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Gao M, Dai MT, Gong GH. Dysfunctional glucose metabolism triggers oxidative stress to induce kidney injury in diabetes. World J Diabetes 2025; 16:102554. [DOI: 10.4239/wjd.v16.i4.102554] [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: 10/21/2024] [Revised: 01/14/2025] [Accepted: 02/05/2025] [Indexed: 02/28/2025] Open
Abstract
In this editorial, we discussed the article published in the recent issue of the World Journal of Diabetes. To understand the effect of mizagliflozin on kidney injury induced by diabetes, we focused on the mechanisms by which high glucose triggers oxidative stress and contributes to kidney injury in diabetes. The high level of unmetabolized glucose reaching the kidney triggers glucose reabsorption by renal tubules, which elevates the cellular glucose level of renal cells. High glucose induces lactate dehydrogenase overexpression and thus shifts glucose metabolism, which causes mitochondrial dysfunction. Mitochondria generate approximately 90% of the reactive oxygen species in cells, whose dysfunction further alters glucose metabolism and enhances reactive oxygen species generation. Oxidative stress stimulates proinflammatory factor production and kidney inflammatory injury. Mizagliflozin decreases glucose reabsorption and thus ameliorates diabetes-induced kidney injury.
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Affiliation(s)
- Meng Gao
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Meng-Ting Dai
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China
| | - Guo-Hua Gong
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China
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2
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Lee SR, Lee HE, Yoo JY, An EJ, Song SJ, Han KH, Cha DR, Bae YS. Nox4-SH3YL1 complex is involved in diabetic nephropathy. iScience 2024; 27:108868. [PMID: 38318360 PMCID: PMC10839645 DOI: 10.1016/j.isci.2024.108868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 10/25/2023] [Accepted: 01/08/2024] [Indexed: 02/07/2024] Open
Abstract
Nox4-derived H2O2 generation plays an important role in the pathogenesis of chronic kidney diseases (CKDs) such as diabetic nephropathy (DN). Here, we showed that SH3 domain-containing Ysc84-like 1 (SH3YL1), a Nox4 cytosolic activator, regulated DN. Streptozotocin (STZ)-induced type Ⅰ diabetic models in SH3YL1 whole-body knockout (KO) mice and podocyte-specific SH3YL1 conditional KO (Nphs2-Cre/SH3YL1fl/fl) mice were established to investigate the function of SH3YL1 in DN. The expression of fibrosis markers and inflammatory cytokines, the generation of oxidative stress, and the loss of podocytes were suppressed in diabetic SH3YL1 KO and Nphs2-Cre/SH3YL1fl/fl mice, compared to diabetic control mice. To extrapolate the observations derived from diabetic mice to clinical implication, we measured the protein level of SH3YL1 in patients DN. In fact, the SH3YL1 level was increased in patients DN. Overall, the SH3YL1-Nox4 complex was identified to play an important role in renal inflammation and fibrosis, resulting in the development of DN.
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Affiliation(s)
- Sae Rom Lee
- Department of Life Sciences, Ewha Womans University, Seoul 03760, Korea
| | - Hye Eun Lee
- Department of Life Sciences, Ewha Womans University, Seoul 03760, Korea
| | - Jung-Yeon Yoo
- Department of Life Sciences, Ewha Womans University, Seoul 03760, Korea
| | - Eun Jung An
- Department of Life Sciences, Ewha Womans University, Seoul 03760, Korea
| | - Soo-Jin Song
- Department of Anatomy, Ewha Womans University College of Medicine, Seoul 07804, Korea
| | - Ki-Hwan Han
- Department of Anatomy, Ewha Womans University College of Medicine, Seoul 07804, Korea
| | - Dae Ryong Cha
- Department of Internal Medicine, Division of Nephrology, Korea University Ansan Hospital, 516 Kojan-Dong, Ansan City, Kyungki-Do 15355, Korea
| | - Yun Soo Bae
- Department of Life Sciences, Ewha Womans University, Seoul 03760, Korea
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Guo C, He J, Deng X, Wang D, Yuan G. Potential therapeutic value of melatonin in diabetic nephropathy: improvement beyond anti-oxidative stress. Arch Physiol Biochem 2023; 129:1250-1261. [PMID: 34048666 DOI: 10.1080/13813455.2021.1933539] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 05/18/2021] [Indexed: 12/23/2022]
Abstract
Diabetic nephropathy (DN) is a common complication of diabetes, and it is also the main cause of chronic renal failure. Physiological/pathological changes mediated by high glucose are the main factors causing injury of DN, including the enhancement of polyol pathway, the accumulation of advanced glycation products (AGEs), and the activation of protein kinase C (PKC) and transforming growth factor-β (TGF-β) signals. In addition, the abnormal activation of renin-angiotensin system (RAS) and oxidative stress are also involved. Melatonin is a physiological hormone mainly secreted by the pineal gland which has been proved to be related to diabetes. Studies have shown that exogenous melatonin intervention can reduce blood glucose and alleviate high glucose mediated pathological damage. At the same time, melatonin also has a strong antioxidant effect, and can inhibit the activation of RAS. Therefore, it is of great significance to explore the therapeutic effect and value of melatonin on DN.
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Affiliation(s)
- Chang Guo
- Department of Nephrology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Jianqiang He
- Department of Nephrology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Xia Deng
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Dong Wang
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Guoyue Yuan
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
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Liu Y, Uruno A, Saito R, Matsukawa N, Hishinuma E, Saigusa D, Liu H, Yamamoto M. Nrf2 deficiency deteriorates diabetic kidney disease in Akita model mice. Redox Biol 2022; 58:102525. [PMID: 36335764 PMCID: PMC9641024 DOI: 10.1016/j.redox.2022.102525] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 10/13/2022] [Accepted: 10/24/2022] [Indexed: 11/06/2022] Open
Abstract
Oxidative stress is an essential component in the progression of diabetic kidney disease (DKD), and the transcription factor NF-E2-related factor-2 (Nrf2) plays critical roles in protecting the body against oxidative stress. To clarify the roles of Nrf2 in protecting against DKD, in this study we prepared compound mutant mice with diabetes and loss of antioxidative defense. Specifically, we prepared compound Ins2Akita/+ (Akita) and Nrf2 knockout (Akita::Nrf2-/-) or Akita and Nrf2 induction (Akita::Keap1FA/FA) mutant mice. Eighteen-week-old Akita::Nrf2-/- mice showed more severe diabetic symptoms than Akita mice. In the Akita::Nrf2-/- mouse kidneys, the glomeruli showed distended capillary loops, suggesting enhanced mesangiolysis. Distal tubules showed dilation and an increase in 8-hydroxydeoxyguanosine-positive staining. In the Akita::Nrf2-/- mouse kidneys, the expression of glutathione (GSH) synthesis-related genes was decreased, and the actual GSH level was decreased in matrix-assisted laser desorption/ionization mass spectrometry imaging analysis. Akita::Nrf2-/- mice exhibited severe inflammation and enhancement of infiltrated macrophages in the kidney. To further examine the progression of DKD, we compared forty-week-old Akita mouse kidney compounds with Nrf2-knockout or Nrf2 mildly induced (Akita::Keap1FA/FA) mice. Nrf2-knockout Akita (Akita::Nrf2-/-) mice displayed severe medullary cast formation, but the formation was ameliorated in Akita::Keap1FA/FA mice. Moreover, in Akita::Keap1FA/FA mice, tubule injury and inflammation-related gene expression were significantly suppressed, which was evident in Akita::Nrf2-/- mouse kidneys. These results demonstrate that Nrf2 contributes to the protection of the kidneys against DKD by suppressing oxidative stress and inflammation.
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Affiliation(s)
- Yexin Liu
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan,Department of Nephrology, Blood Purification Center of the Second Xiangya Hospital, Central South University, Changsha, China
| | - Akira Uruno
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan,Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan,Corresponding author. Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, 9808575, Japan.
| | - Ritsumi Saito
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan,Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Naomi Matsukawa
- Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Eiji Hishinuma
- Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan,Advanced Research Center for Innovations in Next-Generation Medicine Tohoku University, Sendai, Japan
| | - Daisuke Saigusa
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan,Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan,Laboratory of Biomedical and Analytical Sciences, Faculty of Pharma-Science, Teikyo University, Tokyo, Japan
| | - Hong Liu
- Department of Nephrology, Blood Purification Center of the Second Xiangya Hospital, Central South University, Changsha, China
| | - Masayuki Yamamoto
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan,Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan,Corresponding author. Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, 9808575, Japan.
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Luo Q, Cai Y, Zhao Q, Jiang Y, Tian L, Liu Y, Liu WJ. Renal Protective Effects of Melatonin in Animal Models of Diabetes Mellitus-Related Kidney Damage: A Systematic Review and Meta-Analysis. J Diabetes Res 2022; 2022:3770417. [PMID: 35746917 PMCID: PMC9213184 DOI: 10.1155/2022/3770417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 04/05/2022] [Indexed: 12/09/2022] Open
Abstract
Diabetic nephropathy (DN)-chronic kidney damage caused by hyperglycemia-eventually develops into end-stage renal disease (ESRD). Melatonin is a powerful antioxidant that has a wide range of biological activities. Potentially helpful effects of melatonin on diabetic kidney disease have been found in several studies. However, its protective mechanisms are not clear and remain to be explored. In this review (CRD42021285429), we conducted a meta-analysis to estimate the effects and relevant mechanisms of melatonin for diminishing renal injuries in diabetes mellitus models. The Cochrane Library, PubMed, and EMBASE databases up to September 2021 were used. Random- or fixed-effects models were used for calculating the standardized mean difference (SMD) or 90% confidence interval (CI). The risk of bias was estimated using the SYRCLE's RoB tool. Statistical analysis was conducted with RevMan. A total of 15 studies including 224 animals were included in the analysis. The experimental group showed a remarkable decrease in serum creatinine (P = 0.002), blood urea nitrogen (P = 0.02), and urinary albumin excretion rate (UAER) (P < 0.00001) compared with the control group, while the oxidative stress index improved. The experimental group also showed a remarkable increase in superoxide dismutase (P = 0.21), glutathione (P < 0.0001), and catalase (P = 0.04) and a remarkable decrease in MDA (P < 0.00001) content compared with the control group. We concluded that melatonin plays a role in renal protection in diabetic animals by inhibiting oxidative stress. Moreover, it should be noted that fasting blood glucose was reduced in the experimental group compared with the control group. The kidney and body weights of the animals were not decreased in the diabetic animal model compared with the control group.
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Affiliation(s)
- Qian Luo
- Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100700, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Beijing 100700, China
| | - Yuzi Cai
- Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100700, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Beijing 100700, China
| | - Qihan Zhao
- Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100700, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Beijing 100700, China
| | - Yuhua Jiang
- Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100700, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Beijing 100700, China
| | - Lei Tian
- Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100700, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Beijing 100700, China
| | - Yuning Liu
- Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100700, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Beijing 100700, China
| | - Wei Jing Liu
- Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100700, China
- Zhanjiang Key Laboratory of Prevention and Management of Chronic Kidney Disease, Guangdong Medical University, Zhanjiang, Guangdong 524001, China
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Choudhery MS. Strategies to improve regenerative potential of mesenchymal stem cells. World J Stem Cells 2021; 13:1845-1862. [PMID: 35069986 PMCID: PMC8727227 DOI: 10.4252/wjsc.v13.i12.1845] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 07/31/2021] [Accepted: 12/10/2021] [Indexed: 02/06/2023] Open
Abstract
In the last few decades, stem cell-based therapies have gained attention worldwide for various diseases and disorders. Adult stem cells, particularly mesenchymal stem cells (MSCs), are preferred due to their significant regenerative potential in cellular therapies and are currently involved in hundreds of clinical trials. Although MSCs have high self-renewal as well as differentiation potential, such abilities are compromised with “advanced age” and “disease status” of the donor. Similarly, cell-based therapies require high cell number for clinical applications that often require in vitro expansion of cells. It is pertinent to note that aged individuals are the main segment of population for stem cell-based therapies, however; autologous use of stem cells for such patients (aged and diseased) does not seem to give optimal results due to their compromised potential. In vitro expansion to obtain large numbers of cells also negatively affects the regenerative potential of MSCs. It is therefore essential to improve the regenerative potential of stem cells compromised due to “in vitro expansion”, “donor age” and “donor disease status” for their successful autologous use. The current review has been organized to address the age and disease depleted function of resident adult stem cells, and the strategies to improve their potential. To combat the problem of decline in the regenerative potential of cells, this review focuses on the strategies that manipulate the cell environment such as hypoxia, heat shock, caloric restriction and preconditioning with different factors.
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Affiliation(s)
- Mahmood S Choudhery
- Department of Biomedical Sciences, King Edward Medical University, Lahore 54000, Punjab, Pakistan
- Department of Genetics and Molecular Biology, University of Health Sciences, Lahore 54600, Punjab, Pakistan
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LncRNA NEAT1 accelerates the proliferation, oxidative stress, inflammation and fibrosis and suppresses the apoptosis via miR-423-5p/GLIPR2 axis in diabetic nephropathy. J Cardiovasc Pharmacol 2021; 79:342-354. [PMID: 34803150 DOI: 10.1097/fjc.0000000000001177] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 10/19/2021] [Indexed: 11/26/2022]
Abstract
ABSTRACT Diabetic nephropathy (DN) is a serious microvascular complication of diabetes. The aim of our study was to investigate the potential mechanism in DN progression. SV40 MES13 cells were exposed to high concentration of glucose (HG: 30 mmol/L) for 48 h to establish DN cell model in vitro. Bioinformatic software StarBase was adopted to establish long non-coding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (mRNA) axis. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and RNA-pull down assay were performed to verify intermolecular interaction. LncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) was overexpressed in the serum of DN patients. HG time-dependently up-regulated NEAT1 level, and HG promotes cell proliferation, oxidative stress, inflammation and fibrosis and suppressed cell apoptosis in SV40 MES13 cells partly via up-regulating NEAT1. NEAT1 functioned as a molecular sponge of miR-423-5p, and NEAT1 silencing-mediated effects were partly overturned by miR-423-5p interference in HG-induced SV40 MES13 cells. Glioma pathogenesis related-2 (GLIPR2) was a target of miR-423-5p. GLIPR2 overexpression in normal concentration of glucose (NG)-induced SV40 MES13 cells partly simulated HG-induced effects. GLIPR2 overexpression partly reversed NEAT1 interference-induced effects in HG-induced SV40 MES13 cells. LncRNA NEAT1 contributed to HG-induced DN progression via miR-423-5p/GLIPR2 axis in vitro. NEAT1/miR-423-5p/GLIPR2 axis might be potential target for DN treatment.
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Kidney-targeted astaxanthin natural antioxidant nanosystem for diabetic nephropathy therapy. Eur J Pharm Biopharm 2020; 156:143-154. [PMID: 32937179 DOI: 10.1016/j.ejpb.2020.09.005] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 08/28/2020] [Accepted: 09/07/2020] [Indexed: 12/31/2022]
Abstract
Diabetic nephropathy (DN) is a frequent and severe microvascular complication associated with oxidative stress of diabetes mellitus. A novel astaxanthin-based natural antioxidant nanosystem, namely AST-GLU-LIP, with preferential renal uptake and bioavailability were prepared and applied for treatment of diabetic nephropathy in rats. Our results of kidney-targeted evaluation showed that glucose-PEG600-DSPE ligand modified AST liposomes could be specifically transported by overexpressed GLUT1 on the membrane of glomerular mesangial cells and achieved excellent kidney-targeted drug delivery. In addition, the results of pharmacodynamics and therapeutics in DN rats demonstrated that AST-GLU-LIP could improve the bioavailability and antioxidant capacity of AST to scavenge redundant ROS induced by oxidative stress. AST-GLU-LIP could also significantly improve the renal pathological morphology to protect the kidney as a therapeutic drug for diabetic nephropathy.
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Scuto M, Trovato Salinaro A, Modafferi S, Polimeni A, Pfeffer T, Weigand T, Calabrese V, Schmitt CP, Peters V. Carnosine Activates Cellular Stress Response in Podocytes and Reduces Glycative and Lipoperoxidative Stress. Biomedicines 2020; 8:biomedicines8060177. [PMID: 32604897 PMCID: PMC7344982 DOI: 10.3390/biomedicines8060177] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 06/19/2020] [Accepted: 06/23/2020] [Indexed: 01/09/2023] Open
Abstract
Carnosine improves diabetic complications, including diabetic nephropathy, in in vivo models. To further understand the underlying mechanism of nephroprotection, we studied the effect of carnosine under glucose-induced stress on cellular stress response proteins in murine immortalized podocytes, essential for glomerular function. High-glucose stress initiated stress response by increasing intracellular heat shock protein 70 (Hsp70), sirtuin-1 (Sirt-1), thioredoxin (Trx), glutamate-cysteine ligase (gamma-glutamyl cysteine synthetase; γ-GCS) and heme oxygenase-1 (HO-1) in podocytes by 30–50% compared to untreated cells. Carnosine (1 mM) also induced a corresponding upregulation of these intracellular stress markers, which was even more prominent compared to glucose for Hsp70 (21%), γ-GCS and HO-1 (13% and 20%, respectively; all p < 0.001). Co-incubation of carnosine (1 mM) and glucose (25 mM) induced further upregulation of Hsp70 (84%), Sirt-1 (52%), Trx (35%), γ-GCS (90%) and HO-1 (73%) concentrations compared to untreated cells (all p < 0.001). The glucose-induced increase in 4-hydroxy-trans-2-nonenal (HNE) and protein carbonylation was reduced dose-dependently by carnosine by more than 50% (p < 0.001). Although podocytes tolerated high carnosine concentrations (10 mM), high carnosine levels only slightly increased Trx and γ-GCS (10% and 19%, respectively, compared to controls; p < 0.001), but not Hsp70, Sirt-1 and HO-1 proteins (p not significant), and did not modify the glucose-induced oxidative stress response. In podocytes, carnosine induced cellular stress tolerance and resilience pathways and was highly effective in reducing high-glucose-induced glycative and lipoperoxidative stress. Carnosine in moderate concentrations exerted a direct podocyte molecular protective action.
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Affiliation(s)
- Maria Scuto
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95124 Catania, Italy; (M.S.); (A.T.S.); (S.M.); (A.P.)
| | - Angela Trovato Salinaro
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95124 Catania, Italy; (M.S.); (A.T.S.); (S.M.); (A.P.)
| | - Sergio Modafferi
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95124 Catania, Italy; (M.S.); (A.T.S.); (S.M.); (A.P.)
- Centre for Pediatric and Adolescent Medicine, University of Heidelberg, 69117 Heidelberg, Germany; (T.P.); (T.W.); (V.P.)
| | - Alessandra Polimeni
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95124 Catania, Italy; (M.S.); (A.T.S.); (S.M.); (A.P.)
- Centre for Pediatric and Adolescent Medicine, University of Heidelberg, 69117 Heidelberg, Germany; (T.P.); (T.W.); (V.P.)
| | - Tilman Pfeffer
- Centre for Pediatric and Adolescent Medicine, University of Heidelberg, 69117 Heidelberg, Germany; (T.P.); (T.W.); (V.P.)
| | - Tim Weigand
- Centre for Pediatric and Adolescent Medicine, University of Heidelberg, 69117 Heidelberg, Germany; (T.P.); (T.W.); (V.P.)
| | - Vittorio Calabrese
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95124 Catania, Italy; (M.S.); (A.T.S.); (S.M.); (A.P.)
- Correspondence: (V.C.); (C.P.S.)
| | - Claus Peter Schmitt
- Centre for Pediatric and Adolescent Medicine, University of Heidelberg, 69117 Heidelberg, Germany; (T.P.); (T.W.); (V.P.)
- Correspondence: (V.C.); (C.P.S.)
| | - Verena Peters
- Centre for Pediatric and Adolescent Medicine, University of Heidelberg, 69117 Heidelberg, Germany; (T.P.); (T.W.); (V.P.)
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Orabi SH, Abd Eldaium D, Hassan A, Sabagh HSE, Abd Eldaim MA. Allicin modulates diclofenac sodium induced hepatonephro toxicity in rats via reducing oxidative stress and caspase 3 protein expression. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2020; 74:103306. [PMID: 31812117 DOI: 10.1016/j.etap.2019.103306] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 11/21/2019] [Accepted: 11/22/2019] [Indexed: 06/10/2023]
Abstract
PURPOSE This study was designed to evaluate the protective effects of allicin against diclofenac sodium induced hepatonephro toxicity in rats. METHODS Sixty male Wister albino rats were assigned into six groups. The control group received calcium carbonate and corn starch. 2nd group received diclofenac sodium (2 mg/kg bw orally) for 30 days. 3rd group received allicin (45 mg/kg bw orally) for 30 days. 4th group administrated diclofenac sodium as in the 2nd group and allicin (15 mg/kg bw orally) for 30 days. 5th group received diclofenac sodium as in the 2nd group and allicin (30 mg/kg bw orally) for 30 days. 6th group received diclofenac sodium as 2nd and allicin (45 mg/kg bw orally) for 30 days. RESULTS Diclofenac sodium significantly elevated activities of serum aspartate aminotransferase and alanine aminotransferase and serum levels of creatinine and urea. In addition, it induced hyperglycemia, lipid peroxidation, pathological alteration and caspase 3 protein expression in hepatic and renal tissues. However, it decreased reduced glutathione concentration and proliferating cell nuclear antigen protein expression in hepatic tissues. In contrast, allicin modulated the diclofenac sodium induced alteration in liver and kidney functions and structures dose dependently. CONCLUSION This study indicated that allicin had potential preventive effects against diclofenac sodium induced hepatonephro toxicity in rats.
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Affiliation(s)
- Sahar Hassan Orabi
- Department of Biochemistry and Chemistry of Nutrition, Faculty of Veterinary Medicine, University of Sadat City, Sadat City, Egypt.
| | - Doaa Abd Eldaium
- Department of Biochemistry and Chemistry of Nutrition, Faculty of Veterinary Medicine, University of Sadat City, Sadat City, Egypt
| | - Azza Hassan
- Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Cairo, Egypt
| | - Hesham Saad El Sabagh
- Department of Toxicology and Fronsic Medicine, Faculty of Veterinary Medicine, University of Sadat City, Sadat City, Egypt
| | - Mabrouk Attia Abd Eldaim
- Department of Biochemistry and Chemistry of Nutrition, Faculty of Veterinary Medicine, Menoufia University, Sheben Elkom, Egypt; Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, 606-8502, Japan
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Li S, Li W, Wu R, Yin R, Sargsyan D, Raskin I, Kong AN. Epigenome and transcriptome study of moringa isothiocyanate in mouse kidney mesangial cells induced by high glucose, a potential model for diabetic-induced nephropathy. AAPS JOURNAL 2019; 22:8. [PMID: 31807911 DOI: 10.1208/s12248-019-0393-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 11/09/2019] [Indexed: 02/06/2023]
Abstract
Moringa isothiocyanate (MIC-1) is a bioactive constituent found abundantly in Moringa oleifera which possesses antioxidant and anti-inflammation properties. However, epigenome and transcriptome effects of MIC-1 in kidney mesangial cells challenged with high glucose (HG), a pre-condition for diabetic nephropathy (DN) remain unknown. Herein, we examined the transcriptome gene expression and epigenome DNA methylation in mouse kidney mesangial cells (MES13) using next-generation sequencing (NGS) technology. After HG treatment, epigenome and transcriptome were significantly altered. More importantly, MIC-1 exposure reversed some of the changes caused by HG. Integrative analysis of RNA-Seq data identified 20 canonical pathways showing inverse correlations between HG and MIC-1. These pathways included GNRH signaling, P2Y purigenic receptor signaling pathway, calcium signaling, LPS/IL-1-mediated inhibition of RXR function, and oxidative ethanol degradation III. In terms of alteration of DNA methylation patterns, 173 differentially methylation regions (DMRs) between the HG group and low glucose (LG) group and 149 DMRs between the MIC-1 group and the HG group were found. Several HG related DMRs could be reversed by MIC-1 treatment. Integrative analysis of RNA-Seq and Methyl-Seq data yielded a subset of genes associated with HG and MIC-1, and the gene expression changes may be driven by promoter CpG status. These genes include Col4a2, Tceal3, Ret, and Agt. In summary, our study provides novel insights related to transcriptomic and epigenomic/CpG methylomic alterations in MES13 upon challenged by HG but importantly, MIC-1 treatment reverses some of the transcriptome and epigenome/CpG methylome. These results may provide potential molecular targets and therapeutic strategies for DN.
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Affiliation(s)
- Shanyi Li
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA
| | - Wenji Li
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA.,Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, People's Republic of China.,Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225001, People's Republic of China
| | - Renyi Wu
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA
| | - Ran Yin
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA
| | - Davit Sargsyan
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA.,Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy Rutgers, The State University of New Jersey, Piscataway, New Jersey, 08854, USA
| | - Ilya Raskin
- Department of Plant Biology & Pathology, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, 08901, USA
| | - Ah-Ng Kong
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA.
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12
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FOXP1 inhibits high glucose-induced ECM accumulation and oxidative stress in mesangial cells. Chem Biol Interact 2019; 313:108818. [DOI: 10.1016/j.cbi.2019.108818] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 08/12/2019] [Accepted: 09/05/2019] [Indexed: 01/09/2023]
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13
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Oxidative Stress and Renal Fibrosis: Mechanisms and Therapies. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1165:585-604. [PMID: 31399986 DOI: 10.1007/978-981-13-8871-2_29] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Oxidative stress results from the disruption of the redox system marked by a notable overproduction of reactive oxygen species. There are four major sources of reactive oxygen species, including NADPH oxidases, mitochondria, nitric oxide synthases, and xanthine oxidases. It is well known that renal abnormalities trigger the production of reactive oxygen species by diverse mechanisms under various pathologic stimuli, such as acute kidney injury, chronic kidney disease, nephrotic syndrome, and metabolic disturbances. Mutually, accumulating evidences have identified that oxidative stress plays an essential role in tubulointerstitial fibrosis by myofibroblast activation as well as in glomerulosclerosis by mesangial sclerosis, podocyte abnormality, and parietal epithelial cell injury. Given the involvement of oxidative stress in renal fibrosis, therapies targeting oxidative stress seem promising in renal fibrosis management. In this review, we sketch the updated knowledge of the mechanisms of oxidative stress generation during renal diseases, the pathogenic processes of oxidative stress elicited renal fibrosis and treatments targeting oxidative stress during tubulointerstitial fibrosis and glomerulosclerosis.
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14
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Sun HJ, Wu ZY, Cao L, Zhu MY, Liu TT, Guo L, Lin Y, Nie XW, Bian JS. Hydrogen Sulfide: Recent Progression and Perspectives for the Treatment of Diabetic Nephropathy. Molecules 2019; 24:molecules24152857. [PMID: 31390847 PMCID: PMC6696501 DOI: 10.3390/molecules24152857] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 07/29/2019] [Accepted: 08/05/2019] [Indexed: 02/06/2023] Open
Abstract
Diabetic kidney disease develops in approximately 40% of diabetic patients and is a major cause of chronic kidney diseases (CKD) and end stage kidney disease (ESKD) worldwide. Hydrogen sulfide (H2S), the third gasotransmitter after nitric oxide (NO) and carbon monoxide (CO), is synthesized in nearly all organs, including the kidney. Though studies on H2S regulation of renal physiology and pathophysiology are still in its infancy, emerging evidence shows that H2S production by renal cells is reduced under disease states and H2S donors ameliorate kidney injury. Specifically, aberrant H2S level is implicated in various renal pathological conditions including diabetic nephropathy. This review presents the roles of H2S in diabetic renal disease and the underlying mechanisms for the protective effects of H2S against diabetic renal damage. H2S may serve as fundamental strategies to treat diabetic kidney disease. These H2S treatment modalities include precursors for H2S synthesis, H2S donors, and natural plant-derived compounds. Despite accumulating evidence from experimental studies suggests the potential role of the H2S signaling pathway in the treatment of diabetic nephropathy, these results need further clinical translation. Expanding understanding of H2S in the kidney may be vital to translate H2S to be a novel therapy for diabetic renal disease.
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Affiliation(s)
- Hai-Jian Sun
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Zhi-Yuan Wu
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Lei Cao
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Meng-Yuan Zhu
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Teng-Teng Liu
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Lei Guo
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Ye Lin
- School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou 213164, China
| | - Xiao-Wei Nie
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Jin-Song Bian
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
- National University of Singapore (Suzhou) Research Institute, Suzhou 215000, China.
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15
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Chen B, Li Y, Liu Y, Xu Z. circLRP6 regulates high glucose-induced proliferation, oxidative stress, ECM accumulation, and inflammation in mesangial cells. J Cell Physiol 2019; 234:21249-21259. [PMID: 31087368 DOI: 10.1002/jcp.28730] [Citation(s) in RCA: 92] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 03/23/2019] [Accepted: 04/11/2019] [Indexed: 01/01/2023]
Abstract
Aberrant regulation in mesangial cell proliferation, extracellular matrix (ECM) accumulation, oxidative stress, and inflammation under hyperglycemic condition contributes significantly to the occurrence and development of diabetic nephropathy (DN). However, the mechanisms underlying the hyperglycemia-induced dysregulations have not been clearly elucidated. Here, we reported that high mobility group box 1 (HMGB1) was highly elevated in high glucose (HG)-treated mesangial cells, and induced the phosphorylation, nuclear translocation, and DNA binding activity of NF-κB via toll-like receptor 4 (TLR4). Function assays showed that inhibition of HMGB1 mitigated HG-induced proliferation, oxidative stress, ECM accumulation, and inflammation in mesangial cells via TLR4/NF-κB pathway. Increasing evidence has shown that circRNA, a large class of noncoding RNAs, functions by binding with miRNAs and terminating regulation of their target genes. We further investigated whether HMGB1 is involved in circRNA-miRNA-mRNA regulatory network. First, HMGB1 was identified and confirmed to be the target of miR-205, and miR-205 played a protective role against HG-induced cell injure via targeting HMGB1. Then circLRP6 was found to be upregulated in HG-treated mesangial cells, and regulate HG-induced mesangial cell injure via sponging miR-205. Besides, overexpression of miR-205 or knockdown of circLRP6 inhibited the NF-κB signaling pathway. Collectively, these data suggest that circLRP6 regulates HG-induced proliferation, oxidative stress, ECM accumulation, and inflammation in mesangial cells via sponging miR-205, upregulating HMGB1 and activating TLR4/NF-κB pathway. These findings provide a better understanding for the pathogenesis of DN.
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Affiliation(s)
- Bin Chen
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yanhua Li
- Department of Intensive Care Unit, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yang Liu
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Zhonggao Xu
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, China
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16
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Zheng DH, Han ZQ, Wang XX, Ma D, Zhang J. Erythropoietin attenuates high glucose-induced oxidative stress and inhibition of osteogenic differentiation in periodontal ligament stem cell (PDLSCs). Chem Biol Interact 2019; 305:40-47. [DOI: 10.1016/j.cbi.2019.03.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 03/01/2019] [Accepted: 03/09/2019] [Indexed: 12/31/2022]
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17
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Azenabor A, Erivona R, Adejumo E, Ozuruoke D, Azenabor R. Xanthine oxidase activity in type 2 diabetic Nigerians. Diabetes Metab Syndr 2019; 13:2021-2024. [PMID: 31235130 DOI: 10.1016/j.dsx.2019.04.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 04/16/2019] [Indexed: 01/09/2023]
Abstract
AIM This study evaluated the activity of xanthine oxidase in Nigerians with type 2 diabetic mellitus as well as its relationship with lipid peroxidation, inflammatory bio markers and glycemic control indices. METHODS Two hundred and thirty seven (237) subjects, comprising of one hundred and fifty seven (157) DM subjects and eighty (80) aged matched controls participated in this study. Blood samples were collected from the participants for the estimations of xanthine oxidase activity, uric acid, malon diadehyde (MDA), erythrocyte sedimentation rate (ESR), high sensitive c - reactive protein (hs CRP), glucose, fructosamine and glycosylated hemoglobin by standard methods. RESULTS The results of this study showed a significantly increased activity of xanthine oxidase in DM (0.044 ± 0.05μ/mg) compared with apparently healthy controls (0.028 ± 0.00 μ/mg). The mean plasma levels of MDA (42.40 ± 2.50μmol/l) and uric acid (7.22 ± 0.20 mg/dl) in DM were significantly higher (p ≤ 0.05) than healthy non DM group. The mean levels of hs CRP in DM (4.09 ± 0.91μg/ml) was significantly higher than controls (1.30 ± 0.50μg/ml, p = 0.009). While no association of xanthine oxidase was observed with glycemic control indices and hs CRP, a negative association of xanthine oxidase was observed with MDA (r = -0.514, p = 0.000). CONCLUSION Increased activity of xanthine oxidase in DM was associated with increased lipid peroxidation and could be a salient entity towards the onset on complications.
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Affiliation(s)
- Alfred Azenabor
- Department of Medical Laboratory Science, University of Lagos, Nigeria.
| | - Rachel Erivona
- Department of Medical Laboratory Science, University of Benin, Nigeria
| | - Esther Adejumo
- Department of Medical Laboratory Science, Babcock University, Nigeria
| | - Donatus Ozuruoke
- Department of Medical Laboratory Science, Archivers University, Nigeria
| | - Rosemary Azenabor
- School of Engineering and Applied Science, Centennial College, Ontario, Canada
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18
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Akaishi T, Abe M, Okuda H, Ishizawa K, Abe T, Ishii T, Ito S. High glucose level and angiotensin II type 1 receptor stimulation synergistically amplify oxidative stress in renal mesangial cells. Sci Rep 2019; 9:5214. [PMID: 30914692 PMCID: PMC6435641 DOI: 10.1038/s41598-019-41536-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 03/11/2019] [Indexed: 12/12/2022] Open
Abstract
Oxidative stress in renal mesangial cell causes diabetic glomerular changes. High glucose levels and angiotensin II (Ang II) are known to stimulate superoxide production in renal mesangial cells. However, it has been unclear whether Ang II stimulation and pre-conditioning with high glucose affects the same pathway of superoxide production in renal mesangial cells or not. In this study, we examined the levels of oxidative stress under Ang II stimulation in renal mesangial cells preincubated for six hours at various glucose levels. Intracellular levels of reactive oxidative species (ROS) were measured using dihydroethidium or 5′,6′-chloromethyl- 2′,7′ dichlorodihydro-fluorescein diacetate, which facilitates the detection of intracellular ROS under real-time fluorescent microscope. Ang II-induced elevated intracellular ROS levels were detected only when the cells were pre-incubated with high levels of glucose (13.5 mM, 27.8 mM), but was not detected under normal glucose condition (5.5 mM). Production of Ang II-induced intracellular ROS was higher under pre-treatment with 27.8 mM glucose compared to pretreatment with 13.5 mM glucose level. This ROS production in mesangial cells was induced within several minutes of the initiation of Ang II stimulation under high glucose levels. The production of intracellular ROS was significantly reduced in the presence of angiotensin II type1-receptor (AT1R) antagonist, whereas it was augmented in the presence of angiotensin II type2-receptor antagonist. In conclusion, Ang II-induced oxidative stress was augmented by high glucose levels and ROS levels were further alleviated in the presence of AT1R antagonists.
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Affiliation(s)
- Tetsuya Akaishi
- Department of Education and Support for Regional Medicine, Tohoku University Hospital, Sendai, Japan
| | - Michiaki Abe
- Department of Education and Support for Regional Medicine, Tohoku University Hospital, Sendai, Japan. .,Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Hospital, Sendai, Japan.
| | - Hiroshi Okuda
- Department of Education and Support for Regional Medicine, Tohoku University Hospital, Sendai, Japan
| | - Kota Ishizawa
- Department of Education and Support for Regional Medicine, Tohoku University Hospital, Sendai, Japan
| | - Takaaki Abe
- Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Hospital, Sendai, Japan
| | - Tadashi Ishii
- Department of Education and Support for Regional Medicine, Tohoku University Hospital, Sendai, Japan
| | - Sadayoshi Ito
- Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Hospital, Sendai, Japan
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19
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Chen MF, Liou SS, Hong TY, Kao ST, Liu IM. Gigantol has Protective Effects against High Glucose-Evoked Nephrotoxicity in Mouse Glomerulus Mesangial Cells by Suppressing ROS/MAPK/NF-κB Signaling Pathways. Molecules 2018; 24:molecules24010080. [PMID: 30587838 PMCID: PMC6337535 DOI: 10.3390/molecules24010080] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 12/09/2018] [Accepted: 12/16/2018] [Indexed: 01/09/2023] Open
Abstract
Gigantol is a bibenzyl compound derived from several medicinal orchids. This biologically active compound has shown promising therapeutic potential against diabetic cataracts, but whether this compound exerts beneficial effects on the other diabetic microvascular complications remains unclear. This study was carried out to examine effects of gigantol on high glucose-induced renal cell injury in cultured mouse kidney mesangial cells (MES-13). MES-13 cells were pretreated with gigantol (1, 5, 10 or 20 μmol/L) for 1 h followed by further exposure to high (33.3 mmol/L) glucose for 48 h. Gigantol concentration dependently enhanced cell viability followed by high glucose treatment in MES-13 cells. High glucose induced reactive oxygen species (ROS) generation, malondialdehyde production and glutathione deficiency were recoved in MES-13 cells pretreated with gigantol. High glucose triggered cell apoptosis via the the loss of mitochondrial membrane potential, depletion of adenosine triphosphate, upregulation of caspases 9 and 3, enhancement of cytochrome c release, and subsequent interruption of the Bax/Bcl-2 balance. These detrimental effects were ameliorated by gigantol. High glucose also induced activation of JNK, p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) in MES-13 cells, which were blocked by gigantol. The results suggest that treatment MES-13 cells with gigantol halts high glucose-induced renal dysfunction through the suppression of the ROS/MAPK/NF-κB signaling pathways. Our data are of value to the understanding the mechanism for gigantol, and would benefit the study of drug development or food supplement for diabetes and nephropathy.
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Affiliation(s)
- Mei-Fen Chen
- School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan.
- College of Nursing, Chung Hwa University of Medical Technology, Rende Dist, Tainan City 71703, Taiwan.
| | - Shorong-Shii Liou
- Department of Pharmacy and Master Program, Collage of Pharmacy and Health Care, Tajen University, Pingtung County 90741, Taiwan.
| | - Tang-Yao Hong
- Department of Biotechnology, Collage of Pharmacy and Health Care, Tajen University, Pingtung County 90741, Taiwan.
| | - Shung-Te Kao
- School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan.
- Department of Chinese Medicine, China Medical University Hospital, Taichung 40402, Taiwan.
| | - I-Min Liu
- Department of Pharmacy and Master Program, Collage of Pharmacy and Health Care, Tajen University, Pingtung County 90741, Taiwan.
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20
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Al-Kafaji G, Aljadaan A, Kamal A, Bakhiet M. Peripheral blood mitochondrial DNA copy number as a novel potential biomarker for diabetic nephropathy in type 2 diabetes patients. Exp Ther Med 2018; 16:1483-1492. [PMID: 30116398 DOI: 10.3892/etm.2018.6319] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Accepted: 05/02/2018] [Indexed: 12/19/2022] Open
Abstract
The mitochondrial DNA copy number (mtDNA-CN) is a surrogate measure of mitochondrial function and altered mtDNA-CN reflects the oxidant-induced cell damage. A previous study by our group demonstrated that a reduction in the renal mtDNA-CN is implicated in the pathogenesis of diabetic nephropathy (DN), a leading cause of end-stage renal disease in diabetic patients. In the present study, it was investigated whether the mtDNA-CN in the peripheral blood may be utilized as a biomarker for DN in type 2 diabetes (T2D) patients. The study included 50 non-diabetic and 100 diabetic subjects. The diabetic subjects were sub-divided based on their albumin-to-creatinine ratio (ACR) into T2D patients with normoalbuminuria (n=50), DN patients with microalbuminuria (n=29) and DN patients with macroalbuminuria (n=21). The mtDNA-CN was measured in the peripheral blood by real-time polymerase chain reaction analysis. Patients with DN had a lower mtDNA-CN than patients with T2D and healthy controls (P<0.05). A sub-group analysis with stratification by the ACR indicated that a decreased mtDNA-CN was associated with the severity and the presence of DN, as it was lower in DN patients with macroalbuminuria than in DN patients with microalbuminuria and T2D patients with normoalbuminuria (P<0.01). The area under the receiver operating characteristic curve (AUC) for mtDNA-CN was 0.916 (sensitivity, 86% and specificity, 74%) and 0.961 (sensitivity, 96% and specificity, 88%) for differentiating DN patients from T2D patients without DN and from healthy controls, respectively. Furthermore, the AUC of mtDNA-CN for differentiating DN patients with microalbuminuria from those with macroalbuminuria was 0.895 (sensitivity, 83% and specificity, 85%). Multivariate analysis revealed that the mtDNA-CN was significantly associated with the occurrence and progression of DN, even after adjustment for age, mean blood pressure, glycated haemoglobin A1c and total cholesterol (P<0.05). In patients with DN, a decreased mtDNA-CN was negatively correlated with albuminuria and conventional risk factors for DN, and was positively correlated with the estimated glomerular filtration rate. The present results therefore suggest the utilization of circulating mtDNA-CN as a novel biomarker for the early diagnosis of DN and indicate the significance of decreased mtDNA-CN as another independent risk factor for DN.
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Affiliation(s)
- Ghada Al-Kafaji
- Department of Molecular Medicine and Al-Jawhara Centre for Molecular Medicine, Genetics and Inherited Disorders, College of Medicine and Medical Sciences, Arabian Gulf University, Manama 329, Kingdom of Bahrain
| | - Abdulah Aljadaan
- Department of Molecular Medicine and Al-Jawhara Centre for Molecular Medicine, Genetics and Inherited Disorders, College of Medicine and Medical Sciences, Arabian Gulf University, Manama 329, Kingdom of Bahrain
| | - Amer Kamal
- Department of Physiology, College of Medicine and Medical Sciences, Arabian Gulf University, Manama 329, Kingdom of Bahrain
| | - Moiz Bakhiet
- Department of Molecular Medicine and Al-Jawhara Centre for Molecular Medicine, Genetics and Inherited Disorders, College of Medicine and Medical Sciences, Arabian Gulf University, Manama 329, Kingdom of Bahrain
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21
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Lin KY, Shang XL, Guo YS, Zhu PL, Wu ZY, Jiang H, Ruan JM, Zheng WP, You ZB, Lin CJ. Association of Preprocedural Hyperglycemia With Contrast-Induced Acute Kidney Injury and Poor Outcomes After Emergency Percutaneous Coronary Intervention. Angiology 2018; 69:770-778. [PMID: 29463106 DOI: 10.1177/0003319718758140] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
We investigated whether preprocedural hyperglycemia was associated with contrast-induced acute kidney injury (CI-AKI) and long-term outcomes in patients with acute coronary syndrome (ACS) who underwent emergency percutaneous coronary intervention (PCI). Patients (n = 558) with ACS who underwent emergency PCI were consecutively enrolled. Preprocedural hyperglycemia was defined as glucose levels >198 mg/dL (11 mmol/L). The primary outcome was CI-AKI (≥0.3 mg/dL absolute or ≥50% relative serum creatinine increase 48 hours after contrast medium exposure). Overall, 103 (18.5%) patients had preprocedural hyperglycemia and 89 (15.9%) patients developed CI-AKI. The incidence of CI-AKI was significantly higher in patients with hyperglycemia than without (28.2% vs 13.2%; P < .01). Multivariate analysis indicated that preprocedural hyperglycemia was an independent predictor of CI-AKI (odds ratio = 1.971, 95% confidence interval [CI]: 1.129-3.441; P < .05). In addition, preprocedural hyperglycemia was associated with an increased risk of all-cause mortality during the 2-year follow-up (hazard ratio = 2.440, 95% CI: 1.394-4.273; P = .002). Preprocedural hyperglycemia is a significant and independent predictor of CI-AKI and long-term outcomes.
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Affiliation(s)
- Kai-Yang Lin
- 1 Department of Cardiology, Fujian Provincial Hospital, Fujian Cardiovascular Institute, Fujian Medical University, Fuzhou, China.,2 Department of Geriatric Medicine, Fujian Provincial Hospital, Fujian Provincial Institute of Clinical Geriatrics, Fujian Key Laboratory of Geriatrics, Fujian Provincial Center for Geriatrics, Fujian Medical University, Fuzhou, China
| | - Xiu-Ling Shang
- 3 Department of Critical Care Medicine, Fujian Provincial Hospital, Fujian Medical University, Fuzhou, China
| | - Yan-Song Guo
- 1 Department of Cardiology, Fujian Provincial Hospital, Fujian Cardiovascular Institute, Fujian Medical University, Fuzhou, China
| | - Peng-Li Zhu
- 1 Department of Cardiology, Fujian Provincial Hospital, Fujian Cardiovascular Institute, Fujian Medical University, Fuzhou, China
| | - Zhi-Yong Wu
- 1 Department of Cardiology, Fujian Provincial Hospital, Fujian Cardiovascular Institute, Fujian Medical University, Fuzhou, China
| | - Hui Jiang
- 1 Department of Cardiology, Fujian Provincial Hospital, Fujian Cardiovascular Institute, Fujian Medical University, Fuzhou, China
| | - Jing-Ming Ruan
- 1 Department of Cardiology, Fujian Provincial Hospital, Fujian Cardiovascular Institute, Fujian Medical University, Fuzhou, China.,2 Department of Geriatric Medicine, Fujian Provincial Hospital, Fujian Provincial Institute of Clinical Geriatrics, Fujian Key Laboratory of Geriatrics, Fujian Provincial Center for Geriatrics, Fujian Medical University, Fuzhou, China
| | - Wei-Ping Zheng
- 2 Department of Geriatric Medicine, Fujian Provincial Hospital, Fujian Provincial Institute of Clinical Geriatrics, Fujian Key Laboratory of Geriatrics, Fujian Provincial Center for Geriatrics, Fujian Medical University, Fuzhou, China
| | - Zhe-Bin You
- 2 Department of Geriatric Medicine, Fujian Provincial Hospital, Fujian Provincial Institute of Clinical Geriatrics, Fujian Key Laboratory of Geriatrics, Fujian Provincial Center for Geriatrics, Fujian Medical University, Fuzhou, China
| | - Chun-Jin Lin
- 2 Department of Geriatric Medicine, Fujian Provincial Hospital, Fujian Provincial Institute of Clinical Geriatrics, Fujian Key Laboratory of Geriatrics, Fujian Provincial Center for Geriatrics, Fujian Medical University, Fuzhou, China
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22
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Song R, Shi Q, Yang P, Wei R. In vitromembrane damage induced by half-fin anchovy hydrolysates/glucose Maillard reaction products and the effects on oxidative statusin vivo. Food Funct 2018; 9:785-796. [DOI: 10.1039/c7fo01459g] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Through induced H2O2generationin vitro, HAHp(9.0)-G MRPs increased the antioxidant status in normal mice after short-term intake.
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Affiliation(s)
- Ru Song
- School of Food Science and Pharmacy
- Zhejiang Ocean University
- Zhoushan 316022
- China
| | - Qingqing Shi
- School of Food Science and Pharmacy
- Zhejiang Ocean University
- Zhoushan 316022
- China
| | - Peiyu Yang
- School of Food Science and Pharmacy
- Zhejiang Ocean University
- Zhoushan 316022
- China
| | - Rongbian Wei
- School of Marine Science and Technology
- Zhejiang Ocean University
- Zhoushan 316022
- China
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23
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Wang S, Zhao X, Yang S, Chen B, Shi J. Salidroside alleviates high glucose-induced oxidative stress and extracellular matrix accumulation in rat glomerular mesangial cells by the TXNIP-NLRP3 inflammasome pathway. Chem Biol Interact 2017; 278:48-53. [PMID: 29031534 DOI: 10.1016/j.cbi.2017.10.012] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 09/30/2017] [Accepted: 10/11/2017] [Indexed: 01/09/2023]
Abstract
Diabetic nephropathy (DN) is a metabolic disease characterized by mesangial cell proliferation and extracellular matrix (ECM) accumulation. Salidroside (SAL) is the major ingredient in Rhodiola rosea and possesses beneficial effects on DN. This study aimed to evaluate the effect of SAL on high glucose (HG)-induced oxidative stress and ECM accumulation and the underlying mechanism. Rat glomerular mesangial cells HBZY-1 were induced by high glucose (HG) in the presence or absence of SAL. Cell proliferation was measured by CCK-8 assay. The reactive oxygen species (ROS) level, malondialdehyde (MDA) level and superoxide dismutase (SOD) activity were detected to evaluate oxidative stress. The expression levels of ECM proteins including fibronectin (FN) and type IV collagen (Coll IV) were detected by qRT-PCR and western blot analysis. The expressions of thioredoxin-interacting protein (TXNIP), nod-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing CARD (ASC), and caspase-1 were assessed by western blot. Si-TXNIP or si-NC was transfected into HBZY-1 cells to inhibit TXNIP-NLRP3 inflammasome pathway. The results showed that SAL treatment alleviated HG-induced cell proliferation. SAL reduced the levels of ROS and MDA, and induced the SOD activity. Besides, the mRNA and protein expressions of FN and Coll IV were decreased by SAL. The expression levels of TXNIP, NLRP3, ASC, and caspase-1 were reduced in the SAL treated cells. In addition, TXNIP knockdown inhibited TXNIP-NLRP3 inflammasome activation and suppressed HG-induced cell proliferation, oxidative stress, and ECM accumulation. In conclusion, SAL alleviated HG-induced oxidative stress and ECM accumulation in rat glomerular mesangial cells by the TXNIP-NLRP3 inflammasome pathway.
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Affiliation(s)
- Shiying Wang
- Nephrology Department, Huaihe Hospital of Henan University, Kaifeng 475000, Henan Province, China
| | - Xinxin Zhao
- Nephrology Department, Huaihe Hospital of Henan University, Kaifeng 475000, Henan Province, China
| | - Suxia Yang
- Nephrology Department, Huaihe Hospital of Henan University, Kaifeng 475000, Henan Province, China
| | - Baoping Chen
- Nephrology Department, Huaihe Hospital of Henan University, Kaifeng 475000, Henan Province, China
| | - Jun Shi
- Nephrology Department, Huaihe Hospital of Henan University, Kaifeng 475000, Henan Province, China.
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Porosk R, Kilk K, Mahlapuu R, Terasmaa A, Soomets U. Glutathione system in Wolfram syndrome 1‑deficient mice. Mol Med Rep 2017; 16:7092-7097. [PMID: 28901522 DOI: 10.3892/mmr.2017.7419] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2017] [Accepted: 07/27/2017] [Indexed: 11/06/2022] Open
Abstract
Wolfram syndrome 1 (WS) is a rare neurodegenerative disease that is caused by mutations in the Wolfram syndrome 1 (WFS1) gene, which encodes the endoplasmic reticulum (ER) glycoprotein wolframin. The pathophysiology of WS is ER stress, which is generally considered to induce oxidative stress. As WS has a well‑defined monogenetic origin and a model for chronic ER stress, the present study aimed to characterize how glutathione (GSH), a major intracellular antioxidant, was related to the disease and its progression. The concentration of GSH and the activities of reduction/oxidation system enzymes GSH peroxidase and GSH reductase were measured in Wfs1‑deficient mice. The GSH content was lower in most of the studied tissues, and the activities of antioxidative enzymes varied between the heart, kidneys and liver tissues. The results indicated that GSH may be needed for ER stress control; however, chronic ER stress from the genetic syndrome eventually depletes the cellular GSH pool and leads to increased oxidative stress.
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Affiliation(s)
- Rando Porosk
- Department of Biochemistry, Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia
| | - Kalle Kilk
- Department of Biochemistry, Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia
| | - Riina Mahlapuu
- Department of Biochemistry, Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia
| | - Anton Terasmaa
- Centre of Excellence for Genomics and Translational Medicine, Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia
| | - Ursel Soomets
- Department of Biochemistry, Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia
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Destructive effect of non-enzymatic glycation on catalase and remediation via curcumin. Arch Biochem Biophys 2017; 630:81-90. [PMID: 28668706 DOI: 10.1016/j.abb.2017.06.018] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2017] [Revised: 06/25/2017] [Accepted: 06/26/2017] [Indexed: 01/09/2023]
Abstract
Non-enzymatic glycation of proteins is a post-translational modification that is produced by a covalent binding between reducing sugars and amino groups of lysine and arginine residues. In this paper the effect of pathological conditions, derived from hyperglycemia on bovine liver catalase (BLC) as a model protein was considered by measuring enzyme activity, reactive oxygen species (ROS) generation, and changes in catalase conformational properties. We observed that in the presence of glucose, the catalase activity gradually decreased. ROS generation was also involved in the glycation process. Thus, decreased BLC activity was partly considered as a result of ROS generation through glycation. However, in the presence of curcumin the amount of ROS was reduced resulting in increased activity of the glycated catalase. The effect of high glucose level and the potential inhibitory effect of curcumin on aggregation and structural changes of catalase were also investigated. Molecular dynamic simulations also showed that interaction of catalase with curcumin resulted in changes in accessible surface area (ASA) and pKa, two effective parameters of glycation, in potential glycation lysine residues. Thus, the decrease in ASA and increase in pKa of important lysine residues were considered as predominant factors in decreased glycation of BLC by curcumin.
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Nzuza S, Ndwandwe DE, Owira PMO. Naringin protects against HIV-1 protease inhibitors-induced pancreatic β-cell dysfunction and apoptosis. Mol Cell Endocrinol 2016; 437:1-10. [PMID: 27496642 DOI: 10.1016/j.mce.2016.07.041] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Revised: 06/30/2016] [Accepted: 07/31/2016] [Indexed: 02/07/2023]
Abstract
INTRODUCTION The protective effects of grapefruit-derived naringin against HIV-1 Protease Inhibitors (PIs)-associated oxidative damage to pancreatic β-cells and apoptosis were investigated in RIN-5F cells in culture. METHODS Cells in culture medium were challenged with 11-25 mM glucose with or without nelfinavir (1-10 μM), saquinavir (1-10 μM) and atazanavir (5-20 μM), respectively for 24 h to determine insulin secretion. The cells were further treated with nelfinavir (10 μM), saquinavir (10 μM), atazanavir (20 μM) with and without naringin or glibenclamide (10 μM) for 24 h to determine insulin secretion, lipid peroxidation, Superoxide Dismutase (SOD) activity, glutathione (GSH) levels, ATP production and caspase-3 and-9 activities, respectively. RESULTS Glucose-dependent insulin secretion was significantly reduced by PIs in a concentration-dependent manner. Treatment with either naringin or glibenclamide significantly reduced lipid peroxidation, Superoxide Dismutase (SOD) activities and also increased glutathione (GSH) and ATP levels in the cells that were treated with PIs. Furthermore, naringin or glibenclamide significantly reduced caspase-3 and caspase-9 activities in cells that were treated with PIs. CONCLUSIONS PIs impair β-cell functions by increasing oxidative stress and apoptosis. Treatment with naringin protected RIN-5F cells from PI-induced oxidative damage and apoptosis. Our results therefore suggest that nutritional supplements with naringin could prevent pancreatic β-cell dysfunction and the attendant metabolic complications caused by PIs in patients on antiretroviral therapy.
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Affiliation(s)
- Sanelisiwe Nzuza
- Molecular and Clinical Pharmacology Research Laboratory, Department of Pharmacology, Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, P.O. Box X5401, Durban, South Africa
| | - Duduzile E Ndwandwe
- Molecular and Clinical Pharmacology Research Laboratory, Department of Pharmacology, Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, P.O. Box X5401, Durban, South Africa
| | - Peter M O Owira
- Molecular and Clinical Pharmacology Research Laboratory, Department of Pharmacology, Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, P.O. Box X5401, Durban, South Africa.
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Yadranji Aghdam S, Mahmoudpour A. Proteasome Activators, PA28 α and PA28 β, Govern Development of Microvascular Injury in Diabetic Nephropathy and Retinopathy. Int J Nephrol 2016; 2016:3846573. [PMID: 27830089 PMCID: PMC5088333 DOI: 10.1155/2016/3846573] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Revised: 08/08/2016] [Accepted: 09/06/2016] [Indexed: 12/25/2022] Open
Abstract
Diabetic nephropathy (DN) and diabetic retinopathy (DR) are major complications of type 1 and type 2 diabetes. DN and DR are mainly caused by injury to the perivascular supporting cells, the mesangial cells within the glomerulus, and the pericytes in the retina. The genes and molecular mechanisms predisposing retinal and glomerular pericytes to diabetic injury are poorly characterized. In this study, the genetic deletion of proteasome activator genes, PA28α and PA28β genes, protected the diabetic mice in the experimental STZ-induced diabetes model against renal injury and retinal microvascular injury and prolonged their survival compared with wild type STZ diabetic mice. The improved wellbeing and reduced renal damage was associated with diminished expression of Osteopontin (OPN) and Monocyte Chemoattractant Protein-1 (MCP-1) in the glomeruli of STZ-injected PA28α/PA28β double knockout (Pa28αβDKO) mice and also in cultured mesangial cells and retinal pericytes isolated from Pa28αβDKO mice that were grown in high glucose. The mesangial PA28-mediated expression of OPN under high glucose conditions was suppressed by peptides capable of inhibiting the binding of PA28 to the 20S proteasome. Collectively, our findings demonstrate that diabetic hyperglycemia promotes PA28-mediated alteration of proteasome activity in vulnerable perivascular cells resulting in microvascular injury and development of DN and DR.
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Affiliation(s)
- Saeed Yadranji Aghdam
- Reynolds Institute on Aging, Room No. 4151, 629 Jack Stephens Drive, Little Rock, AR 72205, USA
- Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Ali Mahmoudpour
- Norgen Biotek Corp., 3430 Schmon Parkway, Thorold, ON, Canada L2V 4Y6
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Srivastava A, Bhatt NM, Patel TP, Dadheech N, Singh A, Gupta S. Anti-apoptotic and cytoprotective effect of Enicostemma littorale against oxidative stress in Islets of Langerhans. PHARMACEUTICAL BIOLOGY 2016; 54:2061-2072. [PMID: 26974043 DOI: 10.3109/13880209.2016.1141222] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Context Oxidative stress induces apoptosis within Islets of Langerhans in diabetes mellitus (DM). Enicostemma littorale blume, herb of the Gentianaceae family is used as an anti-diabetic agent across rural India. Objective This report demonstrates potent anti-apoptotic and cyto-protective activity of Enicostemma littorale MeOH extract (EL MeOH ext.) against 50 μM H2O2 in isolated rat Islets. Materials and methods In this study, the whole plant methanolic extract of EL with doses 0.25-4 mg/mL each for the preincubation duration of 0.5-4 h against 50 μM H2O2 were tested for optimum protective dose and time by Trypan blue dye exclusion assay. Islet intracellular reactive oxygen species (ROS) was quantified by DCFDA staining and cell death using PS/PI & FDA/PI staining. Further, comet assay, biochemical assessment of caspase-3 and antioxidant enzyme activities along with immunoblotting of PARP-1, caspase-3, TNF-α activation and p-P38 MapK (stress kinase) induction was performed. Results The optimized dose of EL MeOH ext. 2 mg/mL for 2 h was used throughout the study, which significantly decreased total Intracellular ROS and cell death. Further, caspase-3 activity, PARP-1 cleavage, p-P38 MapK (stress kinase) activation and TNF-α levels, which had been significantly elevated, were normalized. Antioxidant enzymes like catalase, superoxide dismutase, reduced glutathione and glutathione peroxidase, along with Comet assay, demonstrated that pretreatment with EL MeOH ext. can augment antioxidant enzyme activities and protect from DNA damage. Discussion and conclusions Significant anti-apoptotic and cyto-protective effects were mediated by EL with Islets of Langerhans subjected to oxidative stress-induced cell death.
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Affiliation(s)
- Abhay Srivastava
- a Molecular Endocrinology and Stem Cell Research Laboratory, Department of Biochemistry, Faculty of Science , The M. S. University of Baroda , Vadodara , Gujarat , India
| | - Niraj M Bhatt
- a Molecular Endocrinology and Stem Cell Research Laboratory, Department of Biochemistry, Faculty of Science , The M. S. University of Baroda , Vadodara , Gujarat , India
| | - Tushar P Patel
- a Molecular Endocrinology and Stem Cell Research Laboratory, Department of Biochemistry, Faculty of Science , The M. S. University of Baroda , Vadodara , Gujarat , India
| | - Nidheesh Dadheech
- a Molecular Endocrinology and Stem Cell Research Laboratory, Department of Biochemistry, Faculty of Science , The M. S. University of Baroda , Vadodara , Gujarat , India
| | - Anubha Singh
- a Molecular Endocrinology and Stem Cell Research Laboratory, Department of Biochemistry, Faculty of Science , The M. S. University of Baroda , Vadodara , Gujarat , India
| | - Sarita Gupta
- a Molecular Endocrinology and Stem Cell Research Laboratory, Department of Biochemistry, Faculty of Science , The M. S. University of Baroda , Vadodara , Gujarat , India
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Roy V, Chenkual L, Gurusubramanian G. Mallotus roxburghianus modulates antioxidant responses in pancreas of diabetic rats. Acta Histochem 2016; 118:152-63. [PMID: 26764087 DOI: 10.1016/j.acthis.2015.12.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Revised: 12/15/2015] [Accepted: 12/17/2015] [Indexed: 12/20/2022]
Abstract
Mallotus roxburghianus has long been used by Mizo tribal people for the treatment of diabetes. Scientific validation at known doses may provide information about its safety and efficacy. Methanolic leaf extract of M. roxburghianus (MRME 100 and 400mg/kg) was tested in comparison with normal and alloxan diabetic rats for 28 days p.o. in terms of body and pancreatic weight, blood glucose level, antioxidant enzymes, expression of visfatin and PCNA, histopathology and histomorphometric measurements of pancreas. The results were evaluated statistically using ANOVA, correlation and regression and Principal component analysis (PCO). MRME (100 and 400mg/kg) treatment significantly (p<0.0001) decreased the body weight, blood glucose level, improved the mass and size of pancreas, elevated the levels of antioxidant enzymes and up regulate the expression of visfatin and PCNA. PCO analysis was good to fitness and prediction distinguishes the therapeutic effects of M. roxburghianus from the alloxan induced diabetic rats. MRME has significant role in protecting animals from alloxan-induced diabetic oxidative stress in pancreas and exhibited promising antihyperglycaemic and antioxidant activities along with significant reversal of disturbed antioxidant status and lipid peroxidative damage. Pancreatic architecture and physiology under diabetic oxidative stress have been significantly modulated by MRME and validated as a drug candidate for antidiabetic treatment. M. roxburghianus treatment restores the antioxidant enzyme system and rejuvenates the islets mass in alloxanized rat by accelerating visfatin and PCNA expression in pancreatic tissue.
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Mapanga RF, Essop MF. Damaging effects of hyperglycemia on cardiovascular function: spotlight on glucose metabolic pathways. Am J Physiol Heart Circ Physiol 2016; 310:H153-73. [DOI: 10.1152/ajpheart.00206.2015] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 10/27/2015] [Indexed: 12/13/2022]
Abstract
The incidence of cardiovascular complications associated with hyperglycemia is a growing global health problem. This review discusses the link between hyperglycemia and cardiovascular diseases onset, focusing on the role of recently emerging downstream mediators, namely, oxidative stress and glucose metabolic pathway perturbations. The role of hyperglycemia-mediated activation of nonoxidative glucose pathways (NOGPs) [i.e., the polyol pathway, hexosamine biosynthetic pathway, advanced glycation end products (AGEs), and protein kinase C] in this process is extensively reviewed. The proposal is made that there is a unique interplay between NOGPs and a downstream convergence of detrimental effects that especially affect cardiac endothelial cells, thereby contributing to contractile dysfunction. In this process the AGE pathway emerges as a crucial mediator of hyperglycemia-mediated detrimental effects. In addition, a vicious metabolic cycle is established whereby hyperglycemia-induced NOGPs further fuel their own activation by generating even more oxidative stress, thereby exacerbating damaging effects on cardiac function. Thus NOGP inhibition, and particularly that of the AGE pathway, emerges as a novel therapeutic intervention for the treatment of cardiovascular complications such as acute myocardial infarction in the presence hyperglycemia.
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Affiliation(s)
- Rudo F. Mapanga
- Cardio-Metabolic Research Group, Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa
| | - M. Faadiel Essop
- Cardio-Metabolic Research Group, Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa
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Xu X, Xiao L, Xiao P, Yang S, Chen G, Liu F, Kanwar YS, Sun L. A glimpse of matrix metalloproteinases in diabetic nephropathy. Curr Med Chem 2015; 21:3244-60. [PMID: 25039784 DOI: 10.2174/0929867321666140716092052] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Revised: 07/06/2014] [Accepted: 07/11/2014] [Indexed: 12/14/2022]
Abstract
Matrix metalloproteinases (MMPs) are proteolytic enzymes belonging to the family of zinc-dependent endopeptidases that are capable of degrading almost all the proteinaceous components of the extracellular matrix (ECM). It is known that MMPs play a role in a number of renal diseases, such as, various forms of glomerulonephritis and tubular diseases, including some of the inherited kidney diseases. In this regard, ECM accumulation is considered to be a hallmark morphologic finding of diabetic nephropathy, which not only is related to the excessive synthesis of matrix proteins, but also to their decreased degradation by the MMPs. In recent years, increasing evidence suggest that there is a good correlation between the activity or expression of MMPs and progression of renal disease in patients with diabetic nephropathy and in various experimental animal models. In such a diabetic milieu, the expression of MMPs is modulated by high glucose, advanced glycation end products (AGEs), TGF-β, reactive oxygen species (ROS), transcription factors and some of the microRNAs. In this review, we focused on the structure and functions of MMPs, and their role in the pathogenesis of diabetic nephropathy.
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Affiliation(s)
| | | | | | | | | | | | | | - L Sun
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan 415800, China..
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Wang C, Blough E, Arvapalli R, Dai X, Triest WE, Leidy JW, Masannat Y, Wu M. Acetaminophen attenuates glomerulosclerosis in obese Zucker rats via reactive oxygen species/p38MAPK signaling pathways. Free Radic Biol Med 2015; 81:47-57. [PMID: 25614458 DOI: 10.1016/j.freeradbiomed.2015.01.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Revised: 12/05/2014] [Accepted: 01/11/2015] [Indexed: 01/09/2023]
Abstract
Focal segmental glomerulosclerosis is a critical pathological lesion in metabolic syndrome-associated kidney disease that, if allowed to proceed unchecked, can lead to renal failure. However, the exact mechanisms underlying glomerulosclerosis remain unclear, and effective prevention strategies against glomerulosclerosis are currently limited. Herein, we demonstrate that chronic low-dose ingestion of acetaminophen (30 mg/kg/day for 6 months) attenuates proteinuria, glomerulosclerosis, podocyte injury, and inflammation in the obese Zucker rat model of metabolic syndrome. Moreover, acetaminophen treatment attenuated renal fibrosis and the expression of profibrotic factors (fibronectin, connective tissue growth factor, transforming growth factor β), reduced inflammatory cell infiltration into the glomeruli, and decreased the expression of monocyte chemoattractant protein, glutathione (GSH) reductase, and nuclear factor erythroid 2-related factor 2, but increased the level of GSH synthetase in obese animals. Further in vivo and in vitro studies using human renal mesangial cells exposed to high glucose or hydrogen peroxide suggested that the renoprotective effects of acetaminophen are characterized by diminished renal oxidative stress and p38MAPK hyperphosphorylation.
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Affiliation(s)
- Cuifen Wang
- Center for Diagnostic Nanosystems, Marshall University, Huntington, WV 25755, USA; School of Pharmacy, Marshall University, Huntington, WV 25755, USA; Southeast University, Nanjing, Jiangsu, China
| | - Eric Blough
- Center for Diagnostic Nanosystems, Marshall University, Huntington, WV 25755, USA; School of Pharmacy, Marshall University, Huntington, WV 25755, USA.
| | - Ravikumar Arvapalli
- Center for Diagnostic Nanosystems, Marshall University, Huntington, WV 25755, USA; School of Pharmacy, Marshall University, Huntington, WV 25755, USA
| | - Xiaoniu Dai
- Southeast University, Nanjing, Jiangsu, China
| | | | - John W Leidy
- Huntington VA Medical Center, Huntington, WV 25704, USA
| | - Yanal Masannat
- Department of Internal Medicine, Joan C. Edwards School of Medicine, Huntington, WV 25755, USA
| | - Miaozong Wu
- Center for Diagnostic Nanosystems, Marshall University, Huntington, WV 25755, USA; School of Pharmacy, Marshall University, Huntington, WV 25755, USA; Department of Internal Medicine, Joan C. Edwards School of Medicine, Huntington, WV 25755, USA.
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Gan F, Zhang Z, Hu Z, Hesketh J, Xue H, Chen X, Hao S, Huang Y, Cole Ezea P, Parveen F, Huang K. Ochratoxin A promotes porcine circovirus type 2 replication in vitro and in vivo. Free Radic Biol Med 2015; 80:33-47. [PMID: 25542137 PMCID: PMC7126689 DOI: 10.1016/j.freeradbiomed.2014.12.016] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Revised: 12/12/2014] [Accepted: 12/15/2014] [Indexed: 12/13/2022]
Abstract
Ochratoxin A (OTA), a worldwide mycotoxin found in food and feeds, is a potent nephrotoxin in animals and humans. Porcine circovirus-associated disease (PCVAD), including porcine dermatitis and nephropathy syndrome, is a worldwide swine disease. To date, little is known concerning the relationship between OTA and porcine circovirus type 2 (PCV2), the primary causative agent of PCVAD. The effects of OTA on PCV2 replication and their mechanisms were investigated in vitro and in vivo. The results in vitro showed that low doses of OTA significantly increased PCV2 DNA copies and the number of infected cells. Maximum effects were observed at 0.05 μg/ml OTA. The results in vivo showed that PCV2 replication was significantly increased in serum and tissues of pigs fed 75 μg/kg OTA compared with the control group and pigs fed 150 μg/kg OTA. In addition, low doses of OTA significantly depleted reduced glutathione and mRNA expression of NF-E2-related factor 2 and γ-glutamylcysteine synthetase; increased reactive oxygen species, oxidants, and malondialdehyde; and induced p38 and ERK1/2 phosphorylation in PK15 cells. Adding N-acetyl-L-cysteine reversed the changes induced by OTA. Knockdown of p38 and ERK1/2 by their respective specific siRNAs or inhibition of p38 and ERK1/2 phosphorylation by their respective inhibitors (SB203580 and U0126) eliminated the increase in PCV2 replication induced by OTA. These data indicate that low doses of OTA promoted PCV2 replication in vitro and in vivo via the oxidative stress-mediated p38/ERK1/2 MAPK signaling pathway. This suggests that low doses of OTA are potentially harmful to animals, as they enhance virus replication, and partly explains why the morbidity and severity of PCVAD vary significantly in different pig farms.
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Affiliation(s)
- Fang Gan
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China
| | - Zheqian Zhang
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China
| | - Zhihua Hu
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China
| | - John Hesketh
- Institute for Cell and Molecular Biosciences, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Hongxia Xue
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China
| | - Xingxiang Chen
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China
| | - Shu Hao
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China
| | - Yu Huang
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China
| | - Patience Cole Ezea
- Institute for Cell and Molecular Biosciences, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Fahmida Parveen
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China
| | - Kehe Huang
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China.
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Keshari KR, Wilson DM, Sai V, Bok R, Jen KY, Larson P, Van Criekinge M, Kurhanewicz J, Wang ZJ. Noninvasive in vivo imaging of diabetes-induced renal oxidative stress and response to therapy using hyperpolarized 13C dehydroascorbate magnetic resonance. Diabetes 2015; 64:344-52. [PMID: 25187363 PMCID: PMC4303960 DOI: 10.2337/db13-1829] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Oxidative stress has been proposed to be a unifying cause for diabetic nephropathy and a target for novel therapies. Here we apply a new endogenous reduction-oxidation (redox) sensor, hyperpolarized (HP) (13)C dehydroascorbate (DHA), in conjunction with MRI to noninvasively interrogate the renal redox capacity in a mouse diabetes model. The diabetic mice demonstrate an early decrease in renal redox capacity, as shown by the lower in vivo HP (13)C DHA reduction to the antioxidant vitamin C (VitC), prior to histological evidence of nephropathy. This correlates with lower tissue reduced glutathione (GSH) concentration and higher NADPH oxidase 4 (Nox4) expression, consistent with increased superoxide generation and oxidative stress. ACE inhibition restores the HP (13)C DHA reduction to VitC with concomitant normalization of GSH concentration and Nox4 expression in diabetic mice. HP (13)C DHA enables rapid in vivo assessment of altered redox capacity in diabetic renal injury and after successful treatment.
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Affiliation(s)
- Kayvan R Keshari
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - David M Wilson
- Department of Radiology & Biomedical Imaging, University of California, San Francisco, San Francisco, CA
| | - Victor Sai
- Department of Radiology & Biomedical Imaging, University of California, San Francisco, San Francisco, CA
| | - Robert Bok
- Department of Radiology & Biomedical Imaging, University of California, San Francisco, San Francisco, CA
| | - Kuang-Yu Jen
- Department of Radiology & Biomedical Imaging, University of California, San Francisco, San Francisco, CA
| | - Peder Larson
- Department of Radiology & Biomedical Imaging, University of California, San Francisco, San Francisco, CA
| | - Mark Van Criekinge
- Department of Radiology & Biomedical Imaging, University of California, San Francisco, San Francisco, CA
| | - John Kurhanewicz
- Department of Radiology & Biomedical Imaging, University of California, San Francisco, San Francisco, CA
| | - Zhen J Wang
- Department of Radiology & Biomedical Imaging, University of California, San Francisco, San Francisco, CA
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Xavier DJ, Takahashi P, Manoel-Caetano FS, Foss-Freitas MC, Foss MC, Donadi EA, Passos GA, Sakamoto-Hojo ET. One-week intervention period led to improvements in glycemic control and reduction in DNA damage levels in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 2014; 105:356-63. [PMID: 25043705 DOI: 10.1016/j.diabres.2014.06.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Revised: 02/01/2014] [Accepted: 06/13/2014] [Indexed: 01/09/2023]
Abstract
AIMS Hyperglycemia leads to increased production of reactive oxygen species (ROS), which reduces cellular antioxidant defenses and induces several DNA lesions. We investigated the effects on DNA damage of a seven-day hospitalization period in patients with type 2 diabetes mellitus (T2DM) to achieve adequate blood glucose levels through dietary intervention and medication treatment, compared with non-diabetic individuals. METHODS DNA damage levels were evaluated by the alkaline comet assay (with modified and without conventional use of hOGG1 enzyme, which detects oxidized DNA bases) for 10 patients and 16 controls. Real time PCR array method was performed to analyze the transcriptional expression of a set of 84 genes implicated in antioxidant defense and response to oxidative stress in blood samples from T2DM patients (n=6) collected before and after the hospitalization period. RESULTS The seven-day period was sufficient to improve glycemic control and to significantly decrease (p<0.05) DNA damage levels in T2DM patients, although those levels were slightly higher than those in control subjects. We also found a tendency towards a decrease in the levels of oxidative DNA damage in T2DM patients after the hospitalization period. However, for all genes analyzed, a statistically significant difference in the transcriptional expression levels was not observed. CONCLUSIONS The study demonstrated that although the transcriptional expression of the genes studied did not show significant alterations, one-week of glycemic control in hospital resulted in a significant reduction in DNA damage levels detected in T2DM patients, highlighting the importance of an adequate glycemic control.
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Affiliation(s)
- Danilo J Xavier
- Department of Genetics, Faculty of Medicine of Ribeirão Preto (FMRP), University of São Paulo-USP, Ribeirão Preto, SP, Brazil
| | - Paula Takahashi
- Department of Genetics, Faculty of Medicine of Ribeirão Preto (FMRP), University of São Paulo-USP, Ribeirão Preto, SP, Brazil
| | - Fernanda S Manoel-Caetano
- Department of Genetics, Faculty of Medicine of Ribeirão Preto (FMRP), University of São Paulo-USP, Ribeirão Preto, SP, Brazil; Department of Biology, Faculty of Philosophy, Sciences and Letters of Ribeirão Preto (FFCLRP), University of São Paulo-USP, Ribeirão Preto, SP, Brazil
| | - Maria C Foss-Freitas
- Department of Internal Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo-USP, Ribeirão Preto, SP, Brazil
| | - Milton C Foss
- Department of Internal Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo-USP, Ribeirão Preto, SP, Brazil
| | - Eduardo A Donadi
- Department of Genetics, Faculty of Medicine of Ribeirão Preto (FMRP), University of São Paulo-USP, Ribeirão Preto, SP, Brazil; Division of Clinical Immunology, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo-USP, Ribeirão Preto, SP, Brazil
| | - Geraldo A Passos
- Department of Genetics, Faculty of Medicine of Ribeirão Preto (FMRP), University of São Paulo-USP, Ribeirão Preto, SP, Brazil; Disciplines of Genetics and Molecular Biology, Department of Morphology, Faculty of Dentistry of Ribeirão Preto, University of São Paulo-USP, Ribeirão Preto, SP, Brazil
| | - Elza T Sakamoto-Hojo
- Department of Genetics, Faculty of Medicine of Ribeirão Preto (FMRP), University of São Paulo-USP, Ribeirão Preto, SP, Brazil; Department of Biology, Faculty of Philosophy, Sciences and Letters of Ribeirão Preto (FFCLRP), University of São Paulo-USP, Ribeirão Preto, SP, Brazil.
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Liu CT, Hsu TW, Chen KM, Tan YP, Lii CK, Sheen LY. The Antidiabetic Effect of Garlic Oil is Associated with Ameliorated Oxidative Stress but Not Ameliorated Level of Pro-inflammatory Cytokines in Skeletal Muscle of Streptozotocin-induced Diabetic Rats. J Tradit Complement Med 2014; 2:135-44. [PMID: 24716126 PMCID: PMC3942916 DOI: 10.1016/s2225-4110(16)30087-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Oxidative stress and inflammatory condition has been broadly accepted being associated with the progression of diabetes. On the other hand, garlic (大蒜 dà suàn, bulb of Allium sativum) has been shown to possess both antioxidant and anti-inflammatory action in several clinical conditions. Our previous study demonstrated that treatment with garlic oil improves oral glucose tolerance and insulin tolerance and improves the insulin-stimulated utilization of glucose to synthesize glycogen in skeletal muscle in streptozotocin (STZ)-induced diabetes, in vivo and ex vivo, respectively. The aim of the present study is to investigate the antioxidant and anti-inflammatory effects of garlic oil (GO) in the skeletal muscle of diabetic rats. Rats with STZ-induced diabetes received GO (10, 50, or 100 mg/kg body weight) or corn oil by gavage every other day for 3 weeks. Control rats received corn oil only. GO dose-dependently improved insulin sensitivity, as assessed by the insulin tolerance test, and oral glucose tolerance. GO significantly elevated total glutathione and glutathione peroxidase activity and lowered the nitrate/nitrite content in skeletal muscle at 50 and 100 mg/kg and significantly elevated glutathione reductase activity and lowered lipid peroxidation at 100 mg/kg. By contrast, GO did not reverse diabetes-induced elevation of IL-1β and TNF-α in skeletal muscle at any tested dose. On the other hand, GO elevated the expression of GLUT4 in skeletal muscle along with glycogen content as observed with PAS staining. In conclusion, the antidiabetic effect of garlic oil is associated with ameliorated oxidative stress in skeletal muscle.
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Affiliation(s)
- Cheng-Tzu Liu
- School of Nutrition, Chung Shan Medical University, Taichung 402, Taiwan ; Department of Nutrition, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Tien-Wei Hsu
- School of Nutrition, Chung Shan Medical University, Taichung 402, Taiwan
| | - Ke-Ming Chen
- Department of Parasitology, Chung Shan Medical University, Taichung 402, Taiwan
| | - Ya-Ping Tan
- School of Nutrition, Chung Shan Medical University, Taichung 402, Taiwan
| | - Chong-Kuei Lii
- Department of Nutrition, China Medical University, Taichung 404, Taiwan
| | - Lee-Yan Sheen
- Graduate Institute of Food Science and Technology, National Taiwan University, Taipei, Taiwan
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Lv C, Wu C, Zhou YH, Shao Y, Wang G, Wang QY. Alpha Lipoic Acid Modulated High Glucose-Induced Rat Mesangial Cell Dysfunction via mTOR/p70S6K/4E-BP1 Pathway. Int J Endocrinol 2014; 2014:658589. [PMID: 25530759 PMCID: PMC4229972 DOI: 10.1155/2014/658589] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Revised: 10/07/2014] [Accepted: 10/08/2014] [Indexed: 01/09/2023] Open
Abstract
The aim of this study was to investigate whether alpha lipoic acid (LA) regulates high glucose-induced mesangial cell proliferation and extracellular matrix production via mTOR/p70S6K/4E-BP1 signaling. The effect of LA on high glucose-induced cell proliferation, fibronectin (FN), and collagen type I (collagen-I) expression and its mechanisms were examined in cultured rat mesangial cells by methylthiazol tetrazolium (MTT) assay, flow cytometry, ELISA assay, and western blot, respectively. LA at a relatively low concentration (0.25 mmol/L) acted as a growth factor in rat mesangial cells, promoted entry of cell cycle into S phase, extracellular matrix formation, and phosphorylated AKT, mTOR, p70S6K, and 4E-BP1. These effects disappeared when AKT expression was downregulated with PI3K/AKT inhibitor LY294002. Conversely, LA at a higher concentration (1.0 mmol/L) inhibited high glucose-induced rat mesangial cell proliferation, entry of cell cycle into S phase, and extracellular matrix exertion, as well as phosphorylation of mTOR, p70S6K, and 4E-BP1 but enhanced the activity of AMPK. However, these effects disappeared when AMPK activity was inhibited with CaMKK inhibitor STO-609. These results suggest that LA dose-dependently regulates mesangial cell proliferation and matrix protein secretion by mTOR/p70S6K/4E-BP1 signaling pathway under high glucose conditions.
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Affiliation(s)
- Chuan Lv
- Division of Endocrinology, First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, China
| | - Can Wu
- Division of Endocrinology, First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, China
| | - Yue-hong Zhou
- Division of Endocrinology, Shenyang No. 8 Hospital, Shenyang, Liaoning 110024, China
| | - Ying Shao
- Division of Endocrinology, First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, China
| | - Guan Wang
- Clinical Medicine of Seven-Year Education, China Medical University, Shenyang, Liaoning 110001, China
| | - Qiu-yue Wang
- Division of Endocrinology, First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, China
- *Qiu-yue Wang:
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Simplified system to investigate alteration of retinal neurons in diabetes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 801:139-43. [PMID: 24664691 DOI: 10.1007/978-1-4614-3209-8_18] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Diabetic retinopathy (DR) is traditionally considered as a microvascular complication in diabetic retinas. Emerging evidences suggest that the alteration of neuronal function and the death of retinal neurons are part of DR pathology. However, surprisingly little is known about how retinal neurons behave in DR. As diabetic animals are chronicle models that are difficult and expensive to maintain, we used a chemical hypoxia model that mimics the later stage of diabetes and investigated its potential in predicting retinal cell behaviors in diabetes in an efficient manner. In this chapter, we discuss the similarities and differences between diabetic and hypoxic models and the usefulness and limitation of the cobalt-chloride-generated hypoxia system in mice for studying retinal neurobiology in diabetes.
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Naito Y, Uchiyama K, Kuroda M, Mizushima K, Aoi W, Kokura S, Ichikawa H, Yoshida N, Yoshikawa T. Laser capture microdissection/GeneChip analysis of gene expression in glomerular cells in diabetic db/db mice. Redox Rep 2013; 9:307-12. [PMID: 15720823 DOI: 10.1179/135100004225006786] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
UNLABELLED Although the gene expression patterns during the development of diabetic nephropathy have been studied in both rodent models and humans, only a small portion of the mRNAs expressed in the mesangium or in glomerular cells has been characterized. In the present study we report larger groups of transcripts displaying significant expression modulation in glomerular cells obtained from the early phase of diabetic nephropathy. METHODS We used 12-week-old female db/db mice, a rodent model of type 2 diabetes, and their non-diabetic db/m litter-mates. Glomerular cells were obtained from the kidneys of mice by laser capture microdissection. Preparation of cRNA and target hybridization were performed according to the Affymetrix GeneChip Eukaryotic Small Sample Target Labeling Assay Protocol (Version II). The gene expression profile was determined by the mouse Expression Set 430A GeneChip. RESULTS By comparison between db/m and db/db mice, 649 probes that increased in expression with the induction of diabetes and 340 probes that decreased in diabetic kidneys were identified. Although some of these genes have previously been shown to play an important role in diabetic nephropathy, the large majority of them have never been demonstrated to be regulated during the development of nephropathy. CONCLUSIONS Although the precise involvement of these genes in diabetic nephropathy remains to be clarified, the data presented here will aid in the identification of genes that play a significant role in this pathological condition.
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Affiliation(s)
- Yuji Naito
- Departments of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
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Xue H, Yuan P, Ni J, Li C, Shao D, Liu J, Shen Y, Wang Z, Zhou L, Zhang W, Huang Y, Yu C, Wang R, Lu L. H(2)S inhibits hyperglycemia-induced intrarenal renin-angiotensin system activation via attenuation of reactive oxygen species generation. PLoS One 2013; 8:e74366. [PMID: 24058553 PMCID: PMC3772925 DOI: 10.1371/journal.pone.0074366] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2013] [Accepted: 07/31/2013] [Indexed: 01/09/2023] Open
Abstract
Decrease in endogenous hydrogen sulfide (H2S) was reported to participate in the pathogenesis of diabetic nephropathy (DN). This study is aimed at exploring the relationship between the abnormalities in H2S metabolism, hyperglycemia-induced oxidative stress and the activation of intrarenal renin-angiotensin system (RAS). Cultured renal mesangial cells (MCs) and streptozotocin (STZ) induced diabetic rats were used for the studies. The expressions of angiotensinogen (AGT), angiotensin converting enzyme (ACE), angiotensin II (Ang II) type I receptor (AT1), transforming growth factor-β1 (TGF-β1) and collagen IV were measured by real time PCR and Western blot. Reactive oxygen species (ROS) production was assessed by fluorescent probe assays. Cell proliferation was analyzed by 5'-bromo-2'-deoxyuridine incorporation assay. Ang II concentration was measured by an enzyme immunoassay. AGT, ACE and AT1 receptor mRNA levels and Ang II concentration were increased in high glucose (HG) -treated MCs, the cell proliferation rate and the production of TGF-β1 and of collagen IV productions were also increased. The NADPH oxidase inhibitor diphenylenechloride iodonium (DPI) was able to reverse the HG-induced RAS activation and the changes in cell proliferation and collagen synthesis. Supplementation of H2S attenuated HG-induced elevations in ROS and RAS activation. Blockade on H2S biosynthesis from cystathione-γ-lyase (CSE) by DL-propargylglycine (PPG) resulted in effects similar to that of HG treatment. In STZ-induced diabetic rats, the changes in RAS were also reversed by H2S supplementation without affecting blood glucose concentration. These data suggested that the decrease in H2S under hyperglycemic condition leads to an imbalance between oxidative and reductive species. The increased oxidative species results in intrarenal RAS activation, which, in turn, contributes to the pathogenesis of renal dysfunction.
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MESH Headings
- Acetophenones/pharmacology
- Angiotensin II Type 1 Receptor Blockers/pharmacology
- Angiotensinogen/genetics
- Angiotensinogen/metabolism
- Animals
- Blood Glucose/metabolism
- Cell Proliferation/drug effects
- Cells, Cultured
- Collagen Type IV/metabolism
- Cystathionine beta-Synthase/genetics
- Cystathionine beta-Synthase/metabolism
- Cystathionine gamma-Lyase/genetics
- Cystathionine gamma-Lyase/metabolism
- Diabetes Mellitus, Experimental/enzymology
- Diabetes Mellitus, Experimental/genetics
- Diabetes Mellitus, Experimental/pathology
- Glucose/pharmacology
- Hydrogen Sulfide/pharmacology
- Hyperglycemia/enzymology
- Hyperglycemia/genetics
- Hyperglycemia/metabolism
- Hyperglycemia/pathology
- Kidney/drug effects
- Kidney/pathology
- Losartan/pharmacology
- Mesangial Cells/drug effects
- Mesangial Cells/metabolism
- Mesangial Cells/pathology
- NADPH Oxidases/metabolism
- Onium Compounds/pharmacology
- Peptidyl-Dipeptidase A/genetics
- Peptidyl-Dipeptidase A/metabolism
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Rats
- Reactive Oxygen Species/metabolism
- Receptor, Angiotensin, Type 1/genetics
- Receptor, Angiotensin, Type 1/metabolism
- Renin-Angiotensin System/drug effects
- Transforming Growth Factor beta1/metabolism
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Affiliation(s)
- Hong Xue
- Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ping Yuan
- Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Pulmonary Circulation Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jun Ni
- Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Chen Li
- Department of Nephrology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Decui Shao
- Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jia Liu
- Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yang Shen
- Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhen Wang
- Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Li Zhou
- Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wei Zhang
- Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yu Huang
- School of Biomedical Sciences and Institute of Vascular Medicine, Chinese University of Hong Kong, Hong Kong, China
| | - Chen Yu
- Department of Nephrology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Rui Wang
- Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Biology, Lakehead University, Thunder Bay, Canada
| | - Limin Lu
- Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China
- * E-mail:
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High glucose-induced oxidative stress increases the copy number of mitochondrial DNA in human mesangial cells. BIOMED RESEARCH INTERNATIONAL 2013; 2013:754946. [PMID: 23984405 PMCID: PMC3745925 DOI: 10.1155/2013/754946] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Accepted: 07/08/2013] [Indexed: 01/01/2023]
Abstract
Oxidative damage to mitochondrial DNA (mtDNA) has been linked to the pathogenicity of diabetic nephropathy. We tested the hypothesis that mtDNA copy number may be increased in human mesangial cells in response to high glucose-induced reactive oxygen species (ROS) to compensate for damaged mtDNA. The effect of manganese superoxide dismutase mimetic (MnTBAP) on glucose-induced mtDNA copy number was also examined. The copy number of mtDNA was determined by real-time PCR in human mesangial cells cultured in 5 mM glucose, 25 mM glucose, and mannitol (osmotic control), as well as in cells cultured in 25 mM glucose in the presence and absence of 200 μM MnTBAP. Intracellular ROS was assessed by confocal microscopy and flow cytometry in human mesangial cells.
The copy number of mtDNA was significantly increased when human mesangial cells were incubated with 25 mM glucose compared to 5 mM glucose and mannitol. In addition, 25 mM glucose rapidly generated ROS in the cells, which was not detected in 5 mM glucose. Furthermore, mtDNA copy number was significantly decreased and maintained to normal following treatment of cells with 25 mM glucose and MnTBAP compared to 25 mM glucose alone. Inclusion of MnTBAP during 25 mM glucose incubation inhibited mitochondrial superoxide in human mesangial cells. Increased mtDNA copy number in human mesangial cells by high glucose could contribute to increased mitochondrial superoxide, and prevention of mtDNA copy number could have potential in retarding the development of diabetic nephropathy.
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Pandya KG, Budhram R, Clark G, Lau-Cam CA. Comparative Evaluation of Taurine and Thiotaurine as Protectants Against Diabetes-Induced Nephropathy in a Rat Model. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2013; 775:371-94. [DOI: 10.1007/978-1-4614-6130-2_29] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Díaz-Flores M, Angeles-Mejia S, Baiza-Gutman LA, Medina-Navarro R, Hernández-Saavedra D, Ortega-Camarillo C, Roman-Ramos R, Cruz M, Alarcon-Aguilar FJ. Effect of an aqueous extract of Cucurbita ficifolia Bouché on the glutathione redox cycle in mice with STZ-induced diabetes. JOURNAL OF ETHNOPHARMACOLOGY 2012; 144:101-108. [PMID: 22960550 DOI: 10.1016/j.jep.2012.08.036] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2012] [Revised: 08/12/2012] [Accepted: 08/25/2012] [Indexed: 06/01/2023]
Abstract
ETHNOPHARMACOLOGICAL IMPORTANCE Cucurbita ficifolia is used in Mexican traditional medicine as an anti-diabetic and anti-inflammatory agent and its actions can be mediated by antioxidant mechanisms. Disturbance in the homeostasis of glutathione has been implicated in the etiology and progression of diabetes mellitus and its complications. MATERIAL AND METHODS It was evaluated, the effect of an aqueous extract of Cucurbita ficifolia on glycemia, plasma lipid peroxidation; as well as levels of reduced (GSH) and oxidized (GSSG) glutathione and activities of enzymes involved in glutathione redox cycle: glutathione peroxidase (GPx) and glutathione reductase (GR) in liver, pancreas, kidney and heart homogenates of streptozotocin-induced diabetic mice. RESULTS Increased blood glucose and lipid peroxidation, together with decreased of GSH concentration, GSH/GSSG ratio and its redox potential (E(h)), and enhanced activity of GPx and GR in liver, pancreas and kidney were the salient features observed in diabetic mice. Administration of the aqueous extract of Cucurbita ficifolia to diabetic mice for 30 days, used at a dose of 200 mg/kg, resulted in a significant reduction in glycemia, polydipsia, hyperphagia and plasma lipid peroxidation. Moreover, GSH was increased in liver, pancreas and kidney, and GSSG was reduced in liver, pancreas and heart, therefore GSH/GSSG ratio and its E(h) were restored. Also, the activities involved in the glutathione cycle were decreased, reaching similar values to controls. CONCLUSIONS An aqueous extract of Cucurbita ficifolia with hypoglycemic action, improve GSH redox state, increasing glutathione pool, GSH, GSH/GSSG ratio and its E(h), mechanism that can explain, at least in part, its antioxidant properties, supporting its use as an alternative treatment for the control of diabetes mellitus, and prevent the induction of complications by oxidative stress.
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Affiliation(s)
- M Díaz-Flores
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, IMSS, México, México.
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Johno H, Nakajima S, Kato H, Yao J, Paton AW, Paton JC, Katoh R, Shimizu F, Kitamura M. Unfolded protein response causes a phenotypic shift of inflamed glomerular cells toward redifferentiation through dual blockade of Akt and Smad signaling pathways. THE AMERICAN JOURNAL OF PATHOLOGY 2012; 181:1977-90. [PMID: 23031256 DOI: 10.1016/j.ajpath.2012.08.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2012] [Revised: 08/01/2012] [Accepted: 08/15/2012] [Indexed: 12/24/2022]
Abstract
During recovery from acute glomerulonephritis, cell proliferation, matrix expansion, and expression of the dedifferentiation marker α-smooth muscle actin (α-SMA) subside spontaneously. However, the molecular mechanisms underlying this recovery process remain elusive. In mesangioproliferative glomerulonephritis, the unfolded protein response (UPR) is induced in activated, dedifferentiated mesangial cells. We investigated the role of the UPR in mesangial cell deactivation and redifferentiation and found that, during experimental glomerulonephritis in rats, reinforcement of the UPR significantly attenuated mesangial cell proliferation, matrix expansion, and expression of α-SMA. Consistent with this in vivo result, induction of the UPR suppressed cell proliferation and transcriptional expression of type IV collagen (ColIV) and α-SMA in activated mesangial cells. The UPR reduced phosphorylation of Akt in vitro and in vivo, and it was responsible for attenuation of cell proliferation. The UPR also preferentially depressed levels of total and phosphorylated Smads without affecting transcriptional levels, and it was responsible for suppression of ColIV and α-SMA. Translational suppression via the eIF2α pathway, but not proteasome-mediated protein degradation, was responsible for the down-regulation of Smads. These results suggest the novel potential of the UPR to facilitate a phenotypic shift of activated glomerular cells toward deactivation and redifferentiation. The UPR may serve as endogenous machinery that supports recovery of glomeruli from acute inflammation.
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Affiliation(s)
- Hisashi Johno
- Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Japan
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Campoio T, Oliveira F, Otton R. Oxidative stress in human lymphocytes treated with fatty acid mixture: Role of carotenoid astaxanthin. Toxicol In Vitro 2011; 25:1448-56. [DOI: 10.1016/j.tiv.2011.04.018] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2011] [Revised: 04/18/2011] [Accepted: 04/19/2011] [Indexed: 01/09/2023]
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In vitro suppression of quercetin on hypertrophy and extracellular matrix accumulation in rat glomerular mesangial cells cultured by high glucose. Fitoterapia 2011; 82:920-6. [DOI: 10.1016/j.fitote.2011.05.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2011] [Revised: 05/03/2011] [Accepted: 05/06/2011] [Indexed: 12/29/2022]
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Piwkowska A, Rogacka D, Audzeyenka I, Jankowski M, Angielski S. High glucose concentration affects the oxidant-antioxidant balance in cultured mouse podocytes. J Cell Biochem 2011; 112:1661-72. [PMID: 21503956 DOI: 10.1002/jcb.23088] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Hyperglycemia is well-recognized and has long-term complications in diabetes mellitus and diabetic nephropathy. In podocytes, the main component of the glomerular barrier, overproduction of reactive oxygen species (ROS) in the presence of high glucose induces dysfunction and increases excretion of albumin in urine. This suggests an impaired antioxidant defense system has a role in the pathogenesis of diabetic nephropathy. We studied expression of NAD(P)H oxidase subunits by Western blotting and immunofluorescence and the activities of the oxidant enzyme, NAD(P)H, and antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT), in mouse podocytes cultured in a high glucose concentration (30 mM). We found long-term (3 and 5 days) exposure of mouse podocytes to high glucose concentrations caused oxidative stress, as evidenced by increased expression of Nox4 and activities of NAD(P)H oxidase (Δ 182%) and SOD (Δ 39%) and decreased activities of GPx (Δ -40%) and CAT (Δ -35%). These biochemical changes were accompanied by a rise in intracellular ROS production and accumulation of hydrogen peroxide in extracellular space. The role of Nox4 in ROS generation was confirmed with Nox4 siRNA. In conclusion, high glucose concentration affects the oxidant-antioxidant balance in mouse podocytes, resulting in enhanced generation of superoxide anions and its attenuated metabolism. These observations suggest free radicals may play an important role in the pathogenesis of diabetic nephropathy.
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Affiliation(s)
- Agnieszka Piwkowska
- Mossakowski Medical Research Center Polish Academy of Sciences, Laboratory of Molecular and Cellular Nephrology, Gdańsk, Poland.
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Jalal R, Bagheri SM, Moghimi A, Rasuli MB. Hypoglycemic effect of aqueous shallot and garlic extracts in rats with fructose-induced insulin resistance. J Clin Biochem Nutr 2011; 41:218-23. [PMID: 18299719 PMCID: PMC2243241 DOI: 10.3164/jcbn.2007031] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2007] [Accepted: 05/11/2007] [Indexed: 12/13/2022] Open
Abstract
The present study has been carried out to investigate the effect of aqueous extract of shallot (Allium ascalonicum) and garlic (Allium satium) on the fasting insulin resistance index (FIRI) and intraperitoneal glucose tolerance test (IPGTT) of fructose-induced insulin resistance rats. Male albino Wistar rats were fed either normal or high-fructose diet for a period of eight weeks. Fasting blood glucose level, fasting blood triglyceride level, FIRI, and the area under the glucose tolerance curve were significantly elevated in fructose-fed animals. Fructose-induced insulin resistance rats treated by aqueous shallot or garlic extract (500 mg/kg body weight/day, i.p.) for duration of eight weeks. Control animals only received normal saline (0.9%). The results showed that neither shallot nor garlic extracts significantly altered the FIRI and the IPGTT at the fourth week after treatment. The fasting blood glucose in fructose-induced insulin resistance animals has been significantly decreased in 8-week treated animals by both shallot and garlic extracts. Shallot extract administration, but not garlic extract, for a period of eight weeks can significantly improve the intraperitoneal glucose tolerance and diminish the FIRI. These results indicate that shallot and garlic extracts have a hypoglycemic influence on the fructose-induced insulin resistance animals and aqueous shallot extract is a stronger hypoglycemic agent than the garlic extract.
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Affiliation(s)
- Razieh Jalal
- Department of Chemistry, Ferdowsi University of Mashhad, Mashhad 91779, Iran
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Waddington RJ, Alraies A, Colombo JS, Sloan AJ, Okazaki J, Moseley R. Characterization of oxidative stress status during diabetic bone healing. Cells Tissues Organs 2011; 194:307-12. [PMID: 21576908 DOI: 10.1159/000324251] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Early events associated with bone healing in patients with type 2 diabetes mellitus appear to be delayed. Hyperglycaemia and an associated increase in oxidative stress are cited as potential factors leading to a change in cellular behaviour. Using an in vivo model monitoring bone formation around implants placed into rat mandibles, we have previously identified that the onset of cell proliferation and osteoblast differentiation are delayed and subsequently prolonged compared with normal bone. This study used the same implant model to characterize oxidative stress biomarkers and primary antioxidant enzyme profiles during diabetic bone healing in vivo. Implants were placed into the sockets of incisors extracted from the mandibles of normal Wistar and diabetic Goto-Kakizaki rats for 3 and 9 weeks after implant insertion. Histochemical analysis confirmed a delay in bone healing around implants in diabetic animals. Immunohistochemical localization of peri-cellular staining for protein carbonyl groups, as a biomarker of oxidized protein content, was slightly higher in diabetic granulation tissue compared with normal tissue. However, no differences were observed in the staining patterns of advanced glycation end products. Minimal differences were observed in the number of cells positive for cytoplasmic superoxide dismutase (SOD)1 or mitochondrial SOD2. Significantly, catalase was absent in diabetic tissues. The results suggest that the oxidative environment in healing bone is differentially affected by hyperglycaemia, particularly in relation to catalase. The significance of these observations for diabetic bone healing is discussed.
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Affiliation(s)
- Rachel J Waddington
- Tissue Engineering and Reparative Dentistry, School of Dentistry, Cardiff University, Heath Park, Cardiff, UK.
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Kanwar YS, Sun L, Xie P, Liu FY, Chen S. A glimpse of various pathogenetic mechanisms of diabetic nephropathy. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2011; 6:395-423. [PMID: 21261520 DOI: 10.1146/annurev.pathol.4.110807.092150] [Citation(s) in RCA: 570] [Impact Index Per Article: 40.7] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Diabetic nephropathy is a well-known complication of diabetes and is a leading cause of chronic renal failure in the Western world. It is characterized by the accumulation of extracellular matrix in the glomerular and tubulointerstitial compartments and by the thickening and hyalinization of intrarenal vasculature. The various cellular events and signaling pathways activated during diabetic nephropathy may be similar in different cell types. Such cellular events include excessive channeling of glucose intermediaries into various metabolic pathways with generation of advanced glycation products, activation of protein kinase C, increased expression of transforming growth factor β and GTP-binding proteins, and generation of reactive oxygen species. In addition to these metabolic and biochemical derangements, changes in the intraglomerular hemodynamics, modulated in part by local activation of the renin-angiotensin system, compound the hyperglycemia-induced injury. Events involving various intersecting pathways occur in most cell types of the kidney.
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Affiliation(s)
- Yashpal S Kanwar
- Departments of Pathology, Northwestern University School of Medicine, Chicago, Illinois 60611, USA.
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