018; 10:4193-4201. [PMID: 30662662 PMCID: PMC6325487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 11/02/2018] [Indexed: 06/09/2023]
Abstract
LncRNAs play significant roles in various cell biological processes. In the present study, we demonstrated that PICART1 expression was down-regulated in non-small cell lung cancer (NSCLC) tissues. Lower expression level of PICART1 was associated with advanced stage. In addition, PICART1 expression was down-regulated in NSCLC cell lines. Overexpression of PICART1 inhibited NSCLC cell growth and induced cell cycle arrest at G2/M phase. Elevated expression of PICART1 suppressed NSCLC cell colony formation and cell invasion. Ectopic expression of PICART1 promoted the expression of epithelial marker E-cadherin while suppressed the mesenchymal marker expression such as N-cadherin and Snail and Vimentin. Furthermore, PICART1 overexpression suppressed AKT phosphorylation and c-Myc expression while inhibited the p21 expression in NSCLC cell. AKT phosphorylation was involved in PICART1 mediated suppression of cell growth and invasion. These results suggested that overexpression of PICART1 suppressed cell growth and invasion partly through regulating AKT signaling pathway in NSCLC.
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Affiliation(s)
- Chunling Zhang
- Department of Pulmonary Disease, The First Affiliated Hospital of Harbin Medical UniversityHarbin 150001, China
| | - Chuanzhi Su
- Department of Pulmonary Disease, Daqing Oil Field General HospitalDaqing 163001, China
| | - Qi Song
- Department of Pulmonary Disease, The First Affiliated Hospital of Harbin Medical UniversityHarbin 150001, China
| | - Fushi Dong
- Department of Pulmonary Disease, The First Affiliated Hospital of Harbin Medical UniversityHarbin 150001, China
| | - Shihuan Yu
- Department of Pulmonary Disease, The First Affiliated Hospital of Harbin Medical UniversityHarbin 150001, China
| | - Jianmin Huo
- Department of Pulmonary Disease, The First Affiliated Hospital of Harbin Medical UniversityHarbin 150001, China
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Tian H, Wu M, Zhou P, Huang C, Ye C, Wang L. The long non-coding RNA MALAT1 is increased in renal ischemia-reperfusion injury and inhibits hypoxia-induced inflammation. Ren Fail 2018; 40:527-533. [PMID: 30277425 PMCID: PMC6171433 DOI: 10.1080/0886022x.2018.1487863] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background: To investigate the expression of long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in renal ischemia-reperfusion injury and explore its role in acute kidney injury. Methods: 18 mice were randomly divided into a sham operation group (Sham) and an ischemia-reperfusion group (IR) in which animals were sacrificed at 6 h or 12 h after surgery. The kidneys were harvested to measure the expression of MALAT1 mRNA. HK2 cells were treated with cobalt chloride (CoCl2) to mimic hypoxia or transfected with siRNA to knockdown MALAT1 before CoCl2 treatment. After that, MALAT1 was analyzed by RT-PCR (reverse transcription-polymerase chain reaction). HIF-1ɑ (hypoxia-inducible factor-1 alpha) and NF-κB (nuclear factor-kappa B) was measured by Western blot. The concentrations of IL-6 (interleukin-6) and TNF-ɑ (tumor necrosis factor-alpha) in the media were detected by ELISA (enzyme-linked immunosorbent assay). Results: The expression of MALAT1 in the IR (6 h/12 h) group was significantly higher than that in the sham group. In HK2 cells, MALAT1 was significantly increased at 1 h, 3 h, and 6 h after CoCl2 treatment but had reduced to the basal level at 12 h and 24 h. Knockdown of MALAT1 by siRNA significantly up-regulated the expression of HIF-1ɑ and NF-κB proteins in CoCl2-treated HK2 cells. In addition, the concentrations of IL-6 and TNF-ɑ were increased by MALAT1 siRNA transfection in CoCl2-treated HK2 cells. Conclusion: The expression of MALAT1 is increased in renal ischemia-reperfusion injury. It is likely that MALAT1 inhibits the hypoxia-induced inflammatory response through the NF-κB pathway.
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Affiliation(s)
- Hongyan Tian
- a Department of Nephrology , The Ninth People's Hospital, Shanghai Jiaotong University School of Medicine , Shanghai , China
| | - Ming Wu
- b Department of Nephrology , Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine , Shanghai , China
| | - Peihui Zhou
- a Department of Nephrology , The Ninth People's Hospital, Shanghai Jiaotong University School of Medicine , Shanghai , China
| | - Chuiguo Huang
- c Department of Urology , the second affiliated hospital of Zhengzhou University , Zhengzhou , Henan , China
| | - Chaoyang Ye
- b Department of Nephrology , Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine , Shanghai , China
| | - Li Wang
- a Department of Nephrology , The Ninth People's Hospital, Shanghai Jiaotong University School of Medicine , Shanghai , China
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SIRT3 a Major Player in Attenuation of Hepatic Ischemia-Reperfusion Injury by Reducing ROS via Its Downstream Mediators: SOD2, CYP-D, and HIF-1 α. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:2976957. [PMID: 30538800 PMCID: PMC6258096 DOI: 10.1155/2018/2976957] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 09/30/2018] [Accepted: 10/08/2018] [Indexed: 12/14/2022]
Abstract
Reactive oxygen species (ROS) production in hepatic ischemia-reperfusion injury (IRI) is a complex process where multiple cellular and molecular pathways are involved. Few of those molecular pathways are under the direct influence of SIRT3 and its downstream mediators. SIRT3 plays a major role in the mechanism of IRI, and its activation has been shown to attenuate the deleterious effect of ROS during IRI via SOD2-, CYP-D-, and HIF-1α-mediated pathways. The objective of this review is to analyze the current knowledge on SIRT3 and its downstream mediators: SOD2, CYP-D, and HIF-1α, and their role in IRI. For the references of this review article, we have searched the bibliographic databases of PubMed, Web of Science databases, MEDLINE, and EMBASE with the headings "SIRT3," "SOD2," "CYP-D," "HIF-1α," and "liver IRI." Priority was given to recent experimental articles that provide information on ROS modulation by these proteins. All the recent advancement demonstrates that activation of SIRT3 can suppress ROS production during IRI through various pathways and few of those are via SOD2, CYP-D, and HIF-1α. This effect can improve the quality of the remnant liver following resection as well as a transplanted liver. More research is warranted to disclose its role in IRI attenuation via this pathway.
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Ge L, Wang Y, Cao Y, Li G, Sun R, Teng P, Wang Y, Bi Y, Guo Z, Yuan Y, Yu D. MiR-429 improved the hypoxia tolerance of human amniotic cells by targeting HIF-1α. Biotechnol Lett 2018; 40:1477-1486. [PMID: 30145667 DOI: 10.1007/s10529-018-2604-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 08/21/2018] [Indexed: 11/30/2022]
Abstract
MicroRNA-429(miR-429) plays an important role in mesenchymal stem cells. Hypoxia-inducible factor 1α (HIF-1α) is a nuclear transcription factor that regulates the proliferation, apoptosis and tolerance to hypoxia of mesenchymal stem cells. HIF-1α is also a target gene of miR-429. We investigated whether miR-429 plays a role in hypoxia tolerance with HIF-1α in human amniotic mesenchymal stem cells (hAMSCs). The expression of miR-429 was increased by hypoxia in hAMSCs. miR-429 expression resulted in decreased HIF-1α protein level, but little effect on HIF-1α mRNA. While overexpression of HIF-1α increased the survival rate and exhibited anti-apoptosis effects in hAMSCs under hypoxia, co-expression of miR-429 reduced survival and increased apoptosis. However, miR-429 silencing with HIF-1α overexpression stimulated cell survival and reduced apoptosis. Co-expression of HIF-1α and miR-429 reduced VEGF and Bcl-2 proteins and increased Bax and C-Caspase-3 levels in hAMSCs under hypoxia compared with cells expressing only HIF-1α; cells with HIF-1α overexpression and miR-429 silencing showed the opposite effects. These results indicate that HIF-1α and angomiR-429 reciprocally antagonized each other, while HIF-1α and antagomiR-429 interacted with each other to regulate survival and apoptosis in hAMSCs under hypoxia. miR-429 increased VEGF and Bcl-2 protein levels and decreased Bax and cleaved Caspase-3 protein levels by promoting the synthesis of HIF-1α. These results indicate that miR-429 negatively regulates the survival and anti-apoptosis ability of hAMSCs by mediating HIF-1α expression and improves the ability of hAMSCs to tolerate hypoxia.
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Affiliation(s)
- Lihao Ge
- Department of Orthopedics, The First Affiliated Hospital, Jinzhou Medical University, Jinzhou, 121001, China
| | - Yuyan Wang
- Department of Gynaecology and Obstetrics, The First Affiliated Hospital, Jinzhou Medical University, Jinzhou, 121001, China
| | - Yang Cao
- Department of Orthopedics, The First Affiliated Hospital, Jinzhou Medical University, Jinzhou, 121001, China
| | - Gang Li
- Department of Orthopedics, Tongji University School of Medicine, Shanghai Tenth People's Hospital, Shanghai, 200092, China
| | - Rui Sun
- Department of Orthopedics, The First Affiliated Hospital, Jinzhou Medical University, Jinzhou, 121001, China
| | - Peng Teng
- Department of Orthopedics, The First Affiliated Hospital, Jinzhou Medical University, Jinzhou, 121001, China
| | - Yansong Wang
- Department of Orthopedics, The First Affiliated Hospital, Jinzhou Medical University, Jinzhou, 121001, China
| | - Yunlong Bi
- Department of Orthopedics, The First Affiliated Hospital, Jinzhou Medical University, Jinzhou, 121001, China
| | - Zhanpeng Guo
- Department of Orthopedics, The First Affiliated Hospital, Jinzhou Medical University, Jinzhou, 121001, China
| | - Yajiang Yuan
- Department of Orthopedics, The First Affiliated Hospital, Jinzhou Medical University, Jinzhou, 121001, China
| | - Deshui Yu
- Department of Orthopedics, The First Affiliated Hospital, Jinzhou Medical University, Jinzhou, 121001, China.
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Tang ZP, Zhao W, Du JK, Ni X, Zhu XY, Lu JQ. miR-494 Contributes to Estrogen Protection of Cardiomyocytes Against Oxidative Stress via Targeting (NF-κB) Repressing Factor. Front Endocrinol (Lausanne) 2018; 9:215. [PMID: 29867756 PMCID: PMC5960695 DOI: 10.3389/fendo.2018.00215] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 04/16/2018] [Indexed: 11/13/2022] Open
Abstract
Oxidative stress plays a pivotal role in the initiation and progression of cardiac diseases. Estrogens have been demonstrated to exert pleiotropic cardioprotective effects, among which antioxidative stress is one of the key effects linking estrogens to cardioprotection. By using a microRNAs (miRs) microarray screening approach, we discovered an increase in miR-494, which is known to exert cardioprotective effects, in estrogen-treated cardiomyocytes. We hypothesized that the upregulation of miR-494 might contribute to estrogen-mediated cardioprotection against oxidative stress. We found that E2 stimulates miR-494 expression via ERα in both cardiomyocytes and the myocardium of female mice. The miR-494 inhibitor attenuated the protective effect of 17β-estradiol (E2) against oxidative stress-induced injury in cardiomyocytes. By contrast, the miR-494 mimic protected cardiomyocytes against oxidative stress-induced cardiomyocyte injury. Using real-time PCR, western blot and dual-luciferase reporter gene analyses, we identified nuclear factor kappa B (NF-κB) repressing factor (NKRF) as the miR-494 target in cardiomyocytes. E2 was found to inhibit NKRF, thus activating NF-κB through a miR-494-dependent mechanism. In addition, the protective effects of E2 and miR-494 against oxidative stress in cardiomyocytes were eliminated by the NF-κB inhibitor. In summary, this study demonstrates for the first time that estrogen inhibits NKRF expression through ERα-mediated upregulation of miR-494 in cardiomyocytes, leading to the activation of NF-κB, which in turn results in an increase in antioxidative defense. ERα-mediated upregulation of miR-494 may contribute to estrogen protection of cardiomyocytes against oxidative stress.
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Affiliation(s)
- Zhi-Ping Tang
- The Key Laboratory of Exercise and Health Sciences of Ministry of Education, School of Kinesiology, Shanghai University of Sport, Shanghai, China
- Department of Physiology, Second Military Medical University, Shanghai, China
- Research Laboratory of Burn and Trauma, PLA 181 Hospital, Guilin, China
| | - Wei Zhao
- Department of Physiology, Second Military Medical University, Shanghai, China
| | - Jian-kui Du
- Department of Physiology, Second Military Medical University, Shanghai, China
| | - Xin Ni
- Department of Physiology, Second Military Medical University, Shanghai, China
| | - Xiao-Yan Zhu
- Department of Physiology, Second Military Medical University, Shanghai, China
- *Correspondence: Xiao-Yan Zhu, ; Jian-Qiang Lu,
| | - Jian-Qiang Lu
- The Key Laboratory of Exercise and Health Sciences of Ministry of Education, School of Kinesiology, Shanghai University of Sport, Shanghai, China
- *Correspondence: Xiao-Yan Zhu, ; Jian-Qiang Lu,
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He Y, Bai J, Liu P, Dong J, Tang Y, Zhou J, Han P, Xing J, Chen Y, Yu X. miR-494 protects pancreatic β-cell function by targeting PTEN in gestational diabetes mellitus. EXCLI JOURNAL 2017; 16:1297-1307. [PMID: 29333131 PMCID: PMC5763094 DOI: 10.17179/excli2017-491] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Accepted: 11/18/2017] [Indexed: 12/13/2022]
Abstract
Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications characterized by insulin resistance and pancreatic β-cell dysfunction. Increasing evidence suggests that microRNAs (miRNAs) play key roles in the diverse types of diabetes, including GDM. However, the underlying mechanisms remain largely unknown. The purpose of this study is to investigate the role of microRNAs in GDM. The microarray data of dysregulated miRNAs in blood and placenta was retrieved in the GEO dataset under the accession number GSE19649. Quantitative reverse transcription PCR (qRT-PCR) was performed to analyze the expression levels of miR-494 in peripheral blood from twenty pairs of gestational diabetes (GDM) women and healthy women. Then, we investigated the effects of miR-494 on the insulin secretion of pancreatic β-cells. Moreover, the role of this miR-494 in regulating the proliferation and apoptosis of pancreatic β-cells were determined by MTT assay and flow cytometry, respectively in INS1 cells transfected with a miR-494 mimic or inhibitor. In addition, the direct target of miR-494 was confirmed using 3' untranslated region (UTR) luciferase reporter assay. Our data demonstrated that the miR-494 level was significantly decreased in the blood of GDM patients, and the low level was associated with a high concentration of blood glucose. Furthermore, overexpression of miR-494 improved pancreatic β-cell dysfunction by enhancing insulin secretion and total insulin content, inducing cell proliferation, and inhibiting cell apoptosis, whereas miR-494 knockdown exhibited decreased insulin secretion and proliferation, as well as stimulated apoptosis. In addition, phosphatase and tensin homolog (PTEN) which has been shown to play a pivotal role in apoptosis, was proved to be a direct target of miR-494 in pancreatic β-cells. More importantly, siRNA-induced downregulation of PTEN reversed the effects of miR-494 knockdown on insulin secretion, cell proliferation, and apoptosis of pancreatic β-cells.
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Affiliation(s)
- Yanfang He
- Department of Obstetrics and Gynecology; Affiliated Hospital of North China University of Science and Technology, Tangshan 063000, China
| | - Jie Bai
- Department of Obstetrics and Gynecology; Affiliated Hospital of North China University of Science and Technology, Tangshan 063000, China
| | - Ping Liu
- Department of Obstetrics and Gynecology; Affiliated Hospital of North China University of Science and Technology, Tangshan 063000, China
| | - Jianxin Dong
- Department of Obstetrics and Gynecology; Affiliated Hospital of North China University of Science and Technology, Tangshan 063000, China
| | - Yajuan Tang
- Department of Obstetrics and Gynecology; Affiliated Hospital of North China University of Science and Technology, Tangshan 063000, China
| | - Jianli Zhou
- Department of Obstetrics and Gynecology; Affiliated Hospital of North China University of Science and Technology, Tangshan 063000, China
| | - Ping Han
- Department of Obstetrics and Gynecology; Affiliated Hospital of North China University of Science and Technology, Tangshan 063000, China
| | - Jun Xing
- Department of Obstetrics and Gynecology; Affiliated Hospital of North China University of Science and Technology, Tangshan 063000, China
| | - Yan Chen
- Department of Obstetrics and Gynecology; Affiliated Hospital of North China University of Science and Technology, Tangshan 063000, China
| | - Xiangyang Yu
- Department of Obstetrics and Gynecology; Affiliated Hospital of North China University of Science and Technology, Tangshan 063000, China
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Liu KX, Chen Q, Chen GP, Huang JC, Huang JF, He XR, Lin T, Lin QC. Inhibition of microRNA-218 reduces HIF-1α by targeting on Robo1 in mice aortic endothelial cells under intermittent hypoxia. Oncotarget 2017; 8:104359-104366. [PMID: 29262646 PMCID: PMC5732812 DOI: 10.18632/oncotarget.22239] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 09/22/2017] [Indexed: 01/10/2023] Open
Abstract
OBJECTIVE To investigate the effects of miR-218 on expression of hypoxia-inducible factors 1α (HIF-1α), vascular endothelial growth factor (VEGF) and cell apoptosis in normal mice aortic endothelial cells under intermittent hypoxia (IH) condition. METHODS Anti-miR-218 inhibitor, miR-negative control and miR-218 mimic were used to tranfect the cells in different groups under IH condition. Both RT-PCR and Western blot were used to determine the expressions of HIF-1α and VEGF. Akt, p-Akt and cell apoptosis related proteins bcl-2, bax and caspase-3 and roundabout 1 (Robo1) were measured using Western blot. Cell apoptosis was evaluated by flow cytometry. Statistical analysis was performed using SPSS 18.0. RESULTS Expression of miR-218 was significantly up-regulated in the IH group and was significantly inhibited when cells were transfected with miR-218 inhibitor. Down regulation of miR-218 could reduce the expression of HIF-1α and VEGF under intermittent hypoxia condition. In cells transfected with miR-218 mimic, expression of HIF-1α and VEGF significantly increased compared with the control. However, when treated with LY294002, the expression of HIF-1α and VEGF both decreased. Apoptosis assay showed that down regulation of miR-218 could inhibit intermittent hypoxia induced cell apoptosis, decrease expression of caspase-3 and bax and increase expression of bcl-2 under intermittent hypoxia condition. At last, silencing Robo1 could significantly enhance the expression of HIF-1α under IH condition. CONCLUSION Inhibition of miR-218 could reduce the expression of HIF-1α and protect against IH-induced apoptosis in mice aortic endothelial cells. The effects were associated with PI3K/AKT pathway and might through targeting of Robo1.
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Affiliation(s)
- Kai-Xiong Liu
- Department of Respiratory Disease, The First Affiliated Hospital, Fujian Medical University, China
- Laboratory of Respiratory Disease of Fujian Medical University, Fuzhou, China
- Fujian Provincial Sleep-disordered Breathing Clinic Center, Fuzhou, China
| | - Qin Chen
- Integrated Chinese and Western Medicine Colleges, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Gong-Ping Chen
- Department of Respiratory Disease, The First Affiliated Hospital, Fujian Medical University, China
- Laboratory of Respiratory Disease of Fujian Medical University, Fuzhou, China
- Fujian Provincial Sleep-disordered Breathing Clinic Center, Fuzhou, China
| | - Jian-Chai Huang
- Department of Respiratory Disease, The First Affiliated Hospital, Fujian Medical University, China
- Laboratory of Respiratory Disease of Fujian Medical University, Fuzhou, China
- Fujian Provincial Sleep-disordered Breathing Clinic Center, Fuzhou, China
| | - Jie-Feng Huang
- Department of Respiratory Disease, The First Affiliated Hospital, Fujian Medical University, China
- Laboratory of Respiratory Disease of Fujian Medical University, Fuzhou, China
- Fujian Provincial Sleep-disordered Breathing Clinic Center, Fuzhou, China
| | - Xin-Ru He
- Department of Respiratory Disease, The First Affiliated Hospital, Fujian Medical University, China
- Laboratory of Respiratory Disease of Fujian Medical University, Fuzhou, China
- Fujian Provincial Sleep-disordered Breathing Clinic Center, Fuzhou, China
| | - Ting Lin
- Department of Respiratory Disease, The First Affiliated Hospital, Fujian Medical University, China
- Laboratory of Respiratory Disease of Fujian Medical University, Fuzhou, China
- Fujian Provincial Sleep-disordered Breathing Clinic Center, Fuzhou, China
| | - Qi-Chang Lin
- Department of Respiratory Disease, The First Affiliated Hospital, Fujian Medical University, China
- Laboratory of Respiratory Disease of Fujian Medical University, Fuzhou, China
- Fujian Provincial Sleep-disordered Breathing Clinic Center, Fuzhou, China
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Zhao C, Li Z, Ji L, Ma J, Ge RL, Cui S. PI3K-Akt Signal Transduction Molecules Maybe Involved in Downregulation of Erythroblasts Apoptosis and Perifosine Increased Its Apoptosis in Chronic Mountain Sickness. Med Sci Monit 2017; 23:5637-5649. [PMID: 29176544 PMCID: PMC5713146 DOI: 10.12659/msm.905739] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Background Chronic mountain sickness (CMS) has a higher incidence in the plateau region. The one of its principal characters is excessive erythrocytosis. The PI3K-Akt pathway plays an important role in the process of erythropoiesis, and could downregulate apoptosis by regulating apoptosis-related molecules. In this paper, we explored the change in apoptosis of erythroblasts and the effect of the PI3K-Akt signal pathway on erythroblasts apoptosis in CMS. Material/Methods A total of 22 CMS and 20 non-CMS participants were involved in this study. Bone marrow mononuclear cells were cultured and treated with celecoxib and perifosine in vitro for 72 hours. The apoptotic rate, the mRNA expressions of Akt, Bcl-xl, and caspase-9, and the protein expressions of Akt, p-Akt, Bcl-xl, and caspase-9 were determined by flow cytometry, quantitative RT-PCR, and western-blot technique. Results The apoptotic rate of cultured erythroblasts was lower in the CMS group than in the non-CMS group. It was increased after perifosine intervention. The mRNA and protein expressions of Akt and Bcl-xl were higher and caspase-9 was lower in the CMS group than the non-CMS group. Perifosine induced decreased Bcl-xl mRNA and proteins and p-Akt proteins, and increased caspase-9 mRNA and proteins in vitro. In the CMS group, the hemoglobin concentration was correlated with apoptotic rate negatively and with Bcl-xl mRNA positively in erythroblasts; the erythroblasts apoptotic rate was negatively associated with the Akt mRNA and Bcl-xl mRNA. Conclusion The erythroblasts apoptosis was downregulated and the PI3K-Akt signal pathway appeared to be involved in the mechanism of decreased erythroblasts apoptosis in CMS.
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Affiliation(s)
- Chengyu Zhao
- Department of Hematology, Affiliated Hospital of Qinghai University, Xining, Qinghai, China (mainland).,Research Center for High Altitude Medicine, Qinghai University, Xining, Qinghai, China (mainland)
| | - Zhanquan Li
- Department of Hematology, Affiliated Hospital of Qinghai University, Xining, Qinghai, China (mainland).,Research Center for High Altitude Medicine, Qinghai University, Xining, Qinghai, China (mainland)
| | - Linhua Ji
- Department of Hematology, Affiliated Hospital of Qinghai University, Xining, Qinghai, China (mainland).,Research Center for High Altitude Medicine, Qinghai University, Xining, Qinghai, China (mainland)
| | - Jie Ma
- Department of Hematology, Affiliated Hospital of Qinghai University, Xining, Qinghai, China (mainland).,Research Center for High Altitude Medicine, Qinghai University, Xining, Qinghai, China (mainland)
| | - Ri-Li Ge
- Research Center for High Altitude Medicine, Qinghai University, Xining, Qinghai, China (mainland)
| | - Sen Cui
- Department of Hematology, Affiliated Hospital of Qinghai University, Xining, Qinghai, China (mainland).,Research Center for High Altitude Medicine, Qinghai University, Xining, Qinghai, China (mainland)
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miR-494 up-regulates the PI3K/Akt pathway via targetting PTEN and attenuates hepatic ischemia/reperfusion injury in a rat model. Biosci Rep 2017; 37:BSR20170798. [PMID: 28842516 PMCID: PMC5603753 DOI: 10.1042/bsr20170798] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 08/20/2017] [Accepted: 08/22/2017] [Indexed: 01/11/2023] Open
Abstract
A rat HIRI model was constructed and treated with an intraperitoneal injection of agomir-miR-494 or agomir-NC (negative control) for 7 days after the surgery. The pathophysiological changes in sham-operated rats, HIRI, HIRI + agomir-miR-494, and HIRI + agomir-NC were compared. The effect of miR-494 was also assessed in an H2O2-induced apoptosis model. Hepatic AML12 cells were transfected with mimics NC or miR-494 mimics, followed by 6-h H2O2 treatment. Cell proliferation and apoptosis were detected by CCK8 assay and flow cytometry, respectively. Further, the miR-494 target gene was identified by luciferase reporter assay, and verified both in vitro and in vivo experiments. The activity of AKT pathway was further analyzed in vivo by Western blot. HIRI + agomir-miR-494 rats exhibited significantly higher miR-494 expression, lower serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and glutamate dehydrogenase (GLDH) level, lower hepatic MDA, TOA, and OSI, alleviated hepatic necrosis, reduced hepatocyte apoptosis, and decreased expression of apoptosis-related proteins, when compared with HIRI + agomir-NC rats (P<0.05 or 0.01). After H2O2 treatment, AML-12 cells transfected with miR-494 mimics had significantly higher proliferation and lower apoptosis rate compared with mimics NC group (P<0.01). PTEN was identified as an miR-494 target gene. PTEN expression was significantly down-regulated in AML12 cells transfected with miR-494 mimics, and was up-regulated by treatment of miR-494 inhibitor (P<0.01). Moreover, HIRI + agomir-miR-494 rats exhibited significantly lower PTEN expression, and higher p-AKT, p-mTOR, and p-p70S6K levels compared with HIRI + agomir-NC rats. Therefore, miR-494 protected rats against hepatic ischemia/reperfusion (I/R) injury through down-regulating its downstream target gene PTEN, leading to the activation of PI3K/AKT signaling pathway.
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Inhibition of miR-302 Suppresses Hypoxia-Reoxygenation-Induced H9c2 Cardiomyocyte Death by Regulating Mcl-1 Expression. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:7968905. [PMID: 28491238 PMCID: PMC5405583 DOI: 10.1155/2017/7968905] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 01/30/2017] [Accepted: 03/07/2017] [Indexed: 11/18/2022]
Abstract
MicroRNAs play important roles in cell proliferation, differentiation, and apoptosis, and their expression influences cardiomyocyte apoptosis resulting from ischemia-induced myocardial infarction. Here, we determined the role of miR expression in cardiomyocyte apoptosis during hypoxia and reoxygenation. The rat cardiomyocyte cell line H9c2 was incubated for 3 h in normal or hypoxia medium, followed by reoxygenation for 24 h and transfection with a miR-302 mimic or antagomir. The effect of miR-302 on myeloid leukemia cell-differentiation protein-1 (Mcl-1) expression was determined by western blot, real-time polymerase chain reaction, and luciferase reporter assays, with cell viability assays. We observed that miR-302 expression was elevated by hypoxia/reoxygenation injury and increased further or decreased by transfection of the miR-302 mimic or miR-302 antagomir, respectively. Additionally, elevated miR-302 levels increased apoptosis-related protein levels and cardiomyocyte apoptosis, and luciferase reporter assays revealed miR-302 binding to the Mcl-1 mRNA 3' untranslated region. Our findings suggested that miR-302 overexpression aggravated hypoxia/reoxygenation-mediated cardiomyocyte apoptosis by inhibiting antiapoptotic Mcl-1 expression, thereby activating proapoptotic molecules. Furthermore, results indicating cardiomyocyte rescue from hypoxia/reoxygenation injury following treatment with miR-302 antagomir suggested that miR-302 inhibition might constitute a therapeutic strategy for protection against cardiomyocyte apoptosis during hypoxia/reoxygenation injury.
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Hosszu A, Antal Z, Lenart L, Hodrea J, Koszegi S, Balogh DB, Banki NF, Wagner L, Denes A, Hamar P, Degrell P, Vannay A, Szabo AJ, Fekete A. σ1-Receptor Agonism Protects against Renal Ischemia-Reperfusion Injury. J Am Soc Nephrol 2017; 28:152-165. [PMID: 27056295 PMCID: PMC5198266 DOI: 10.1681/asn.2015070772] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Accepted: 03/05/2016] [Indexed: 11/03/2022] Open
Abstract
Mechanisms of renal ischemia-reperfusion injury remain unresolved, and effective therapies are lacking. We previously showed that dehydroepiandrosterone protects against renal ischemia-reperfusion injury in male rats. Here, we investigated the potential role of σ1-receptor activation in mediating this protection. In rats, pretreatment with either dehydroepiandrosterone or fluvoxamine, a high-affinity σ1-receptor agonist, improved survival, renal function and structure, and the inflammatory response after sublethal renal ischemia-reperfusion injury. In human proximal tubular epithelial cells, stimulation by fluvoxamine or oxidative stress caused the σ1-receptor to translocate from the endoplasmic reticulum to the cytosol and nucleus. Fluvoxamine stimulation in these cells also activated nitric oxide production that was blocked by σ1-receptor knockdown or Akt inhibition. Similarly, in the postischemic rat kidney, σ1-receptor activation by fluvoxamine triggered the Akt-nitric oxide synthase signaling pathway, resulting in time- and isoform-specific endothelial and neuronal nitric oxide synthase activation and nitric oxide production. Concurrently, intravital two-photon imaging revealed prompt peritubular vasodilation after fluvoxamine treatment, which was blocked by the σ1-receptor antagonist or various nitric oxide synthase blockers. In conclusion, in this rat model of ischemia-reperfusion injury, σ1-receptor agonists improved postischemic survival and renal function via activation of Akt-mediated nitric oxide signaling in the kidney. Thus, σ1-receptor activation might provide a therapeutic option for renoprotective therapy.
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Affiliation(s)
- Adam Hosszu
- MTA-SE Lendulet Diabetes Research Group and
- First Department of Pediatrics
| | | | | | | | | | | | | | | | - Adam Denes
- Laboratory of Neuroimmunology, Institute of Experimental Medicine, Budapest, Hungary; and
| | - Peter Hamar
- Institute of Pathophysiology, Semmelweis University, Budapest, Hungary
| | - Peter Degrell
- Department of Pathology, Moritz Kaposi General Hospital, Kaposvar, Hungary
| | - Adam Vannay
- MTA-SE Pediatrics and Nephrology Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary
| | - Attila J Szabo
- First Department of Pediatrics
- MTA-SE Pediatrics and Nephrology Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary
| | - Andrea Fekete
- MTA-SE Lendulet Diabetes Research Group and
- First Department of Pediatrics
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Cai F, Li J, Liu Y, Zhang Z, Hettiarachchi DS, Li D. Effect of ximenynic acid on cell cycle arrest and apoptosis and COX-1 in HepG2 cells. Mol Med Rep 2016; 14:5667-5676. [PMID: 27840952 DOI: 10.3892/mmr.2016.5920] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Accepted: 07/22/2016] [Indexed: 11/06/2022] Open
Abstract
Ximenynic acid is a conjugated enyne fatty acid, which is currently of interest due to its anti-inflammatory activity. Due to the association between inflammation and cancer, the present study was designed to investigate the anti‑cancer activity of ximenynic acid in the HepG2 human hepatoma cell line and the underlying mechanisms. The current study demonstrated the anti‑proliferation and pro‑apoptosis activities of ximenynic acid by cell viability assay and flow cytometry analysis. The expression of anti‑apoptosis protein silent information regulator T1 (SIRT1) was significantly suppressed by ximenynic acid. Furthermore, ximenynic acid blocked G1/S phase transition by inhibiting the protein expression of the cell cycle‑associated protein general control of amino acid synthesis yeast homolog like 2 (GCN5L2), and the mRNA expression of cyclin D3 and cyclin E1. Furthermore, ximenynic acid suppressed the expression of angiogenesis‑associated genes, including vascular endothelial growth factor (VEGF)‑B and VEGF‑C. Finally, ximenynic acid significantly inhibited the expression of cyclooxygenase‑1 (COX‑1) mRNA and protein, however COX‑2 expression was not reduced. The results of the present study suggested that ximenynic acid may inhibit growth of HepG2 cells by selective inhibition of COX‑1 expression, which leads to cell cycle arrest, and alters the apoptosis pathway and expression of angiogenic factors. The current study aimed to investigate whether ximenynic acid might be developed as novel anticancer agent.
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Affiliation(s)
- Fang Cai
- Department of Food Science and Nutrition, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China
| | - Jianying Li
- Institute of Developmental and Regenerative Biology, Hangzhou Normal University, Hangzhou, Zhejiang 310000, P.R. China
| | - Yandi Liu
- School of Pharmacy, Curtin Health Innovation Research Institute, Curtin University, Perth 02042G, Australia
| | - Zunyi Zhang
- Institute of Developmental and Regenerative Biology, Hangzhou Normal University, Hangzhou, Zhejiang 310000, P.R. China
| | - D S Hettiarachchi
- School of Pharmacy, Curtin Health Innovation Research Institute, Curtin University, Perth 02042G, Australia
| | - Duo Li
- Department of Food Science and Nutrition, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China
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Tian C, Zheng G, Zhuang H, Li X, Hu D, Zhu L, Wang T, You MJ, Zhang Y. MicroRNA-494 Activation Suppresses Bone Marrow Stromal Cell-Mediated Drug Resistance in Acute Myeloid Leukemia Cells. J Cell Physiol 2016; 232:1387-1395. [PMID: 27696394 DOI: 10.1002/jcp.25628] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Accepted: 09/30/2016] [Indexed: 12/21/2022]
Affiliation(s)
- Chen Tian
- Department of Hematology; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy; Tianjin Medical University Cancer Institute and Hospital; Tianjin People's Republic of China
| | - Guoguang Zheng
- State Key Laboratory of Experimental Hematology; Institute of Hematology and Blood Diseases Hospital; Chinese Academy of Medical Sciences and Peking Union Medical College; Tianjin People's Republic of China
| | - Hongqing Zhuang
- Department of Hematology; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy; Tianjin Medical University Cancer Institute and Hospital; Tianjin People's Republic of China
| | - Xubin Li
- Department of Hematology; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy; Tianjin Medical University Cancer Institute and Hospital; Tianjin People's Republic of China
| | - Dongzhi Hu
- Department of Hematology; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy; Tianjin Medical University Cancer Institute and Hospital; Tianjin People's Republic of China
| | - Lei Zhu
- Department of Hematology; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy; Tianjin Medical University Cancer Institute and Hospital; Tianjin People's Republic of China
| | - Tengteng Wang
- Department of Hematology; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy; Tianjin Medical University Cancer Institute and Hospital; Tianjin People's Republic of China
| | - Mingjian James You
- Department of Hematopathology; University of Texas MD Anderson Cancer Center; Houston Texas
| | - Yizhuo Zhang
- Department of Hematology; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy; Tianjin Medical University Cancer Institute and Hospital; Tianjin People's Republic of China
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Wu D, Chen B, Cui F, He X, Wang W, Wang M. Hypoxia-induced microRNA-301b regulates apoptosis by targeting Bim in lung cancer. Cell Prolif 2016; 49:476-83. [PMID: 27352910 PMCID: PMC6495957 DOI: 10.1111/cpr.12264] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Accepted: 04/27/2016] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVES Worldwide, lung cancer accounts for the majority of cancer-related deaths. Aberrant expression of miRNAs has increasingly been reported to be associated with tumour progression. This study aimed to explore the role of miR-301b in regulating apoptosis in lung cancer. MATERIALS AND METHODS Expression of miR-301b was assessed by real-time PCR in cell lines, human patient tissues and cells treated under hypoxia and DMOG. Scramble siRNA, miR-301b inhibitor and miR-301b mimics were transfected into lung cancer cells to determine their effects on apoptosis. Additionally, a mouse xenograft model was used to explore functions of miR-301b on apoptosis, in vivo. Finally, relationships between Bim and miR-301b levels were explored by luciferase reporter assay and Western blotting. RESULTS We found that miR-301b was highly expressed in lung cancer tissues and cell lines. Expression of miR-301b was induced by hypoxia, and miR-301b suppressed expression of Bim by targeting its 3'UTR. Functionally, ectopic expression of miR-301b enhanced cell population growth, reduced apoptosis and reduced sensitivity of cells to chemotherapy. In the xenograft model, overexpression of miR-301b promoted tumour growth. Additionally, miR-301b and Bim expression were inversely correlated in clinical lung cancer samples. CONCLUSIONS This study provides new insights into the function of miRNA-301b in lung cancer and suggests that miRNA-301b could be a potential molecular target for chemotherapy.
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Affiliation(s)
- Duoguang Wu
- Department of OncologyNanfangHospital Southern Medical UniversityGuangzhouChina
- Department of Thoracic SurgeryThe Sun Yat‐Sen Memorial Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Baishen Chen
- Department of OncologyNanfangHospital Southern Medical UniversityGuangzhouChina
- Department of Thoracic SurgeryThe Sun Yat‐Sen Memorial Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Fei Cui
- Department of OncologyNanfangHospital Southern Medical UniversityGuangzhouChina
- Department of Thoracic SurgeryThe Sun Yat‐Sen Memorial Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Xiaotian He
- Department of OncologyNanfangHospital Southern Medical UniversityGuangzhouChina
- Department of Thoracic SurgeryThe Sun Yat‐Sen Memorial Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Wenjian Wang
- Department of OncologyNanfangHospital Southern Medical UniversityGuangzhouChina
- Department of Thoracic SurgeryThe Sun Yat‐Sen Memorial Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Minghui Wang
- Department of OncologyNanfangHospital Southern Medical UniversityGuangzhouChina
- Department of Thoracic SurgeryThe Sun Yat‐Sen Memorial Hospital of Sun Yat‐Sen UniversityGuangzhouChina
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Covington SM, Bauler LD, Toledo-Pereyra LH. Akt: A Therapeutic Target in Hepatic Ischemia-Reperfusion Injury. J INVEST SURG 2016; 30:47-55. [PMID: 27463073 DOI: 10.1080/08941939.2016.1206999] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Liver transplantation is the second most common transplant procedure in the United States. A leading cause of post-transplantation organ dysfunction is I/R injury. During I/R injury, the serine/threonine kinase Akt is activated, stimulating downstream mediators to promote cellular survival. Due to the cellular effects of Akt, therapeutic manipulation of the Akt pathway can help reduce cellular damage during hepatic I/R that occurs during liver transplantation. OBJECTIVE A full description of therapeutic options available that target Akt to reduce hepatic I/R injury has not been addressed within the literature. The purpose of this review is to illuminate advances in the manipulation of Akt that can be used to therapeutically target I/R injury in the liver. METHODS An in depth literature review was performed using the Scopus and PubMed databases. A total of 75 published articles were utilized for this manuscript. Terminology searched includes a combination of "hepatic ischemia/reperfusion injury", "Akt/PKB", "preconditioning" and "postconditioning." RESULTS Four principal methods that reduce I/R injury include hepatic pre- and postconditioning, pharmacological intervention and future miRNA/gene therapy. Discussed therapies used serum alanine aminotransferase levels, liver histology and phosphorylation of downstream mediators to confirm the Akt protective effect. CONCLUSION The activation of Akt from the reviewed therapies has resulted in predictable reduction in hepatocyte damage using the previously mentioned measurements. In a clinical setting, these therapies could potentially be used in combination to achieve better outcomes in hepatic transplant patients. Evidence supporting reduced I/R injury through Akt activation warrants further studies in human clinical trials.
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Affiliation(s)
- Stephen M Covington
- a Michigan State University College of Osteopathic Medicine , East Lansing, Michigan , USA
| | - Laura D Bauler
- b Division of Epidemiology and Biostatistics , Western Michigan University Homer Stryker M.D. School of Medicine , Kalamazoo , Michigan , USA
| | - Luis H Toledo-Pereyra
- b Division of Epidemiology and Biostatistics , Western Michigan University Homer Stryker M.D. School of Medicine , Kalamazoo , Michigan , USA
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miR-190 Enhances HIF-Dependent Responses to Hypoxia in Drosophila by Inhibiting the Prolyl-4-hydroxylase Fatiga. PLoS Genet 2016; 12:e1006073. [PMID: 27223464 PMCID: PMC4880290 DOI: 10.1371/journal.pgen.1006073] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 04/30/2016] [Indexed: 02/07/2023] Open
Abstract
Cellular and systemic responses to low oxygen levels are principally mediated by Hypoxia Inducible Factors (HIFs), a family of evolutionary conserved heterodimeric transcription factors, whose alpha- and beta-subunits belong to the bHLH-PAS family. In normoxia, HIFα is hydroxylated by specific prolyl-4-hydroxylases, targeting it for proteasomal degradation, while in hypoxia the activity of these hydroxylases decreases due to low oxygen availability, leading to HIFα accumulation and expression of HIF target genes. To identify microRNAs required for maximal HIF activity, we conducted an overexpression screen in Drosophila melanogaster, evaluating the induction of a HIF transcriptional reporter. miR-190 overexpression enhanced HIF-dependent biological responses, including terminal sprouting of the tracheal system, while in miR-190 loss of function embryos the hypoxic response was impaired. In hypoxic conditions, miR-190 expression was upregulated and required for induction of HIF target genes by directly inhibiting the HIF prolyl-4-hydroxylase Fatiga. Thus, miR-190 is a novel regulator of the hypoxia response that represses the oxygen sensor Fatiga, leading to HIFα stabilization and enhancement of hypoxic responses.
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Elliott DM, Nagarkatti M, Nagarkatti PS. 3,39-Diindolylmethane Ameliorates Staphylococcal Enterotoxin B–Induced Acute Lung Injury through Alterations in the Expression of MicroRNA that Target Apoptosis and Cell-Cycle Arrest in Activated T Cells. J Pharmacol Exp Ther 2016; 357:177-87. [PMID: 26818958 PMCID: PMC4809322 DOI: 10.1124/jpet.115.226563] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 01/26/2016] [Indexed: 12/20/2022] Open
Abstract
3,39-Diindolylmethane (DIM), a natural indole found in cruciferous vegetables, has significant anti-cancer and anti-inflammatory properties. In this current study, we investigated the effects of DIM on acute lung injury (ALI) induced by exposure to staphylococcal enterotoxin B (SEB). We found that pretreatment of mice with DIM led to attenuation of SEB-induced inflammation in the lungs, vascular leak, and IFN-g secretion. Additionally, DIM could induce cell-cycle arrest and cell death in SEB-activated T cells in a concentration-dependent manner. Interestingly, microRNA (miRNA) microarray analysis uncovered an altered miRNA profile in lung-infiltrating mononuclear cells after DIM treatment of SEB-exposed mice. Moreover, computational analysis of miRNA gene targets and regulation networks indicated that DIM alters miRNA in the cell death and cell-cycle progression pathways. Specifically, DIM treatment significantly downregulated several miRNA and a correlative increase associated gene targets. Furthermore, overexpression and inhibition studies demonstrated that DIM-induced cell death, at least in part, used miR-222. Collectively, these studies demonstrate for the first time that DIM treatment attenuates SEB-induced ALI and may do so through the induction of microRNAs that promote apoptosis and cell-cycle arrest in SEB-activated T cells.
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Tay J, Tiao J, Hughes Q, Gilmore G, Baker R. Therapeutic Potential of miR-494 in Thrombosis and Other Diseases: A Review. Aust J Chem 2016. [DOI: 10.1071/ch16020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Functional nucleic acids, such as microRNAs (miRNAs), have been implicated in the pathophysiology of many diseases. The miRNA expression profiles of various cancers including haematological malignancies are well defined, but the role of miRNAs in haemostasis and the regulation of coagulation is poorly understood. We identified that miR-494 is oestrogen responsive and directly targets the anticoagulant protein, Protein S, as a mechanism for acquiring Protein S deficiency under high oestrogenic conditions such as during pregnancy and oral contraceptive use. Furthermore, previous studies have also characterised miR-494 to be involved in many biological processes. This paper reviews the current knowledge in the role of miRNAs in regulating haemostatic proteins and the known biological functions of miR-494, highlighting miR-494 as an emerging therapeutic target, with an overview of the strategy we have employed in identifying functional nucleic acids such as miRNAs that target haemostatic factors and the therapeutic potential of miR-494-directed therapy for the treatment of thrombotic disorders.
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Liu Y, Liu WB, Liu KJ, Ao L, Cao J, Zhong JL, Liu JY. Extremely Low-Frequency Electromagnetic Fields Affect the miRNA-Mediated Regulation of Signaling Pathways in the GC-2 Cell Line. PLoS One 2015; 10:e0139949. [PMID: 26439850 PMCID: PMC4595420 DOI: 10.1371/journal.pone.0139949] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 09/18/2015] [Indexed: 11/24/2022] Open
Abstract
Extremely low-frequency electromagnetic fields (ELF-EMFs) can affect male reproductive function, but the underlying mechanism of this effect remains unknown. miRNA-mediated regulation has been implicated as an important epigenetic mechanism for regulatory pathways. Herein, we profiled miRNA expression in response to ELF-EMFs in vitro. Mouse spermatocyte-derived GC–2 cells were intermittently exposed to a 50 Hz ELF-EMF for 72 h (5 min on/10 min off) at magnetic field intensities of 1 mT, 2 mT and 3 mT. Cell viability was assessed using the CCK–8 assay. Apoptosis and the cell cycle were analyzed with flow cytometry. miRNA expression was profiled using Affymetrix Mouse Genechip miRNA 3.0 arrays. Our data showed that the growth, apoptosis or cell cycle arrest of GC–2 cells exposed to the 50 Hz ELF-EMF did not significantly change. However, we identified a total of 55 miRNAs whose expression significantly changed compared with the sham group, including 19 differentially expressed miRNAs (7 miRNAs were upregulated, and 12 were downregulated) in the 1 mT exposure group and 36 (9 miRNAs were upregulated, and 27 were downregulated) in the 3 mT exposure group. The changes in the expression of 15 selected miRNAs measured by real-time PCR were consistent with the microarray results. A network analysis was used to predict core miRNAs and target genes, including miR-30e-5p, miR-210-5p, miR-196b-5p, miR-504-3p, miR-669c-5p and miR-455-3p. We found that these miRNAs were differentially expressed in response to different magnetic field intensities of ELF-EMFs. GO term and KEGG pathway annotation based on the miRNA expression profiling results showed that miRNAs may regulate circadian rhythms, cytokine-cytokine receptor interactions and the p53 signaling pathway. These results suggested that miRNAs could serve as potential biomarkers, and the miRNA-mediated regulation of signaling pathways might play significant roles in the biological effects of ELF-EMFs.
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Affiliation(s)
- Yong Liu
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, China
- College of Bioengineering, Chongqing University, Chongqing, China
| | - Wen-bin Liu
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Kai-jun Liu
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Lin Ao
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Jia Cao
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Julia Li Zhong
- College of Bioengineering, Chongqing University, Chongqing, China
- * E-mail: (JLZ); (JYL)
| | - Jin-yi Liu
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, China
- * E-mail: (JLZ); (JYL)
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Salvianolic acid A shows selective cytotoxicity against multidrug-resistant MCF-7 breast cancer cells. Anticancer Drugs 2015; 26:210-23. [PMID: 25419632 DOI: 10.1097/cad.0000000000000184] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Multidrug resistance (MDR) is a major cause for incurable breast cancer. Salvianolic acid A (SAA), the hydrophilic polyphenolic derivative of Salvia miltiorrhiza Bunge (Danshen/Red Sage), was examined for cytotoxicities to MDR MCF-7 human breast cancer cells and their parental counterparts. We have shown that SAA inhibited proliferation, caused cell cycle arrest at the S phase, and induced apoptosis dose dependently to the two kinds of cancer cells. However, the resistant cells were significantly susceptible to the inhibition of SAA compared with the parental cells. SAA increased the level of reactive oxygen species (ROS) by 6.2-fold in the resistant cells, whereas the level of SAA-induced ROS changed only by 1.6-fold in their parental counterparts. Thus, the data showed that the selective cytotoxicity resulted from the hypersensitivity of the resistant cells to the strongly elevated ROS by SAA. In addition, SAA-triggered apoptosis was associated with increased caspase-3 activity, disrupted mitochondrial membrane potential, downregulated Bcl-2 expression, and upregulated Bax expression in the resistant cells. Moreover, SAA downregulated the level of P-glycoprotein, which was overexpressed in the resistant cells. This indicated that SAA modulated MDR. Furthermore, SAA showed higher antitumor activity than did doxorubicin in xenografts established from the resistant cells. The present work raised a possibility that SAA might be considered a potential choice to overcome MDR for the selective susceptibility of the resistant breast cancer cells to SAA treatment.
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Guo Y, Feng L, Zhou Y, Sheng J, Long D, Li S, Li Y. Systematic review with meta-analysis: HIF-1α attenuates liver ischemia–reperfusion injury. Transplant Rev (Orlando) 2015; 29:127-34. [DOI: 10.1016/j.trre.2015.05.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 05/03/2015] [Indexed: 01/17/2023]
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Sun G, Peng H. HIF-1α-induced microRNA-210 reduces hypoxia-induced osteoblast MG-63 cell apoptosis. Biosci Biotechnol Biochem 2015; 79:1232-9. [PMID: 26037388 DOI: 10.1080/09168451.2014.1003128] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
To better understand the ischemic-hypoxia-induced fracture healing impairment, we determined in this study the microRNA-210 expression in broken bone specimens and in osteoblasts under hypoxia and then determined the influence of microRNA-210 overexpression on the osteoblast cell proliferation and apoptosis. Results demonstrated that microRNA-210 expression was upregulated with an association with HIF-1α overexpression in clinical human catagmatic tissues and was upregulated HIF-1α-dependently in response to hypoxia in osteoblast MG-63 cells. CCK-8 assay indicated that microRNA-210 upregulation by microRNA-210 mimics reduced the chemotherapeutic 5-FU-induced osteoblast cell death, and colony formation assay demonstrated that microRNA-210 mimics promoted osteoblast cells growth. Moreover, the microRNA-210 mimics transfection inhibited the hypoxia-induced MG-63 cell apoptosis via inhibiting the activation of caspase 3 and caspase 9. Therefore, our research indicated a protective role of microRNA-210 in response to hypoxia. And microRNA-210 might serve as a protective role in bone fracture healing.
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Affiliation(s)
- Guanwen Sun
- a Orthopaedics Department , Renmin Hospital of Wuhan University , Wuhan , China
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Morita T, Ishikawa M, Sakamoto A. Identical MicroRNAs Regulate Liver Protection during Anaesthetic and Ischemic Preconditioning in Rats: An animal study. PLoS One 2015; 10:e0125866. [PMID: 25974021 PMCID: PMC4431739 DOI: 10.1371/journal.pone.0125866] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 03/25/2015] [Indexed: 12/19/2022] Open
Abstract
Anaesthetic preconditioning (APC) and ischemic preconditioning (IPC) ameliorate liver ischemia-reperfusion (I/R) injury and are important for regulating hepatic I/R injury. MicroRNAs (miRNAs) are short, noncoding RNA molecules of 21-23 nucleotides in length, and are currently under intensive investigation regarding their ability to regulate gene expression in a wide range of species. miRNA activity is involved in controlling a wide range of biological functions and processes. We evaluated whether APC and IPC are mediated by the same miRNAs by performing comprehensive miRNA screening experiments in a rat model of hepatic I/R injury. Twenty-one rats were randomly divided into three groups (n = 7/group): control (mock preconditioning), APC, and IPC. Control rats were subjected to 60 min of hepatic ischemia followed by 4 h of reperfusion, whereas the APC and IPC groups were preconditioned with 2% sevoflurane and hepatic ischemia for 10 min prior to ischemia-reperfusion, respectively. Liver samples were collected to measure miRNA levels after 3 h of reperfusion, and gene networks and canonical pathways were identified using Ingenuity Pathway Analysis (IPA). Blood samples were collected to measure the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Although haemodynamic parameters did not vary among the groups, AST and ALT levels were significantly higher in the control group than in the APC and IPC groups. Comprehensive miRNA screening experiments revealed that most miRNAs altered in the APC group were common to those in the IPC group. IPA identified five miRNAs related to the Akt-glycogen synthase kinase-3β (GSK-3β)-cyclin D1 pathway that were significantly affected by both preconditioning strategies. The application of either APC or IPC to ameliorate hepatic I/R injury results in expression of several common miRNAs that are related to the Akt-GSK-cyclin D1 pathway.
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Affiliation(s)
- Tomonori Morita
- Department of Anesthesiology and Pain Medicine, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, Japan
| | - Masashi Ishikawa
- Department of Anesthesiology and Pain Medicine, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, Japan
| | - Atsuhiro Sakamoto
- Department of Anesthesiology and Pain Medicine, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, Japan
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Protective Effect of Berberine Pretreatment in Hepatic Ischemia/Reperfusion Injury of Rat. Transplant Proc 2015; 47:275-82. [DOI: 10.1016/j.transproceed.2015.01.010] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2014] [Accepted: 01/14/2015] [Indexed: 02/07/2023]
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