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Guo Z, Wu M, Chen L, Chen H, Wu J, Xie Q, Lin G, Lian D, Peng J, Shen A. Neferine attenuates hypertensive cardiomyocyte apoptosis and modulates key signaling pathways: An in vivo and in vitro study. Eur J Pharmacol 2025; 994:177393. [PMID: 39956263 DOI: 10.1016/j.ejphar.2025.177393] [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: 11/12/2024] [Revised: 02/13/2025] [Accepted: 02/14/2025] [Indexed: 02/18/2025]
Abstract
BACKGROUND Although neferine exhibits obvious therapeutic effects against hypertension, its effects on cardiac protection remain unknown. PURPOSE This study aimed to investigate its potential cardioprotective effects and associated mechanisms. METHODS Spontaneously hypertensive rats (SHRs) were randomly divided into four groups, namely SHR, SHR + Neferine-L (2.5 mg/kg/day), SHR + Neferine-M (5 mg/kg/day), and SHR + Neferine-H (10 mg/kg/day). Wistar Kyoto rats were used as control. Various concentrations of neferine or double distilled water were then administered intragastrically for 10 weeks. Thereafter, cardiac function, pathological changes, cell apoptosis, and reactive oxygen species (ROS) accumulation, as well as their underlying mechanisms, were evaluated in SHRs and/or hypoxia-induced H9c2 cells. RESULT Neferine treatment significantly mitigated the decrease in left ventricular ejection fraction and fractional shortening and increase in left ventricular mass, end-systolic volume, and cardiac injury in SHRs. In SHR cardiac tissues, neferine treatment reversed 154 upregulated and 108 and downregulated transcripts. Pathway enrichment analysis found that multiple pathways were commonly enriched, including the apoptosis, PI3K-Akt, MAPK, and HIF-1 pathways. Consistently, neferine treatment significantly mitigated cardiomyocyte apoptosis, restored mitochondrial membrane depolarization, and reduced ROS accumulation. Mechanistically, neferine treatment significantly decreased the phosphorylation of ERK, p38 MAPK, and JNK; the Bax/Bcl-2 ratio; and the expression of HIF-1α, NADPH oxidase 4, and cleaved caspases-3 and -9 but increased the phosphorylation of PI3K and Akt and the expression of CD31. CONCLUSION Neferine treatment effectively mitigated hypertensive cardiomyocyte apoptosis and attenuated the abnormal activation of multiple signaling pathways, including the PI3K/Akt, MAPK, and HIF-1 pathways.
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Affiliation(s)
- Zhi Guo
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, 350122, China
| | - Meizhu Wu
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, 350122, China
| | - Lingqi Chen
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, 350122, China; Overseas Education College, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China
| | - Hong Chen
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, 350122, China
| | - Jinkong Wu
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, 350122, China
| | - Qiurong Xie
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, 350122, China
| | - Guosheng Lin
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, 350122, China
| | - Dawei Lian
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, 350122, China
| | - Jun Peng
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, 350122, China.
| | - Aling Shen
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, 350122, China; Department of Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, 100091, China; National Clinical Research Center for Cardiovascular Diseases of Traditional Chinese Medicine, Beijing, 100091, China.
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Li Z, Zhou D, Wu T, Lee H, Zheng F, Dai Y, Yue H. A novel glycopeptide from mountain-cultivated ginseng residue protects type 2 diabetic symptoms-induced heart failure. JOURNAL OF ETHNOPHARMACOLOGY 2025; 336:118723. [PMID: 39181285 DOI: 10.1016/j.jep.2024.118723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 08/15/2024] [Accepted: 08/20/2024] [Indexed: 08/27/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Mountain-cultivated Panax ginseng C.A.Mey. (MCG) with high market price and various properties was valuable special local product in Northeast of Asia. MCG has been historically used to mitigate heart failure (HF) for thousand years, HF is a clinical manifestation of deficiency of "heart-qi" in traditional Chinese medicine. However, there was little report focus on the activities of extracted residue of MCG. AIM OF THE STUDY A novel glycopeptide (APMCG-1) was isolated from step ethanol precipitations of alkaline protease-assisted extract from MCG residue. MATERIALS AND METHODS The molecular weight and subunit structure of APMCG-1 were determined by FT-IR, HPLC and GPC technologies, as well as the H9c2 cells, Tg (kdrl:EGFP) zebrafish were performed to evaluated the protective effect of APMCG-1. RESULTS APMCG-1 was identified as a glycopeptide containing seven monosaccharides and seven amino acids via O-lined bonds. Further, in vitro, APMCG-1 significantly decreased reactive oxygen species production and lactate dehydrogenase contents in palmitic acid (PA)-induced H9c2 cells. APMCG-1 also attenuated endoplasmic reticulum stress and mitochondria-mediated apoptosis in H9c2 cells via the PI3K/AKT signaling pathway. More importantly, APMCG-1 reduced the blood glucose, lipid contents, the levels of heart injury, oxidative stress and inflammation of 5 days post fertilization Tg (kdrl:EGFP) zebrafish with type 2 diabetic symptoms in vivo. CONCLUSIONS APMCG-1 protects PA-induced H9c2 cells while reducing cardiac dysfunction in zebrafish with type 2 diabetic symptoms. The present study provides a new insight into the development of natural glycopeptides as heart-related drug therapies.
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Affiliation(s)
- Zhuoran Li
- Changchun University of Chinese Medicine, Changchun 130117, China.
| | - Dongyue Zhou
- Changchun University of Chinese Medicine, Changchun 130117, China.
| | - Tongchuan Wu
- Changchun University of Chinese Medicine, Changchun 130117, China.
| | - Hyogeun Lee
- Jeju National University, Jeju 63243, Republic of Korea.
| | - Fei Zheng
- Changchun University of Chinese Medicine, Changchun 130117, China.
| | - Yulin Dai
- Changchun University of Chinese Medicine, Changchun 130117, China.
| | - Hao Yue
- Changchun University of Chinese Medicine, Changchun 130117, China.
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Zhang H, Zhao X, Wei W, Shen C. Nimbolide protects against diabetic cardiomyopathy by regulating endoplasmic reticulum stress and mitochondrial function via the Akt/mTOR pathway. Tissue Cell 2024; 90:102478. [PMID: 39053131 DOI: 10.1016/j.tice.2024.102478] [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: 02/18/2024] [Revised: 06/07/2024] [Accepted: 07/14/2024] [Indexed: 07/27/2024]
Abstract
Nimbolide has been demonstrated to possess protective properties against gestational diabetes mellitus and diabetic retinopathy. However, the role and molecular mechanism of nimbolide in diabetic cardiomyopathy (DCM) remain unknown. Diabetes was induced in rats via a single injection of streptozotocin (STZ) and then the diabetic rats were administered nimbolide (5 mg/kg and 20 mg/kg) or dimethyl sulfoxide daily for 12 weeks. H9c2 cardiomyocytes were exposed to high glucose (25 mM glucose) to mimic DCM in vitro. The protective effects of nimbolide against DCM were evaluated in vivo and in vitro. The potential molecular mechanism of nimbolide in DCM was further explored. We found that nimbolide dose-dependently decreased blood glucose and improved body weight of diabetic rats. Additionally, nimbolide dose-dependently improved cardiac function, alleviated myocardial injury/fibrosis, and inhibited endoplasmic reticulum (ER) stress and apoptosis in diabetic rats. Moreover, nimbolide dose-dependently improved mitochondrial function and activated the Akt/mTOR signaling. We consistently demonstrated the cardioprotective effects of nimbolide in an in vitro model of DCM. The involvement of ER stress and mitochondrial pathways were further confirmed by using inhibitors of ER stress and mitochondrial division. By applying a specific Akt inhibitor SC66, the cardioprotective effects of nimbolide were partially blocked. Our study indicated that nimbolide alleviated DCM by activating Akt/mTOR pathway. Nimbolide may be a novel therapeutic agent for DCM treatment.
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Affiliation(s)
| | | | - Wei Wei
- Hainan Second Health School, Wuzhishan 572200, China
| | - Chunjian Shen
- Department of Cardiothoracic Surgery, The Fourth People's Hospital of Shenyang, Shenyang 110000, China.
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Mohammed Abdul KS, Han K, Guerrero AB, Wilson CN, Kulkarni A, Purcell NH. Increased PHLPP1 expression through ERK-4E-BP1 signaling axis drives nicotine induced oxidative stress related damage of cardiomyocytes. J Mol Cell Cardiol 2024; 193:100-112. [PMID: 38851627 DOI: 10.1016/j.yjmcc.2024.05.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 05/30/2024] [Accepted: 05/31/2024] [Indexed: 06/10/2024]
Abstract
Nicotine, a key constituent of tobacco/electronic cigarettes causes cardiovascular injury and mortality. Nicotine is known to induce oxidative stress and mitochondrial dysfunction in cardiomyocytes leading to cell death. However, the underlying mechanisms remain unclear. Pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) is a member of metal-dependent protein phosphatase (PPM) family and is known to dephosphorylate several AGC family kinases and thereby regulate a diverse set of cellular functions including cell growth, survival, and death. Our lab has previously demonstrated that PHLPP1 removal reduced cardiomyocyte death and cardiac dysfunction following injury. Here, we present a novel finding that nicotine exposure significantly increased PHLPP1 protein expression in the adolescent rodent heart. Building upon our in vivo finding, we determined the mechanism of PHLPP1 expression in cardiomyocytes. Nicotine significantly increased PHLPP1 protein expression without altering PHLPP2 in cardiomyocytes. In cardiomyocytes, nicotine significantly increased NADPH oxidase 4 (NOX4), which coincided with increased reactive oxygen species (ROS) and increased cardiomyocyte apoptosis which were dependent on PHLPP1 expression. PHLPP1 expression was both necessary and sufficient for nicotine induced mitochondrial dysfunction. Mechanistically, nicotine activated extracellular signal-regulated protein kinases (ERK1/2) and subsequent eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) to increase PHLPP1 protein expression. Inhibition of protein synthesis with cycloheximide (CHX) and 4EGI-1 abolished nicotine induced PHLPP1 protein expression. Moreover, inhibition of ERK1/2 activity by U0126 significantly blocked nicotine induced PHLPP1 expression. Overall, this study reveals a novel mechanism by which nicotine regulates PHLPP1 expression through ERK-4E-BP1 signaling axis to drive cardiomyocyte injury.
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Affiliation(s)
| | - Kimin Han
- Cardiovascular Signaling Division, Huntington Medical Research Institutes, Pasadena, California, USA
| | - Alyssa B Guerrero
- Cardiovascular Signaling Division, Huntington Medical Research Institutes, Pasadena, California, USA
| | - Cekia N Wilson
- Cardiovascular Signaling Division, Huntington Medical Research Institutes, Pasadena, California, USA
| | - Amogh Kulkarni
- Cardiovascular Signaling Division, Huntington Medical Research Institutes, Pasadena, California, USA
| | - Nicole H Purcell
- Cardiovascular Signaling Division, Huntington Medical Research Institutes, Pasadena, California, USA; Cardiovascular Division, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, USA.
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Wu J, Cui Y, Ding W, Zhang J, Wang L. The protective effect of Macrostemonoside T from Allium macrostemon Bunge against Isoproterenol-Induced myocardial injury via the PI3K/Akt/mTOR signaling pathway. Int Immunopharmacol 2024; 133:112086. [PMID: 38642441 DOI: 10.1016/j.intimp.2024.112086] [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: 02/27/2024] [Revised: 03/31/2024] [Accepted: 04/10/2024] [Indexed: 04/22/2024]
Abstract
Myocardial injury (MI) signifies a pathological aspect of cardiovascular diseases (CVDs) such as coronary artery disease, diabetic cardiomyopathy, and myocarditis. Macrostemonoside T (MST) has been isolated from Allium macrostemon Bunge (AMB), a key traditional Chinese medicine (TCM) used for treating chest stuffiness and pains. Although MST has demonstrated considerable antioxidant activity in vitro, its protective effect against MI remains unexplored. To investigate MST's effects in both in vivo and in vitro models of isoproterenol (ISO)-induced MI and elucidate its underlying molecular mechanisms. This study established an ISO-induced MI model in rats and assessed H9c2 cytotoxicity to examine MST's impact on MI. Various assays, including histopathological staining, TUNEL staining, immunohistochemical staining, DCFH-DA staining, JC-1 staining, ELISA technique, and Western blot (WB), were utilized to explore the potential molecular mechanisms of MI protection. In vivo experiments demonstrated that ISO caused myocardial fiber disorders, elevated cardiac enzyme levels, and apoptosis. However, pretreatment with MST significantly mitigated these detrimental changes. In vitro experiments revealed that MST boosted antioxidant enzyme levels and suppressed malondialdehyde (MDA) production in H9c2 cells. Concurrently, MST inhibited ISO-induced reactive oxygen species (ROS) production and mitigated the decline in mitochondrial membrane potential, thereby reducing the apoptosis rate. Moreover, pretreatment with MST elevated the expression levels of p-PI3K, p-Akt, and p-mTOR, indicating activation of the PI3K/Akt/mTOR signaling pathway and consequent protection against MI. MST attenuated ISO-induced MI in rats by impeding apoptosis through activation of the PI3K/Akt/mTOR signaling pathway. This study presents potential avenues for the development of precursor drugs for CVDs.
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Affiliation(s)
- Jianfa Wu
- Department of Traditional Chinese Medicine, College of Traditional Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
| | - Ying Cui
- Department of Traditional Chinese Medicine, College of Traditional Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
| | - Weixing Ding
- Department of Traditional Chinese Medicine, College of Traditional Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
| | - Jing Zhang
- Department of Traditional Chinese Medicine, College of Traditional Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China.
| | - Lulu Wang
- School of Medicine, Changchun Sci-Tech University, Changchun 130600, China.
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Shepard BD, Chau J, Kurtz R, Rosenberg AZ, Sarder P, Border SP, Ginley B, Rodriguez O, Albanese C, Knoer G, Greene A, De Souza AMA, Ranjit S, Levi M, Ecelbarger CM. Nascent shifts in renal cellular metabolism, structure, and function due to chronic empagliflozin in prediabetic mice. Am J Physiol Cell Physiol 2024; 326:C1272-C1290. [PMID: 38602847 PMCID: PMC11193535 DOI: 10.1152/ajpcell.00446.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 02/21/2024] [Accepted: 02/21/2024] [Indexed: 04/13/2024]
Abstract
Sodium-glucose cotransporter, type 2 inhibitors (SGLT2i) are emerging as the gold standard for treatment of type 2 diabetes (T2D) with renal protective benefits independent of glucose lowering. We took a high-level approach to evaluate the effects of the SGLT2i, empagliflozin (EMPA) on renal metabolism and function in a prediabetic model of metabolic syndrome. Male and female 12-wk-old TallyHo (TH) mice, and their closest genetic lean strain (Swiss-Webster, SW) were treated with a high-milk-fat diet (HMFD) plus/minus EMPA (@0.01%) for 12-wk. Kidney weights and glomerular filtration rate were slightly increased by EMPA in the TH mice. Glomerular feature analysis by unsupervised clustering revealed sexually dimorphic clustering, and one unique cluster relating to EMPA. Periodic acid Schiff (PAS) positive areas, reflecting basement membranes and mesangium were slightly reduced by EMPA. Phasor-fluorescent life-time imaging (FLIM) of free-to-protein bound NADH in cortex showed a marginally greater reliance on oxidative phosphorylation with EMPA. Overall, net urine sodium, glucose, and albumin were slightly increased by EMPA. In TH, EMPA reduced the sodium phosphate cotransporter, type 2 (NaPi-2), but increased sodium hydrogen exchanger, type 3 (NHE3). These changes were absent or blunted in SW. EMPA led to changes in urine exosomal microRNA profile including, in females, enhanced levels of miRs 27a-3p, 190a-5p, and 196b-5p. Network analysis revealed "cancer pathways" and "FOXO signaling" as the major regulated pathways. Overall, EMPA treatment to prediabetic mice with limited renal disease resulted in modifications in renal metabolism, structure, and transport, which may preclude and underlie protection against kidney disease with developing T2D.NEW & NOTEWORTHY Renal protection afforded by sodium glucose transporter, type 2 inhibitors (SGLT2i), e.g., empagliflozin (EMPA) involves complex intertwined mechanisms. Using a novel mouse model of obesity with insulin resistance, the TallyHo/Jng (TH) mouse on a high-milk-fat diet (HMFD), we found subtle changes in metabolism including altered regulation of sodium transporters that line the renal tubule. New potential epigenetic determinants of metabolic changes relating to FOXO and cancer signaling pathways were elucidated from an altered urine exosomal microRNA signature.
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Affiliation(s)
- Blythe D Shepard
- Department of Human Science, Georgetown University, Washington, District of Columbia, United States
| | - Jennifer Chau
- Department of Medicine,Georgetown University, Washington, District of Columbia, United States
| | - Ryan Kurtz
- Department of Human Science, Georgetown University, Washington, District of Columbia, United States
| | - Avi Z Rosenberg
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland, United States
| | - Pinaki Sarder
- J Crayton Pruitt Department of Biomedical Engineering, University of Florida, Gainesville, Florida, United States
| | - Samuel P Border
- J Crayton Pruitt Department of Biomedical Engineering, University of Florida, Gainesville, Florida, United States
| | - Brandon Ginley
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland, United States
- Department of Computational Cell Biology, Anatomy, and Pathology, State University of New York at Buffalo, Buffalo, New York, United States
| | - Olga Rodriguez
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, United States
- Center for Translational Imaging, Georgetown University, Washington, District of Columbia, United States
| | - Chris Albanese
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, United States
- Center for Translational Imaging, Georgetown University, Washington, District of Columbia, United States
- Department of Radiology, Georgetown University, Washington, District of Columbia, United States
| | - Grace Knoer
- Center for Translational Imaging, Georgetown University, Washington, District of Columbia, United States
| | - Aarenee Greene
- Department of Medicine,Georgetown University, Washington, District of Columbia, United States
| | - Aline M A De Souza
- Department of Medicine,Georgetown University, Washington, District of Columbia, United States
| | - Suman Ranjit
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, District of Columbia, United States
- Microscopy & Imaging Shared Resources, Georgetown University, Washington, District of Columbia, United States
| | - Moshe Levi
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, District of Columbia, United States
| | - Carolyn M Ecelbarger
- Department of Medicine,Georgetown University, Washington, District of Columbia, United States
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Cheng FE, Li Z, Bai X, Jing Y, Zhang J, Shi X, Li T, Li W. Investigation on the mechanism of the combination of eremias multiocellata and cisplatin in reducing chemoresistance of gastric cancer based on in vitro and in vivo experiments. Aging (Albany NY) 2024; 16:3386-3403. [PMID: 38345573 PMCID: PMC10929809 DOI: 10.18632/aging.205540] [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: 08/16/2023] [Accepted: 01/11/2024] [Indexed: 03/06/2024]
Abstract
BACKGROUND Cisplatin (DDP) is one of the important chemotherapy drugs for patients with advanced gastric cancer and metastasis, but its resistance is a bottleneck problem that affects clinical efficacy and patient survival. Eremias multiocellata (EM) is a traditional Chinese herbal medicine, which has been used in the treatment of precancerous lesions, gastric cancer, liver fibrosis, and other digestive diseases. However, the mechanism of reducing chemotherapy resistance to gastric cancer is still unclear. METHODS We used the MTT assay to evaluate the proliferative viability of gastric cancer parental cell line MKN45 and its drug-resistant cell line MKN45/DDP, and compared their drug-resistance indices. The migration and invasion abilities of MKN45/DDP drug-resistant cells were evaluated using the Transwell assay. Apoptosis in MKN45/DDP drug-resistant cells was detected using flow cytometry. The effect of a combination of EM and cisplatin on the levels of reactive oxygen species (ROS) and lipid peroxides (LPO) in cisplatin-resistant gastric cancer cells was detected using ROS fluorescent probes and a lipid peroxidation assay kit in conjunction with flow cytometry. The effect of EM combined with cisplatin on the level of iron ions was detected by fluorescence probe and confocal laser technique. Hematoxylin-eosin staining (HE staining) was used to detect the histopathologic morphology of drug-resistant gastric cancer in nude mice. Ferroptosis-related proteins were measured using immunohistochemistry. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) was used to detect tumor drug resistance-related genes. The NF-κB/Snail pathway-related proteins, PI3K/AKT/mTOR pathway-related proteins, and drug resistance-related proteins were detected by Western blot. RESULTS AND CONCLUSIONS The results of in vitro and in vivo experiments showed that EM combined with DDP could effectively inhibit the migration and invasive ability of MKN45/DDP cells, as well as induce apoptosis of MKN45/DDP cells; the combination of the two drugs could significantly increase the levels of ROS, lipid peroxidation and divalent ferric ions in MKN45/DDP cells, at the same time reducing the levels of Ferroptosis-related proteins, which could induce Ferroptosis. In addition, EM combined with DDP can also exert the effect of reversing DDP resistance and increasing the sensitivity of gastric cancer drug-resistant cells to DDP by regulating the NF-κB/Snail signaling pathway, PI3K/AKT/mTOR signaling pathway, and the expression of drug resistance-related proteins and genes.
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Affiliation(s)
- Fan-e Cheng
- School of Traditional Chinese Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia, China
| | - Zheng Li
- School of Traditional Chinese Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia, China
| | - Xing Bai
- School of Basic Medicine, Zhejiang University of Chinese Medicine, Hangzhou 310053, Zhejiang, China
| | - Yanyan Jing
- Graduate School, Tianjin University of Chinese Medicine, Tianjin 300193, Tianjin, China
| | - Junfei Zhang
- School of Traditional Chinese Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia, China
| | - Xiaoqian Shi
- School of Traditional Chinese Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia, China
| | - Tingting Li
- School of Traditional Chinese Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia, China
| | - Weiqiang Li
- Key Laboratory of Ningxia Minority Medicine Modernization Ministry of Education, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
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Zhong L, Li J, Yu J, Cao X, Du J, Liang L, Yang M, Yue Y, Zhao M, Zhou T, Lin J, Wang X, Shen X, Zhong Y, Wang Y, Shu Z. Anemarrhena asphodeloides Bunge total saponins ameliorate diabetic cardiomyopathy by modifying the PI3K/AKT/HIF-1α pathway to restore glycolytic metabolism. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117250. [PMID: 37832811 DOI: 10.1016/j.jep.2023.117250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 09/10/2023] [Accepted: 09/28/2023] [Indexed: 10/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Based on the theory of traditional Chinese medicine (TCM), diabetic cardiomyopathy (DCM) belongs to the category of "Xiaoke disease" according to the symptoms, and "stasis-heat" is the main pathogenesis of DCM. The Chinese medicine Anemarrhena asphodeloides Bunge (AAB), as a representative of heat-clearing and engendering fluid, is often used clinically in the treatment of DCM. Anemarrhena asphodeloides Bunge total saponins (RATS) are the main bioactive components of AAB, the modern pharmacologic effects of RATS are anti-inflammatory, hypoglycemic, and cardioprotective. However, the potential protective mechanisms of RATS against DCM remain largely undiscovered. AIM OF THE STUDY The primary goal of this study was to explore the effect of RATS on DCM and its mechanism of action. MATERIALS AND METHODS Streptozotocin and a high-fat diet were used to induce DCM in rats. UHPLC/Q-TOF-MS was used to determine the chemical components of RATS. The degenerative alterations and apoptotic cells in the heart were assessed by HE staining and TUNEL. Network pharmacology was used to anticipate the probable targets and important pathways of RATS. The alterations in metabolites and main metabolic pathways in heart tissue were discovered using 1 H-NMR metabolomics. Ultimately, immunohistochemistry was used to find critical pathway protein expression. RESULTS First of all, UHPLC/Q-TOF-MS analysis showed that RATS contained 11 active ingredients. In animal experiments, we found that RATS lowered blood glucose and lipid levels in DCM rats, and alleviated cardiac pathological damage, and decreased cardiomyocyte apoptosis. Furthermore, the study found that RATS effectively reduced inflammatory factor release and the level of oxidative stress. Mechanistically, RATS downregulated the expression levels of PI3K, AKT, HIF-1α, LDHA, and GLUT4 proteins. Additionally, glycolysis was discovered to be a crucial pathway for RATS in the therapy of DCM. CONCLUSIONS Our findings suggest that the protective effect of RATS on DCM may be attributed to the inhibition of the PI3K/AKT/HIF-1α pathway and the correction of glycolytic metabolism.
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Affiliation(s)
- Luyang Zhong
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Jianhua Li
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Jiamin Yu
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Xia Cao
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Jieyong Du
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Lanyuan Liang
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Mengru Yang
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Yimin Yue
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Mantong Zhao
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Tong Zhou
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Jiazi Lin
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Xiao Wang
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Xuejuan Shen
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Yanmei Zhong
- New Drug Research and Development Center, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
| | - Yi Wang
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
| | - Zunpeng Shu
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
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9
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Feng X, Deng M, Zhang L, Pan Q. Impact of gut microbiota and associated mechanisms on postprandial glucose levels in patients with diabetes. J Transl Int Med 2023; 11:363-371. [PMID: 38130636 PMCID: PMC10732577 DOI: 10.2478/jtim-2023-0116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2023] Open
Abstract
Diabetes and its complications are serious medical and global burdens, often manifesting as postprandial hyperglycemia. In recent years, considerable research attention has focused on relationships between the gut microbiota and circulating postprandial glucose (PPG). Different population studies have suggested that PPG is closely related to the gut microbiota which may impact PPG via short-chain fatty acids (SCFAs), bile acids (BAs) and trimethylamine N-oxide (TMAO). Studies now show that gut microbiota models can predict PPG, with individualized nutrition intervention strategies used to regulate gut microbiota and improve glucose metabolism to facilitate the precision treatment of diabetes. However, few studies have been conducted in patients with diabetes. Therefore, little is known about the relationships between the gut microbiota and PPG in this cohort. Thus, more research is required to identify key gut microbiota and associated metabolites and pathways impacting PPG to provide potential therapeutic targets for PPG.
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Affiliation(s)
- Xinyuan Feng
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Beijing100730 ,China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing100730, China
| | - Mingqun Deng
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Beijing100730 ,China
| | - Lina Zhang
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Beijing100730 ,China
| | - Qi Pan
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Beijing100730 ,China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing100730, China
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10
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Wu C, Zhang W, Luo Y, Cheng C, Wang X, Jiang Y, Li S, Luo L, Yang Y. Zebrafish ppp1r21 mutant as a model for the study of primary biliary cholangitis. J Genet Genomics 2023; 50:1004-1013. [PMID: 37271428 DOI: 10.1016/j.jgg.2023.05.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 05/05/2023] [Accepted: 05/22/2023] [Indexed: 06/06/2023]
Abstract
Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease that progresses to fibrosis and cirrhosis, resulting from the gradual destruction of intrahepatic bile ducts. Exploring genetic variants associated with PBC is essential to understand the pathogenesis of PBC. Here we identify a zebrafish balloon dog (blg) mutant with intrahepatic bile duct branching defects, exhibiting several key pathological PBC-like features, including immunodominant autoantigen PDC-E2 production, cholangiocyte apoptosis, immune cell infiltration, inflammatory activation, and liver fibrosis. blg encodes the protein phosphatase 1 regulatory subunit 21 (Ppp1r21), which is enriched in the liver and its peripheral tissues and plays a vital role in the early intrahepatic bile duct formation stage. Further studies show an excessive activation of the PI3K/AKT/mTOR pathway in the hepatic tissues in the mutant, while treatment with the pathway inhibitor LY294002 and rapamycin partially rescues intrahepatic bile duct branching defects and alleviates the PBC-like symptoms. These findings implicate the potential role of the Ppp1r21-mediated PI3K/AKT/mTOR pathway in the pathophysiology of PBC.
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Affiliation(s)
- Chaoying Wu
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China
| | - Wenfeng Zhang
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China
| | - Yiyu Luo
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China
| | - Chaoqing Cheng
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China
| | - Xinjuan Wang
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China
| | - Yan Jiang
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China
| | - Shuang Li
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China
| | - Lingfei Luo
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China
| | - Yun Yang
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China.
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11
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Wang YJ, Wang YL, Jiang XF, Li JE. Molecular targets and mechanisms of Jiawei Jiaotai Pill on diabetic cardiomyopathy based on network pharmacology. World J Diabetes 2023; 14:1659-1671. [DOI: 10.4239/wjd.v14.i11.1659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 07/12/2023] [Accepted: 10/08/2023] [Indexed: 11/14/2023] Open
Abstract
BACKGROUND Jiawei Jiaotai Pill is commonly used in clinical practice to reduce apoptosis, increase insulin secretion, and improve blood glucose tolerance. However, its mechanism of action in the treatment of diabetic cardiomyopathy (DCM) remains unclear, hindering research efforts aimed at developing drugs specifically for the treatment of DCM.
AIM To explore the pharmacodynamic basis and molecular mechanism of Jiawei Jiaotai Pill in DCM treatment.
METHODS We explored various databases and software, including the Traditional Chinese Medicine Systems Pharmacology Database, Uniport, PubChem, GenCards, String, and Cytoscape, to identify the active components and targets of Jiawei Jiaotai Pill, and the disease targets in DCM. Protein-protein interaction network, gene ontology, and Kyoto Encyclopedia of Genes and Genomes analyses were used to determine the mechanism of action of Jiawei Jiaotai Pill in treating DCM. Molecular docking of key active components and core targets was verified using AutoDock software.
RESULTS Total 42 active ingredients and 142 potential targets of Jiawei Jiaotai Pill were identified. There were 100 common targets between the DCM and Jiawei Jiaotai Pills. Through this screening process, TNF, IL6, TP53, EGFR, INS, and other important targets were identified. These targets are mainly involved in the positive regulation of the mitogen-activated protein kinase (MAPK) MAPK cascade, response to xenobiotic stimuli, response to hypoxia, positive regulation of gene expression, positive regulation of cell proliferation, negative regulation of the apoptotic process, and other biological processes. It was mainly enriched in the AGE-RAGE signaling pathway in diabetic complications, DCM, PI3K-Akt, interleukin-17, and MAPK signaling pathways. Molecular docking results showed that Jiawei Jiaotai Pill's active ingredients had good docking activity with DCM's core target.
CONCLUSION The active components of Jiawei Jiaotai Pill may play a role in the treatment of DCM by reducing oxidative stress, cardiomyocyte apoptosis and fibrosis, and maintaining metabolic homeostasis.
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Affiliation(s)
- Yu-Juan Wang
- Department of Otolaryngology, Shaanxi Provincial People’s Hospital, Xi’an 710068, Shaaxi Province, China
| | - Yan-Li Wang
- Department of Pediatrics, Affiliated Hospital of Traditional Chinese Medicine, Xinjiang Medical University, Urumqi 830000, Xinjiang Uygur Autonomous Region, China
| | - Xiao-Fan Jiang
- Department of Chinese Medicine, Shaanxi Provincial People’s Hospital, Xi’an 710068, Shaaxi Province, China
| | - Juan-E Li
- Department of Chinese Medicine, Shaanxi Provincial People’s Hospital, Xi’an 710068, Shaaxi Province, China
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12
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Wang J, Yang H, Wang C, Kan C. Cyp2e1 knockdown attenuates high glucose-induced apoptosis and oxidative stress of cardiomyocytes by activating PI3K/Akt signaling. Acta Diabetol 2023; 60:1219-1229. [PMID: 37195324 DOI: 10.1007/s00592-023-02110-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Accepted: 04/26/2023] [Indexed: 05/18/2023]
Abstract
AIMS Cyp2e1 is a crucial CYP450 enzyme participating in diabetes and cardiovascular disorder. However, the role of Cyp2e1 in diabetic cardiomyopathy (DCM) has never been reported. Thus, we intended to identify the effects of Cyp2e1 on cardiomyocytes under high glucose (HG) conditions. METHODS Identification of differentially expressed genes in DCM and control rats was performed using bioinformatics analysis based on GEO database. The Cyp2e1-knockdown H9c2 and HL-1 cells were established through transfection with si-Cyp2e1. Western blot analysis was performed to determine the expression levels of Cyp2e1, apoptosis-related proteins and PI3K/Akt signaling-associated proteins. TUNEL assay was performed to assess apoptotic rate. Reactive oxygen species (ROS) generation was examined by DCFH2-DA staining assay. RESULTS From the bioinformatics analysis, Cyp2e1 was confirmed as an upregulated gene in DCM tissues. In vitro assays proved that Cyp2e1 expression was markedly increased in HG-induced H9c2 and HL-1 cells. Cyp2e1 knockdown attenuated HG-induced apoptosis in both H9c2 and HL-1 cells, as proved by deceased apoptotic rate, relative cleaved caspase-3/caspase-3 level, and caspase-3 activity. Cyp2e1 knockdown reduced ROS generation and elevated the expression level of nuclear Nrf2 in HG-induced H9c2 and HL-1 cells. Increased relative levels of p-PI3K/PI3K and p-Akt/Akt were found in Cyp2e1-knockdown H9c2 and HL-1 cells. Inhibition of PI3K/Akt using LY294002 reversed the inhibitory effects of Cyp2e1 knockdown on cell apoptosis and ROS generation on cardiomyocytes. CONCLUSIONS Cyp2e1 knockdown attenuated HG-induced apoptosis and oxidative stress by activating PI3K/Akt signaling in cardiomyocytes. These findings suggested that Cyp2e1 might be potentially used as an effective therapeutic strategy for DCM.
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Affiliation(s)
- Jianying Wang
- Department of Endocrinology, Nanshi Hospital Affiliated to Henan University, Nanyang, 473065, Henan Province, China
| | - Han Yang
- Department of Endocrinology, Nanshi Hospital Affiliated to Henan University, Nanyang, 473065, Henan Province, China
| | - Chao Wang
- Department of Geriatrics, Nanshi Hospital Affiliated to Henan University, Nanyang, 473065, Henan Province, China
| | - Cuie Kan
- Department of Intensive Care Unit, Huai'an Second Peopl's Hospital and The Affiliated Huai'an Hospital of Xuzhou Medical University, 62 South Huaihai Road, Huai'an, 223300, Jiangsu, China.
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13
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Chandra K, Swathi M, Keerthana B, Gopan S, Ghantasala JP, Joshi MB, Thondamal M, Parsa KVL. PHLPP1 regulates PINK1-parkin signalling and life span. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166718. [PMID: 37060964 DOI: 10.1016/j.bbadis.2023.166718] [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: 02/13/2023] [Revised: 04/05/2023] [Accepted: 04/06/2023] [Indexed: 04/17/2023]
Abstract
Adaptability to intracellular or extracellular cues is essential for maintaining cellular homeostasis. Metabolic signals intricately control the morphology and functions of mitochondria by regulating bioenergetics and metabolism. Here, we describe the involvement of PHLPP1, a Ser/Thr phosphatase, in mitochondrial homeostasis. Microscopic analysis showed the enhanced globular structure of mitochondria in PHLPP1-depleted HEK 293T and C2C12 cells, while forced expression of PHLPP1 promoted mitochondrial tubularity. We show that PHLPP1 promoted pro-fusion markers MFN2 and p-DRP1Ser637 levels using over-expression and knockdown strategies. Contrastingly, PHLPP1 induced mitochondrial fragmentation by augmenting pro-fission markers, t-DRP1 and pDrp1Ser616 upon mitochondrial stress. At the molecular level, PHLPP1 interacted with and caused dephosphorylation of calcineurin, a p-DRP1Ser637 phosphatase, under basal conditions. Likewise, PHLPP1 dimerized with PINK1 under basal conditions. However, the interaction of PHLPP1 with both calcineurin and PINK1 was impaired upon CCCP and oligomycin-induced mitochondrial stress. Interestingly, upon mitochondrial membrane depolarization, PHLPP1 promoted PINK1 stabilization and parkin recruitment to mitochondria, and thereby activated the mitophagy machinery providing a molecular explanation for the dual effects of PHLPP1 on mitochondria under different conditions. Consistent with our in-vitro findings, depletion of phlp-2, ortholog of PHLPP1 in C. elegans, led to mitochondrial fission under basal conditions, extended the lifespan of the worms, and enhanced survival of worms subjected to paraquat-induced oxidative stress.
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Affiliation(s)
- Kanika Chandra
- Centre for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad 500046, India; Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - M Swathi
- Centre for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad 500046, India
| | - B Keerthana
- Centre for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad 500046, India; Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Sooraj Gopan
- Centre for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad 500046, India
| | | | - Manjunath B Joshi
- Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Manjunatha Thondamal
- Department of Biotechnology, GITAM School of Technology, Gandhi Institute of Technology and Management (GITAM) (Deemed to be University), Visakhapatnam 530045, India
| | - Kishore V L Parsa
- Centre for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad 500046, India.
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14
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Ning S, Zhang S, Guo Z. MicroRNA-494 regulates high glucose-induced cardiomyocyte apoptosis and autophagy by PI3K/AKT/mTOR signalling pathway. ESC Heart Fail 2023; 10:1401-1411. [PMID: 36772911 PMCID: PMC10053280 DOI: 10.1002/ehf2.14311] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 12/08/2022] [Accepted: 01/16/2023] [Indexed: 02/12/2023] Open
Abstract
AIMS Diabetic cardiomyopathy (DCM) is one of the major cardiovascular complications of diabetes. However, the mechanism of DCM is not fully understood. Studies have confirmed that certain microRNAs (miRNAs/miRs) are key regulators of DCM. The aim of this study was to investigate the role and mechanism of microRNA (miR)-494 in cardiomyocyte apoptosis and autophagy induced by high glucose (HG). METHODS AND RESULTS By establishing a rat DCM model and an HG-treated H9c2 cells injury model, cardiac function was detected by echocardiography, myocardial tissue was stained by immunohistochemistry, and Cell Counting Kit-8 assay and lactate dehydrogenase assay were used to detect the cardiomyocyte injury. Cell apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labelling staining, and western blotting was used to detect death and autophagy. The results showed that the expression level of miR-494 was higher in the myocardial tissue of DCM rats and the myocardial cells of H9c2 treated with HG. Compared with the corresponding negative control groups, miR-494 mimics enhanced HG-induced apoptosis and autophagy, whereas miR-494 inhibitors showed the opposite effect, corresponding PI3K, AKT, and mTOR phosphorylation level has changed. CONCLUSIONS These findings identify that miR-494 could regulate cell apoptosis and autophagy through PI3K/AKT/mTOR signalling pathway, participating in the regulation of cardiomyocyte cell damage after HG. These findings provide new insights for the further study of the molecular mechanism and treatment of DCM.
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Affiliation(s)
- Shuwei Ning
- Henan Key Laboratory of Cardiac Remodeling and Transplantation, Zhengzhou No. 7 People's Hospital, No. 17 Jingnan 5th Road, Zhengzhou, Henan, 450016, China
| | - Siqi Zhang
- Henan Key Laboratory of Cardiac Remodeling and Transplantation, Zhengzhou No. 7 People's Hospital, No. 17 Jingnan 5th Road, Zhengzhou, Henan, 450016, China
| | - Zhikun Guo
- Henan Key Laboratory of Cardiac Remodeling and Transplantation, Zhengzhou No. 7 People's Hospital, No. 17 Jingnan 5th Road, Zhengzhou, Henan, 450016, China.,Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
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15
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Tan X, Chen YF, Zou SY, Wang WJ, Zhang NN, Sun ZY, Xian W, Li XR, Tang B, Wang HJ, Gao Q, Kang PF. ALDH2 attenuates ischemia and reperfusion injury through regulation of mitochondrial fusion and fission by PI3K/AKT/mTOR pathway in diabetic cardiomyopathy. Free Radic Biol Med 2023; 195:219-230. [PMID: 36587924 DOI: 10.1016/j.freeradbiomed.2022.12.097] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 12/16/2022] [Accepted: 12/27/2022] [Indexed: 12/31/2022]
Abstract
The function of mitochondrial fusion and fission is one of the important factors causing ischemia-reperfusion (I/R) injury in diabetic myocardium. Aldehyde dehydrogenase 2 (ALDH2) is abundantly expressed in heart, which involved in the regulation of cellular energy metabolism and stress response. However, the mechanism of ALDH2 regulating mitochondrial fusion and fission in diabetic myocardial I/R injury has not been elucidated. In the present study, we found that the expression of ALDH2 was downregulated in rat diabetic myocardial I/R model. Functionally, the activation of ALDH2 resulted in the improvement of cardiac hemodynamic parameters and myocardial injury, which were abolished by the treatment of Daidzin, a specific inhibitor of ALDH2. In H9C2 cardiomyocyte hypoxia-reoxygenation model, ALDH2 regulated the dynamic balance of mitochondrial fusion and fission and maintained mitochondrial morphology stability. Meanwhile, ALDH2 reduced mitochondrial ROS levels, and apoptotic protein expression in cardiomyocytes, which was associated with the upregulation of phosphorylation (p-PI3KTyr458, p-AKTSer473, p-mTOR). Moreover, ALDH2 suppressed the mitoPTP opening through reducing 4-HNE. Therefore, our results demonstrated that ALDH2 alleviated the ischemia and reperfusion injury in diabetic cardiomyopathy through inhibition of mitoPTP opening and activation of PI3K/AKT/mTOR pathway.
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Affiliation(s)
- Xin Tan
- Department of Cardiovascular Disease, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Yong-Feng Chen
- Department of Cardiovascular Disease, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Shi-Ying Zou
- Department of Cardiovascular Disease, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Wei-Jie Wang
- Department of Cardiovascular Disease, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Ning-Ning Zhang
- Department of Cardiovascular Disease, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Zheng-Yu Sun
- Department of Cardiovascular Disease, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Wei Xian
- Department of Cardiovascular Disease, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Xiao-Rong Li
- Department of Cardiovascular Disease, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Bi Tang
- Department of Cardiovascular Disease, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Hong-Ju Wang
- Department of Cardiovascular Disease, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Qin Gao
- Department of Physiology, Bengbu Medical College, Bengbu, China; Key Laboratory of Basic and Clinical Cardiovascular and Cerebrovascular Diseases, Bengbu Medical College, Bengbu, China.
| | - Pin-Fang Kang
- Department of Cardiovascular Disease, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China; Key Laboratory of Basic and Clinical Cardiovascular and Cerebrovascular Diseases, Bengbu Medical College, Bengbu, China.
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16
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Tawfik MK, Badran DI, Keshawy MM, Makary S, Abdo M. Alternate-day fat diet and exenatide modulate the brain leptin JAK2/STAT3/SOCS3 pathway in a fat diet-induced obesity and insulin resistance mouse model. Arch Med Sci 2023; 19:1508-1519. [PMID: 37732053 PMCID: PMC10507768 DOI: 10.5114/aoms/158534] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Accepted: 12/24/2022] [Indexed: 09/22/2023] Open
Abstract
Introduction Obesity is one of the most burdensome health problems and is closely linked to leptin resistance. The study examined whether an alternate-day high-fat diet (ADF) and/or GLP-1 agonist (exenatide) modulate brain leptin resistance caused by a high-fat diet (HFD). Material and methods Sixty adult male mice were divided into 6 groups: (i) normal palatable diet (NPD), (ii) exenatide control (NPD received exenatide) (iii) HFD, (iv) ADF treated, (v) exenatide treated, (vi) ADF and exenatide treated. All animal groups were fed a HFD for 8 weeks, before they received treatment (ADF and/or exenatide) for 8 additional weeks. Body weight was assessed at the start and at the end of the experiment. Lipid profile, brain leptin and its receptor expression with the leptin-sensitive pathway, JAK2/STAT3/SOCS3/PTP1B, fasting blood glucose (FBG), serum insulin, liver metabolic handling via its regulators IRS1/PI3K/GLUT4 for hyperinsulinemia/obesity-induced PDK3/NAFLD2 modification, and liver enzymes were determined at the end of the experiment. Results ADF and exenatide reduced body weight and FBG in HFD-obese mice (p < 0.05). The combined ADF and exenatide regimen enhanced the brain anorexic leptin/JAK2/STAT3 and attenuated the SOCS3/PTP1B pathway (p < 0.05). The ADF/exenatide anorexigenic brain effect also modulated liver glucose via IRS1/PI3K/GLUT4 expression (p < 0.05), attenuating NAFLD2 and PDK3 expression (p < 0.05). Liver enzymes and the histopathological profile confirmed the improvement. Conclusions In HFD caloric consumption, a combination of ADF and GLP-1 agonist enhances the brain leptin anorexigenic effect with the improvement of the metabolic sequelae of hyperinsulinemia, hyperlipidemia and liver steatosis.
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Affiliation(s)
- Mona K. Tawfik
- Department of Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Dahlia I. Badran
- Department of Biochemistry, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
- Department of Biochemistry, Faculty of Medicine, Badr University, Cairo, Egypt
| | - Mohammed M. Keshawy
- Department of Internal Medicine, Nephrology Division, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Samy Makary
- Department of Physiology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Mohamed Abdo
- Department of Physiology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
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Liao Y, Peng X, Li X, Wu D, Qiu S, Tang X, Zhang D. CircRNA_45478 promotes ischemic AKI by targeting the miR-190a-5p/PHLPP1 axis. FASEB J 2022; 36:e22633. [PMID: 36315192 DOI: 10.1096/fj.202201070r] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 10/02/2022] [Accepted: 10/18/2022] [Indexed: 11/05/2022]
Abstract
A few studies suggested that circular RNAs were involved in the development of ischemic acute kidney injury (AKI). However, the function and regulation mechanism of circRNA_45478 in ischemic AKI remains unknown. In the present study, ischemic injury induced the expressions of circRNA_45478 in mouse proximal tubule-derived cell lines (BUMPT cells) and kidneys of C57BL/6 mice. Functionally, circRNA_45478 mediated I/R-induced apoptosis in BUMPT cells. Mechanistically, circRNA_45478 upregulated the expression of Pleckstrin homology (PH) domain leucine-rich repeat protein phosphatase 1 (PHLPP1) via sponging of microRNA (miR)-190a-5p. Finally, inhibition of circRNA_45478 significantly alleviated the progression of ischemic AKI through regulation of the miR-190a-5p/PHLPP1 pathway. Taken together, our data showed that circRNA_45478/miR-190a-5p/PHLPP1 axis mediated the progression of ischemic AKI.
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Affiliation(s)
- Yingjun Liao
- Department of Emergency Medicine, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China.,Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Xiongjun Peng
- Department of Medical Equipment, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Xiaozhou Li
- Department of Emergency Medicine, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China.,Emergency Medicine and Difficult Diseases Institute, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Dengke Wu
- Department of Emergency Medicine, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China.,Emergency Medicine and Difficult Diseases Institute, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Shuangfa Qiu
- Department of Emergency Medicine, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China.,Emergency Medicine and Difficult Diseases Institute, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Xianming Tang
- Department of Emergency Medicine, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China.,Emergency Medicine and Difficult Diseases Institute, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Dongshan Zhang
- Department of Emergency Medicine, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China.,Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China.,Emergency Medicine and Difficult Diseases Institute, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
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18
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Balamurugan K, Chandra K, Sai Latha S, Swathi M, Joshi MB, Misra P, Parsa KVL. PHLPPs: Emerging players in metabolic disorders. Drug Discov Today 2022; 27:103317. [PMID: 35835313 DOI: 10.1016/j.drudis.2022.07.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 06/21/2022] [Accepted: 07/07/2022] [Indexed: 12/15/2022]
Abstract
That reversible protein phosphorylation by kinases and phosphatases occurs in metabolic disorders is well known. Various studies have revealed that a multi-faceted and tightly regulated phosphatase, pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP)-1/2 displays robust effects in cardioprotection, ischaemia/reperfusion (I/R), and vascular remodelling. PHLPP1 promotes foamy macrophage development through ChREBP/AMPK-dependent pathways. Adipocyte-specific loss of PHLPP2 reduces adiposity, improves glucose tolerance,and attenuates fatty liver via the PHLPP2-HSL-PPARα axis. Discoveries of PHLPP1-mediated insulin resistance and pancreatic β cell death via the PHLPP1/2-Mst1-mTORC1 triangular loop have shed light on its significance in diabetology. PHLPP1 downregulation attenuates diabetic cardiomyopathy (DCM) by restoring PI3K-Akt-mTOR signalling. In this review, we summarise the functional role of, and cellular signalling mediated by, PHLPPs in metabolic tissues and discuss their potential as therapeutic targets.
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Affiliation(s)
- Keerthana Balamurugan
- Center for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy's Institute of Life Sciences (DRILS), University of Hyderabad Campus, Hyderabad 500046, Telangana, India; Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India
| | - Kanika Chandra
- Center for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy's Institute of Life Sciences (DRILS), University of Hyderabad Campus, Hyderabad 500046, Telangana, India; Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India
| | - S Sai Latha
- Center for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy's Institute of Life Sciences (DRILS), University of Hyderabad Campus, Hyderabad 500046, Telangana, India
| | - M Swathi
- Center for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy's Institute of Life Sciences (DRILS), University of Hyderabad Campus, Hyderabad 500046, Telangana, India
| | - Manjunath B Joshi
- Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India
| | - Parimal Misra
- Center for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy's Institute of Life Sciences (DRILS), University of Hyderabad Campus, Hyderabad 500046, Telangana, India
| | - Kishore V L Parsa
- Center for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy's Institute of Life Sciences (DRILS), University of Hyderabad Campus, Hyderabad 500046, Telangana, India.
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19
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Malakoti F, Mohammadi E, Akbari Oryani M, Shanebandi D, Yousefi B, Salehi A, Asemi Z. Polyphenols target miRNAs as a therapeutic strategy for diabetic complications. Crit Rev Food Sci Nutr 2022; 64:1865-1881. [PMID: 36069329 DOI: 10.1080/10408398.2022.2119364] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
MiRNAs are a large group of non-coding RNAs which participate in different cellular pathways like inflammation and oxidation through transcriptional, post-transcriptional, and epigenetic regulation. In the post-transcriptional regulation, miRNA interacts with the 3'-UTR of mRNAs and prevents their translation. This prevention or dysregulation can be a cause of pathological conditions like diabetic complications. A huge number of studies have revealed the association between miRNAs and diabetic complications, including diabetic nephropathy, cardiomyopathy, neuropathy, retinopathy, and delayed wound healing. To address this issue, recent studies have focused on the use of polyphenols as selective and safe drugs in the treatment of diabetes complications. In this article, we will review the involvement of miRNAs in diabetic complications' occurrence or development. Finally, we will review the latest findings on targeting miRNAs by polyphenols like curcumin, resveratrol, and quercetin for diabetic complications therapy.
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Affiliation(s)
- Faezeh Malakoti
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Erfan Mohammadi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahsa Akbari Oryani
- Department of Pathology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Darioush Shanebandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bahman Yousefi
- Research Center for Integrative Medicine in Aging, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Azadeh Salehi
- Faculty of Pharmacy, Islamic Azad University of Tehran Branch, Tehran, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, I.R. Iran
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20
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Yang J, Ye J, Ma T, Tang F, Huang L, Liu Z, Tian S, Cheng X, Zhang L, Guo Z, Tu F, He M, Xu X, Lu X, Wu Y, Zeng X, Zou J, Wang X, Peng W, Zhang P. Tripartite motif-containing protein 11 promotes hepatocellular carcinogenesis through ubiquitin-proteasome-mediated degradation of pleckstrin homology domain leucine-rich repeats protein phosphatase 1. Hepatology 2022; 76:612-629. [PMID: 34767673 DOI: 10.1002/hep.32234] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 10/12/2021] [Accepted: 10/18/2021] [Indexed: 12/26/2022]
Abstract
BACKGROUND AND AIMS HCC is one of the main types of primary liver cancer, with high morbidity and mortality and poor treatment effect. Tripartite motif-containing protein 11 (TRIM11) has been shown to promote tumor formation in lung cancer, breast cancer, gastric cancer, and so on. However, the specific function and mechanism of TRIM11 in HCC remain open for study. APPROACH AND RESULTS Through clinical analysis, we found that the expression of TRIM11 was up-regulated in HCC tissues and was associated with high tumor node metastasis (TNM) stages, advanced histological grade, and poor patient survival. Then, by gain- and loss-of-function investigations, we demonstrated that TRIM11 promoted cell proliferation, migration, and invasion in vitro and tumor growth in vivo. Mechanistically, RNA sequencing and mass spectrometry analysis showed that TRIM11 interacted with pleckstrin homology domain leucine-rich repeats protein phosphatase 1 (PHLPP1) and promoted K48-linked ubiquitination degradation of PHLPP1 and thus promoted activation of the protein kinase B (AKT) signaling pathway. Moreover, overexpression of PHLPP1 blocked the promotional effect of TRIM11 on HCC function. CONCLUSIONS Our study confirmed that TRIM11 plays an oncogenic role in HCC through the PHLPP1/AKT signaling pathway, suggesting that targeting TRIM11 may be a promising target for the treatment of HCC.
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Affiliation(s)
- Juan Yang
- Gannan Innovation and Translational Medicine Research Institute, Department of Oncology, First Affiliated Hospital, Gannan Medical University, Ganzhou, China
| | - Jianming Ye
- Gannan Innovation and Translational Medicine Research Institute, Department of Oncology, First Affiliated Hospital, Gannan Medical University, Ganzhou, China.,Jiangxi Clinical Medical Research Center for Cancer, Ganzhou, China
| | - Tengfei Ma
- Department of Neurology, Huanggang Central Hospital, Huanggang, China.,Huanggang Institute of Translational Medicine, Huanggang, China
| | - Fangfang Tang
- Gannan Innovation and Translational Medicine Research Institute, Department of Oncology, First Affiliated Hospital, Gannan Medical University, Ganzhou, China.,Jiangxi Clinical Medical Research Center for Cancer, Ganzhou, China
| | - Li Huang
- Gannan Innovation and Translational Medicine Research Institute, Department of Oncology, First Affiliated Hospital, Gannan Medical University, Ganzhou, China.,Jiangxi Clinical Medical Research Center for Cancer, Ganzhou, China
| | - Zhen Liu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Song Tian
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xu Cheng
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Li Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhenli Guo
- Gannan Innovation and Translational Medicine Research Institute, Department of Oncology, First Affiliated Hospital, Gannan Medical University, Ganzhou, China.,Jiangxi Clinical Medical Research Center for Cancer, Ganzhou, China
| | - Fuping Tu
- Gannan Innovation and Translational Medicine Research Institute, Department of Oncology, First Affiliated Hospital, Gannan Medical University, Ganzhou, China.,Jiangxi Clinical Medical Research Center for Cancer, Ganzhou, China
| | - Miao He
- Gannan Innovation and Translational Medicine Research Institute, Department of Oncology, First Affiliated Hospital, Gannan Medical University, Ganzhou, China.,Jiangxi Clinical Medical Research Center for Cancer, Ganzhou, China
| | - Xueming Xu
- Gannan Innovation and Translational Medicine Research Institute, Department of Oncology, First Affiliated Hospital, Gannan Medical University, Ganzhou, China.,Jiangxi Clinical Medical Research Center for Cancer, Ganzhou, China
| | - Xiaojuan Lu
- Gannan Innovation and Translational Medicine Research Institute, Department of Oncology, First Affiliated Hospital, Gannan Medical University, Ganzhou, China.,Jiangxi Clinical Medical Research Center for Cancer, Ganzhou, China
| | - Yanyang Wu
- Gannan Innovation and Translational Medicine Research Institute, Department of Oncology, First Affiliated Hospital, Gannan Medical University, Ganzhou, China.,Jiangxi Clinical Medical Research Center for Cancer, Ganzhou, China
| | - Xiaoli Zeng
- Gannan Innovation and Translational Medicine Research Institute, Department of Oncology, First Affiliated Hospital, Gannan Medical University, Ganzhou, China.,Jiangxi Clinical Medical Research Center for Cancer, Ganzhou, China
| | - Jiahua Zou
- Cancer Center of Huanggang Central Hospital, Huanggang, China
| | - Xiangcai Wang
- Gannan Innovation and Translational Medicine Research Institute, Department of Oncology, First Affiliated Hospital, Gannan Medical University, Ganzhou, China.,Jiangxi Clinical Medical Research Center for Cancer, Ganzhou, China
| | - Weijie Peng
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, China.,Jiangxi Province Key Laboratory of Biomaterials and Biofabrication for Tissue Engineering, Gannan Medical University, Ganzhou, China
| | - Peng Zhang
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
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21
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Støle TP, Lunde M, Shen X, Martinsen M, Lunde PK, Li J, Lockwood F, Sjaastad I, Louch WE, Aronsen JM, Christensen G, Carlson CR. The female syndecan-4−/− heart has smaller cardiomyocytes, augmented insulin/pSer473-Akt/pSer9-GSK-3β signaling, and lowered SCOP, pThr308-Akt/Akt and GLUT4 levels. Front Cell Dev Biol 2022; 10:908126. [PMID: 36092718 PMCID: PMC9452846 DOI: 10.3389/fcell.2022.908126] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 07/06/2022] [Indexed: 11/13/2022] Open
Abstract
Background: In cardiac muscle, the ubiquitously expressed proteoglycan syndecan-4 is involved in the hypertrophic response to pressure overload. Protein kinase Akt signaling, which is known to regulate hypertrophy, has been found to be reduced in the cardiac muscle of exercised male syndecan-4−/− mice. In contrast, we have recently found that pSer473-Akt signaling is elevated in the skeletal muscle (tibialis anterior, TA) of female syndecan-4−/− mice. To determine if the differences seen in Akt signaling are sex specific, we have presently investigated Akt signaling in the cardiac muscle of sedentary and exercised female syndecan-4−/− mice. To get deeper insight into the female syndecan-4−/− heart, alterations in cardiomyocyte size, a wide variety of different extracellular matrix components, well-known syndecan-4 binding partners and associated signaling pathways have also been investigated.Methods: Left ventricles (LVs) from sedentary and exercise trained female syndecan-4−/− and WT mice were analyzed by immunoblotting and real-time PCR. Cardiomyocyte size and phosphorylated Ser473-Akt were analyzed in isolated adult cardiomyocytes from female syndecan-4−/− and WT mice by confocal imaging. LV and skeletal muscle (TA) from sedentary male syndecan-4−/− and WT mice were immunoblotted with Akt antibodies for comparison. Glucose levels were measured by a glucometer, and fasting blood serum insulin and C-peptide levels were measured by ELISA.Results: Compared to female WT hearts, sedentary female syndecan-4−/− LV cardiomyocytes were smaller and hearts had higher levels of pSer473-Akt and its downstream target pSer9-GSK-3β. The pSer473-Akt inhibitory phosphatase PHLPP1/SCOP was lowered, which may be in response to the elevated serum insulin levels found in the female syndecan-4−/− mice. We also observed lowered levels of pThr308-Akt/Akt and GLUT4 in the female syndecan-4−/− heart and an increased LRP6 level after exercise. Otherwise, few alterations were found. The pThr308-Akt and pSer473-Akt levels were unaltered in the cardiac and skeletal muscles of sedentary male syndecan-4−/− mice.Conclusion: Our data indicate smaller cardiomyocytes, an elevated insulin/pSer473-Akt/pSer9-GSK-3β signaling pathway, and lowered SCOP, pThr308-Akt/Akt and GLUT4 levels in the female syndecan-4−/− heart. In contrast, cardiomyocyte size, and Akt signaling were unaltered in both cardiac and skeletal muscles from male syndecan-4−/− mice, suggesting important sex differences.
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Affiliation(s)
- Thea Parsberg Støle
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
- *Correspondence: Thea Parsberg Støle,
| | - Marianne Lunde
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
- K. G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Xin Shen
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
- K. G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Marita Martinsen
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
- K. G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Per Kristian Lunde
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
- K. G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Jia Li
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
- K. G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Francesca Lockwood
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
- K. G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Ivar Sjaastad
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
- K. G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - William Edward Louch
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
- K. G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Jan Magnus Aronsen
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
- Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Geir Christensen
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
- K. G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Cathrine Rein Carlson
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
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22
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Li X, Zhang DQ, Wang X, Zhang Q, Qian L, Song R, Zhao X, Li X. Irisin alleviates high glucose-induced hypertrophy in H9c2 cardiomyoblasts by inhibiting endoplasmic reticulum stress. Peptides 2022; 152:170774. [PMID: 35219808 DOI: 10.1016/j.peptides.2022.170774] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 02/14/2022] [Accepted: 02/22/2022] [Indexed: 12/16/2022]
Abstract
BACKGROUND Endoplasmic reticulum stress (ERS) plays an important role in the process of myocardial hypertrophy in diabetic cardiomyopathy (DCM). Irisin, a novel cytokine, has been found to protect against cardiac diastolic dysfunction in DCM. We aimed to investigate the role of irisin in cardiac hypertrophy and to elucidate the underlying mechanisms. METHODS H9c2 cells were induced with 33 mM glucose to construct a cardiac hypertrophy cell model, which was then treated with irisin in the presence or absence of the ERS inducer tunicamycin (TM). The cell surface area was measured by FITC-phalloidin staining. The atrial natriuretic peptide levels were detected by an enzyme-linked immunosorbent assay. Furthermore, the expression of the ERS-related proteins, P-PERK, PERK, IRE1α and GRP78, was detected by western blotting. RESULTS Irisin significantly reduced myocardial hypertrophy and suppressed high glucose (HG)-induced oxidative stress. Meanwhile, the protective effect of irisin on cardiomyoblasts was reversed by the ERS inducer, TM. Additionally, we detected ERS-associated signaling pathway proteins and found that irisin significantly reduced the protein expression levels of GRP78 and p-PERK/PERK. CONCLUSION These results suggest that irisin ameliorates HG-induced cardiac hypertrophy by inhibiting ERS.
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Affiliation(s)
- Xiujun Li
- School of Clinical Medicine, Chifeng University, Hongshan, Chifeng, Inner Mongolia, China
| | - Da-Qi Zhang
- Department of Neurology, The First Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Xiaohui Wang
- Department of Laboratory, Affiliated Hospital of Chifeng University, Chifeng, Inner Mongolia, China
| | - Qin Zhang
- Department of Stomatology, Affiliated Hospital of Chifeng University, Inner Mongolia, China
| | - Liu Qian
- Liu Qian, Department of Pharmacology, College of Basic Medicine, Chifeng University, Inner Mongolia, China
| | - Rongjing Song
- Department of Pharmacy, Peking University People's Hospital, Beijing, China
| | - Xuecheng Zhao
- Department of Emergency Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Xiuli Li
- School of Stomatology, Chifeng University, Inner Mongolia, China.
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23
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STAT4 regulates cardiomyocyte apoptosis in rat models of diabetic cardiomyopathy. Acta Histochem 2022; 124:151872. [PMID: 35367814 DOI: 10.1016/j.acthis.2022.151872] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 02/25/2022] [Accepted: 02/25/2022] [Indexed: 11/01/2022]
Abstract
OBJECTIVE This study aimed to investigate the protective role of the signal transducer and activator of transcription 4 (STAT4) in diabetic cardiomyopathy. MATERIALS AND METHODS Male Sprague-Dawley (SD) rats (6-8 weeks old) were purchased from the Experimental Animal Center of Zhengzhou University. The rats were randomly divided into the control and diabetic cardiomyopathy groups. Rat models of diabetic cardiomyopathy were established by a high-sugar and high-fat diet combined with a peritoneal injection of streptozocin. Pathological changes in the heart were visualized using Hematoxylin-eosin (HE) staining and Masson's staining. Moreover, cell apoptosis was detected using terminal deoxyribonucleotidyl transferase (TdT)-mediated biotin-16-dUTP nick-end labeling (TUNEL) staining and Annexin V apoptosis detection kit. Furthermore, H9C2 cells were transfected with lentivirus overexpressing STAT4 and treated with high glucose. The CCK-8 assay was performed to determine cell viability. Finally, Western blotting was used to determine the expression of STAT4, Bax, and Bcl-2. RESULTS The myocardial tissue of the diabetic cardiomyopathy models showed hypertrophy, myocardial fibrosis and collagen deposition. Furthermore, TUNEL staining showed increased apoptosis and decreased expression of STAT4 in the myocardial cells. Moreover, the myocardial tissues of the DCM models showed increased expression of Bax/Bcl-2 and a high percentage of Annexin V positive cells. The H9C2 cells showed decreased expression of STAT4 following high glucose treatment. However, the H9C2 cells overexpressing STAT4 showed decreased expression of Bax/Bcl-2 and reduced percentage of Annexin V positive cells. CONCLUSION The DCM group had decreased myocardial expression of STAT4. Furthermore, overexpression of STAT4 was shown to reduce high glucose-induced apoptosis.
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24
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Jiang T, Wang H, Liu L, Song H, Zhang Y, Wang J, Liu L, Xu T, Fan R, Xu Y, Wang S, Shi L, Zheng L, Wang R, Song J. CircIL4R activates the PI3K/AKT signaling pathway via the miR-761/TRIM29/PHLPP1 axis and promotes proliferation and metastasis in colorectal cancer. Mol Cancer 2021; 20:167. [PMID: 34922544 PMCID: PMC8684286 DOI: 10.1186/s12943-021-01474-9] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 12/01/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Accumulating studies have revealed that aberrant expression of circular RNAs (circRNAs) is widely involved in the tumorigenesis and progression of malignant cancers, including colorectal cancer (CRC). Nevertheless, the clinical significance, levels, features, biological function, and molecular mechanisms of novel circRNAs in CRC remain largely unexplored. METHODS CRC-related circRNAs were identified through bioinformatics analysis and verified in clinical specimens by qRT-PCR and in situ hybridization (ISH). Then, in vitro and in vivo experiments were performed to determine the clinical significance of, functional roles of, and clinical characteristics associated with circIL4R in CRC specimens and cells. Mechanistically, RNA pull-down, fluorescence in situ hybridization (FISH), luciferase reporter, and ubiquitination assays were performed to confirm the underlying mechanism of circIL4R. RESULTS CircIL4R was upregulated in CRC cell lines and in sera and tissues from CRC patients and was positively correlated with advanced clinicopathological features and poor prognosis. Functional experiments demonstrated that circIL4R promotes CRC cell proliferation, migration, and invasion via the PI3K/AKT signaling pathway. Mechanistically, circIL4R was regulated by TFAP2C and competitively interacted with miR-761 to enhance the expression of TRIM29, thereby targeting PHLPP1 for ubiquitin-mediated degradation to activate the PI3K/AKT signaling pathway and consequently facilitate CRC progression. CONCLUSIONS Our findings demonstrate that upregulation of circIL4R plays an oncogenic role in CRC progression and may serve as a promising diagnostic and prognostic biomarker for CRC detection and as a potential therapeutic target for CRC treatment.
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Affiliation(s)
- Tao Jiang
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China.,Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China
| | - Hongyu Wang
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China.,The Graduate School, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Lianyu Liu
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China.,The Graduate School, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Hu Song
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China.,Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China
| | - Yi Zhang
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China.,Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China
| | - Jiaqi Wang
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China.,Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China
| | - Lei Liu
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China.,The Graduate School, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Teng Xu
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China.,Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China
| | - Ruizhi Fan
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China.,Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China
| | - Yixin Xu
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China.,Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China
| | - Shuai Wang
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China.,The Graduate School, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Linsen Shi
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China.,Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China
| | - Li Zheng
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China
| | - Renhao Wang
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China. .,Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China.
| | - Jun Song
- Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China. .,Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China.
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miR-190-5p Alleviates Myocardial Ischemia-Reperfusion Injury by Targeting PHLPP1. DISEASE MARKERS 2021; 2021:8709298. [PMID: 34868398 PMCID: PMC8639278 DOI: 10.1155/2021/8709298] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 11/09/2021] [Accepted: 11/11/2021] [Indexed: 11/17/2022]
Abstract
Objective Myocardial ischemia-reperfusion (I/R) injury (MIRI) refers to the more serious myocardial injury after blood flow recovery, which seriously affects the prognosis of patients with ischemic cardiomyopathy. This study explored the new targets for MIRI treatment by investigating the effects of miR-190-5p and its downstream target on the structure and function of myocardial cells. Methods We injected agomir miR-190-5p into the tail vein of rats to increase the expression of miR-190-5p in rat myocardial cells and made an I/R rat model by coronary artery occlusion. We used 2,3,5-triphenyl tetrazolium chloride staining, lactate dehydrogenase (LDH) detection, echocardiography, and hematoxylin-eosin (HE) staining to determine the degree of myocardial injury in I/R rats. In addition, we detected the expression of inflammatory factors and apoptosis-related molecules in rat serum and myocardial tissue to determine the level of inflammation and apoptosis in rat myocardium. Finally, we determined the downstream target of miR-190-5p by Targetscan system and dual luciferase reporter assay. Results The expression of miR-190-5p in an I/R rat myocardium was significantly lower than that in normal rats. After treatment of I/R rats with agomir miR-190-5p, the ischemic area of rat myocardium and the concentration of LDH decreased. The results of echocardiography and HE staining also found that overexpression of miR-190-5p improved the structure and function of rat myocardium. miR-190-5p was also found to improve the viability of H9c2 cells in vitro and reduce the level of apoptosis of H9c2 cells. The results of Targetscan system and dual luciferase reporter assay found that miR-190-5p targeted to inhibit pleckstrin homology domain leucine-rich repeat protein phosphatase 1 (PHLPP1). In addition, inhibition of PHLPP1 was found to improve the viability of H9c2 cells. Conclusion Therefore, miR-190-5p can reduce the inflammation and apoptosis of myocardium by targeting PHLPP1, thereby alleviating MIRI.
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Lupse B, Annamalai K, Ibrahim H, Kaur S, Geravandi S, Sarma B, Pal A, Awal S, Joshi A, Rafizadeh S, Madduri MK, Khazaei M, Liu H, Yuan T, He W, Gorrepati KDD, Azizi Z, Qi Q, Ye K, Oberholzer J, Maedler K, Ardestani A. Inhibition of PHLPP1/2 phosphatases rescues pancreatic β-cells in diabetes. Cell Rep 2021; 36:109490. [PMID: 34348155 PMCID: PMC8421018 DOI: 10.1016/j.celrep.2021.109490] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 06/06/2021] [Accepted: 07/14/2021] [Indexed: 12/16/2022] Open
Abstract
Pancreatic β-cell failure is the key pathogenic element of the complex metabolic deterioration in type 2 diabetes (T2D); its underlying pathomechanism is still elusive. Here, we identify pleckstrin homology domain leucine-rich repeat protein phosphatases 1 and 2 (PHLPP1/2) as phosphatases whose upregulation leads to β-cell failure in diabetes. PHLPP levels are highly elevated in metabolically stressed human and rodent diabetic β-cells. Sustained hyper-activation of mechanistic target of rapamycin complex 1 (mTORC1) is the primary mechanism of the PHLPP upregulation linking chronic metabolic stress to ultimate β-cell death. PHLPPs directly dephosphorylate and regulate activities of β-cell survival-dependent kinases AKT and MST1, constituting a regulatory triangle loop to control β-cell apoptosis. Genetic inhibition of PHLPPs markedly improves β-cell survival and function in experimental models of diabetes in vitro, in vivo, and in primary human T2D islets. Our study presents PHLPPs as targets for functional regenerative therapy of pancreatic β cells in diabetes.
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Affiliation(s)
- Blaz Lupse
- Centre for Biomolecular Interactions Bremen, University of Bremen, 28359 Bremen, Germany
| | - Karthika Annamalai
- Centre for Biomolecular Interactions Bremen, University of Bremen, 28359 Bremen, Germany
| | - Hazem Ibrahim
- Centre for Biomolecular Interactions Bremen, University of Bremen, 28359 Bremen, Germany
| | - Supreet Kaur
- Centre for Biomolecular Interactions Bremen, University of Bremen, 28359 Bremen, Germany
| | - Shirin Geravandi
- Centre for Biomolecular Interactions Bremen, University of Bremen, 28359 Bremen, Germany
| | - Bhavishya Sarma
- Centre for Biomolecular Interactions Bremen, University of Bremen, 28359 Bremen, Germany
| | - Anasua Pal
- Centre for Biomolecular Interactions Bremen, University of Bremen, 28359 Bremen, Germany
| | - Sushil Awal
- Centre for Biomolecular Interactions Bremen, University of Bremen, 28359 Bremen, Germany
| | - Arundhati Joshi
- Centre for Biomolecular Interactions Bremen, University of Bremen, 28359 Bremen, Germany
| | - Sahar Rafizadeh
- Centre for Biomolecular Interactions Bremen, University of Bremen, 28359 Bremen, Germany
| | - Murali Krishna Madduri
- Centre for Biomolecular Interactions Bremen, University of Bremen, 28359 Bremen, Germany
| | - Mona Khazaei
- Centre for Biomolecular Interactions Bremen, University of Bremen, 28359 Bremen, Germany
| | - Huan Liu
- Centre for Biomolecular Interactions Bremen, University of Bremen, 28359 Bremen, Germany
| | - Ting Yuan
- Centre for Biomolecular Interactions Bremen, University of Bremen, 28359 Bremen, Germany
| | - Wei He
- Centre for Biomolecular Interactions Bremen, University of Bremen, 28359 Bremen, Germany
| | | | - Zahra Azizi
- Centre for Biomolecular Interactions Bremen, University of Bremen, 28359 Bremen, Germany; Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran 1449614535, Iran
| | - Qi Qi
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Keqiang Ye
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Jose Oberholzer
- Charles O. Strickler Transplant Center, University of Virginia Medical Center, Charlottesville, VA 22903, USA
| | - Kathrin Maedler
- Centre for Biomolecular Interactions Bremen, University of Bremen, 28359 Bremen, Germany.
| | - Amin Ardestani
- Centre for Biomolecular Interactions Bremen, University of Bremen, 28359 Bremen, Germany; Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran 1449614535, Iran.
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FBXO22, ubiquitination degradation of PHLPP1, ameliorates rotenone induced neurotoxicity by activating AKT pathway. Toxicol Lett 2021; 350:1-9. [PMID: 34182063 DOI: 10.1016/j.toxlet.2021.06.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 06/18/2021] [Accepted: 06/23/2021] [Indexed: 12/23/2022]
Abstract
Parkinson's disease (PD) is a neurodegenerative disease caused by the lacking of dopaminergic neurons. Many reports have illustrated that rotenone is applied to establish the experimental model of PD, which simulates PD-like symptoms. FBXO22 is a poorly understood protein that may be involved in neurological disorders. However, little is known about FBXO22 in PD. In this study, first, SH-SY5Y cells were treated with rotenone to construct PD model in vitro. It was discovered that the FBXO22 expression was down-regulated following rotenone treatment. Additionally, overexpression of FBXO22 reduced rotenone treatment-mediated cell apoptosis in SH-SY5Y cells. In view of the ubiquitination effect of FBXO22, our study uncovered that FBXO22 bound with and degraded PHLPP1 by ubiquitination. Next, the effects of PHLPP1 on AKT pathway in PD were further explored. It was demonstrated that PHLPP1 inactivated AKT pathway through down-regulating the pAKT/AKT and pmTOR/mTOR levels. Through rescue assays, the results showed that PHLPP1 overexpression partially reversed the reduction of rotenone induced neurotoxicity caused by FBXO22 overexpression. Finally, we found that overexpression of FBXO22 alleviated rotenone-induced PD symptoms in rat model. Moreover, it was discovered that l-dopa treatment could not affect the FBXO22 expression in PD. In conclusion, findings from our work proved that FBXO22 degraded PHLPP1 by ubiquitination to ameliorate rotenone induced neurotoxicity, which attributed to activate AKT pathway. This work suggested that FBXO22 may be an effective biological marker for PD treatment.
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Zhang B, Li X, Liu G, Zhang C, Zhang X, Shen Q, Sun G, Sun X. Peroxiredomin-4 ameliorates lipotoxicity-induced oxidative stress and apoptosis in diabetic cardiomyopathy. Biomed Pharmacother 2021; 141:111780. [PMID: 34130124 DOI: 10.1016/j.biopha.2021.111780] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 05/11/2021] [Accepted: 05/25/2021] [Indexed: 02/05/2023] Open
Abstract
Diabetic cardiomyopathy (DCM), one severe complication in the diabetes, leads to high mortality in the diabetic patients. However, the understanding of molecular mechanisms underlying DCM is far from completion. Herein, we investigated the disease-related differences in the proteomes of DCM based on db/db mice and verified the protective roles of peroxiredoxin-4 (Prdx4) in H9c2 cardiomyocytes treated by palmitic acid (PA). Fasting blood glucose (FBG) and cardiac function was detected in the 6-month-old control and diabetic mice. The hearts were then collected and analyzed by a coupled label-free and mass spectrometry approach. In vivo investigation indicated that body weight and FBG of db/db mice markedly increased, and diabetic heart exhibited obvious cardiac hypertrophy and lipid droplet accumulation, and cardiac dysfunction as is indicated by the increases of left ventricle posterior wall thickness in systole (LVPWd) and diastole (LVPWs), and reduction of fractional shortening (FS). We used proteomic analysis and then detected a grand total of 2636 proteins. 175 differentially expressed proteins (DEPs) were markedly detected in the diabetic heart. Thereinto, Prdx4 was markedly down-regulated in the diabetic heart. In vitro experiments revealed that 250 μM PA significantly inhibited viability of H9c2 cell. PA induced much accumulation of lipid droplet in cardiomyocytes and resulted in an increase of mRNA expressions of lipogenic genes (FASN and SCD1) and cardiac hypertrophic genes. Additionally, protein level of Prdx4 evidently reduced in the PA-treated H9c2 cell. It was further found that shRNA-mediated Prdx4 knockdown exacerbated PA-induced oxidative stress and cardiomyocyte apoptosis, whereas overexpressing Prdx4 in the H9c2 cells noteworthily limited PA-induced ROS generation and cardiomyocytes apoptosis. These data collectively reveal the essential role of abnormal Prdx4 in pathological alteration of DCM, and provide potentially therapeutic target for the prevention of DCM.
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Affiliation(s)
- Bin Zhang
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China.
| | - Xiaoya Li
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China.
| | - Guoxin Liu
- Department of Pharmacy, The Third People's Hospital of Qingdao, Qingdao 266071, Shandong, China.
| | - Chenyang Zhang
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China.
| | - Xuelian Zhang
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China.
| | - Qiang Shen
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China.
| | - Guibo Sun
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China.
| | - Xiaobo Sun
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China.
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Weaver SR, Taylor EL, Zars EL, Arnold KM, Bradley EW, Westendorf JJ. Pleckstrin homology (PH) domain and Leucine Rich Repeat Phosphatase 1 (Phlpp1) Suppresses Parathyroid Hormone Receptor 1 (Pth1r) Expression and Signaling During Bone Growth. J Bone Miner Res 2021; 36:986-999. [PMID: 33434347 PMCID: PMC8131217 DOI: 10.1002/jbmr.4248] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 12/06/2020] [Accepted: 12/24/2020] [Indexed: 12/20/2022]
Abstract
Endochondral ossification is tightly controlled by a coordinated network of signaling cascades including parathyroid hormone (PTH). Pleckstrin homology (PH) domain and leucine rich repeat phosphatase 1 (Phlpp1) affects endochondral ossification by suppressing chondrocyte proliferation in the growth plate, longitudinal bone growth, and bone mineralization. As such, Phlpp1-/- mice have shorter long bones, thicker growth plates, and proportionally larger growth plate proliferative zones. The goal of this study was to determine how Phlpp1 deficiency affects PTH signaling during bone growth. Transcriptomic analysis revealed greater PTH receptor 1 (Pth1r) expression and enrichment of histone 3 lysine 27 acetylation (H3K27ac) at the Pth1r promoter in Phlpp1-deficient chondrocytes. PTH (1-34) enhanced and PTH (7-34) attenuated cell proliferation, cAMP signaling, cAMP response element-binding protein (CREB) phosphorylation, and cell metabolic activity in Phlpp1-inhibited chondrocytes. To understand the role of Pth1r action in the endochondral phenotypes of Phlpp1-deficient mice, Phlpp1-/- mice were injected with Pth1r ligand PTH (7-34) daily for the first 4 weeks of life. PTH (7-34) reversed the abnormal growth plate and long-bone growth phenotypes of Phlpp1-/- mice but did not rescue deficits in bone mineral density or trabecular number. These results show that elevated Pth1r expression and signaling contributes to increased proliferation in Phlpp1-/- chondrocytes and shorter bones in Phlpp1-deficient mice. Our data reveal a novel molecular relationship between Phlpp1 and Pth1r in chondrocytes during growth plate development and longitudinal bone growth. © 2021 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
| | | | | | | | - Elizabeth W. Bradley
- Department of Orthopedic Surgery and Stem Cell Institute, University of Minnesota, Minneapolis, MN
| | - Jennifer J. Westendorf
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
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Zhang M, Wang X, Liu M, Liu D, Pan J, Tian J, Jin T, Xu Y, An F. Inhibition of PHLPP1 ameliorates cardiac dysfunction via activation of the PI3K/Akt/mTOR signalling pathway in diabetic cardiomyopathy. J Cell Mol Med 2020; 24:4612-4623. [PMID: 32150791 PMCID: PMC7176843 DOI: 10.1111/jcmm.15123] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 12/18/2019] [Accepted: 02/11/2020] [Indexed: 12/20/2022] Open
Abstract
Background Pleckstrin homology (PH) domain leucine‐rich repeat protein phosphatase 1 (PHLPP1) is a kind of serine/threonine phosphatase, whose dysregulation is accompanied with numerous human diseases. However, its role in diabetic cardiomyopathy remains unclear. We explored the underlying function and mechanism of PHLPP1 in diabetic cardiomyopathy (DCM). Method In vivo, Type 1 diabetic rats were induced by intraperitoneal injection of 60 mg/kg streptozotocin (STZ). Lentivirus‐mediated short hairpin RNA (shRNA) was used to knock down the expression of PHLPP1. In vitro, primary neonatal rat cardiomyocytes and H9C2 cells were incubated in 5.5 mmol/L glucose (normal glucose, NG) or 33.3 mmol/L glucose (high glucose, HG). PHLPP1 expression was inhibited by PHLPP1‐siRNA to probe into the function of PHLPP1 in high glucose‐induced apoptosis in H9c2 cells. Results Diabetic rats showed up‐regulated PHLPP1 expression, left ventricular dysfunction, increased myocardial apoptosis and fibrosis. PHLPP1 inhibition alleviated cardiac dysfunction. Additionally, PHLPP1 inhibition significantly reduced HG‐induced apoptosis and restored PI3K/AKT/mTOR pathway activity in H9c2 cells. Furthermore, pretreatment with LY294002, an inhibitor of PI3K/Akt/mTOR pathway, abolished the anti‐apoptotic effect of PHLPP1 inhibition. Conclusion Our study indicated that PHLPP1 inhibition alleviated cardiac dysfunction via activating the PI3K/Akt/mTOR signalling pathway in DCM. Therefore, PHLPP1 may be a novel therapeutic target for human DCM.
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Affiliation(s)
- Mingjun Zhang
- Department of Cardiology, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Xuyang Wang
- Department of Cardiology, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Ming Liu
- Department of Cardiology, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Dian Liu
- Department of Cardiology, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Jinyu Pan
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital of Shandong First Medical University, Jinan, China
| | - Jingjing Tian
- Department of Cardiology, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Tao Jin
- Department of Cardiology, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Yunfan Xu
- College of Life Sciences, Sichuan University, Chengdu, China
| | - Fengshuang An
- Department of Cardiology, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
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