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Li Y, Fan C, Jiang F, Zhang J, Li Y, Jiang Y, Zhang R, Yu Z, Wang S. Identification of LIMK1 as a biomarker in clear cell renal cell carcinoma: from data mining to validation. J Cancer Res Clin Oncol 2025; 151:104. [PMID: 40056237 PMCID: PMC11890329 DOI: 10.1007/s00432-025-06146-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 02/20/2025] [Indexed: 03/10/2025]
Abstract
PURPOSE Clear cell renal cell carcinoma (ccRCC) is one of the most common types of renal cancer. LIM kinase 1 (LIMK1) reportedly plays an important role in tumorigenesis. However, the involvement of LIMK1 in the progression of ccRCC remains ambiguous. METHODS Based on the TCGA and CPTAC databases, the expression of LIMK1 in ccRCC was evaluated. In the TCGA-ccRCC cohort, the relationships between LIMK1 and immune cell infiltration as well as immune checkpoints were assessed. The high expression of LIMK1 in ccRCC was verified by qRT-PCR in four RCC cell lines. Immunohistochemistry was used to evaluate the expression of LIMK1 in clinical samples. The association between LIMK1 expression and survival prognosis was explored via Kaplan-Meier survival curve in the TCGA-ccRCC and local cohorts. The effects of LIMK1 knockdown on the proliferation, migration, and invasion abilities of RCC cells were evaluated via colony, CCK-8, wound healing, and Transwell assays. RESULTS Elevated expression level of LIMK1 was found in the TCGA-ccRCC cohort and was confirmed in RCC cell lines and clinical samples. Up-regulation of LIMK1 was found to be correlated with poor prognosis in TCGA-ccRCC and external cohorts. In addition, high-LIMK1 was associated with clinicopathological stage, immune cell infiltration and immune checkpoint in ccRCC. Importantly, knockdown of LIMK1 diminished the capability of proliferation, migration, and invasion in RCC cells. CONCLUSION LIMK1 may serve as a promising diagnostic and prognostic biomarker of ccRCC.
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Affiliation(s)
- Yifei Li
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Congcong Fan
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Feng Jiang
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Jingnan Zhang
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Yanzhen Li
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Yanjie Jiang
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Rui Zhang
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Zhixian Yu
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Siqi Wang
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
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Tambe PK, Shetty MP, Rana K, Bharati S. Targeted Modulation of Mitochondrial Oxidative Stress Ameliorates 5-Fluorouracil-Induced Renal Injury in BALB/c Mice. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2025; 2025:8892026. [PMID: 40225412 PMCID: PMC11986914 DOI: 10.1155/omcl/8892026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 02/15/2025] [Indexed: 04/15/2025]
Abstract
Background: The present study reports the protective effect conferred by scavenging mitochondrial oxidative stress (mtOS) in 5-fluorouracil (5-FU)-induced renal injury. Methods: 5-FU renal toxicity model was created by administering 5-FU (12 mg/kg b.w. intraperitoneally [i.p.], for 4 days) to male BALB/c mice. The protective effect of mitochondria-targeted antioxidant (MTA), Mito-TEMPO coadministered at a dosage of 0.1 mg/kg b.w. i.p., was established in terms of levels/expressions of renal injury markers, histopathological alterations, oxidative DNA damage, proinflammatory markers, mtOS, mitochondrial dysfunction, and modulation of apoptotic proteins and apoptotic cell death. Results: A significant rise in the levels of serum urea, uric acid, and creatinine was noted after 5-FU administration to the animals. Immunohistochemical and ELISA findings demonstrated significant decrease in podocin and conversely a significant increase in neutrophil gelatinase-associated lipocalin (NGAL) expression after 5-FU challenge. The histopathological analysis further revealed Bowman's capsule dilation, glomerular condensation, and vacuolar degeneration. Mito-TEMPO treatment significantly lowered renal injury markers, reversed the expressions of podocin and NGAL to normal, and restored normal histoarchitecture of renal tissue. Mitochondrial reactive oxygen species (mtROS), mtLPO, activity of mitochondrial enzyme complexes, and mitochondrial antioxidant defense status were significantly improved in Mito-TEMPO protected group as compared to the 5-FU group. Further, significantly decreased expression of 8-OHdG, reduction in apoptotic cell death, and modulation of apoptotic proteins Bax, Bcl-2, and caspase-3 were noted in Mito-TEMPO protected group, indicating its protective effect against 5-FU-induced renal injury. Conclusion: The approach of targeting mtOS using MTA, Mito-TEMPO, may prove as safe adjuvant in alleviating renal toxicity during 5-FU chemotherapy.
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Affiliation(s)
- Prasad Kisan Tambe
- Department of Nuclear Medicine, Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Maya P. Shetty
- Department of Nuclear Medicine, Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Komal Rana
- Manipal Government of Karnataka Bioincubator Advanced Research Centre, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Sanjay Bharati
- Department of Nuclear Medicine, Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal, Karnataka, India
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Jiang H, Wang Y, Duan X, Guo S, Fan X, Zhou T, Li J, He J, Yang J, Jin H. Spatially Resolved Metabolomics and Network Pharmacology Reveal Extract D Nephrotoxicity Mechanisms in Pleuropterus multiflorus Thunb. TOXICS 2025; 13:182. [PMID: 40137509 PMCID: PMC11946316 DOI: 10.3390/toxics13030182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Accepted: 02/25/2025] [Indexed: 03/29/2025]
Abstract
As a traditional Chinese medicine, the adverse hepatotoxicity effects of Pleuropterus multiflorus (Thunb.) Nakai (PM) have been documented. However, nephrotoxicity has been neglected as studies related to kidney toxicity mechanisms are limited. Our previous research reported that extract D [95% ethanol (EtOH) elution, PM-D] in a 70% EtOH PM extract showed more significant hepatotoxicity than other extracts. In the current study, PM-D was continuously administered to mice for 7 days at a dose of 2 g/kg (equivalent to a human dose of 219.8 mg/kg), which increased renal biochemical indexes and caused pathological kidney injury, suggesting renal toxicity. Therefore, network pharmacology and spatially resolved metabolomics were conducted to explore nephrotoxicity mechanisms underpinning PM-D. Network pharmacology indicated that BCL2, HSP90, ESR1, and CTNNB1 genes were core targets, while the phosphoinositide 3-kinase (PI3K)/protein kinase B(AKT)/signaling pathway was significantly enriched. Spatially resolved metabolomics indicated heterogeneous metabolite distribution in the kidney, further indicating that PM-D nephrotoxic metabolic pathways were enriched for α-linolenic acid and linoleic acid metabolism, pyrimidine metabolism, carnitine synthesis, and branched-chain fatty acid oxidation. Our comprehensive analyses highlighted that nephrotoxicity mechanisms were related to oxidative stress and apoptosis induced by disordered energy metabolism, lipid metabolism issues, and imbalanced nucleotide metabolism, which provide a platform for further research into PM nephrotoxicity mechanisms.
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Affiliation(s)
- Haiyan Jiang
- New Drug Safety Evaluation Center, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; (H.J.); (X.D.); (X.F.); (J.L.)
| | - Ying Wang
- National Institutes for Food and Drug Control, Beijing 102629, China;
| | - Xiaoyan Duan
- New Drug Safety Evaluation Center, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; (H.J.); (X.D.); (X.F.); (J.L.)
| | - Shushu Guo
- Department of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China;
| | - Xiaoyu Fan
- New Drug Safety Evaluation Center, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; (H.J.); (X.D.); (X.F.); (J.L.)
| | - Tianyu Zhou
- College of Pharmacy, Shaanxi University of Traditional Chinese Medicine, Xianyang 712046, China;
| | - Jie Li
- New Drug Safety Evaluation Center, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; (H.J.); (X.D.); (X.F.); (J.L.)
| | - Jiuming He
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China;
- NMPA Key Laboratory for Safety Research and Evaluation of Innovative Drug, Beijing 102206, China
| | - Jianbo Yang
- National Institutes for Food and Drug Control, Beijing 102629, China;
| | - Hongtao Jin
- New Drug Safety Evaluation Center, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; (H.J.); (X.D.); (X.F.); (J.L.)
- NMPA Key Laboratory for Safety Research and Evaluation of Innovative Drug, Beijing 102206, China
- Beijing Union-Genius Pharmaceutical Technology Development Co., Ltd., Beijing 100176, China
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Liu Z, Zhou Y, Lu J, Gong T, Ibáñez E, Cifuentes A, Lu W. Microfluidic biosensors for biomarker detection in body fluids: a key approach for early cancer diagnosis. Biomark Res 2024; 12:153. [PMID: 39639411 PMCID: PMC11622463 DOI: 10.1186/s40364-024-00697-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 11/22/2024] [Indexed: 12/07/2024] Open
Abstract
Early detection of cancer significantly improves patient outcomes, with biomarkers offering a promising avenue for earlier and more precise diagnoses. Microfluidic biosensors have emerged as a powerful tool for detecting these biomarkers in body fluids, providing enhanced sensitivity, specificity, and rapid analysis. This review focuses on recent advances in microfluidic biosensors from 2018 to 2024, detailing their operational principles, fabrication techniques, and integration with nanotechnology for cancer biomarker detection. Additionally, we have reviewed recent innovations in several aspects of microfluidic biosensors, such as novel detection technologies, nanomaterials and novel microfluidic chip structures, which significantly enhance detection capabilities. We highlight key biomarkers pertinent to early cancer detection and explore how these innovations in biosensor technology contribute to the evolving landscape of personalized medicine. We further explore how these technologies could be incorporated into clinical cancer diagnostic workflows to improve early detection and treatment outcomes. These innovations could help enable more precise and personalized cancer diagnostics. In addition, this review addresses several important issues such as enhancing the scalability and sensitivity of these biosensors in clinical settings and points out future possibilities of combining artificial intelligence diagnostics with microfluidic biosensors to optimize their practical applications. This overview aims to guide future research and clinical applications by addressing current challenges and identifying opportunities for further development in the field of biomarker research.
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Affiliation(s)
- Zhiting Liu
- School of Medicine and Health, Harbin Institute of Technology, 92 Xidazhi Street, Nangang District, Harbin, 150001, China
- National and Local Joint Engineering Laboratory for Synthesis Transformation and Separation of Extreme Environmental Nutrients, 92 Xidazhi Street, Nangang District, Harbin, 150001, China
| | - Yingyu Zhou
- School of Medicine and Health, Harbin Institute of Technology, 92 Xidazhi Street, Nangang District, Harbin, 150001, China.
- Zhengzhou Research Institute, Harbin Institute of Technology, Zhengzhou, Henan, China.
- National and Local Joint Engineering Laboratory for Synthesis Transformation and Separation of Extreme Environmental Nutrients, 92 Xidazhi Street, Nangang District, Harbin, 150001, China.
| | - Jia Lu
- School of Mechatronics Engineering, Harbin Institute of Technology, 92 Xidazhi Street, Nangang District, Harbin, 150001, China.
- Zhengzhou Research Institute, Harbin Institute of Technology, Zhengzhou, Henan, China.
| | - Ting Gong
- School of Medicine and Health, Harbin Institute of Technology, 92 Xidazhi Street, Nangang District, Harbin, 150001, China
- National and Local Joint Engineering Laboratory for Synthesis Transformation and Separation of Extreme Environmental Nutrients, 92 Xidazhi Street, Nangang District, Harbin, 150001, China
| | - Elena Ibáñez
- Laboratory of Foodomics, Institute of Food Science Research, CIAL, CSIC, Nicolás Cabrera 9, Madrid, 28049, Spain
| | - Alejandro Cifuentes
- Laboratory of Foodomics, Institute of Food Science Research, CIAL, CSIC, Nicolás Cabrera 9, Madrid, 28049, Spain
| | - Weihong Lu
- School of Medicine and Health, Harbin Institute of Technology, 92 Xidazhi Street, Nangang District, Harbin, 150001, China.
- Zhengzhou Research Institute, Harbin Institute of Technology, Zhengzhou, Henan, China.
- National and Local Joint Engineering Laboratory for Synthesis Transformation and Separation of Extreme Environmental Nutrients, 92 Xidazhi Street, Nangang District, Harbin, 150001, China.
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Wang S, Liu T, Ren C, Zhao Y, Qiao S, Zhang Y, Pang S. Heterogeneous graph inference with range constrainted L 2,1-collaborative matrix factorization for small molecule-miRNA association prediction. Comput Biol Chem 2024; 110:108078. [PMID: 38677013 DOI: 10.1016/j.compbiolchem.2024.108078] [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: 02/06/2024] [Revised: 04/03/2024] [Accepted: 04/16/2024] [Indexed: 04/29/2024]
Abstract
MicroRNAs (miRNAs) play a vital role in regulating gene expression and various biological processes. As a result, they have been identified as effective targets for small molecule (SM) drugs in disease treatment. Heterogeneous graph inference stands as a classical approach for predicting SM-miRNA associations, showcasing commendable convergence accuracy and speed. However, most existing methods do not adequately address the inherent sparsity in SM-miRNA association networks, and imprecise SM/miRNA similarity metrics reduce the accuracy of predicting SM-miRNA associations. In this research, we proposed a heterogeneous graph inference with range constrained L2,1-collaborative matrix factorization (HGIRCLMF) method to predict potential SM-miRNA associations. First, we computed the multi-source similarities of SM/miRNA and integrated these similarity information into a comprehensive SM/miRNA similarity. This step improved the accuracy of SM and miRNA similarity, ensuring reliability for the subsequent inference of the heterogeneity map. Second, we used a range constrained L2,1-collaborative matrix factorization (RCLMF) model to pre-populate the SM-miRNA association matrix with missing values. In this step, we developed a novel matrix decomposition method that enhances the robustness and formative nature of SM-miRNA edges between SM networks and miRNA networks. Next, we built a well-established SM-miRNA heterogeneous network utilizing the processed biological information. Finally, HGIRCLMF used this network data to infer unknown association pair scores. We implemented four cross-validation experiments on two distinct datasets, and HGIRCLMF acquired the highest areas under the curve, surpassing six state-of-the-art computational approaches. Furthermore, we performed three case studies to validate the predictive power of our method in practical application.
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Affiliation(s)
- Shudong Wang
- College of Computer Science and Technology, Qingdao Institute of Software, China University of Petroleum, Qingdao 266580, China
| | - Tiyao Liu
- College of Computer Science and Technology, Qingdao Institute of Software, China University of Petroleum, Qingdao 266580, China
| | - Chuanru Ren
- College of Computer Science and Technology, Qingdao Institute of Software, China University of Petroleum, Qingdao 266580, China
| | - Yawu Zhao
- College of Computer Science and Technology, Qingdao Institute of Software, China University of Petroleum, Qingdao 266580, China
| | - Sibo Qiao
- College of Computer Science and Technology, Qingdao Institute of Software, China University of Petroleum, Qingdao 266580, China
| | - Yuanyuan Zhang
- School of Information and Control Engineering, Qingdao University of Technology, Qingdao 266525, China.
| | - Shanchen Pang
- College of Computer Science and Technology, Qingdao Institute of Software, China University of Petroleum, Qingdao 266580, China
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Mansoori R, Kazemi S, Almasi D, Hosseini SM, Karim B, Nabipour M, Moghadamnia AA. Therapeutic benefit of melatonin in 5-fluorouracil-induced renal and hepatic injury. Basic Clin Pharmacol Toxicol 2024; 134:397-411. [PMID: 38129993 DOI: 10.1111/bcpt.13976] [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: 08/13/2023] [Revised: 12/06/2023] [Accepted: 12/20/2023] [Indexed: 12/23/2023]
Abstract
Nephrotoxicity and hepatotoxicity include increased oxidative stress and apoptosis; as a result, liver and kidney damage are related to its pathogenesis. These are significant side effects caused in cancer patients treated with 5-FU. In the research, 25 rats were divided into five groups, including control, 5-FU and 5-FU + 2.5, 5 and 10 mg/kg melatonin (MEL), and the protective impact of MEL against 5-FU-induced hepatorenal damage in rats was investigated. 5-FU caused significant harm, resulting in severe renal failure and histopathological changes. It also increased BUN, creatinine and hepatic function markers levels while decreasing superoxide dismutase and glutathione peroxidase activity. Additionally, 5-FU led to a notable increase in malondialdehyde content. However, MEL co-administration to rats reversed most biochemical and histologic effects. In the control and MEL + 5-FU groups, the values were comparable. The doses of MEL treatment had a significant positive impact on 5-FU-induced oxidative stress, apoptosis, lipid peroxidation and kidney damage. Our data concluded that MEL has an ameliorative effect on hepatorenal damage caused by 5-FU.
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Affiliation(s)
- Razieh Mansoori
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
- Department of Pharmacology and Toxicology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Sohrab Kazemi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Darya Almasi
- Department of Pharmacology and Toxicology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
- Pharmaceutical Sciences Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | | | - Bardia Karim
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Majid Nabipour
- Cancer Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Ali Akbar Moghadamnia
- Pharmaceutical Sciences Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
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Tavakoli Pirzaman A, Mansoori R, Hosseini SM, Abolhosseini A, Khosravi S, Moghadamnia AA, Kazemi S. The effect of melatonin on capecitabine-induced hepatic and renal toxicity in rats. Hum Exp Toxicol 2024; 43:9603271231223506. [PMID: 38179616 DOI: 10.1177/09603271231223506] [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] [Indexed: 01/06/2024]
Abstract
BACKGROUND Capecitabine (CAPE), an antimetabolite chemotherapy, can induce hepatic and renal toxicity. Melatonin (MEL), a neurohormone, possesses antioxidant, anti-apoptotic and anti-inflammatory effects. This study investigated the impact of MEL on capecitabine-induced hepatic and renal toxicity. METHODS AND MATERIALS Twenty-five male Wistar rats were categorized into five groups for the study. The groups included a control group, MEL10 group (rats receiving daily intraperitoneal injections of 5 mg/kg MEL), CAPE 500 group (rats receiving weekly intraperitoneal injections of 500 mg/kg CAPE), CAPE + MEL five group, and CAPE + MEL 10 group. All groups were treated for a duration of 6 weeks. Various hematological, serological, biochemical, and histopathological assessments were conducted to evaluate the objective of the study. RESULTS The administration of CAPE led to significant liver and kidney toxicity, as evidenced by elevated levels of malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NO), as well as serological markers including AST, ALT, ALP, BUN, and creatinine. CAPE exposure also resulted in a reduction in total antioxidant capacity (TAC) and glutathione peroxidase (GPx) levels. Histological examination revealed hyperemia in both liver and kidney tissues exposed to CAPE. However, treatment with MEL demonstrated positive effects. MEL administration alleviated oxidative stress, reduced levels of liver enzymes, BUN, and creatinine, and ameliorated histopathological degenerations. MEL also increased GPx and TAC levels. Moreover, MEL treatment aided in restoring the body weight that was lost due to CAPE exposure. CONCLUSION Our findings indicated that the administration of MEL in rats significantly enhanced the hepatic and renal toxicity induced by CAPE.
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Affiliation(s)
| | - Razieh Mansoori
- Department of Pharmacology and Toxicology, School of Medicine, Babol University of Medical Science, Babol, Iran
| | | | - Ali Abolhosseini
- Student Research Committee, Babol University of Medical Science, Babol, Iran
| | - Sahar Khosravi
- Cancer Research Center, Health Research Institute, Babol University of Medical Science, Babol, Iran
| | - Ali Akbar Moghadamnia
- Pharmaceutical Sciences Research Center, Health Research Institute, Babol University of Medical Science, Babol, Iran
| | - Sohrab Kazemi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Science, Babol, Iran
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Jarosz-Popek J, Eyileten C, Gager GM, Nowak A, Szwed P, Wicik Z, Palatini J, von Lewinski D, Sourij H, Siller-Matula JM, Postula M. The interaction between non-coding RNAs and SGLT2: A review. Int J Cardiol 2023; 398:131419. [PMID: 39492411 DOI: 10.1016/j.ijcard.2023.131419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 09/19/2023] [Accepted: 10/03/2023] [Indexed: 11/05/2024]
Abstract
Sodium-glucose cotransporter 2 (SGLT2, SLC5A2) is a promising target for a new class of drug primarily established as kidney-targeting as well as emerging class of glucose-lowering drugs in diabetes. Studies showed that SGLT2 inhibitors also have a systemic impact via indirectly targeting the heart and kidneys which exerts broad cardio- and nephroprotective effects. Additionally, as cancer cells tightly require glucose supply, studies also questioned how SGLT2 inhibitors impact molecular pathology and cellular metabolism in cancer hallmarks. However, the exact molecular mechanisms responsible for those benefits have not been fully discovered. MicroRNAs (miRNA) and circularRNAs (circRNAs) are endogenous, single-stranded, non-coding RNAs (ncRNAs) that can control protein-coding genes, affecting significant molecular and cellular processes regulating homeostasis. CircRNAs particularly regulate gene expression at the transcriptional and post-transcriptional level by sponging to miRNAs and by altering interactions between proteins.
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Affiliation(s)
- Joanna Jarosz-Popek
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland; Doctoral School, Medical University of Warsaw, Warsaw, Poland
| | - Ceren Eyileten
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland; Genomics Core Facility, Centre of New Technologies, University of Warsaw, Warsaw, Poland
| | - Gloria M Gager
- Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna 1090, Austria; Department of Clinical Pharmacology, Medical University of Vienna, Vienna 1090, Austria
| | - Anna Nowak
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland; Doctoral School, Medical University of Warsaw, Warsaw, Poland
| | - Piotr Szwed
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland
| | - Zofia Wicik
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland; Department of Neurochemistry, Institute of Psychiatry and Neurology, Sobieskiego 9 Street, Warsaw 02-957, Poland
| | - Jeff Palatini
- Genomics Core Facility, Centre of New Technologies, University of Warsaw, Warsaw, Poland
| | - Dirk von Lewinski
- Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Graz, Austria
| | - Harald Sourij
- Division of Endocrinology and Diabetology, Interdisciplinary Metabolic Medicine Trials Unit, Medical University of Graz, Graz, Austria
| | - Jolanta M Siller-Matula
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland; Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna 1090, Austria
| | - Marek Postula
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland.
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Yan H, Huang X, Xu J, Zhang Y, Chen J, Xu Z, Li H, Wang Z, Yang X, Yang B, He Q, Luo P. Chloroquine Intervenes Nephrotoxicity of Nilotinib through Deubiquitinase USP13-Mediated Stabilization of Bcl-XL. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2302002. [PMID: 37452432 PMCID: PMC10502815 DOI: 10.1002/advs.202302002] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/30/2023] [Indexed: 07/18/2023]
Abstract
Nephrotoxicity has become prominent due to the increase in the clinical use of nilotinib, a second-generation BCR-ABL1 inhibitor in the first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia. To date, the mechanism of nilotinib nephrotoxicity is still unknown, leading to a lack of clinical intervention strategies. Here, it is found that nilotinib could induce glomerular atrophy, renal tubular degeneration, and kidney fibrosis in an animal model. Mechanistically, nilotinib induces intrinsic apoptosis by specifically reducing the level of BCL2 like 1 (Bcl-XL) in both vascular endothelial cells and renal tubular epithelial cells, as well as in vivo. It is confirmed that chloroquine (CQ) intervenes with nilotinib-induced apoptosis and improves mitochondrial integrity, reactive oxygen species accumulation, and DNA damage by reversing the decreased Bcl-XL. The intervention effect is dependent on the alleviation of the nilotinib-induced reduction in ubiquitin specific peptidase 13 (USP13) and does not rely on autophagy inhibition. Additionally, it is found that USP13 abrogates cell apoptosis by preventing excessive ubiquitin-proteasome degradation of Bcl-XL. In conclusion, the research reveals the molecular mechanism of nilotinib's nephrotoxicity, highlighting USP13 as an important regulator of Bcl-XL stability in determining cell fate, and provides CQ analogs as a clinical intervention strategy for nilotinib's nephrotoxicity.
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Affiliation(s)
- Hao Yan
- Center for Drug Safety Evaluation and Research of Zhejiang UniversityCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou310058China
| | - Xiangliang Huang
- Center for Drug Safety Evaluation and Research of Zhejiang UniversityCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou310058China
| | - Jiangxin Xu
- Center for Drug Safety Evaluation and Research of Zhejiang UniversityCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou310058China
| | - Ying Zhang
- Center for Drug Safety Evaluation and Research of Zhejiang UniversityCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou310058China
| | - Jiajia Chen
- Center for Drug Safety Evaluation and Research of Zhejiang UniversityCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou310058China
| | - Zhifei Xu
- Center for Drug Safety Evaluation and Research of Zhejiang UniversityCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou310058China
| | - Hui Li
- Center for Drug Safety Evaluation and Research of Zhejiang UniversityCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou310058China
| | - Zeng Wang
- Department of PharmacyZhejiang Cancer HospitalHangzhou310005China
| | - Xiaochun Yang
- Center for Drug Safety Evaluation and Research of Zhejiang UniversityCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou310058China
| | - Bo Yang
- Institute of Pharmacology & ToxicologyCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou310058China
| | - Qiaojun He
- Center for Drug Safety Evaluation and Research of Zhejiang UniversityCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou310058China
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang UniversityHangzhou310018China
| | - Peihua Luo
- Center for Drug Safety Evaluation and Research of Zhejiang UniversityCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou310058China
- Department of CardiologySecond Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou310009China
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10
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Wang S, Liu T, Ren C, Wu W, Zhao Z, Pang S, Zhang Y. Predicting potential small molecule-miRNA associations utilizing truncated schatten p-norm. Brief Bioinform 2023; 24:bbad234. [PMID: 37366591 DOI: 10.1093/bib/bbad234] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 06/05/2023] [Accepted: 06/06/2023] [Indexed: 06/28/2023] Open
Abstract
MicroRNAs (miRNAs) have significant implications in diverse human diseases and have proven to be effectively targeted by small molecules (SMs) for therapeutic interventions. However, current SM-miRNA association prediction models do not adequately capture SM/miRNA similarity. Matrix completion is an effective method for association prediction, but existing models use nuclear norm instead of rank function, which has some drawbacks. Therefore, we proposed a new approach for predicting SM-miRNA associations by utilizing the truncated schatten p-norm (TSPN). First, the SM/miRNA similarity was preprocessed by incorporating the Gaussian interaction profile kernel similarity method. This identified more SM/miRNA similarities and significantly improved the SM-miRNA prediction accuracy. Next, we constructed a heterogeneous SM-miRNA network by combining biological information from three matrices and represented the network with its adjacency matrix. Finally, we constructed the prediction model by minimizing the truncated schatten p-norm of this adjacency matrix and we developed an efficient iterative algorithmic framework to solve the model. In this framework, we also used a weighted singular value shrinkage algorithm to avoid the problem of excessive singular value shrinkage. The truncated schatten p-norm approximates the rank function more closely than the nuclear norm, so the predictions are more accurate. We performed four different cross-validation experiments on two separate datasets, and TSPN outperformed various most advanced methods. In addition, public literature confirms a large number of predictive associations of TSPN in four case studies. Therefore, TSPN is a reliable model for SM-miRNA association prediction.
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Affiliation(s)
- Shudong Wang
- College of Computer Science and Technology, Qingdao Institute of Software, China University of Petroleum, Qingdao 266580, China
| | - Tiyao Liu
- College of Computer Science and Technology, Qingdao Institute of Software, China University of Petroleum, Qingdao 266580, China
| | - Chuanru Ren
- College of Computer Science and Technology, Qingdao Institute of Software, China University of Petroleum, Qingdao 266580, China
| | - Wenhao Wu
- College of Computer Science and Technology, Qingdao Institute of Software, China University of Petroleum, Qingdao 266580, China
| | - Zhiyuan Zhao
- College of Computer Science and Technology, Qingdao Institute of Software, China University of Petroleum, Qingdao 266580, China
| | - Shanchen Pang
- College of Computer Science and Technology, Qingdao Institute of Software, China University of Petroleum, Qingdao 266580, China
| | - Yuanyuan Zhang
- College of Information and Control Engineering, Qingdao University of Technology, Qingdao 266580, China
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11
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ZHANG XJ, LIN JM, CHEN SL, LIN CJ, PENG J, YANG XD, ZHAO JY. Electroacupuncture at “Zusanli(ST36)” alleviates 5-fluorouracil-induced renal injury in colorectal cancer-bearing mice by exerting effects on oxidative stress, inflammatory responses, and cell apoptosis. WORLD JOURNAL OF ACUPUNCTURE-MOXIBUSTION 2023; 33:244-251. [DOI: 10.1016/j.wjam.2023.05.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/13/2023]
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12
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da Silva MC, Fabiano LC, da Costa Salomão KC, de Freitas PLZ, Neves CQ, Borges SC, de Souza Carvalho MDG, Breithaupt-Faloppa AC, de Thomaz AA, Dos Santos AM, Buttow NC. A Rodent Model of Human-Dose-Equivalent 5-Fluorouracil: Toxicity in the Liver, Kidneys, and Lungs. Antioxidants (Basel) 2023; 12:antiox12051005. [PMID: 37237871 DOI: 10.3390/antiox12051005] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 04/24/2023] [Indexed: 05/28/2023] Open
Abstract
5-Fluorouracil (5-FU) is a chemotherapy drug widely used to treat a range of cancer types, despite the recurrence of adverse reactions. Therefore, information on its side effects when administered at a clinically recommended dose is relevant. On this basis, we examined the effects of the 5-FU clinical treatment on the integrity of the liver, kidneys, and lungs of rats. For this purpose, 14 male Wistar rats were divided into treated and control groups and 5-FU was administered at 15 mg/kg (4 consecutive days), 6 mg/kg (4 alternate days), and 15 mg/kg on the 14th day. On the 15th day, blood, liver, kidney, and lung samples were collected for histological, oxidative stress, and inflammatory evaluations. We observed a reduction in the antioxidant markers and an increase in lipid hydroperoxides (LOOH) in the liver of treated animals. We also detected elevated levels of inflammatory markers, histological lesions, apoptotic cells, and aspartate aminotransferase. Clinical treatment with 5-FU did not promote inflammatory or oxidative alterations in the kidney samples; however, histological and biochemical changes were observed, including increased serum urea and uric acid. 5-FU reduces endogenous antioxidant defenses and increases LOOH levels in the lungs, suggesting oxidative stress. Inflammation and histopathological alterations were also detected. The clinical protocol of 5-FU promotes toxicity in the liver, kidneys, and lungs of healthy rats, resulting in different levels of histological and biochemical alterations. These results will be useful in the search for new adjuvants to attenuate the adverse effects of 5-FU in such organs.
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Affiliation(s)
- Mariana Conceição da Silva
- Biological Physics and Cell Signaling Laboratory, Institute of Biology, Department of Structural and Functional Biology, State University of Campinas, Campinas 13083-970, SP, Brazil
| | - Lilian Catarim Fabiano
- Department of Morphological Science, State University of Maringá, Maringá 87020-900, PR, Brazil
| | | | | | - Camila Quaglio Neves
- Department of Morphological Science, State University of Maringá, Maringá 87020-900, PR, Brazil
| | | | - Maria das Graças de Souza Carvalho
- Biological Physics and Cell Signaling Laboratory, Institute of Biology, Department of Structural and Functional Biology, State University of Campinas, Campinas 13083-970, SP, Brazil
| | - Ana Cristina Breithaupt-Faloppa
- Laboratório de Cirurgia Cardiovascular e Fisiopatologia da Circulação (LIM-11), Instituto do Coração (InCor), Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-904, SP, Brasil
| | - André Alexandre de Thomaz
- Quantum Electronic Department, Institute of Physics Gleb Wataghin, State University of Campinas, Campinas 13083-872, SP, Brazil
| | - Aline Mara Dos Santos
- Biological Physics and Cell Signaling Laboratory, Institute of Biology, Department of Structural and Functional Biology, State University of Campinas, Campinas 13083-970, SP, Brazil
| | - Nilza Cristina Buttow
- Department of Morphological Science, State University of Maringá, Maringá 87020-900, PR, Brazil
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13
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Luo ZD, Wang YF, Zhao YX, Yu LC, Li T, Fan YJ, Zeng SJ, Zhang YL, Zhang Y, Zhang X. Emerging roles of non-coding RNAs in colorectal cancer oxaliplatin resistance and liquid biopsy potential. World J Gastroenterol 2023; 29:1-18. [PMID: 36683709 PMCID: PMC9850945 DOI: 10.3748/wjg.v29.i1.1] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 10/11/2022] [Accepted: 11/04/2022] [Indexed: 01/04/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignancies of the digestive tract, with the annual incidence and mortality increasing consistently. Oxaliplatin-based chemotherapy is a preferred therapeutic regimen for patients with advanced CRC. However, most patients will inevitably develop resistance to oxaliplatin. Many studies have reported that non-coding RNAs (ncRNAs), such as microRNAs, long non-coding RNAs, and circular RNAs, are extensively involved in cancer progression. Moreover, emerging evidence has revealed that ncRNAs mediate chemoresistance to oxaliplatin by transcriptional and post-transcriptional regulation, and by epigenetic modification. In this review, we summarize the mechanisms by which ncRNAs regulate the initiation and development of CRC chemoresistance to oxaliplatin. Furthermore, we investigate the clinical application of ncRNAs as promising biomarkers for liquid CRC biopsy. This review provides new insights into overcoming oxaliplatin resistance in CRC by targeting ncRNAs.
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Affiliation(s)
- Zheng-Dong Luo
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
| | - Yi-Feng Wang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
| | - Yu-Xiao Zhao
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
| | - Long-Chen Yu
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
| | - Tian Li
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
| | - Ying-Jing Fan
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
| | - Shun-Jie Zeng
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
| | - Yan-Li Zhang
- Department of Clinical Laboratory, Shandong Provincial Third Hospital, Jinan 250012, Shandong Province, China
| | - Yi Zhang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
| | - Xin Zhang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
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14
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Pirzaman AT, Ebrahimi P, Doostmohamadian S, Karim B, Almasi D, Madani F, Moghadamnia A, Kazemi S. 5-Flourouracil-induced toxicity in both male and female reproductive systems: A narrative review. Hum Exp Toxicol 2023; 42:9603271231217988. [PMID: 38064424 DOI: 10.1177/09603271231217988] [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] [Indexed: 12/18/2023]
Abstract
The chemotherapeutic drug 5-flourouracil (5FU) is frequently used to treat a wide range of solid malignant tumors, such as colorectal, pancreatic, gastric, breast, and head and neck cancers. Its antitumoral effects are achieved by interfering with the synthesis of RNA and DNA and by inhibiting thymidylate synthase in both malignant and non-malignant cells. Therefore, it can be responsible for severe toxicities in crucial body organs, including heart, liver, kidney, and reproductive system. Given the fact that 5FU-induced reproductive toxicity may limit the clinical application of this drug, in this study, we aimed to discuss the main locations and mechanisms of the 5FU-induced reproductive toxicity. Initially, we discussed the impact of 5FU on the male reproductive system, which leads to damage of the seminiferous epithelial cells and the development of vacuoles in Sertoli cells. Although no noticeable changes occur at the histopathological level, there is a decrease in the weight of the prostate. Additionally, 5FU causes significant abnormalities in spermatogenesis, including germ cell shedding, spermatid halo formation, polynucleated giant cells, and decreased sperm count. Finally, in females, 5FU-induced reproductive toxicity is characterized by the presence of atretic secondary and antral follicles with reduced numbers of growing follicles, ovarian weight, and maturity impairment.
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Affiliation(s)
- Ali Tavakoli Pirzaman
- Student research committee, Health Research Center, Babol University of Medical Science, Babol, Iran
| | - Pouyan Ebrahimi
- Student research committee, Health Research Center, Babol University of Medical Science, Babol, Iran
| | | | - Bardia Karim
- Student research committee, Health Research Center, Babol University of Medical Science, Babol, Iran
| | - Darya Almasi
- Pharmaceutical Sciences Research Center, Health Research Institute, Babol University of Medical Science, Babol, Iran
| | - Fatemeh Madani
- Department of Pharmacology and Toxicology, School of Medicine, Babol University of Medical Science, Babol, Iran
| | - Ahmadreza Moghadamnia
- Student research committee, Health Research Center, Babol University of Medical Science, Babol, Iran
| | - Sohrab Kazemi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Science, Babol, Iran
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15
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Hałka J, Spaleniak S, Kade G, Antosiewicz S, Sigorski D. The Nephrotoxicity of Drugs Used in Causal Oncological Therapies. Curr Oncol 2022; 29:9681-9694. [PMID: 36547174 PMCID: PMC9776938 DOI: 10.3390/curroncol29120760] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 11/25/2022] [Accepted: 11/29/2022] [Indexed: 12/14/2022] Open
Abstract
In recent years, a dynamic development of oncology has been observed, resulting from the increasingly frequent occurrence of neoplasms and therefore, increasing population of patients. The most effective form of therapy for cancer patients is complex multidisciplinary specialized disease management, including nephro-oncology care. Different forms of renal function impairment are frequently diagnosed in cancer patients. They are caused by different co-morbidities existing before starting the oncologic treatment as well as the direct undesirable effects of this therapy which may cause temporary or irreversible damage of the urinary system-especially kidneys. According to different therapeutic programs, in such cases the degree of renal damage is often crucial for the possibility of further anti-cancer treatment. Medical personnel responsible for delivering care to oncology patients should be properly educated on current methods of prevention and treatment of renal complications resulting from anti-cancer therapy. The development of oncologic medicines design, including especially immuno-oncological agents, obliges us to learn new patomechanisms determining potential adverse effects, including renal complications. This publication is focused on the most important undesirable nephrotoxic effects of the frequently used anti-cancer drugs.
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Affiliation(s)
- Janusz Hałka
- Department of Clinical Hematology, Warmian-Masurian Cancer Center of the Ministry of the Interior and Administration’s Hospital, Wojska Polskiego 37, 10-228 Olsztyn, Poland
| | - Sebastian Spaleniak
- Department of Internal Diseases and Nephrodiabetology, Medical University of Lodz, Żeromskiego 113, 90-549 Lodz, Poland
- Correspondence:
| | - Grzegorz Kade
- Warmian-Masurian Cancer Center of the Ministry of the Interior and Administration’s Hospital, Wojska Polskiego 37, 10-228 Olsztyn, Poland
| | - Stefan Antosiewicz
- Military Institute of Aviation Medicine, Center of Aeromedical Examination and Occupational Medicine, Zygmunta Krasińskiego 54/56, 01-755 Warsaw, Poland
| | - Dawid Sigorski
- Department of Oncology, Collegium Medicum, University of Warmia and Mazury, Aleja Warszawska 30, 11-082 Olsztyn, Poland
- Department of Oncology and Immuno-Oncology, Warmian-Masurian Cancer Center of the Ministry of the Interior and Administration’s Hospital, Wojska Polskiego 37, 10-228 Olsztyn, Poland
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16
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Micro-Players of Great Significance-Host microRNA Signature in Viral Infections in Humans and Animals. Int J Mol Sci 2022; 23:ijms231810536. [PMID: 36142450 PMCID: PMC9504570 DOI: 10.3390/ijms231810536] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/04/2022] [Accepted: 09/08/2022] [Indexed: 11/22/2022] Open
Abstract
Over time, more and more is becoming known about micro-players of great significance. This is particularly the case for microRNAs (miRNAs; miR), which have been found to participate in the regulation of many physiological and pathological processes in both humans and animals. One such process is viral infection in humans and animals, in which the host miRNAs—alone or in conjunction with the virus—interact on two levels: viruses may regulate the host’s miRNAs to evade its immune system, while the host miRNAs can play anti- or pro-viral roles. The purpose of this comprehensive review is to present the key miRNAs involved in viral infections in humans and animals. We summarize the data in the available literature, indicating that the signature miRNAs in human viral infections mainly include 12 miRNAs (i.e., miR-155, miR-223, miR-146a, miR-122, miR-125b, miR-132, miR-34a, miR -21, miR-16, miR-181 family, let-7 family, and miR-10a), while 10 miRNAs are commonly found in animals (i.e., miR-155, miR-223, miR-146a, miR-145, miR-21, miR-15a/miR-16 cluster, miR-181 family, let-7 family, and miR-122) in this context. Knowledge of which miRNAs are involved in different viral infections and the biological functions that they play can help in understanding the pathogenesis of viral diseases, facilitating the future development of therapeutic agents for both humans and animals.
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17
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Free fatty acid-induced miR-181a-5p stimulates apoptosis by targeting XIAP and Bcl2 in hepatic cells. Life Sci 2022; 301:120625. [PMID: 35551953 DOI: 10.1016/j.lfs.2022.120625] [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: 03/11/2022] [Revised: 05/04/2022] [Accepted: 05/06/2022] [Indexed: 11/22/2022]
Abstract
AIMS Non-alcoholic fatty liver disease is one of the major health concerns in the World. The dietary free fatty acids (FFAs) affect the metabolic status of the hepatocytes by modulating cellular pathways. In this study, we showed that free fatty acids stimulate apoptosis by upregulating miR-181a-5p expression, which in turn targets XIAP and Bcl2. METHODS Huh7 cells were incubated with FFAs for 72 h and the expression of XIAP, Bcl2, bax, pAkt, Akt, PTEN and β-actin were determined by Western blots, and miR-181a-5p expression was determined using real-time RT-PCR. The Huh7 cells were transfected with either miR-181a-5p pre-miRs or anti-miR-181a-5p and the regulation of apoptosis and proliferation was studied. Three groups of C57BL/6 mice (n = 6 per group) were fed with standard diet, CSAA or CDAA diet for 6, 18, 32 and 54 weeks. Total protein and RNA were isolated from the liver tissues and used for Western blots and real-time RT-PCR respectively. KEY FINDINGS FFAs inhibited Akt phosphorylation, expression of XIAP and Bcl2, while upregulating the expression of PTEN, bax, and miR-181a-5p in Huh7 cells. Similar results were observed when the Huh7 cells were transfected with miR-181a-5p premiRs, while these changes were reversed in anti-miR-181a-5p-transfected, FFA-treated Huh7 cells. The CDAA-fed mice showed a significant inhibition of Akt phosphorylation, XIAP and Bcl2, whereas PTEN and bax expression were upregulated. The expression of miR-181a-5p was also significantly higher in CDAA-fed mice. SIGNIFICANCE These findings showed that free fatty acids induced apoptosis via upregulating miR-181a-5p in hepatic cells.
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18
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Abstract
It has been estimated that nearly 80% of anticancer drug-treated patients receive potentially nephrotoxic drugs, while the kidneys play a central role in the excretion of anticancer drugs. Nephrotoxicity has long been a serious complication that hampers the effectiveness of cancer treatment and continues to influence both mortality and length of hospitalization among cancer patients exposed to either conventional cytotoxic agents or targeted therapies. Kidney injury arising from anticancer drugs tends to be associated with preexisting comorbidities, advanced cancer stage, and the use of concomitant non-chemotherapeutic nephrotoxic drugs. Despite the prevalence and impact of kidney injury on therapeutic outcomes, the field is sorely lacking in an understanding of the mechanisms driving cancer drug-induced renal pathophysiology, resulting in quite limited and largely ineffective management of anticancer drug-induced nephrotoxicity. Consequently, there is a clear imperative for understanding the basis for nephrotoxic manifestations of anticancer agents for the successful management of kidney injury by these drugs. This article provides an overview of current preclinical research on the nephrotoxicity of cancer treatments and highlights prospective approaches to mitigate cancer therapy-related renal toxicity.
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Affiliation(s)
- Chaoling Chen
- Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, United States
| | - Dengpiao Xie
- Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, United States
| | - David A Gewirtz
- Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, United States
| | - Ningjun Li
- Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, United States.
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19
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Zhang X, Wang Q, Zhang J, Song M, Shao B, Han Y, Yang X, Li Y. The Protective Effect of Selenium on T-2-Induced Nephrotoxicity Is Related to the Inhibition of ROS-Mediated Apoptosis in Mice Kidney. Biol Trace Elem Res 2022; 200:206-216. [PMID: 33547999 DOI: 10.1007/s12011-021-02614-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 01/26/2021] [Indexed: 02/04/2023]
Abstract
T-2 toxin is produced by the Fusarium genus. Ingestion of food or feed contaminated by T-2 toxin will cause damage to kidney. Selenium (Se), an essential trace element, showed the significant protective effects against kidney and renal cell damage induced by toxic substances. To explore the protective effects and mechanisms of Se against T-2-induced renal lesions, forty-eight male Kunming mice were exposed to T-2 toxin (1.0 mg/kg) and/or Se (0.2 mg/kg) for 28 days. In this study, we found that Se alleviated T-2-induced nephrotoxicity, presenting as increasing the body weight and kidney coefficient, relieving the renal structure injury, decreasing the contents of renal function-related biomarkers, decreasing the levels of reactive oxygen species (ROS), and increasing the mitochondrial membrane potential in T-2 toxin-treated mice. In addition, inhibition of renal cell apoptosis by Se was associated with blocking the mitochondrial pathway in T-2 toxin-treated mice, presenting as decreasing the protein expression of cytochrome-c, activities of caspase-3/9, as well as regulating the protein and mRNA expressions of Bax and Bcl-2. These results documented that the alleviating effect of Se on T-2-induced nephrotoxicity is related to the inhibition of ROS-mediated renal apoptosis.
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Affiliation(s)
- Xuliang Zhang
- Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, NO. 600, Changjiang Road, Xiangfang District, Harbin, 150030, Heilongjiang, China
| | - Qi Wang
- Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, NO. 600, Changjiang Road, Xiangfang District, Harbin, 150030, Heilongjiang, China
| | - Jian Zhang
- Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, NO. 600, Changjiang Road, Xiangfang District, Harbin, 150030, Heilongjiang, China
| | - Miao Song
- Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, NO. 600, Changjiang Road, Xiangfang District, Harbin, 150030, Heilongjiang, China
| | - Bing Shao
- Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, NO. 600, Changjiang Road, Xiangfang District, Harbin, 150030, Heilongjiang, China
| | - Yanfei Han
- Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, NO. 600, Changjiang Road, Xiangfang District, Harbin, 150030, Heilongjiang, China
| | - Xu Yang
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450002, Henan, China
| | - Yanfei Li
- Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, NO. 600, Changjiang Road, Xiangfang District, Harbin, 150030, Heilongjiang, China.
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20
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El-Sherbiny M, Fahmy EK, Eisa NH, Said E, Elkattawy HA, Ebrahim HA, Elsherbiny NM, Ghoneim FM. Nanogold Particles Suppresses 5-Flurouracil-Induced Renal Injury: An Insight into the Modulation of Nrf-2 and Its Downstream Targets, HO-1 and γ-GCS. Molecules 2021; 26:molecules26247684. [PMID: 34946766 PMCID: PMC8707269 DOI: 10.3390/molecules26247684] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 12/10/2021] [Accepted: 12/16/2021] [Indexed: 11/16/2022] Open
Abstract
The development of the field of nanotechnology has revolutionized various aspects in the fields of modern sciences. Nano-medicine is one of the primary fields for the application of nanotechnology techniques. The current study sheds light on the reno-protective impacts of gold nano-particles; nanogold (AuNPs) against 5-flurouracil (5-FU)-induced renal toxicity. Indeed, the use of 5-FU has been associated with kidney injury which greatly curbs its therapeutic application. In the current study, 5-FU injection was associated with a significant escalation in the indices of renal injury, i.e., creatinine and urea. Alongside this, histopathological and ultra-histopathological changes confirmed the onset of renal injury. Both gene and/or protein expression of nuclear factor erythroid 2-related factor 2 (Nrf-2) and downstream antioxidant enzymes revealed consistent paralleled anomalies. AuNPs administration induced a significant renal protection on functional, biochemical, and structural levels. Renal expression of the major sensor of the cellular oxidative status Nrf-2 escalated with a paralleled reduction in the renal expression of the other contributor to this axis, known as Kelch-like ECH-associated protein 1 (Keap-1). On the level of the effector downstream targets, heme oxygenase 1 (HO-1) and gamma-glutamylcysteine synthetase (γ-GCS) AuNPs significantly restored their gene and protein expression. Additionally, combination of AuNPs with 5-FU showed better cytotoxic effect on MCF-7 cells compared to monotreatments. Thus, it can be inferred that AuNPs conferred reno-protective impact against 5-FU with an evident modulatory impact on Nrf-2/Keap-1 and its downstream effectors, HO-1 and γ-GCS, suggesting its potential use in 5-FU regimens to improve its therapeutic outcomes and minimize its underlying nephrotoxicity.
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Affiliation(s)
- Mohamed El-Sherbiny
- Department of Basic Medical Sciences, College of Medicine, Almaarefa University, P.O. Box 71666, Riyadh 11597, Saudi Arabia; (M.E.-S.); (H.A.E.)
- Department of Anatomy and Embryology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Eslam K. Fahmy
- Medical Physiology Department, College of Medicine, Zagazig University, Zagazig 44519, Egypt;
- Medical Physiology Department, Faculty of Medicine, Northern Border University, Arar 91431, Saudi Arabia
| | - Nada H. Eisa
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;
| | - Eman Said
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;
- Faculty of Pharmacy, New Mansoura University, New Mansoura 7723730, Egypt
| | - Hany A. Elkattawy
- Department of Basic Medical Sciences, College of Medicine, Almaarefa University, P.O. Box 71666, Riyadh 11597, Saudi Arabia; (M.E.-S.); (H.A.E.)
- Medical Physiology Department, College of Medicine, Zagazig University, Zagazig 44519, Egypt;
- Zagazig Obesity Management & Research Unit, College of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Hasnaa Ali Ebrahim
- Department of Basic Medical Sciences, College of Medicine, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia;
| | - Nehal M. Elsherbiny
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia
- Correspondence:
| | - Fatma M. Ghoneim
- Histology and Cell Biology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt;
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Chen X, Zhou C, Wang CC, Zhao Y. Predicting potential small molecule-miRNA associations based on bounded nuclear norm regularization. Brief Bioinform 2021; 22:6353837. [PMID: 34404088 DOI: 10.1093/bib/bbab328] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 07/24/2021] [Accepted: 07/26/2021] [Indexed: 12/14/2022] Open
Abstract
Mounting evidence has demonstrated the significance of taking microRNAs (miRNAs) as the target of small molecule (SM) drugs for disease treatment. Given the fact that exploring new SM-miRNA associations through biological experiments is extremely expensive, several computing models have been constructed to reveal the possible SM-miRNA associations. Here, we built a computing model of Bounded Nuclear Norm Regularization for SM-miRNA Associations prediction (BNNRSMMA). Specifically, we first constructed a heterogeneous SM-miRNA network utilizing miRNA similarity, SM similarity, confirmed SM-miRNA associations and defined a matrix to represent the heterogeneous network. Then, we constructed a model to complete this matrix by minimizing its nuclear norm. The Alternating Direction Method of Multipliers was adopted to minimize the nuclear norm and obtain predicted scores. The main innovation lies in two aspects. During completion, we limited all elements of the matrix within the interval of (0,1) to make sure they have practical significance. Besides, instead of strictly fitting all known elements, a regularization term was incorporated to tolerate the noise in integrated similarities. Furthermore, four kinds of cross-validations on two datasets and two types of case studies were performed to evaluate the predictive performance of BNNRSMMA. Finally, BNNRSMMA attained areas under the curve of 0.9822 (0.8433), 0.9793 (0.8852), 0.8253 (0.7350) and 0.9758 ± 0.0029 (0.8759 ± 0.0041) under global leave-one-out cross-validation (LOOCV), miRNA-fixed LOOCV, SM-fixed LOOCV and 5-fold cross-validation based on Dataset 1(Dataset 2), respectively. With regard to case studies, plenty of predicted associations have been verified by experimental literatures. All these results confirmed that BNNRSMMA is a reliable tool for inferring associations.
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Affiliation(s)
- Xing Chen
- Artificial Intelligence Research Institute, China University of Mining and Technology, Xuzhou 221116, China
| | - Chi Zhou
- School of Information and Control Engineering, China University of Mining and Technology, Xuzhou 221116, China
| | - Chun-Chun Wang
- School of Information and Control Engineering, China University of Mining and Technology, Xuzhou 221116, China
| | - Yan Zhao
- School of Information and Control Engineering, China University of Mining and Technology, Xuzhou 221116, China
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Zhu J, Zhang X, Xie H, Wang Y, Zhang X, Lin Z. Cardiomyocyte Stim1 Deficiency Exacerbates Doxorubicin Cardiotoxicity by Magnification of Endoplasmic Reticulum Stress. J Inflamm Res 2021; 14:3945-3958. [PMID: 34421306 PMCID: PMC8373307 DOI: 10.2147/jir.s304520] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 06/08/2021] [Indexed: 01/13/2023] Open
Abstract
INTRODUCTION Doxorubicin (Dox) is an effective anticancer agent; however, its cardiotoxicity remains a challenge. Dysfunction of intracellular calcium ion (Ca2+) is implicated in the process of Dox-induced cardiomyocyte apoptosis. Although store-operated Ca2+ entry (SOCE) is suggested to be responsible for Ca2+ entry in cardiomyocytes, the direct role of store-operated Ca2+ channels in Dox-related cardiomyocyte apoptosis is unknown. MATERIALS AND METHODS Cardiomyocyte Stim1-specific knockout or overexpression mice were treated with Dox. Cardiomyocytes were pretreated with Stim1 adenovirus or siRNA followed by Dox incubation in vitro. Cardiac function and underlying mechanisms echocardiography were assessed via immunofluorescence, flow cytometry, real-time PCR, Western blotting and immunoprecipitation. RESULTS We observed the inhibition of Stim1 expression, association of Stim1 to Orai1 or Trpc1, and SOCE in Dox-treated mouse myocardium and cardiomyocytes. Orai1 and Trpc1 expression remained unchanged. Cardiomyocyte-specific deficiency of Stim1 exacerbated Dox-induced cardiac dysfunction and myocardial apoptosis. However, specific overexpression of Stim1 in the myocardium was associated with amelioration of cardiac dysfunction and myocardial apoptosis. In vitro, STIM1 knockdown potentiated Dox-induced AC16 human cardiomyocyte apoptosis. This apoptosis was attenuated by STIM1 upregulation. Moreover, STIM1 downregulation enhanced Dox-induced endoplasmic reticulum (ER) stress in cardiomyocytes. In contrast, STIM1 overexpression inhibited the activation of the above molecular markers of ER stress. Immunoprecipitation assay showed that STIM1 interacted with GRP78 in cardiomyocytes. This interaction was attenuated in response to Dox treatment. CONCLUSION Our data demonstrate that cardiomyocyte STIM1 binding to GRP78 ameliorates Dox cardiotoxicity by inhibiting pro-apoptotic ER stress.
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Affiliation(s)
- Jiang Zhu
- Department of Anesthesiology, The Second Affiliated Hospital of Soochow University, Suzhou, 215008, Jiangsu, People’s Republic of China
| | - Xia Zhang
- Department of Anesthesiology, Wuzhong People’s Hospital, Suzhou, Jiangsu, 215128, People’s Republic of China
| | - Hong Xie
- Department of Anesthesiology, The Second Affiliated Hospital of Soochow University, Suzhou, 215008, Jiangsu, People’s Republic of China
| | - Yuye Wang
- Department of Anesthesiology, The Second Affiliated Hospital of Soochow University, Suzhou, 215008, Jiangsu, People’s Republic of China
| | - Xiaoxiao Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Soochow University, Suzhou, 215008, Jiangsu, People’s Republic of China
| | - Zhaoheng Lin
- Intensive Care Unit, People’s Hospital of Xishuangbanna Dai Nationality Autonomous Prefecture, Jinghong City, 666100, Yunnan, People’s Republic of China
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Fan X, Gu W, Gao Y, Ma N, Fan C, Ci X. Daphnetin ameliorated GM-induced renal injury through the suppression of oxidative stress and apoptosis in mice. Int Immunopharmacol 2021; 96:107601. [PMID: 33812255 DOI: 10.1016/j.intimp.2021.107601] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 02/25/2021] [Accepted: 03/18/2021] [Indexed: 02/06/2023]
Abstract
Gentamicin (GM), an aminoglycoside antibiotic, is one of the most effective drugs used in the treatment of various types of bacterial infections, but the major adverse effect and drug-induced nephrotoxicity of GM limit its clinical applications. Daphnetin (Daph) is a natural coumarin derivative that is clinically used to treat rheumatoid arthritis and coagulopathy and exhibits antioxidant effects. However, the effect of Daph on GM-induced nephrotoxicity has not yet been elucidated. This study investigated Daph-mediated protection against GM-induced nephrotoxicity in mice and explored the underlying mechanisms of GM-induced renal dysfunction in mice. We found that Daph treatment significantly reduced GM-induced nephrotoxicity mainly by ameliorating renal injury in mice and attenuating cell damage in vitro. Mechanistically, we found that Daph upregulated the expression level of Nrf2 and its regulated antioxidant enzymes HO-1, NQO1, GCLC and GCLM in vivo and in vitro. GM upregulated the expression levels of NOX4, cleaved Caspase-3 and p53 and the BAX/BCL2 ratio in vivo to stimulate oxidative stress and apoptosis. However, Daph treatment significantly improved the oxidative stress and apoptosis caused by GM, thereby exerting antioxidative and antiapoptotic effects. Our study was the first to suggest that the natural product Daph protects against GM-induced nephrotoxicity through the activation of Nrf2 which regulates oxidative stress and apoptosis. The pharmacological activation of Nrf2 may be useful as a novel therapy to prevent renal injury.
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Affiliation(s)
- Xiaoye Fan
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin 130001, China
| | - Wenjing Gu
- Department of Otolaryngology Head and Neck Surgery, The First Hospital of Jilin University, Changhun, Jilin 130001, China
| | - Yun Gao
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin 130001, China
| | - Ning Ma
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin 130001, China
| | - Changqing Fan
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin 130001, China
| | - Xinxin Ci
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin 130001, China.
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Zheng T, Tan Y, Qiu J, Xie Z, Hu X, Zhang J, Na N. Alternative polyadenylation trans-factor FIP1 exacerbates UUO/IRI-induced kidney injury and contributes to AKI-CKD transition via ROS-NLRP3 axis. Cell Death Dis 2021; 12:512. [PMID: 34011928 PMCID: PMC8134587 DOI: 10.1038/s41419-021-03751-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 04/20/2021] [Accepted: 04/21/2021] [Indexed: 12/20/2022]
Abstract
NLRP3, a decisive role in inflammation regulation, is obviously upregulated by oxidative stress in kidney injury. The NLRP3 upregulation leads to unsolved inflammation and other pathological effects, contributing to aggravation of kidney injury and even transition to chronic kidney disease (CKD). However, the mechanism for NLRP3 upregulation and further aggravation of kidney injury remains largely elusive. In this study, we found NLRP3 3'UTR was shortened in response to kidney injury in vivo and oxidative stress in vitro. Functionally, such NLRP3 3'UTR shortening upregulated NLRP3 expression and amplified inflammation, fibrogenesis, ROS production and apoptosis, depending on stabilizing NLRP3 mRNA. Mechanistically, FIP1 was found to bind to pPAS of NLRP3 mRNA via its arginine-rich domain and to induce NLRP3 3'UTR shortening. In addition, FIP1 was upregulated in CKD specimens and negatively associated with renal function of CKD patients. More importantly, we found FIP1 was upregulated by oxidative stress and required for oxidative stress-induced NLRP3 upregulation, inflammation activation, cell damage and apoptosis. Finally, we proved that FIP1 silencing attenuated the inflammation activation, fibrogenesis, ROS production and apoptosis induced by UUO or IRI. Taken together, our results demonstrated that oxidative stress-upregulated FIP1 amplified inflammation, fibrogenesis, ROS production and apoptosis via inducing 3'UTR shortening of NLRP3, highlighting the importance of crosstalk between oxidative stress and alternative polyadenylation in AKI-CKD transition, as well as the therapeutic potential of FIP1 in kidney injury treatment.
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Affiliation(s)
- Tong Zheng
- Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yuqin Tan
- Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
| | - Jiang Qiu
- Department of Organ Transplantation, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zhenwei Xie
- Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiao Hu
- Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jinhua Zhang
- Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Ning Na
- Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
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Liu YY, Liu X, Zhou JG, Liang SJ. MicroRNA-302a promotes neointimal formation following carotid artery injury in mice by targeting PHLPP2 thus increasing Akt signaling. Acta Pharmacol Sin 2021; 42:550-559. [PMID: 32694755 PMCID: PMC8115114 DOI: 10.1038/s41401-020-0440-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Accepted: 05/12/2020] [Indexed: 01/12/2023]
Abstract
The excessive proliferation and migration of smooth muscle cells (SMCs) play an important role in restenosis following percutaneous coronary interventions. MicroRNAs are able to target various genes and involved in the regulation of diverse cellular processes including cell growth and proliferation. In this study we investigated whether and how MicroRNAs regulated vascular SMC proliferation and vascular remodeling following carotid artery injury in mice. We showed that carotid artery injury-induced neointimal formation was remarkably ameliorated in microRNA (miR)-302 heterozygous mice and SMC-specific miR-302 knockout mice. In contrast, delivery of miR-302a adenovirus to the injured carotid artery enhanced neointimal formation. Upregulation of miR-302a enhanced the proliferation and migration of mouse aorta SMC (MASMC) in vitro by promoting cell cycle transition, whereas miR-302a inhibition caused the opposite results. Moreover, miR-302a promoted Akt activation by corporately decreasing Akt expression and increasing Akt phosphorylation in MASMCs. Application of the Akt inhibitor GSK690693 (5 μmol/L) counteracted the functions of miR-302a in promoting MASMC proliferation and migration. We further revealed that miR-302a directly targeted at the 3' untranslated region of PH domain and leucine rich repeat protein phosphatase 2 (PHLPP2) and negatively regulated PHLPP2 expression. Restoration of PHLPP2 abrogated the effects of miR-302a on Akt activation and MASMC motility. Furthermore, knockdown of PHLPP2 largely abolished the inhibition of neointimal formation that was observed in miR-302 heterozygous mice. Our data demonstrate that miR-302a exacerbates SMC proliferation and restenosis through increasing Akt signaling by targeting PHLPP2.
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Affiliation(s)
- Ying-Ying Liu
- Department of Pharmacology, and Cardiac & Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Xiu Liu
- Department of Pharmacology, and Cardiac & Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Jia-Guo Zhou
- Department of Pharmacology, and Cardiac & Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Si-Jia Liang
- Department of Pharmacology, and Cardiac & Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
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Su Q, Xu Y, Cai R, Dai R, Yang X, Liu Y, Kong B. miR-146a inhibits mitochondrial dysfunction and myocardial infarction by targeting cyclophilin D. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 23:1258-1271. [PMID: 33717647 PMCID: PMC7907681 DOI: 10.1016/j.omtn.2021.01.034] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 01/28/2021] [Indexed: 12/18/2022]
Abstract
Increasing evidence suggests that mitochondrial microRNAs (miRNAs) are implicated in the pathogenesis of cardiovascular diseases; however, their roles in ischemic heart disease remain unclear. Herein, we demonstrate that miR-146a is enriched in the mitochondrial fraction of cardiomyocytes, and its level significantly decreases after ischemic reperfusion (I/R) challenge. Cardiomyocyte-specific knockout of miR-146a aggravated myocardial infarction, apoptosis, and cardiac dysfunction induced by the I/R injury. Overexpression of miR-146a suppressed anoxia/reoxygenation-induced cardiomyocyte apoptosis by inhibiting the mitochondria-dependent apoptotic pathway and increasing the Bcl-2/Bax ratio. miR-146a overexpression also blocked mitochondrial permeability transition pore opening and attenuated the loss of mitochondrial membrane potential and cytochrome c leakage; meanwhile, miR-146a knockdown elicited the opposite effects. Additionally, miR-146a overexpression decreased cyclophilin D protein, not mRNA, expression. The luciferase reporter assay revealed that miR-146a binds to the coding sequence of the cyclophilin D gene. Restoration of cyclophilin D reversed the inhibitory action of miR-146a on cardiomyocyte apoptosis. Furthermore, cardiomyocyte-specific cyclophilin D deletion completely abolished the exacerbation of myocardial infarction and apoptosis observed in miR-146a cardiomyocyte-deficient mice. Collectively, these findings demonstrate that nuclear miR-146a translocates into the mitochondria and regulates mitochondrial function and cardiomyocyte apoptosis. Our study unveils a novel role for miR-146a in ischemic heart disease.
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Affiliation(s)
- Qiang Su
- Department of Cardiology, The Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, China
| | - Yuli Xu
- Department of Cardiology, The Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, China
| | - Ruping Cai
- Department of Cardiology, The Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, China
| | - Rixin Dai
- Department of Cardiology, The Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, China
| | - Xiheng Yang
- Department of Cardiology, The Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, China
| | - Yang Liu
- Department of Cardiology, The Second People’s Hospital of Nanning City, The Third Affiliated Hospital of Guangxi Medical University, Nanning 530031, Guangxi, China
| | - Binghui Kong
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
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Identifying Key MicroRNAs Targeted by Narenmandula in a Rodent Nephropathy Model. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:9196379. [PMID: 33299464 PMCID: PMC7707998 DOI: 10.1155/2020/9196379] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 11/06/2020] [Indexed: 12/14/2022]
Abstract
Background Untreated nephropathy can progress to renal failure. The traditional Mongolian remedy Narenmandula regulates the kidney “yang.” This study aimed to identify key microRNAs (miRNAs) targeted by Narenmandula in a rat model of nephropathy. Methods Fifteen rats exhibiting normal renal function were randomized to three study arms. Nephropathy was induced in n = 10 rats using doxorubicin hydrochloride, followed by either Narenmandula treatment (treatment group) or no treatment (control group). In n = 5 rats, no doxorubicin was given and renal function remained unchanged (healthy group). Microarray analysis identified miRNAs which were differentially expressed (DE-miRNAs) between groups. Target genes of DE-miRNAs were predicted using miRWalk version 2.0, followed by enrichment analysis using DAVID, and construction of the miRNA coregulatory network using Cytoscape. Results Nephropathy was successfully induced, with doxorubicin resulting in differential expression of 3645 miRNAs (1324 upregulated and 2321 downregulated). Narenmandula treatment induced differential expression of a total of 159 miRNAs (102 upregulated and 57 downregulated). Upregulated DE-miRNAs (e.g., miR-497-5p, miR-195-5p, miR-181a-5p, miR-181c-5p, and miR-30e-5p) and downregulated DE-miRNAs (e.g., miR-330-3p and miR-214-3p) regulated a high number of target genes. Moreover, the miRNA pairs (e.g., miR-195-5p—miR-497-5p, miR-181a-5p—miR-181c-5p, and miR-30e-5p—miR-30a-5p) coregulated a high number of genes. Enrichment analysis indicated functional synergy between miR-30e-5p—miR-30a-3p, miR-34a-5p—miR-30e-5p, miR-30e-5p—miR-195-3p, and miR-30a-3p—miR-195-3p pairs. Conclusion Narenmandula may modulate doxorubicin-induced nephropathy via targeting miR-497-5p, miR-195-5p, miR-181a-5p, miR-181c-5p, miR-30e-5p, miR-330-3p, miR-214-3p, miR-34a-5p, miR-30a-3p, and miR-30a-5p.
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28
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Zhang L, Yang F, Yan Q. Candesartan ameliorates vascular smooth muscle cell proliferation via regulating miR-301b/STAT3 axis. Hum Cell 2020; 33:528-536. [PMID: 32170715 DOI: 10.1007/s13577-020-00333-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Accepted: 02/13/2020] [Indexed: 12/31/2022]
Abstract
Excessive vascular smooth muscle cell (VSMC) proliferation contributes to vascular remodeling and stroke during hypertension. Blockade of Angiotensin (AngII) type 1 receptor (AT1R) is shown to effectively attenuate VSMC proliferation and vascular remodeling, while the mechanisms underlying these protective effects are unclear. Here, we investigated whether the amelioration of VSMC proliferation mediated by candesartan, an AT1R blocker, could be associated with miRNA regulation. Based on the published data in rat aortic smooth muscle cells (RASMCs), we discovered that candesartan specifically reversed the AngII-induced decrease of miR-301b level in RASMCs and human aortic smooth muscle cells (HASMCs). Knockdown of miR-301b abolished candesartan-mediated inhibition of HASMC proliferation via promoting cell cycle transition. Computational analysis showed that miR-301b targets at 3'UTR of STAT3. MiR-301b upregulation inhibited the luciferase activity and protein expression of STAT3, whereas miR-301b knockdown increased STAT3 luciferase activity and expression. Furthermore, downregulation of STAT3 markedly abrogated the effects of miR-301b inhibition on candesartan-mediated HASMC proliferation, invasion, and migration. Collectively, this study suggests that miR-301b may be a novel molecular target of candesartan and provides a new understanding for the mechanisms underlying the cardiovascular effects of candesartan.
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Affiliation(s)
- Ling Zhang
- Department of Pharmacy, Xiantao First People's Hospital, No. 29 Mianzhou Road, Xiantao, 433000, Hubei, China.
| | - Fan Yang
- Department of Pharmacy, Xiantao First People's Hospital, No. 29 Mianzhou Road, Xiantao, 433000, Hubei, China
| | - Qiong Yan
- Department of Pharmacy, Huazhong University of Science and Technology Hospital, Wuhan, 430074, Hubei, China
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29
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Chen L, Xiong Y, Yan C, Zhou W, Endo Y, Xue H, Hu Y, Hu L, Leng X, Liu J, Lin Z, Mi B, Liu G. LncRNA KCNQ1OT1 accelerates fracture healing via modulating miR-701-3p/FGFR3 axis. FASEB J 2020; 34:5208-5222. [PMID: 32060985 DOI: 10.1096/fj.201901864rr] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 01/13/2020] [Accepted: 02/02/2020] [Indexed: 12/14/2022]
Abstract
Emerging evidence highlights the role of the long noncoding RNA (lncRNA) KCNQ1OT1 in fracture healing. Osteoblast proliferation, migration, and survival are pivotal during this process. In this study, we aimed to improve our understanding of the regulatory role of lncRNA KCNQ1OT1 during osteoblast proliferation, migration, and survival. We searched the gene expression omnibus databases and LncBase Experimental V.2 to identify key microRNAs (miRNAs) targets of KCNQ1OT1. MiR-701-3p was selected as a differentially expressed miRNA and RNA immunoprecipitation assays were performed to verify its interaction with KCNQ1OT1. Fibroblast growth factor receptor 3 (FGFR3) was also identified as a target of miR-701-3p. We further identified KCNQ1OT1 as a competing endogenous RNA of miR-701-3p that could influence osteoblast proliferation, migration, and apoptosis in vitro and in vivo. Taken together, our results indicate that the KCNQ1OT1/miR-701-3p/FGFR3 axis is an important regulator of osteoblast proliferation, migration, and apoptosis, and provide a new therapeutic avenue for fracture healing.
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Affiliation(s)
- Lang Chen
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan Xiong
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chenchen Yan
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wu Zhou
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yori Endo
- Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Hang Xue
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yiqiang Hu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liangcong Hu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xingzhu Leng
- Department of Biomedical Sciences, UMC Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Jing Liu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ze Lin
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bobin Mi
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guohui Liu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Satari A, Amini SA, Raeisi E, Lemoigne Y, Heidarian E. Synergetic Impact of Combined 5-Fluorouracil and Rutin on Apoptosis in PC3 Cancer Cells through the Modulation of P53 Gene Expression. Adv Pharm Bull 2019; 9:462-469. [PMID: 31592435 PMCID: PMC6773939 DOI: 10.15171/apb.2019.055] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Revised: 02/15/2019] [Accepted: 03/06/2019] [Indexed: 12/22/2022] Open
Abstract
Purpose: Prostate cancer is as far the most prevalent male cancer. Rutin (a glycoside from
quercetin flavonoid) displays antioxidant activity leading to cell apoptosis. Combined effects of
rutin with the widely used anti-cancer drug, 5-fluorouracil (5-FU), on prostate cancer cell line
(PC3) was investigated herein.
Methods: Different concentrations of combined 5-FU and rutin were applied to PC3 cells
compared to separate treatment for 48 hours. Cell viability, as well p53 gene expression
respectively were assessed by MTT assay and real-time quantitative polymerase chain reaction
(qPCR). Changes of Bcl-2 signal protein and apoptosis were determined using western blot
and flow cytometry procedures, respectively. Clonogenic assay was used to colony counts
assessment.
Results: 50% inhibitory concentration (IC50) of separate cell treatment with either rutin and
5-FU respectively were 900 μM and 3Mm, while combination index (CI) of combined 5-FU
/rutin application reached a level of synergistic effects (0.33). Combination of 5-FU/rutin
enhanced apoptosis and p53 gene expression in PC3 cells. PC3 cell colony counts and Bcl-2
signaling protein were decreased by 5-FU/rutin combination.
Conclusion: Synergistic effects of 5-FU/rutin combination on PC3 cells line enhanced apoptosis,
p53 gene expression, and down-regulation of Bcl-2 protein, compared to control separate
application. 5-FU/rutin combination does seem an interesting therapeutic pathway to be further
investigated.
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Affiliation(s)
- Atefeh Satari
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Sayed Asadollah Amini
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Elham Raeisi
- Department of Medical Physics & Radiology, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | | | - Esfandiar Heidarian
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
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Mohamed DI, Khairy E, Saad SST, Habib EK, Hamouda MA. Potential protective effects of Dapagliflozin in gentamicin induced nephrotoxicity rat model via modulation of apoptosis associated miRNAs. Gene 2019; 707:198-204. [PMID: 31075409 DOI: 10.1016/j.gene.2019.05.009] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 04/14/2019] [Accepted: 05/06/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Drug-induced kidney injury (DIKI) can be manifested with progressive chronic kidney diseases or end-stage renal diseases. Understanding the molecular disarrangements caused by DIKI is an attractive point of interest. A class of non-coding RNA called microRNAs (miRNAs) is known to play a major role in regulation of gene expression and signaling pathways making miRNAs excellent targets for new therapeutic agents. AIM OF THE STUDY We aimed to investigate the role of miRNA 21 and 181a in gentamicin (GNT) induced nephrotoxicity rat model and the protective effect of Dapagliflozin (DAPA) in modulating their expression through studying its effect on renal function as well as renal histopathological changes. MATERIALS AND METHODS Wistar rats were used and divided into: naïve, DAPA, GNT and DAPA + GNT groups. In all studied groups, kidney function, oxidative stress, apoptosis markers and miRNAs' expression in serum and renal biopsies were investigated in addition to the histopathological studies to identify its early renoprotective effect. RESULTS DAPA was found to improve kidney function, oxidative stress markers, decrease apoptosis of renal tubular cells and increase miR-21 but decrease the expression of miR-181a with restoration of the renal architecture after 14 days of treatment in GNT induced nephrotoxicity rat model. CONCLUSIONS DAPA produced significant decrease in renal expression of miR-181a on the other hand it increased the expression of renal miR-21, this may introduce a novel early protective effect of DAPA against GNT-induced nephrotoxicity.
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Affiliation(s)
- Doaa I Mohamed
- Clinical Pharmacology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Eman Khairy
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Ain Shams University, P.O. Box 11381, Abbassia, Cairo, Egypt
| | - Sherin S T Saad
- Clinical Pharmacology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Eman K Habib
- Anatomy and Embryology Department, Faculty of Medicine, Ain Shams University, P.O. Box 11381, Abbassia, Cairo, Egypt
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Wang Z, Fang Z, Lu R, Zhao H, Gong T, Liu D, Hong L, Ma J, Zhang M. MicroRNA-204 Potentiates the Sensitivity of Acute Myeloid Leukemia Cells to Arsenic Trioxide. Oncol Res 2019; 27:1035-1042. [PMID: 30982490 PMCID: PMC7848422 DOI: 10.3727/096504019x15528367532612] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Although arsenic trioxide (ATO) is a well-known antileukemic drug used for acute promyelocytic leukemia treatment, the development of ATO resistance is still a big challenge. We previously reported that microRNA-204 (miR-204) was involved in the regulation of acute myeloid leukemia (AML) cell apoptosis, but its role in chemoresistance is poorly understood. In the present study, we showed that miR-204 was significantly increased in AML cells after ATO treatment. Interestingly, the increased miR-204 level that was negatively correlated with ATO induced the decrease in cell viability and baculoviral inhibition of apoptosis protein repeat-containing 6 (BIRC6) expression. Overexpression of miR-204 potentiated ATO-induced AML cell growth inhibition and apoptosis. Furthermore, miR-204 directly targets to the 3′-UTR of BIRC6. Upregulation of miR-204 decreased BIRC6 luciferase activity and expression, which subsequently enhanced the expression of p53. Restoration of BIRC6 markedly reversed the effect of miR-204 on the regulation of AML cell sensitivity to ATO. Taken together, our study demonstrates that miR-204 decreases ATO chemoresistance in AML cells at least partially via promoting BIRC6/p53-mediated apoptosis. miR-204 represents a novel target of ATO, and upregulation of miR-204 may be a useful strategy to improve the efficacy of ATO in AML treatment.
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Affiliation(s)
- Zhiguo Wang
- Department of Hematology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi Province, P.R. China
| | - Zehui Fang
- Department of Endocrinology, the 4th Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, P.R. China
| | - Runzhang Lu
- Department of Bone Marrow Transplantation, Harbin Hematological Cancer Institute, Harbin the First Hospital, Harbin Province, P.R. China
| | - Hongli Zhao
- Department of Endocrinology, the 4th Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, P.R. China
| | - Tiejun Gong
- Department of Bone Marrow Transplantation, Harbin Hematological Cancer Institute, Harbin the First Hospital, Harbin Province, P.R. China
| | - Dong Liu
- Department of Bone Marrow Transplantation, Harbin Hematological Cancer Institute, Harbin the First Hospital, Harbin Province, P.R. China
| | - Luojia Hong
- Department of Endocrinology, the 4th Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, P.R. China
| | - Jun Ma
- Department of Bone Marrow Transplantation, Harbin Hematological Cancer Institute, Harbin the First Hospital, Harbin Province, P.R. China
| | - Mei Zhang
- Department of Hematology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi Province, P.R. China
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Yang C, He L, Chen G, Ning Z, Xia Z. LRRC8A potentiates temozolomide sensitivity in glioma cells via activating mitochondria-dependent apoptotic pathway. Hum Cell 2019; 32:41-50. [PMID: 30426452 DOI: 10.1007/s13577-018-0221-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 11/04/2018] [Indexed: 02/06/2023]
Abstract
Chloride (Cl-), a primary anion in the extracellular fluid, plays an important role in a variety of physiological and pathological processes, such as cell apoptosis and proliferation. However, the information about Cl- in cancer cell apoptosis and chemoresistance is poorly understood. In the present study, we found that temozolomide (TMZ) treatment led to a decrease in intracellular concentration of Cl- ([Cl-]i) in both U87 and TMZ-resistant U87/R glioma cells. The decrease in [Cl-]i was more noticeable in U87 cells than in U87/R cells. Moreover, the expression of LRRC8A was reduced in U87/R cells compared with U87 cells. LRRC8A downregulation inhibited TMZ, induced the decrease in [Cl-]i and abolished the difference of [Cl-]i between U87 cells and U87/R cells. Knockdown of LRRC8A using small interfering RNA attenuated TMZ-induced U87 cell growth inhibition and apoptosis, while overexpression of LRRC8A by adenoviral infection enhanced the effect of TMZ on U87 and U87/R cell viability and apoptosis. Furthermore, LRRC8A downregulation inhibited TMZ-induced mitochondria-dependent apoptosis, including elevated Bcl-2 expression, reduced Bax expression, cytochrome c release, and caspase nine and caspase three activation. On the contrary, upregulation of LRRC8A augmented the activation of mitochondria-dependent apoptotic pathway in U87 and U87/R cells. In conclusion, this study demonstrates that LRRC8A potentiates TMZ-induced glioma cell apoptosis via promoting mitochondria-dependent apoptosis, suggesting that LRRC8A can be represented as a novel target for drug resistance treatment in glioma cells.
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Affiliation(s)
- Chao Yang
- Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-Sen University, 58th Zhongshan Road II, Guangzhou, 510089, China
| | - Longshuang He
- Department of Neurosurgery, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510080, China
| | - Gaofei Chen
- School of Nursing, Guangdong Pharmaceutical University, Guangzhou, 510089, China
| | - Zeqian Ning
- Department of Neurosurgery, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510080, China
| | - Zhibai Xia
- Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-Sen University, 58th Zhongshan Road II, Guangzhou, 510089, China.
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Wang ZF, Sun WY, Yu DH, Zhao Y, Xu HM, He YF, Li HJ. Rotundic acid enhances the impact of radiological toxicity on MCF-7 cells through the ATM/p53 pathway. Int J Oncol 2018; 53:2269-2277. [PMID: 30226600 DOI: 10.3892/ijo.2018.4544] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 07/26/2018] [Indexed: 11/06/2022] Open
Abstract
Although radiation therapy is a powerful anticancer modality, radiation- induced stress response and gene expression with adaptive resistance may severely compromise the effectiveness of radiation. The function of rotundic acid (RA) on inducing apoptosis in the human breast cancer cell line MCF-7 has been investigated in a previous study. In the present study, the combined effect of chemotherapy and radiotherapy on reducing side effects was examined. The results of an MTT assay revealed that radiation (0.5, 2 and 10 Gy) effectively inhibit MCF-7 cell viability in a dose-dependent manner, consistent with the effects of RA (2, 5 and 12.5 µM). Interestingly, a lower dose of radiation (1 Gy) combined with RA (5 µM) exhibited a greater inhibition efficiency compared with a high dose of radiation alone. Flow cytometry revealed that radiation combined with RA induced the apoptosis of MCF-7 cells. Using western blotting, it was demonstrated that radiation induced the expression of ataxia-telangiectasia mutated (ATM) and p53 protein, and that RA enhanced this effect. On examining the potential underlying mechanism, it was revealed that radiation and RA combined induce Bcl-2-associated X protein expression and cell apoptosis in MCF-7 cells. An ATM inhibitor was able to restore the effect of radiation and RA on inducing MCF-7 cell apoptosis. These results suggest that the ATM/p53 pathway directly participates in radiation and RA-induced apoptosis in MCF-7 cells. RA has the potential for development as a novel drug for the treatment of human breast cancer combined with radiation therapy, given that the combined side effects are reduced.
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Affiliation(s)
- Zhong-Feng Wang
- Department of Immunity, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Wen-Yi Sun
- Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmaceutical Sciences in Jilin University, Changchun, Jilin 130021, P.R. China
| | - De-Hai Yu
- Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yan Zhao
- College of Chinese Medicinal Materials, Jilin Agriculture University, Changchun, Jilin 130000, P.R. China
| | - Hong-Mei Xu
- Department of Obstetrics, The First Hospital, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yu-Fang He
- Institute of Phytochemistry, Jilin Academy of Chinese Medicine Sciences, Changchun, Jilin 130000, P.R. China
| | - Hai-Jun Li
- Department of Immunity, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
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Lin Z, Li Y, Gong G, Xia Y, Wang C, Chen Y, Hua L, Zhong J, Tang Y, Liu X, Zhu B. Restriction of H1N1 influenza virus infection by selenium nanoparticles loaded with ribavirin via resisting caspase-3 apoptotic pathway. Int J Nanomedicine 2018; 13:5787-5797. [PMID: 30310281 PMCID: PMC6165773 DOI: 10.2147/ijn.s177658] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
INTRODUCTION Ribavirin (RBV) is a broad-spectrum antiviral drug. Selenium nanoparticles (SeNPs) attract much attention in the biomedical field and are used as carriers of drugs in current research studies. In this study, SeNPs were decorated by RBV, and the novel nanoparticle system was well characterized. Madin-Darby Canine Kidney cells were infected with H1N1 influenza virus before treatment with RBV, SeNPs, and SeNPs loaded with RBV (Se@RBV). METHODS AND RESULTS MTT assay showed that Se@RBV nanoparticles protect cells during H1N1 infection in vitro. Se@RBV depressed virus titer in the culture supernatant. Intracellular localization detection revealed that Se@RBV accumulated in lysosome and escaped to cytoplasm as time elapsed. Furthermore, activation of caspase-3 was resisted by Se@RBV. Expressions of proteins related to caspase-3, including cleaved poly-ADP-ribose polymerase, caspase-8, and Bax, were downregulated evidently after treatment with Se@RBV compared with the untreated infection group. In addition, phosphorylations of phosphorylated 38 (p38), JNK, and phosphorylated 53 (p53) were inhibited as well. In vivo experiments indicated that Se@RBV was found to prevent lung injury in H1N1-infected mice through hematoxylin and eosin staining. Tunel test of lung tissues present that DNA damage reached a high level but reduced substantially when treated with Se@RBV. Immunohistochemical test revealed an identical result with the in vitro experiment that activations of caspase-3 and proteins on the apoptosis pathway were restrained by Se@RBV treatment. CONCLUSION Taken together, this study elaborates that Se@RBV is a novel promising agent against H1N1 influenza virus infection.
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Affiliation(s)
- Zhengfang Lin
- Department of Center Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China, ;
| | - Yinghua Li
- Department of Center Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China, ;
| | - Guifang Gong
- Department of Obstetrics Gynecology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Yu Xia
- Department of Center Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China, ;
| | - Changbing Wang
- Department of Center Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China, ;
| | - Yi Chen
- Department of Center Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China, ;
| | - Liang Hua
- Department of Center Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China, ;
| | - Jiayu Zhong
- Department of Center Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China, ;
| | - Ying Tang
- Department of Center Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China, ;
| | - Xiaomin Liu
- Department of Center Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China, ;
| | - Bing Zhu
- Department of Center Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China, ;
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