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Aluko EO, David UE, Ojetola AA, Fasanmade AA. Aqueous extract of Peristrophe bivalvis (L.) Merr. leaf reversed the detrimental effects of nitric oxide synthase inhibitor on blood lipid profile and glucose level. PLoS One 2024; 19:e0308338. [PMID: 39240961 PMCID: PMC11379291 DOI: 10.1371/journal.pone.0308338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 07/21/2024] [Indexed: 09/08/2024] Open
Abstract
There is evidence that nitric oxide (NO) modulates the metabolism of glucose and lipid, and some antihypertensive medications have been shown to affect glucose and lipid metabolism. Peristrophe bivalvis is a medicinal plant that has been shown to have antihypertensive properties. The study investigated the effect of aqueous extract of Peristrophe bivalvis leaf (APB) on fasting blood glucose level (FBG) and lipid profile in rats pretreated with nitro-L-arginine methyl ester (L-NAME). Male Wistar rats (150-170 g, n=30) were randomly divided into two groups: control (CT, n=5) and L-NAME pretreated (n=25). CT received 5 mL/kg of distilled water [DW]) while L-NAME pretreated group received 60 mg/kg of L-NAME (L-NAME60) for eight weeks. After eight weeks, the L-NAME pretreated group was randomly subdivided into L-NAME group (LN), L-NAME recovery group (LRE), L-NAME ramipril group (LRA), and L-NAME APB group (LAPB). The groups received L-NAME60+DW, DW, L-NAME60+10 mg/kg ramipril, and L-NAME60+APB (200 mg/kg), respectively, for five weeks. Serum NO, lipid profile, cyclic guanosine monophosphate (cGMP), and insulin were measured by spectrophotometry, assay kits, and ELISA, respectively. Data were analysed using ANOVA at p < 0.05. At the eighth week, a fall in FBG and an increase in triglyceride, total cholesterol, and low-density lipoprotein cholesterol were recorded in L8 compared to CT. The same effects were also noticed in the thirteenth week in LN. However, FBG was significantly increased and lipid levels were decreased in LAPB compared to LN. A significant increase was observed in cGMP level in LAPB compared to LN. The study showed that APB corrected the hyperlipidemia and hypoglycemia caused by L-NAME, and this effect might be via the activation of cGMP.
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Affiliation(s)
- Esther Oluwasola Aluko
- Physiology Department, Faculty of Basic Medical Sciences, University of Uyo, Uyo, Akwa-Ibom State, Nigeria
| | - Ubong Edem David
- Physiology Unit, Ajayi Crowther University, Oyo, Oyo State, Nigeria
| | - Abodunrin Adebayo Ojetola
- Department of Physiology, Faculty of Basic Medical Sciences, Adeleke University, Ede, Osun State, Nigeria
| | - Adesoji Adedipe Fasanmade
- Department of Physiology, Faculty of Basic Medical Sciences, University of Ibadan, Ibadan, Oyo State, Nigeria
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Oxidative stress in metabolic diseases: current scenario and therapeutic relevance. Mol Cell Biochem 2023; 478:185-196. [PMID: 35764861 DOI: 10.1007/s11010-022-04496-z] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 06/01/2022] [Indexed: 01/17/2023]
Abstract
The metabolic syndrome is a clustering condition of increased abdominal obesity in concert with hyperglycemia, insulin resistance, hypertension, and dyslipidemia. It confers higher risk of metabolic diseases such as diabetes and ischemic heart disease and has been observed to be associated with high morbidity and mortality. It is a progressive pathological process for diabetes-induced complications and appears to be multifactorial in origin. Several preclinical, clinical, and epidemiological reports have shown a persistent link between the metabolic syndrome and oxidative stress. There is pronounced imbalance between pro-oxidants and anti-oxidants with increased production of oxidizing molecules, depletion of anti-oxidants, and consequently accumulation of protein and lipid oxidation products in the cell in metabolic syndrome. The increased cellular pro-oxidant activity also results in altered molecular pathways, mitochondrial dysfunction, deregulation in cell cycle control, chromosomal aberrations, inflammation, and overall decreased biological activity as well as impairment of the antioxidant systems. Here, the focus of our review article will be on the formation of oxidative species, the interplay between metabolic syndrome and oxidative stress, and its potential implications in therapeutic approaches.
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El Okle OS, Tohamy HG, Althobaiti SA, Soliman MM, Ghamry HI, Farrag F, Shukry M. Ornipural® Mitigates Malathion-Induced Hepato-Renal Damage in Rats via Amelioration of Oxidative Stress Biomarkers, Restoration of Antioxidant Activity, and Attenuation of Inflammatory Response. Antioxidants (Basel) 2022; 11:antiox11040757. [PMID: 35453442 PMCID: PMC9031224 DOI: 10.3390/antiox11040757] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/07/2022] [Accepted: 04/08/2022] [Indexed: 02/01/2023] Open
Abstract
The current study was instigated by investigating the ameliorative potential of Ornipural® solution against the hepato-renal toxicity of malathion. A total number of 35 male Wistar albino rats were divided equally into five groups. Group 1 served as control and received normal saline intraperitoneally. Group 2, the sham group, were administered only corn oil (vehicle of malathion) orally. Group 3 was orally intoxicated by malathion in corn oil at a dose of 135 mg/kg BW via intra-gastric gavage. Group 4 received malathion orally concomitantly with Ornipural® intraperitoneally. Group 5 was given Ornipural® solution in saline via intraperitoneal injection at a dose of (1 mL/kg BW). Animals received the treatment regime for 30 days. Histopathological examination revealed the harmful effect of malathion on hepatic and renal tissue. The results showed that malathion induced a significant decrease in body weight and marked elevation in the activity of liver enzymes, LDH, and ACP. In contrast, the activity of AchE and Paraoxonase was markedly decreased. Moreover, there was a significant increase in the serum content of bilirubin, cholesterol, and kidney injury markers. A significant elevation in malondialdehyde, nitric oxide (nitrite), and 8-hydroxy-2-deoxyguanosine was observed, along with a substantial reduction in antioxidant activity. Furthermore, malathion increased tumor necrosis factor-alpha, the upregulation of IL-1B, BAX, and IFN-β genes, and the downregulation of Nrf2, Bcl2, and HO-1 genes. Concurrent administration of Ornipural® with malathion attenuated the detrimental impact of malathion through ameliorating metabolic biomarkers, restoring antioxidant activity, reducing the inflammatory response, and improving pathologic microscopic alterations. It could be concluded that Ornipural® solution demonstrates hepatorenal defensive impacts against malathion toxicity at biochemical, antioxidants, molecular, and cellular levels.
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Affiliation(s)
- Osama S. El Okle
- Departement of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Alexandria University, Alexandria 22758, Egypt;
| | - Hossam G. Tohamy
- Departement of Pathology, Faculty of Veterinary Medicine, Alexandria University, Alexandria 22758, Egypt;
| | - Saed A. Althobaiti
- Biology Department, Turabah University College, Taif University, Taif 21995, Saudi Arabia;
| | - Mohamed Mohamed Soliman
- Clinical Laboratory Sciences Department, Turabah University College, Taif University, Taif 21995, Saudi Arabia;
| | - Heba I. Ghamry
- Department of Home Economics, College of Home Economics, King Khalid University, P.O. Box 960, Abha 61421, Saudi Arabia;
| | - Foad Farrag
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt;
| | - Mustafa Shukry
- Department of Physiology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
- Correspondence:
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Cellular Crosstalk between Endothelial and Smooth Muscle Cells in Vascular Wall Remodeling. Int J Mol Sci 2021; 22:ijms22147284. [PMID: 34298897 PMCID: PMC8306829 DOI: 10.3390/ijms22147284] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/25/2021] [Accepted: 07/01/2021] [Indexed: 12/24/2022] Open
Abstract
Pathological vascular wall remodeling refers to the structural and functional changes of the vessel wall that occur in response to injury that eventually leads to cardiovascular disease (CVD). Vessel wall are composed of two major primary cells types, endothelial cells (EC) and vascular smooth muscle cells (VSMCs). The physiological communications between these two cell types (EC–VSMCs) are crucial in the development of the vasculature and in the homeostasis of mature vessels. Moreover, aberrant EC–VSMCs communication has been associated to the promotor of various disease states including vascular wall remodeling. Paracrine regulations by bioactive molecules, communication via direct contact (junctions) or information transfer via extracellular vesicles or extracellular matrix are main crosstalk mechanisms. Identification of the nature of this EC–VSMCs crosstalk may offer strategies to develop new insights for prevention and treatment of disease that curse with vascular remodeling. Here, we will review the molecular mechanisms underlying the interplay between EC and VSMCs. Additionally, we highlight the potential applicable methodologies of the co-culture systems to identify cellular and molecular mechanisms involved in pathological vascular wall remodeling, opening questions about the future research directions.
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Kohlhaas J, Jäger MA, Lust L, De La Torre C, Hecker M, Korff T. Endothelial cells control vascular smooth muscle cell cholesterol levels by regulating 24-dehydrocholesterol reductase expression. Exp Cell Res 2021; 399:112446. [PMID: 33422461 DOI: 10.1016/j.yexcr.2020.112446] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 11/24/2020] [Accepted: 12/15/2020] [Indexed: 10/22/2022]
Abstract
Communication of vascular cells is essential for the control of organotypic functions of blood vessels. In this context, vascular endothelial cells (EC) act as potent regulators of vascular smooth muscle cell (VSMC) functions such as contraction and relaxation. However, the impact of ECs on the gene expression pattern of VSMCs is largely unknown. Here, we investigated changes of the VSMC transcriptome by utilizing 3D human vascular organoids organized as a core of VSMCs enclosed by a monolayer of ECs. Microarray-based analyses indicated that interaction with ECs for 48 h down-regulates expression of genes in VSMCs controlling rate-limiting steps of the cholesterol biosynthesis such as HMGCR, HMGCS1, DHCR24 and DHCR7. Protein analyses revealed a decrease in the abundance of DHCR24 (24-dehydrocholesterol reductase) and lower cholesterol levels in VSMCs co-cultured with ECs. On the functional level, the blockade of the DHCR24 activity impaired adhesion, migration and proliferation of VSMCs. Collectively, these findings indicate that ECs have the capacity to instruct VSMCs to shut down the expression of DHCR24 thereby limiting their cholesterol biosynthesis, which may support their functional steady state.
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Affiliation(s)
- Johanna Kohlhaas
- Institute of Physiology and Pathophysiology, Department of Cardiovascular Physiology, Heidelberg University, Germany
| | - Marius Andreas Jäger
- Institute of Physiology and Pathophysiology, Department of Cardiovascular Physiology, Heidelberg University, Germany
| | - Leandra Lust
- Institute of Physiology and Pathophysiology, Department of Cardiovascular Physiology, Heidelberg University, Germany
| | - Carolina De La Torre
- Center of Medical Research, Medical Faculty Mannheim, Heidelberg University, Germany
| | - Markus Hecker
- Institute of Physiology and Pathophysiology, Department of Cardiovascular Physiology, Heidelberg University, Germany
| | - Thomas Korff
- Institute of Physiology and Pathophysiology, Department of Cardiovascular Physiology, Heidelberg University, Germany; European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Germany.
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Emerging role of microRNAs in ischemic stroke with comorbidities. Exp Neurol 2020; 331:113382. [DOI: 10.1016/j.expneurol.2020.113382] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 06/07/2020] [Accepted: 06/14/2020] [Indexed: 02/06/2023]
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Apostolova N, Iannantuoni F, Gruevska A, Muntane J, Rocha M, Victor VM. Mechanisms of action of metformin in type 2 diabetes: Effects on mitochondria and leukocyte-endothelium interactions. Redox Biol 2020; 34:101517. [PMID: 32535544 PMCID: PMC7296337 DOI: 10.1016/j.redox.2020.101517] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 03/13/2020] [Accepted: 03/20/2020] [Indexed: 12/12/2022] Open
Abstract
Type 2 diabetes (T2D) is a very prevalent, multisystemic, chronic metabolic disorder closely related to atherosclerosis and cardiovascular diseases. It is characterised by mitochondrial dysfunction and the presence of oxidative stress. Metformin is one of the safest and most effective anti-hyperglycaemic agents currently employed as first-line oral therapy for T2D. It has demonstrated additional beneficial effects, unrelated to its hypoglycaemic action, on weight loss and several diseases, such as cancer, cardiovascular disorders and metabolic diseases, including thyroid diseases. Despite the vast clinical experience gained over several decades of use, the mechanism of action of metformin is still not fully understood. This review provides an overview of the existing literature concerning the beneficial mitochondrial and vascular effects of metformin, which it exerts by diminishing oxidative stress and reducing leukocyte-endothelium interactions. Specifically, we describe the molecular mechanisms involved in metformin's effect on gluconeogenesis, its capacity to interfere with major metabolic pathways (AMPK and mTORC1), its action on mitochondria and its antioxidant effects. We also discuss potential targets for therapeutic intervention based on these molecular actions.
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Affiliation(s)
- Nadezda Apostolova
- Department of Pharmacology, University of Valencia - FISABIO (Foundation for the Promotion of Health and Biomedical Research in the Valencian Region), Valencia, Spain; CIBERehd (Biomedical Research Networking Centre on Hepatic and Digestive Diseases), Valencia, Spain.
| | - Francesca Iannantuoni
- Service of Endocrinology and Nutrition. University Hospital Doctor Peset, FISABIO, Valencia, Spain
| | - Aleksandra Gruevska
- Department of Pharmacology, University of Valencia - FISABIO (Foundation for the Promotion of Health and Biomedical Research in the Valencian Region), Valencia, Spain
| | - Jordi Muntane
- Institute of Biomedicine of Seville (IBiS), University Hospital "Virgen del Rocío"/CSIC/University of Seville, Seville, Spain
| | - Milagros Rocha
- CIBERehd (Biomedical Research Networking Centre on Hepatic and Digestive Diseases), Valencia, Spain; Service of Endocrinology and Nutrition. University Hospital Doctor Peset, FISABIO, Valencia, Spain
| | - Victor M Victor
- CIBERehd (Biomedical Research Networking Centre on Hepatic and Digestive Diseases), Valencia, Spain; Service of Endocrinology and Nutrition. University Hospital Doctor Peset, FISABIO, Valencia, Spain; Department of Physiology, University of Valencia, Valencia, Spain.
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Velagic A, Qin C, Woodman OL, Horowitz JD, Ritchie RH, Kemp-Harper BK. Nitroxyl: A Novel Strategy to Circumvent Diabetes Associated Impairments in Nitric Oxide Signaling. Front Pharmacol 2020; 11:727. [PMID: 32508651 PMCID: PMC7248192 DOI: 10.3389/fphar.2020.00727] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Accepted: 05/01/2020] [Indexed: 12/19/2022] Open
Abstract
Diabetes is associated with an increased mortality risk due to cardiovascular complications. Hyperglycemia-induced oxidative stress underlies these complications, leading to an impairment in endogenous nitric oxide (NO•) generation, together with reductions in NO• bioavailability and NO• responsiveness in the vasculature, platelets and myocardium. The latter impairment of responsiveness to NO•, termed NO• resistance, compromises the ability of traditional NO•-based therapeutics to improve hemodynamic status during diabetes-associated cardiovascular emergencies, such as acute myocardial infarction. Whilst a number of agents can ameliorate (e.g. angiotensin converting enzyme [ACE] inhibitors, perhexiline, statins and insulin) or circumvent (e.g. nitrite and sGC activators) NO• resistance, nitroxyl (HNO) donors offer a novel opportunity to circumvent NO• resistance in diabetes. With a suite of vasoprotective properties and an ability to enhance cardiac inotropic and lusitropic responses, coupled with preserved efficacy in the setting of oxidative stress, HNO donors have intact therapeutic potential in the face of diminished NO• signaling. This review explores the major mechanisms by which hyperglycemia-induced oxidative stress drives NO• resistance, and the therapeutic potential of HNO donors to circumvent this to treat cardiovascular complications in type 2 diabetes mellitus.
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Affiliation(s)
- Anida Velagic
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
- Central Clinical School, Monash University, Melbourne, VIC, Australia
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia
| | - Chengxue Qin
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
- Central Clinical School, Monash University, Melbourne, VIC, Australia
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia
| | - Owen L. Woodman
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia
| | - John D. Horowitz
- Basil Hetzel Institute, Queen Elizabeth Hospital, University of Adelaide, Adelaide, SA, Australia
| | - Rebecca H. Ritchie
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
- Central Clinical School, Monash University, Melbourne, VIC, Australia
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
| | - Barbara K. Kemp-Harper
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
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9
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de Macedo FHP, Aires RD, Fonseca EG, Ferreira RCM, Machado DPD, Chen L, Zhang FX, Souza IA, Lemos VS, Romero TRL, Moutal A, Khanna R, Zamponi GW, Cruz JS. TNF-α mediated upregulation of Na V1.7 currents in rat dorsal root ganglion neurons is independent of CRMP2 SUMOylation. Mol Brain 2019; 12:117. [PMID: 31888677 PMCID: PMC6937926 DOI: 10.1186/s13041-019-0538-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 12/17/2019] [Indexed: 12/24/2022] Open
Abstract
Clinical and preclinical studies have shown that patients with Diabetic Neuropathy Pain (DNP) present with increased tumor necrosis factor alpha (TNF-α) serum concentration, whereas studies with diabetic animals have shown that TNF-α induces an increase in NaV1.7 sodium channel expression. This is expected to result in sensitization of nociceptor neuron terminals, and therefore the development of DNP. For further study of this mechanism, dissociated dorsal root ganglion (DRG) neurons were exposed to TNF-α for 6 h, at a concentration equivalent to that measured in STZ-induced diabetic rats that developed hyperalgesia. Tetrodotoxin sensitive (TTXs), resistant (TTXr) and total sodium current was studied in these DRG neurons. Total sodium current was also studied in DRG neurons expressing the collapsin response mediator protein 2 (CRMP2) SUMO-incompetent mutant protein (CRMP2-K374A), which causes a significant reduction in NaV1.7 membrane cell expression levels. Our results show that TNF-α exposure increased the density of the total, TTXs and TTXr sodium current in DRG neurons. Furthermore, TNF-α shifted the steady state activation and inactivation curves of the total and TTXs sodium current. DRG neurons expressing the CRMP2-K374A mutant also exhibited total sodium current increases after exposure to TNF-α, indicating that these effects were independent of SUMOylation of CRMP2. In conclusion, TNF-α sensitizes DRG neurons via augmentation of whole cell sodium current. This may underlie the pronociceptive effects of TNF-α and suggests a molecular mechanism responsible for pain hypersensitivity in diabetic neuropathy patients.
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Affiliation(s)
| | - Rosária Dias Aires
- Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Esdras Guedes Fonseca
- Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | | | | | - Lina Chen
- Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital research Institute, University of Calgary, Calgary, Canada
| | - Fang-Xiong Zhang
- Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital research Institute, University of Calgary, Calgary, Canada
| | - Ivana A Souza
- Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital research Institute, University of Calgary, Calgary, Canada
| | - Virgínia Soares Lemos
- Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | | | - Aubin Moutal
- Department of Pharmacology, University of Arizona, Tucson, AZ, USA
| | - Rajesh Khanna
- Department of Pharmacology, University of Arizona, Tucson, AZ, USA
| | - Gerald W Zamponi
- Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital research Institute, University of Calgary, Calgary, Canada.
| | - Jader S Cruz
- Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Brazil.
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Wu J, Li X, Fang H, Yi Y, Chen D, Long Y, Gao X, Wei X, Chen CYO. Investigation of synergistic mechanism and identification of interaction site of aldose reductase with the combination of gigantol and syringic acid for prevention of diabetic cataract. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2016; 16:286. [PMID: 27520089 PMCID: PMC4983052 DOI: 10.1186/s12906-016-1251-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Accepted: 07/29/2016] [Indexed: 11/23/2022]
Abstract
BACKGROUND Gigantol and syringic acid (SA) have been shown to synergistically prevent formation of diabetic cataract (DC). However, the exact mechanism of this effect is unknown. Here, we investigate the effect of these compounds on the activity of aldose reductase (AR) and cataract formation. METHODS We examined the synergistic anti-cataract efficacy of gigantol and SA in the high glucose- and streptozotocin -induced DC rat model; synergism was evaluated using Jin's formula. We investigated possible mechanisms of action by measuring AR expression and activity and levels of sorbitol using enzyme kinetics, Western blot, and RT-PCR. Finally, we examined binding interaction between AR and both compounds using a combination of site-directed mutagenesis, recombinant expression of wild-type and mutant proteins, and enzyme kinetics. RESULTS Combination treatment of gigantol and SA synergistically protected both HLECs(human lens epithelial cells) grown in vitro and DC formation in STZ-induced rats in vivo. Synergism was attributed to inhibition of AR activity, downregulation of AR expression via impaired transcription, and decreased sorbitol levels. Enzyme kinetics studies showed that the activity of an AR Asn160Ala mutant protein was significantly decreased compared to wild-type AR, confirming that Asn160 is a key residue for interaction between AR and both compounds. CONCLUSION Combined administration of gigantol and SA synergize to enhance anti-cataract efficacy. The synergistic effect is mainly attributed to disruption of the polyol pathway and inhibition of AR activity.
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Affiliation(s)
- Jie Wu
- Department of Histology and Embryology, Guangzhou University of Chinese Medicine, 510006, Guangzhou, China
| | - Xue Li
- Department of Histology and Embryology, Guangzhou University of Chinese Medicine, 510006, Guangzhou, China
| | - Hua Fang
- Department of Histology and Embryology, Guangzhou University of Chinese Medicine, 510006, Guangzhou, China.
| | - Yanqun Yi
- Department of Histology and Embryology, Guangzhou University of Chinese Medicine, 510006, Guangzhou, China
| | - Dan Chen
- Department of Histology and Embryology, Guangzhou University of Chinese Medicine, 510006, Guangzhou, China
| | - Yan Long
- Department of Histology and Embryology, Guangzhou University of Chinese Medicine, 510006, Guangzhou, China
| | - Xinxin Gao
- Department of Histology and Embryology, Guangzhou University of Chinese Medicine, 510006, Guangzhou, China
| | - Xiaoyong Wei
- Department of Histology and Embryology, Guangzhou University of Chinese Medicine, 510006, Guangzhou, China.
- Antioxidants Research Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, 02111, Boston, MA, USA.
| | - C-Y Oliver Chen
- Antioxidants Research Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, 02111, Boston, MA, USA
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11
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Tangvarasittichai S. Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus. World J Diabetes 2015; 6:456-480. [PMID: 25897356 PMCID: PMC4398902 DOI: 10.4239/wjd.v6.i3.456] [Citation(s) in RCA: 751] [Impact Index Per Article: 75.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Revised: 11/21/2014] [Accepted: 01/12/2015] [Indexed: 02/05/2023] Open
Abstract
Oxidative stress is increased in metabolic syndrome and type 2 diabetes mellitus (T2DM) and this appears to underlie the development of cardiovascular disease, T2DM and diabetic complications. Increased oxidative stress appears to be a deleterious factor leading to insulin resistance, dyslipidemia, β-cell dysfunction, impaired glucose tolerance and ultimately leading to T2DM. Chronic oxidative stress, hyperglycemia and dyslipidemia are particularly dangerous for β-cells from lowest levels of antioxidant, have high oxidative energy requirements, decrease the gene expression of key β-cell genes and induce cell death. If β-cell functioning is impaired, it results in an under production of insulin, impairs glucose stimulated insulin secretion, fasting hyperglycemia and eventually the development of T2DM.
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12
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Matsuda M, Shimomura I. Increased oxidative stress in obesity: implications for metabolic syndrome, diabetes, hypertension, dyslipidemia, atherosclerosis, and cancer. Obes Res Clin Pract 2014; 7:e330-41. [PMID: 24455761 DOI: 10.1016/j.orcp.2013.05.004] [Citation(s) in RCA: 438] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Obesity, especially of the abdominal type, is a health problem that constitutes metabolic syndrome and increases the incidence of various diseases, including diabetes, hypertension, dyslipidemia, atherosclerosis, and cancer. Various mechanisms linking obesity to these associated diseases have been postulated. One candidate is oxidative stress, which has been implicated in vascular complications of diabetes and in pancreatic -cell failure in diabetes. Notably, obese people without diabetes also display elevated levels of systemic oxidative stress. In addition, levels of oxidative stress are increased in the adipose tissue in obese mice. Treating obese mice with antioxidant agents attenuates the development of diabetes. In 3T3-L1 adipocytes, increases in reactive oxygen species (ROS) occur with lipid accumulation; the addition of free fatty acids elevates ROS generation further. Thus, adipose tissue represents an important source of ROS; ROS may contribute to the development of obesity-associated insulin resistance and type 2 diabetes. Moreover, the levels of oxidative stress present in several other types of cells or tis-sues, including those in the brain, arterial walls, and tumors, have been implicated in the pathogenesis associated with hypertension, atherosclerosis, and cancer. The increased levels of systemic oxidative stress that occur in obesity may contribute to the obesity-associated development of these diseases.
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Antidiabetic Effects of Carassius auratus Complex Formula in High Fat Diet Combined Streptozotocin-Induced Diabetic Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2014; 2014:628473. [PMID: 24511320 PMCID: PMC3910437 DOI: 10.1155/2014/628473] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Accepted: 12/13/2013] [Indexed: 12/18/2022]
Abstract
Carassius auratus complex formula, including Carassius auratus, Rhizoma dioscoreae, Lycium chinense, and Rehmannia glutinosa Libosch, is a combination prescription of traditional Chinese medicine, which has always been used to treat diabetes mellitus in ancient China. In this study, we provided experimental evidence for the use of Carassius auratus complex formula in the treatment of high fat diet combined streptozotocin- (STZ-) induced type 2 diabetes. Carassius auratus complex formula aqueous extract was prepared and the effects of it on blood glucose, serum insulin, adipose tissue weight, oral glucose tolerance test (OGTT), total cholesterol, and triglyceride (TG) levels in mice were measured. Moreover, adiponectin, TG synthesis related gene expressions, and the inhibitory effect of aldose reductase (AR) were performed to evaluate its antidiabetic effects. After the 8-week treatment, blood glucose, insulin levels, and adipose tissue weight were significantly decreased. OGTT and HOMA-IR index showed improved glucose tolerance. It could also lower plasma TG, TC, and liver TG levels. Furthermore, Carassius auratus complex formula could inhibit the activity of AR and restore adiponectin expression in serum. Based on these findings, it is suggested that Carassius auratus complex formula possesses potent anti-diabetic effects on high fat diet combined STZ-induced diabetic mice.
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Cortez M, Singleton JR, Smith AG. Glucose intolerance, metabolic syndrome, and neuropathy. ACTA ACUST UNITED AC 2014; 126:109-22. [DOI: 10.1016/b978-0-444-53480-4.00009-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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15
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Lin S, Xu PC, Huang QE, Jia JY, Jia ZH, Wei L, Zheng ZF, Shang WY. Development of diabetic nephropathy in nude mice. J Endocrinol Invest 2013; 36:938-43. [PMID: 23666500 DOI: 10.3275/8962] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND Immune dysfunction is very common in diabetes mellitus (DM). However, there is no evidence whether such immune dysfunction can influence the development of DM, especially the development of diabetic nephropathy (DN). AIM To investigate the influence of absence of T cells on DN. MATERIALS AND METHODS Balb/c nude mice and Balb/c wild-type nude (WT) mice were injected with streptozotocin (STZ). Serum tumor necrosis factor α (TNF-α), blood glucose, body weight, urine albumin/creatinine ratio and rate of kidney weight to body weight (KW/BW) were measured. RESULTS After modeling, there was no difference of blood glucose level between nude mice and WT mice except at week 2 (28.3 ± 4.9 mmol/l vs 23.1 ± 3.9 mmol/l, p<0.01). At week 4, the serum TNF- α level of nude mice got to 175.08 ± 46.03 pg/ml (p<0.05, compared with baseline level 80.19 ± 8.46 pg/ml), whereas the TNF- α levels of WT mice was stable. At week 4, the body weight of nude mice was lower than that of WT mice (14.7 ± 3.15 g vs 17.97 ± 2.85 g, p<0.05); the urine albumin/creatinine ratio (Alb/Cr) of nude mice was higher than that of WT mice (50.96 ± 5.57 mg/mmol vs 41.09 ± 5.79 mg/mmol, p<0.05); the kidney weight to body weight of nude mice was higher than that of WT mice (0.01352 ± 0.00163 vs 0.01173 ± 0.00131, p<0.05). Correlation analysis showed urine Alb/Cr positively correlated with serum TNF-α level at week 4 (r = 0.588, p<0.01). At week 4, the increase of type IV collagen in the glomeruli was more prominent in diabetic nude mice than in diabetic WT mice (p<0.05). CONCLUSIONS Absence of T cells in DM might influence the development of DN.
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Affiliation(s)
- S Lin
- Department of Nephrology, General Hospital of Tianjin Medical University, Tianjin 300052, China.
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16
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Chatzopoulou M, Pegklidou K, Papastavrou N, Demopoulos VJ. Development of aldose reductase inhibitors for the treatment of inflammatory disorders. Expert Opin Drug Discov 2013; 8:1365-80. [PMID: 24090200 DOI: 10.1517/17460441.2013.843524] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Accumulating evidence attributes a significant role to aldose reductase (ALR2) in the pathogenesis of several inflammatory pathologies. Aldose reductase inhibitors (ARIs) were found to attenuate reactive oxygen species (ROS) production both in vitro and in vivo. Thus, they disrupt signaling cascades that lead to the production of cytokines/chemokines, which induce and exacerbate inflammation. As a result, ARIs might hold a significant therapeutic potential as alternate anti-inflammatory drugs. AREAS COVERED The authors present a comprehensive review of the current data that support the central role of ALR2 in several inflammatory pathologies (i.e., diabetes, cancer, sepsis, asthma and ocular inflammation). Further, the authors describe the potential underlying molecular mechanisms and provide a commentary on the status of ARIs in this field. EXPERT OPINION It is important that future efforts focus on delineating all the steps of the molecular mechanism that implicates ALR2 in inflammatory pathologies. At the same time, utilizing the previous efforts in the field of ARIs, several candidates that have been proven safe in the clinic may be evaluated for their clinical significance as anti-inflammatory medication. Finally, structurally novel ARIs, designed to target specifically the proinflammatory subpocket of ALR2, should be pursued.
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Affiliation(s)
- Maria Chatzopoulou
- Aristotle University of Thessaloniki, School of Pharmacy, Department of Pharmaceutical Chemistry , 54124 Thessaloniki , Greece ;
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17
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Huntjens B, Charman WN, Workman H, Hosking SL, O’Donnell C. Short-term stability in refractive status despite large fluctuations in glucose levels in diabetes mellitus type 1 and 2. PLoS One 2012; 7:e52947. [PMID: 23285232 PMCID: PMC3532445 DOI: 10.1371/journal.pone.0052947] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2012] [Accepted: 11/26/2012] [Indexed: 11/26/2022] Open
Abstract
PURPOSE This work investigates how short-term changes in blood glucose concentration affect the refractive components of the diabetic eye in patients with long-term Type 1 and Type 2 diabetes. METHODS Blood glucose concentration, refractive error components (mean spherical equivalent MSE, J0, J45), central corneal thickness (CCT), anterior chamber depth (ACD), crystalline lens thickness (LT), axial length (AL) and ocular aberrations were monitored at two-hourly intervals over a 12-hour period in: 20 T1DM patients (mean age ± SD) 38±14 years, baseline HbA1c 8.6±1.9%; 21 T2DM patients (mean age ± SD) 56±11 years, HbA1c 7.5±1.8%; and in 20 control subjects (mean age ± SD) 49±23 years, HbA1c 5.5±0.5%. The refractive and biometric results were compared with the corresponding changes in blood glucose concentration. RESULTS Blood glucose concentration at different times was found to vary significantly within (p<0.0005) and between groups (p<0.0005). However, the refractive error components and ocular aberrations were not found to alter significantly over the day in either the diabetic patients or the control subjects (p>0.05). Minor changes of marginal statistical or optical significance were observed in some biometric parameters. Similarly there were some marginally significant differences between the baseline biometric parameters of well-controlled and poorly-controlled diabetic subjects. CONCLUSION This work suggests that normal, short-term fluctuations (of up to about 6 mM/l on a timescale of a few hours) in the blood glucose levels of diabetics are not usually associated with acute changes in refractive error or ocular wavefront aberrations. It is therefore possible that factors other than refractive error fluctuations are sometimes responsible for the transient visual problems often reported by diabetic patients.
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Affiliation(s)
- Byki Huntjens
- Division of Optometry and Visual Science, City University London, London, United Kingdom
| | - W. Neil Charman
- Faculty of Life Sciences, The University of Manchester, London, United Kingdom
| | - Helena Workman
- School of Life and Health Sciences, Aston University, Birmingham, United Kingdom
| | - Sarah L. Hosking
- Division of Optometry and Visual Science, City University London, London, United Kingdom
- Department of Ophthalmology, University of Melbourne, Melbourne, Australia
| | - Clare O’Donnell
- Faculty of Life Sciences, The University of Manchester, London, United Kingdom
- School of Life and Health Sciences, Aston University, Birmingham, United Kingdom
- Optegra Eye Sciences, Manchester, United Kingdom
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18
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Sartini S, Cosconati S, Marinelli L, Barresi E, Di Maro S, Simorini F, Taliani S, Salerno S, Marini AM, Da Settimo F, Novellino E, La Motta C. Benzofuroxane Derivatives as Multi-Effective Agents for the Treatment of Cardiovascular Diabetic Complications. Synthesis, Functional Evaluation, and Molecular Modeling Studies. J Med Chem 2012; 55:10523-31. [DOI: 10.1021/jm301124s] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Stefania Sartini
- Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa,
Italy
| | - Sandro Cosconati
- Dipartimento Scienze e Tecnologie
Ambientali, Biologiche e Farmaceutiche, Seconda Università di Napoli, Via Vivaldi 43, 81100 Caserta, Italy
| | - Luciana Marinelli
- Dipartimento di Chimica
Farmaceutica
e Tossicologica, Università di Napoli “Federico II”, Via D. Montesano, 49, 80131 Napoli, Italy
| | - Elisabetta Barresi
- Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa,
Italy
| | - Salvatore Di Maro
- Dipartimento di Chimica
Farmaceutica
e Tossicologica, Università di Napoli “Federico II”, Via D. Montesano, 49, 80131 Napoli, Italy
| | - Francesca Simorini
- Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa,
Italy
| | - Sabrina Taliani
- Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa,
Italy
| | - Silvia Salerno
- Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa,
Italy
| | - Anna Maria Marini
- Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa,
Italy
| | - Federico Da Settimo
- Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa,
Italy
| | - Ettore Novellino
- Dipartimento di Chimica
Farmaceutica
e Tossicologica, Università di Napoli “Federico II”, Via D. Montesano, 49, 80131 Napoli, Italy
| | - Concettina La Motta
- Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa,
Italy
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Goodwill AG, Frisbee JC. Oxidant stress and skeletal muscle microvasculopathy in the metabolic syndrome. Vascul Pharmacol 2012; 57:150-9. [PMID: 22796585 DOI: 10.1016/j.vph.2012.07.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2012] [Revised: 06/19/2012] [Accepted: 07/04/2012] [Indexed: 01/22/2023]
Abstract
The evolution of the metabolic syndrome in afflicted individuals is, in part, characterized by the development of a severely pro-oxidant state within the vasculature. It has been previously demonstrated by many investigators that this increasingly pro-oxidant state can have severe negative implications for many relevant processes within the vasculature, including the coordination of dilator/constrictor tone or reactivity, the structural adaptations of the vascular wall or distal networks, as well as the integrated regulation of perfusion resistance across and throughout the vascular networks. The purpose of this review article is to present the different sources of oxidant stress within the setting of the metabolic syndrome, the available mechanism for attempts at regulation and the vascular outcomes associated with this condition. It is anticipated that this overview will help readers and investigators to more effectively design experiments and interpret their results within the extremely complicated setting of metabolic syndrome.
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Affiliation(s)
- Adam G Goodwill
- Department of Physiology and Pharmacology, West Virginia University School of Medicine, Morgantown, WV 26506, United States
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20
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Manna P, Sil PC. Arjunolic acid: beneficial role in type 1 diabetes and its associated organ pathophysiology. Free Radic Res 2012; 46:815-830. [PMID: 22486656 DOI: 10.3109/10715762.2012.683431] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
In this review article, we describe the most recent development of the beneficial effect of arjunolic acid (AA) in reducing type 1 diabetic pathophysiology. Diabetic mellitus is a serious and growing health problem worldwide. Increasing evidence suggest that oxidative stress plays a pivotal role in the pathogenesis of diabetes and its associated complications. Use of antioxidant supplements as a complimentary therapeutic approach in diabetes has, therefore, been seriously considered worldwide. AA, a natural pentacyclic triterpenoid saponin, is well known for various biological functions including antioxidant activity. It could prevent the increased production of ROS, RNS, AGEs, and the 8OHdG/2dG ratio and increase the intracellular antioxidant defence system. Signal transduction studies showed that AA could prevent hyperglycaemia induced activation of MAPKs, PKC, NF-κB signalling cascades and apoptotic cell death. Combining, AA supplements could be regarded as beneficial therapeutics in the treatment of diabetes and its associated complications.
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Affiliation(s)
- Prasenjit Manna
- Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, LA, USA
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21
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Kador PF, O'Meara JD, Blessing K, Marx DB, Reinhardt RA. Efficacy of Structurally Diverse Aldose Reductase Inhibitors on Experimental Periodontitis in Rats. J Periodontol 2011; 82:926-33. [DOI: 10.1902/jop.2010.100442] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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Abstract
Diabetes mellitus is one of the leading causes of death, and the majority of these deaths are associated with cardiovascular diseases. Development and progression of myocardial infarction leading to heart failure is much more complex and multifactorial in diabetics compared with non-diabetics. Despite significant advances in pharmacological interventions and surgical techniques, the disease progression leading to diabetic end-stage heart failure remains very high. Recently, cell therapy has gained much attention as an alternative approach to treat various heart diseases. However, transplanted stem cell studies in diabetic animal models are very limited. In this review, we discuss the pathogenesis of the diabetic infarcted heart and the potential of stem cell therapy to repair and regenerate.
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Khullar M, Al-Shudiefat AARS, Ludke A, Binepal G, Singal PK. Oxidative stress: a key contributor to diabetic cardiomyopathy. Can J Physiol Pharmacol 2011; 88:233-40. [PMID: 20393588 DOI: 10.1139/y10-016] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Diabetes and its associated complications are major known health disorders. Diabetes mellitus increases the risk of cardiovascular morbidity and mortality by promoting cardiomyopathy. It appears to arise as a result of the diabetic state, at times independent of vascular or valvular pathology. It manifests initially as asymptomatic diastolic dysfunction, which progresses to symptomatic heart failure. The compliance of the heart wall is decreased and contractile function is impaired. The pathophysiology of diabetic cardiomyopathy is incompletely understood but appears to be multifactorial in origin. Several hypotheses have been proposed, including oxidative stress, inflammation, endothelial dysfunction, metabolic derangements, abnormalities in ion homeostasis, alterations in structural proteins, and interstitial fibrosis. Amongst these various mechanisms, an increase in reactive oxygen species, leading to oxidative stress, has received significant experimental support. This review focuses on the role of oxidative stress in the pathogenesis of diabetic cardiomyopathy and the potential of antioxidant therapy.
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Affiliation(s)
- Madhu Khullar
- Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
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24
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Hattori T, Matsubara A, Taniguchi K, Ogura Y. Aldose reductase inhibitor fidarestat attenuates leukocyte-endothelial interactions in experimental diabetic rat retina in vivo. Curr Eye Res 2010; 35:146-54. [PMID: 20136425 DOI: 10.3109/02713680903447918] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE Dysregulation of the polyol pathway has been implicated as a major cause of diabetic retinopathy. The aldose reductase inhibitor fidarestat was recently reported to prevent retinal oxidative stress and overexpression of vascular endothelial growth factor (VEGF) protein in diabetic rats. In this study, we investigated the effect of fidarestat on leukocyte-endothelial cell interactions in an in vivo experimental model for diabetic retina. MATERIALS AND METHODS Diabetes was induced in six-week-old male Long-Evans rats by intraperitoneal injection of streptozotocin (STZ) (75 mg/kg). The rats were divided into four experimental groups: non-diabetic control rats, untreated diabetic rats, and diabetic rats treated with a low (4 mg/kg/day) or high (16 mg/kg/day) oral dose of fidarestat. After four weeks of treatment, accumulated leukocytes in the retina were counted in vivo by acridine orange digital fluorography. Intercellular adhesion molecule-1 (ICAM-1) and VEGF-164 mRNA levels in the retina were analyzed using the quantitative reverse transcription-polymerase chain reaction. ICAM-1 protein expression in the retina was investigated by immunohistochemistry. RESULTS Fidarestat treatment significantly decreased concentrations of sorbitol and fructose in the retinas of STZ-induced diabetic rats. Leukocyte accumulation in the retinas of fidarestat-treated rats was significantly less than in the untreated diabetic group (P < 0.01). Fidarestat treatment significantly reduced the expression ICAM-1 mRNA, but not VEGF-164 mRNA, in the retina of diabetic rats. Immunohistochemical study also revealed the suppressive effect of fidarestat on expression of ICAM-1. CONCLUSIONS Oral administration of fidarestat attenuated leukocyte accumulation in the retina of STZ induced-diabetic rats, suggesting that fidarestat may have a therapeutic role in preventing the progression of diabetic retinopathy.
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Affiliation(s)
- Tomoaki Hattori
- Department of Ophthalmology and Visual Sciences, Nagoya City University Graduate School of Medicine, 1 Kawasumi, Nagoya, Japan
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25
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Kim J, Kim CS, Sohn E, Kim H, Jeong IH, Kim JS. Lens epithelial cell apoptosis initiates diabetic cataractogenesis in the Zucker diabetic fatty rat. Graefes Arch Clin Exp Ophthalmol 2010; 248:811-8. [PMID: 20162295 DOI: 10.1007/s00417-010-1313-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2009] [Revised: 01/17/2010] [Accepted: 01/18/2010] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND It has been suggested that damage of lens epithelial cell (LEC) may play an important role in cataract formation. Nitric oxide is involved in cataract development. Here, we investigated the relationship between LEC damage and iNOS expression in the Zucker diabetic fatty (ZDF) rat. METHODS At 21 weeks of age, the eyes were enucleated and the lens opacity was then examined. Apoptosis were detected by TUNEL assay, and the expression of iNOS and NF-kappaB activation were studied by immunohistochemistry and southwestern histochemistry respectively. RESULTS In 21-week-old male ZDF rats, cataract was developed, TUNEL-positive LECs were markedly increased, and the expression levels of iNOS mRNA and protein were significantly upregulated. The expression pattern of iNOS was closely correlated with apoptotic change of LECs. In addition, advanced glycation end products (AGEs) were accumulated in cytoplasm of LECs. Activated NF-kappaB was mainly detected in nucleus of LECs. CONCLUSIONS The higher expressions of AGEs, NF-kappaB and iNOS in LECs of diabetic rats suggest that these factors are involved in apoptosis of LEC alterations related to diabetic cataract.
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Affiliation(s)
- Junghyun Kim
- Diabetic Complications Research Center, Division of Traditional Korean Medicine (TKM) Integrated Research, Korea Institute of Oriental Medicine, 483 Exporo, Yuseong-gu, Daejeon, 305-811, South Korea.
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Hill BG, Ramana KV, Cai J, Bhatnagar A, Srivastava SK. Measurement and identification of S-glutathiolated proteins. Methods Enzymol 2010; 473:179-97. [PMID: 20513478 DOI: 10.1016/s0076-6879(10)73009-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Protein thiol modifications occur under both physiological and pathological conditions and can regulate protein function, redox signaling, and cell viability. The thiolation of proteins by glutathione (GSH) appears to be a particularly important mode of posttranslational modification that is increased under conditions of oxidative or nitrosative stress. Modification of proteins by glutathiolation has been shown to affect the structure and function of several susceptible proteins and protect them from subsequent oxidative injury. In many cases, the glutathiolated proteins are low in abundance, and dethiolation occurs readily. Therefore, sensitive, reliable, and reproducible methods are required for measuring both the total levels of protein glutathiolation and for identifying glutathiolated proteins under given conditions. These methods necessitate the preservation or the controlled removal of the GSH adducts during sample preparation for the accurate measurement of total S-glutathiolation and for the identification of protein-GSH adducts. In this chapter, we briefly review and provide protocols for chemical, mass spectrometric, immunological, and radioactive tagging techniques, for measuring protein S-glutathiolation in cells and tissues.
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Affiliation(s)
- Bradford G Hill
- Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky, USA
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27
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Lin D, Harris R, Stutzman R, Zampighi GA, Davidson H, Takemoto DJ. Protein Kinase C-γ Activation in the Early Streptozotocin Diabetic Rat Lens. Curr Eye Res 2009; 32:523-32. [PMID: 17612968 DOI: 10.1080/02713680701418124] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
PURPOSE The purpose of this study is to demonstrate the early activation of the protein kinase C-gamma (PKC-gamma) pathway in the streptozotocin (STZ)-induced diabetic rat lens. METHODS Twelve-week-old male and female Sprague-Dawley rats were injected with 80 mg/kg (body weight) of STZ (N-[methylnitrosocarbamoyl]-D-glucosamine) intraperitoneally. Very high glucose (VHG) diabetes was defined as a nonfasting blood glucose level of at least 450 mg/dl, confirmed by daily monitoring with Accu-Check Advantage test strips, and occurred about 2 weeks after STZ administration. All assayed lenses were from VHG or age-matched control rats, harvested within 24 hr of VHG detection. PKC-gamma activation was measured by enzyme activity assay and by Western blotting to show autophosphorylation on Thr514. Cellular insulin-like growth factor-1 (IGF-1), PKC-gamma phosphorylation of Cx43 on Ser368, and activation of phospholipase C-gamma 1 (PLC-gamma 1), extracellular signal-regulated kinase (ERK1/2), and caspase-3 were determined by Western blotting. Endogenous diacylglycerol (DAG) levels were measured with a DAG assay kit. Lens gap junction activity was determined by the microinjection/Lucifer yellow dye transfer assay. Electron microscopy was applied to affirm fiber cell damage in the VHG diabetic lenses. RESULTS In the lenses of VHG diabetic rats, PKC-gamma enzyme was activated. PKC-gamma could be further activated by 400 nM phorbol-12-myristate-13-acetate (PMA), but the PKC-gamma protein levels remained constant. No elevation of IGF-1 level was observed. Western blots showed that activation of PKC-gamma may be due to activation of PLC-gamma 1, which synthesized endogenous DAG, a native PKC activator. The level of PKC-gamma -catalyzed phosphorylation of Cx43 on Ser368 and resulting inhibition of lens gap junction dye transfer activity was increased in the VHG diabetic lenses. At this early time period, the diabetic lens showed no activation of either caspase-3 or ERK1/2. Only a single fiber cell layer deep within the cortex (approximately 90 cell layers from capsule surface) showed vacuoles and damaged cell connections. CONCLUSIONS Early activation of PLC-gamma 1 and elevated DAG were observed within VHG diabetic lenses. These were correlated with activation of PKC-gamma, phosphorylation of Cx43 on Ser368, and inhibition of dye transfer. Abnormal signaling from PKC-gamma to Cx43 in the epithelial cells/early fiber cells, observed within VHG diabetic lenses, may be responsible for fiber cell damage deeper in the lens cortex.
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Affiliation(s)
- Dingbo Lin
- Department of Biochemistry, Kansas State University, Manhattan, Kansas 66506, USA
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Yousif MHM, Benter IF, Dunn KMJ, Dahly-Vernon AJ, Akhtar S, Roman RJ. Role of 20-hydroxyeicosatetraenoic acid in altering vascular reactivity in diabetes. ACTA ACUST UNITED AC 2009; 29:1-12. [PMID: 19302551 DOI: 10.1111/j.1474-8673.2009.00426.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
1 This study examined the role of 20-hydroxyeicosatetraenoic (20-HETE) in altering vascular function in streptozotocin (STZ)-induced diabetic rats. 2 The expression of CYP4A protein and the formation of 20-HETE were elevated in the kidney, but not in the renal or mesenteric vasculature, of diabetic animals. The vasoconstrictor responses to norepinephrine (NE), endothelin-1 (ET-1), and angiotensin II (Ang II) were significantly enhanced in the isolated perfused mesenteric vascular bed and renal artery segments of diabetic rats. Chronic treatment of the diabetic rats with 1-aminobenzotriazole (ABT, 50 mg kg(-1) alt(-1) diem) or N-hydroxy-N'-(4-butyl-2-methylphenyl) formamidine (HET0016, 2.5 mg kg(-1) day(-1)) attenuated the responses to these vasoconstrictors in both vascular beds. 3 The synthesis of 20-HETE in renal microsomes was reduced by >80% confirming that the doses of ABT and HET0016 were sufficient to achieve system blockade. Addition of HET0016 (1 microM) in vitro also normalized the enhanced vascular responsiveness of renal and mesenteric vessels obtained from diabetic animals to NE and inhibited the formation of 20-HETE by >90% while having no effect on the formation of epoxides. Vasodilator responses to carbachol and histamine were reduced in the mesenteric vasculature, but not in renal arteries, of diabetic rats. Treatment of the diabetic animals with HET0016 improved vasodilator responses in both vascular beds. Vascular sensitivity to exogenous 20-HETE was elevated in the mesenteric bed of diabetic animals compared to controls. 4 These results suggest that 20-HETE contributes to the elevation in vascular reactivity in diabetic animals. This effect is not due to increased vascular expression of CYP4A but may be related to either enhanced agonist-induced release of substrate (arachidonic acid) by the CaMKII/Ras-GTPase system and/or elevated vascular responsiveness to 20-HETE by the CaMKII/Ras-GTPase system and/or elevated vascular responsiveness to 20-HETE.
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Affiliation(s)
- M H M Yousif
- Department of Pharmacology & Toxicology, Kuwait University, Kuwait
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Baba SP, Wetzelberger K, Hoetker JD, Bhatnagar A. Posttranslational glutathiolation of aldose reductase (AKR1B1): a possible mechanism of protein recovery from S-nitrosylation. Chem Biol Interact 2009; 178:250-8. [PMID: 19061876 PMCID: PMC2929757 DOI: 10.1016/j.cbi.2008.11.007] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2008] [Revised: 11/06/2008] [Accepted: 11/07/2008] [Indexed: 11/26/2022]
Abstract
Nitric oxide (NO) is an important regulator of the catalytic activity of aldose reductase (AR). It reacts with the active site cysteines of AR and this reaction results in the formation of several kinetically distinct forms of the protein. The catalytic activity of AR is increased in the ischemic heart and this increase in activity is associated with NO-dependent modification of AR. During reperfusion, the enzyme reverts back to its un-activated form. Although, AR activation has been linked to thiol oxidation, the mechanisms of de-activation remain unclear. Here we report that treatment of recombinant human AR (AKR1B1) by a non-thiol-based NO-donor (DEANO) results in activation and S-nitrosylation of the protein. The nitrosylated (ARSNO), but not the reduced (ARSH), protein reacted with reduced glutathione (GSH) and this reaction resulted in the formation of glutathiolated AR (ARSSG). The modification of AR by NO was site-specific at Cys-298 and was not affected by selective mutation of the neighboring residue, Cys-303 to an alanine. Incubation of the glutathiolated AR (ARSSG) with GSH resulted in the regeneration of the reduced form of the protein (ARSH). Treatment of nitrosylated AR (ARSNO) with ascorbic acid also led to the conversion of the protein to its reduced form. These observations suggest that intracellular reductants such as GSH and ascorbate could convert the nitrosylated form of AR to its basal or reduced state. In general, such reductive reactions might represent a common mechanism for denitrosylating proteins or an "off" switch in NO-mediated signaling pathways involving protein S-nitrosylation reactions.
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Affiliation(s)
- Shahid Pervez Baba
- Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40202, United States
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30
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Reddy ABM, Ramana KV, Srivastava S, Bhatnagar A, Srivastava SK. Aldose reductase regulates high glucose-induced ectodomain shedding of tumor necrosis factor (TNF)-alpha via protein kinase C-delta and TNF-alpha converting enzyme in vascular smooth muscle cells. Endocrinology 2009; 150:63-74. [PMID: 18772236 PMCID: PMC2630901 DOI: 10.1210/en.2008-0677] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Chronic low-grade inflammation has emerged as a key contributor to the cardiovascular complications of diabetes, however, the mechanisms by which diabetes increases inflammation remain poorly understood. Here, we report that exposure to high glucose (HG) stimulates ectodomain shedding of TNF-alpha from rat aortic smooth muscle cells in culture. Our results show that exposure to HG decreases membrane-associated TNF-alpha. This decrease in unprocessed TNF-alpha was prevented by the aldose reductase (AR) inhibitor sorbinil and AR small interference RNA. Treatment with HG, but not equimolar mannitol or 3-O-methyl glucose, resulted in phosphorylation and activation of TNF-alpha converting enzyme (TACE) (ADAM17), which were attenuated by sorbinil or AR-specific small interference RNA. HG-induced TACE phosphorylation and TNF-alpha processing were also prevented by TNF-alpha protease inhibitor-1, an inhibitor of TACE. Inhibition of protein kinase C (PKC)-delta by rottlerin prevented HG-induced TACE activation and the accumulation of unprocessed TNF-alpha. Treatment with sorbinil decreased elevated levels of circulating TNF-alpha in streptozotocin-treated diabetic rats. Sorbinil treatment also decreased the expression of TNF-alpha, matrix metalloproteinase-2, matrix metalloproteinase-9, and increased tissue inhibitor of metalloproteinase-3 in vascular smooth muscle cells treated with HG and in balloon-injured carotid arteries of diabetic rats. These results indicate that HG-induced TNF-alpha shedding could be attributed to TACE activation, which is regulated, in part, by PKC-delta and AR. Therefore, inhibition of TACE by TNF-alpha protease inhibitor-1, or pharmacological inhibition of PKC-delta or AR may represent useful strategies for treating vascular inflammation associated with diabetes.
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Affiliation(s)
- Aramati B M Reddy
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555-0647, USA
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31
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Xiao T, Shoeb M, Siddiqui MS, Zhang M, Ramana KV, Srivastava SK, Vasiliou V, Ansari NH. Molecular cloning and oxidative modification of human lens ALDH1A1: implication in impaired detoxification of lipid aldehydes. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2009; 72:577-84. [PMID: 19296407 PMCID: PMC5645793 DOI: 10.1080/15287390802706371] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
Earlier studies showed that human lens ALDH1A1 plays a critical role in protection against oxidative stress-induced cytotoxicity in human lens epithelial cells (HLEC), and opacification of rat and mouse lens. The complete coding sequence of ALDH1A1 was cloned from human lens cDNA library by using PCR methods and expressed it in Escherichia coli. The cloned human lens ALDH1A1 cDNA encodes a 501-amino-acid protein (molecular mass = 54.8 kD) that is 100% identical to human liver ALDH1A1 and shares significant identity with the same isozyme from other tissues and species. The purified recombinant human lens ALDH1A1 exhibited optimal catalytic activity at pH 8 and preferred NAD(+) as cofactor and specifically catalyzed the oxidation of toxic lipid aldehydes such as 4-hydroxynonenal (HNE; K(m) = 4.8 microM) and malonaldehyde (K(m) MDA = 3.5 microM). Citral, disulfiram, and cyanamide were found to inhibit human lens ALDH1A1 at IC50 values of 55, 101, and 22610 microM, respectively, whereas diethylstilbestrol (DES) was found to be an activator (EC(50), 1.3 microM). Further, modification of recombinant human lens ALDH1A1 with nitric oxide donors such as S-nitroso-N-acetylpenicillamine (SNAP) and S-nitrosoglutathione (GSNO) significantly inhibited the enzyme activity. It therefore appears that activation of ALDH1A1, which efficiently catalyzes the detoxification of lipid-derived toxic aldehydes, and/or prevention of its oxidative modification may be novel therapeutic interventions against oxidative stress-induced lens pathologies.
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Affiliation(s)
- Tianlin Xiao
- Departments of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas
| | - Mohammad Shoeb
- Departments of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas
| | | | - Min Zhang
- Departments of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas
| | - Kota V. Ramana
- Departments of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas
| | - Satish K. Srivastava
- Departments of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas
| | - Vasilis Vasiliou
- Molecular Toxicology and Environmental Health Sciences Program, Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, Colorado, USA
| | - Naseem H. Ansari
- Departments of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas
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32
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Ochoa MC, Razquin C, Zalba G, Martínez-González MA, Martínez JA, Marti A. G allele of the -930A>G polymorphism of the CYBA gene is associated with insulin resistance in obese subjects. J Physiol Biochem 2008; 64:127-33. [PMID: 19043982 DOI: 10.1007/bf03168240] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
It has been shown that NADPH oxidase plays a role in oxidative stress which has been involved in the development of metabolic syndrome. The -930A/G polymorphism of the CYBA gene (that codes p22phox, a major component of the NADPH oxidase) has been associated with human hypertension and with a reduction in NADPH oxidase activity. In this work, we have examined the influence of the -930A/G polymorphism on obesity risk and insulin resistance in a case-control study of Spanish subjects (n=313). In the obese group (n=159), there was a statistically significant association between the GG genotype of the -930A/G polymorphism of the CYBA gene and fasting insulin levels and HOMA index. This outcome agrees with previous findings concerning functional analyses of this polymorphism and reinforces the hypothesis that insulin resistance is associated with oxidative stress. In conclusion, a protective effect in carriers of the -930A/G polymorphism of the p22phox gene against insulin resistance in a population of Spanish obese adults has been found.
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Affiliation(s)
- M C Ochoa
- Department of Nutrition, Food Science, Physiology and Toxicology, University of Navarra, Pamplona, Spain
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Disruption of the Nitric Oxide Signaling System in Diabetes. Cardiovasc Endocrinol 2008. [DOI: 10.1007/978-1-59745-141-3_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
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Narendra M, Kavitha G, Helah Kiranmai A, Raghava Rao N, Varadacharyulu NC. Chronic exposure to pyrethroid-based allethrin and prallethrin mosquito repellents alters plasma biochemical profile. CHEMOSPHERE 2008; 73:360-364. [PMID: 18657844 DOI: 10.1016/j.chemosphere.2008.05.070] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2007] [Revised: 04/13/2008] [Accepted: 05/27/2008] [Indexed: 05/26/2023]
Abstract
Continuous exposure of humans to pyrethroid-based mosquito repellents for longer durations may lead to adverse health effects. No information is available on long-term use of these mosquito repellents pertaining to the biochemical changes in human subjects. Therefore, the present study is an attempt to evaluate the status of health in human volunteers exposed to two commercially available mosquito repellent pyrethroids, allethrin and prallethrin, in terms of changes in plasma biochemical profile. Results of this study showed less but significant increase in the levels of plasma glucose, phospholipids, nitrite and nitrate, lipidperoxides with a decrease in plasma cholesterol. No significant changes were observed in the contents of total protein, albumin, globulin, HDL-C and LDL-C. However, SGPT activity increased significantly in persons exposed to only allethrin. Though the present investigation involving a limited number of human subjects indicates the onset of both protective changes as well as derangement in metabolism, a detailed and rigorous study is greatly warranted to arrive at a definite conclusion about the effects of pyrethroid mosquito repellents.
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Affiliation(s)
- M Narendra
- Department of Biochemistry, Sri Krishnadevaraya University, Anantapur 515 003, India
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35
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Grattagliano I, Palmieri VO, Portincasa P, Moschetta A, Palasciano G. Oxidative stress-induced risk factors associated with the metabolic syndrome: a unifying hypothesis. J Nutr Biochem 2008; 19:491-504. [PMID: 17855068 DOI: 10.1016/j.jnutbio.2007.06.011] [Citation(s) in RCA: 200] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2007] [Revised: 06/05/2007] [Accepted: 06/18/2007] [Indexed: 01/18/2023]
Abstract
Although the biochemical steps linking insulin resistance with the metabolic syndrome have not been completely clarified, mounting experimental and clinical evidence indicate oxidative stress as an attractive candidate for a central pathogenic role since it potentially explains the appearance of all risk factors and supports the clinical manifestations. In fact, metabolic syndrome patients exhibit activation of biochemical pathways leading to increased delivery of reactive oxygen species, decreased antioxidant protection and increased lipid peroxidation. The described associations between increased abdominal fat storage, liver steatosis and systemic oxidative stress, the diminished concentration of nitric oxide derivatives and antioxidant vitamins and the endothelial oxidative damages observed in subjects with the metabolic syndrome definitively support oxidative stress as the common second-level event in a unifying pathogenic view. Moreover, it has been observed that oxidative stress regulates the expression of genes governing lipid and glucose metabolism through activation or inhibition of intracellular sensors. Diet constituents can modulate redox reactions and the oxidative stress extent, thus also acting on nuclear gene expression. As a consequence of the food-gene interaction, metabolic syndrome patients may express different disease features and extents according to the different pathways activated by oxidative stress-modulated effectors. This view could also explain family differences and interethnic variations in determining risk factor appearance. This review mechanistically focused on oxidative stress events leading to individual disease factor appearance in metabolic syndrome patients and their setting for a more helpful clinical approach.
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Affiliation(s)
- Ignazio Grattagliano
- Department of Internal Medicine and Public Medicine, University Medical School of Bari, Clinica Medica "A. Murri," 70124 Bari, Italy
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36
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Wang N, Huang K, Zou H, Shi Y, Zhu J, Tang W, Xu X. No association found between the promoter variants of TNF-alpha and diabetic retinopathy in Chinese patients with type 2 diabetes. Curr Eye Res 2008; 33:377-83. [PMID: 18398712 DOI: 10.1080/02713680802008220] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
PURPOSE Necrosis tumor factor (TNF) is known to be associated with diabetic retinopathy (DR). The objective of this study was to examine the genetic variations of TNF-alpha and assess their possible relationship to DR in type 2 diabetic patients in the Chinese population. MATERIALS AND METHODS We conducted a case-control association study between the promoter variants of TNF-alpha and diabetic retinopathy in Chinese patients with type 2 diabetes. We selected three variants in the promoter region of TNF-alpha, namely rs1800629, rs1041981, and rs2857713. RESULTS No individual SNP nor any haplotype was found to be associated with DR in our study. CONCLUSION This is the first study to report TNF-alpha polymorphisms in patients with DR in the Chinese population. The results suggest that the variants among the promoter of TNF-alpha are unlikely to play a major role in the susceptibility to DR in Chinese patients with type 2 diabetes.
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Affiliation(s)
- N Wang
- Department of Ophthalmology, Shanghai Jiaotong University, Affiliated First People's Hospital, Shanghai, PR China
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37
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Kaiserova K, Tang XL, Srivastava S, Bhatnagar A. Role of nitric oxide in regulating aldose reductase activation in the ischemic heart. J Biol Chem 2008; 283:9101-12. [PMID: 18223294 PMCID: PMC2431016 DOI: 10.1074/jbc.m709671200] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2007] [Revised: 01/24/2008] [Indexed: 01/04/2023] Open
Abstract
Aldose reductase (AR) catalyzes the reduction of several aldehydes ranging from lipid peroxidation products to glucose. The activity of AR is increased in the ischemic heart due to oxidation of its cysteine residues, but the underlying mechanisms remain unclear. To examine signaling mechanisms regulating AR activation, we studied the role of nitric oxide (NO). Treatment with the NO synthase (NOS) inhibitor, N-nitro-l-arginine methyl ester prevented ischemia-induced AR activation and myocardial sorbitol accumulation in rat hearts subjected to global ischemia ex vivo or coronary ligation in situ, whereas inhibition of inducible NOS and neuronal NOS had no effect. Activation of AR in the ischemic heart was abolished by pretreatment with peroxynitrite scavengers hesperetin or 5, 10, 15, 20-tetrakis-[4-sulfonatophenyl]-porphyrinato-iron [III]. Site-directed mutagenesis and electrospray ionization mass spectrometry analyses showed that Cys-298 of AR was readily oxidized to sulfenic acid by peroxynitrite. Treatment with bradykinin and insulin led to a phosphatidylinositol 3-kinase (PI3K)-dependent increase in the phosphorylation of endothelial NOS at Ser-1177 and, even in the absence of ischemia, was sufficient in activating AR. Activation of AR by bradykinin and insulin was reversed upon reduction with dithiothreitol or by inhibiting NOS or PI3K. Treatment with AR inhibitors sorbinil or tolrestat reduced post-ischemic recovery in the rat hearts subjected to global ischemia and increased the infarct size when given before ischemia or upon reperfusion. These results suggest that AR is a cardioprotective protein and that its activation in the ischemic heart is due to peroxynitrite-mediated oxidation of Cys-298 to sulfenic acid via the PI3K/Akt/endothelial NOS pathway.
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Affiliation(s)
- Karin Kaiserova
- Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40202, USA
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38
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Barski OA, Tipparaju SM, Bhatnagar A. The aldo-keto reductase superfamily and its role in drug metabolism and detoxification. Drug Metab Rev 2008; 40:553-624. [PMID: 18949601 PMCID: PMC2663408 DOI: 10.1080/03602530802431439] [Citation(s) in RCA: 381] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The aldo-keto reductase (AKR) superfamily comprises enzymes that catalyze redox transformations involved in biosynthesis, intermediary metabolism, and detoxification. Substrates of AKRs include glucose, steroids, glycosylation end-products, lipid peroxidation products, and environmental pollutants. These proteins adopt a (beta/alpha)(8) barrel structural motif interrupted by a number of extraneous loops and helixes that vary between proteins and bring structural identity to individual families. The human AKR family differs from the rodent families. Due to their broad substrate specificity, AKRs play an important role in the phase II detoxification of a large number of pharmaceuticals, drugs, and xenobiotics.
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Affiliation(s)
- Oleg A Barski
- Division of Cardiology, Department of Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky 40202, USA.
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39
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Toth E, Racz A, Toth J, Kaminski PM, Wolin MS, Bagi Z, Koller A. Contribution of polyol pathway to arteriolar dysfunction in hyperglycemia. Role of oxidative stress, reduced NO, and enhanced PGH(2)/TXA(2) mediation. Am J Physiol Heart Circ Physiol 2007; 293:H3096-104. [PMID: 17873009 DOI: 10.1152/ajpheart.01335.2006] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Hyperglycemia increases glucose metabolism via the polyol pathway, which results in elevations of intracellular sorbitol concentration. Thus we hypothesized that elevated level of sorbitol contributes to the development of hyperglycemia-induced dysfunction of microvessels. In isolated, pressurized (80 mmHg) rat gracilis muscle arterioles (approximately 150 microm), high glucose treatment (25 mM) induced reduction in flow-dependent dilation (from maximum of 39 +/- 2% to 15 +/- 1%), which was significantly mitigated by an aldose reductase inhibitor, zopolrestat (maximum 27 +/- 2%). Increasing doses of sorbitol (10(-10)-10(-4) M) elicited dose-dependent constrictions (maximum 22 +/- 3%), which were abolished by endothelium removal, a prostaglandin H(2)/thromboxane A(2) (PGH(2)/TXA(2)) receptor (TP) antagonist SQ-29548, or superoxide dismutase (SOD) plus catalase (CAT). Incubation of arterioles with sorbitol (10(-7) M) reduced flow-dependent dilations (from maximum of 39 +/- 2% to 20 +/- 1.5%), which was not further affected by inhibition of nitric oxide synthase by N(omega)-nitro-l-arginine methyl ester but was prevented by SOD plus CAT and mitigated by SQ-29548. Nitric oxide donor sodium nitroprusside-induced (10(-9)-10(-6) M) dilations were also decreased in a SQ-29548 and SOD plus CAT-reversible manner, whereas adenosine dilations were not affected by sorbitol exposure. Sorbitol significantly increased arterial superoxide production detected by lucigenin-enhanced chemiluminescence, which was inhibited by SOD plus CAT. Sorbitol treatment also increased arterial formation of 3-nitrotyrosine. We suggest that hyperglycemia by elevating intracellular sorbitol induces oxidative stress, which interferes with nitric oxide bioavailability and promotes PGH(2)/TXA(2) release, both of which affect regulation of vasomotor responses of arterioles. Thus increased activity of the polyol pathway may contribute to the development of microvascular dysfunction in diabetes mellitus.
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Affiliation(s)
- Erika Toth
- Department of Physiology, Semmelweis University, Budapest, Hungary
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40
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Hasuike Y, Moriguchi R, Hata R, Miyagawa K, Kuragano T, Aizawa M, Yamamoto S, Yanase K, Izumi M, Tanimoto T, Nakanishi T. Role of aldose reductase in the peritoneal changes of patients undergoing peritoneal dialysis. Am J Nephrol 2007; 27:622-9. [PMID: 17851230 DOI: 10.1159/000108358] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2007] [Accepted: 08/06/2007] [Indexed: 11/19/2022]
Abstract
BACKGROUND/AIMS The mesothelium of patients undergoing peritoneal dialysis (PD) is exposed to glucose in dialysate. Glucose metabolites 3-deoxyglucosone and advanced glycation endproducts (AGEs) in the PD fluid induce peritoneal damage. Circulating factors also affect the peritoneum in the uremic model and predialysis patients. Aldose reductase (AR) generates precursors of 3-deoxyglucosone. We have reported AR acceleration in uremic patients. Therefore, AR acceleration might affect the peritoneum. The purpose of this study was to evaluate the AR level in PD patients and to determine the factors that change the peritoneum of these patients. METHODS We measured the PD effluent (eff-) concentration of cancer antigen 125 (CA125) as a marker of mesothelial viability in PD patients. Erythrocyte AR, eff-, and plasma (p-) concentrations of 3-deoxyglucosone, AGEs, and malondialdehyde were also studied in 30 PD patients, 18 patients undergoing hemodialysis, and 8 control subjects. RESULTS In the PD group, AR, p-3-deoxyglucosone, p-AGEs, and p-malondialdehyde were higher than in the control group. The predictors for eff-CA125 were not only PD duration and eff-3-deoxyglucosone, but also AR. CONCLUSION AR was upregulated in PD patients. AR acceleration may affect the peritoneum in these patients. Further studies are needed to clarify the role of AR in PD patients.
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Affiliation(s)
- Yukiko Hasuike
- Department of Nephrology and Dialysis, Hyogo College of Medicine, Hyogo, Japan.
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Rao AA, Thota H, Gumpeny RS, Akula A, Changalasetty SB, Challa SR, Ravavarapu T, Akula SP, Divakar C, Srinivas K, Das UN. Bioinformatics analysis of diabetic retinopathy using functional protein sequences. Med Hypotheses 2007; 70:148-55. [PMID: 17548166 DOI: 10.1016/j.mehy.2007.03.033] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2007] [Accepted: 03/06/2007] [Indexed: 01/08/2023]
Abstract
Diabetic retinopathy is the leading cause of blindness among patients with diabetes mellitus. We evaluated the role of several proteins that are likely to be involved in diabetic retinopathy by employing multiple sequence alignment using ClustalW tool and constructed a phylogram tree using functional protein sequences extracted from NCBI. Phylogram was constructed using Neighbor-Joining Algorithm in bioinformatics approach. It was observed that aldose reductase and nitric oxide synthase are closely associated with diabetic retinopathy. It is likely that vascular endothelial growth factor, pro-inflammatory cytokines, advanced glycation end products, and adhesion molecules that also play a role in diabetic retinopathy may do so by modulating the activities of aldose reductase and nitric oxide synthase. These results imply that methods designed to normalize aldose reductase and nitric oxide synthase activities could be of significant benefit in the prevention and treatment of diabetic retinopathy.
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Affiliation(s)
- Allam Appa Rao
- Department of Computer Science and Systems Engineering, Andhra University, Visakhapatnam 530 003, India.
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Benter IF, Yousif MHM, Cojocel C, Al-Maghrebi M, Diz DI. Angiotensin-(1-7) prevents diabetes-induced cardiovascular dysfunction. Am J Physiol Heart Circ Physiol 2007; 292:H666-72. [PMID: 17213482 DOI: 10.1152/ajpheart.00372.2006] [Citation(s) in RCA: 136] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The aim of this study was to test the hypothesis that treatment with angiotensin-(1-7) [ANG-(1-7)] or ANG-(1-7) nonpeptide analog AVE-0991 can produce protection against diabetes-induced cardiovascular dysfunction. We examined the influence of chronic treatment (4 wk) with ANG-(1-7) (576 microg.kg(-1).day(-1) ip) or AVE-0991 (576 microg.kg(-1).day(-1) ip) on proteinuria, vascular responsiveness of isolated carotid and renal artery ring segments and mesenteric bed to vasoactive agonists, and cardiac recovery from ischemia-reperfusion in streptozotocin-treated rats (diabetes). Animals were killed 4 wk after induction of diabetes and/or treatment with ANG-(1-7) or AVE-0991. There was a significant increase in urine protein (231 +/- 2 mg/24 h) in diabetic animals compared with controls (88 +/- 6 mg/24 h). Treatment of diabetic animals with ANG-(1-7) or AVE-0991 resulted in a significant reduction in urine protein compared with vehicle-treated diabetic animals (183 +/- 16 and 149 +/- 15 mg/24 h, respectively). Treatment with ANG-(1-7) or AVE-0991 also prevented the diabetes-induced abnormal vascular responsiveness to norepinephrine, endothelin-1, angiotensin II, carbachol, and histamine in the perfused mesenteric bed and isolated carotid and renal arteries. In isolated perfused hearts, recovery of left ventricular function from 40 min of global ischemia was significantly better in ANG-(1-7)- or AVE-0991-treated animals. These results suggest that activation of ANG-(1-7)-mediated signal transduction could be an important therapeutic strategy to reduce cardiovascular events in diabetic patients.
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Affiliation(s)
- Ibrahim F Benter
- Dept. of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, P. O. Box 24923, Safat 13110, Kuwait.
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Jiang Y, Calcutt NA, Ramos KM, Rames KM, Mizisin AP. Novel sites of aldose reductase immunolocalization in normal and streptozotocin-diabetic rats. J Peripher Nerv Syst 2007; 11:274-85. [PMID: 17117935 DOI: 10.1111/j.1529-8027.2006.00099.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Glucose metabolism by aldose reductase (AR) is implicated in the pathogenesis of many diabetic complications, including neuropathy. We have re-evaluated the distribution of AR in the sciatic nerve and dorsal root ganglion (DRG) of normal rats, expanded these observations to describe the location of AR in the spinal cord and footpad skin, and investigated whether diabetes alters the distribution of AR. In sciatic nerve, AR was restricted to cytoplasm of myelinated Schwann cells and endothelial cells of epineurial, but not endoneurial, blood vessels. AR immunoreactivity (IR) was present in satellite cells in the DRG. In skin, AR-IR was detected in vascular endothelial cells, Schwann cells of myelinated fibers, and axons of perivascular sympathetic nerves. AR was localized selectively to oligodendrocytes of the white matter of spinal cord. The distribution of AR-IR in sciatic nerve, DRG, skin, and spinal cord was not altered by up to 12 weeks of streptozotocin-induced diabetes. Identification of perineuronal satellite cells, oligodendrocytes, and perivascular sympathetic nerves as AR-expressing cells reveals them as cellular sites with the potential to contribute to diabetic neuropathy.
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Affiliation(s)
- Yun Jiang
- Department of Pathology (Neuropathology), School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
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Elgohary MA, Dowler JG. Incidence and risk factors of Nd:YAG capsulotomy after phacoemulsification in non-diabetic and diabetic patients. Clin Exp Ophthalmol 2006; 34:526-34. [PMID: 16925699 DOI: 10.1111/j.1442-9071.2006.01263.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE To estimate the cumulative incidence and identify the risk factors of posterior capsule opacification (PCO) that required Nd:YAG capsulotomy in non-diabetic and diabetic patients. METHODS Retrospective case-note review of 806 consecutive patients that underwent phacoemulsification and intraocular lens (IOL) implantation, 327 (40.6%) of whom were diabetic. RESULTS The cumulative incidence of Nd:YAG capsulotomy were 10.6%, 14.8%, 21.2% and 28.6% in non-diabetic patients; and 9%, 9.4%, 15.3% and 5.3% in diabetic patients after 1, 2, 3 and 4 years, respectively. A multivariate Cox regression analysis showed that, over the follow-up period, diabetes mellitus was associated with a decreased risk of Nd:YAG capsulotomy (hazard ratio [HR]=0.69; 95% confidence interval [CI] 0.47-0.99; P=0.047), whereas age of 65 years or younger (HR=1.58; 95% CI 1.09-2.27; P=0.02), polymethylmethacrylate (PMMA) (HR=3.98; 95% CI 1.60-9.95; P=0.003) or plate-haptic silicone IOLs (HR=3.75; 95% CI 1.60-8.80; P=0.002) in comparison with three-piece silicone IOLs, postoperative inflammation (HR=2.62; 95% CI 1.56-4.42; P<0.001) and pars plana vitrectomy (HR=1.85; 95% CI 1.20-2.83; P=0.005) were associated with an increased risk. Subgroup analysis showed that in non-diabetic patients, male gender (HR=1.63; 95% CI 1.04-2.57; P=0.03) was an additional risk factor and in diabetic patients there was no significant association between diabetes type, duration or retinopathy grade and the risk of Nd:YAG capsulotomy. CONCLUSION Although diabetes mellitus appears to be associated with a lower long-term incidence and a decreased risk of Nd:YAG capsulotomy, younger age, pars plana vitrectomy, postoperative inflammation, plate-haptic silicone and PMMA IOLs in addition to male gender in non-diabetic patients appear to be associated with a greater risk. Estimation of the incidence and risk factors of PCO should help in patient counselling and to design methods to reduce or prevent its development.
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Affiliation(s)
- Mostafa A Elgohary
- Medical Retina Service, Moorfields Eye Hospital, London, UK, and Tanta Ophthalmology University Hospital, Egypt.
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Dragomir E, Simionescu M. Monocyte chemoattractant protein-1--a major contributor to the inflammatory process associated with diabetes. Arch Physiol Biochem 2006; 112:239-44. [PMID: 17178597 DOI: 10.1080/13813450601094672] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
There is evidence that strongly suggests that inflammation plays an important role in diabetes and cardiovascular diseases. The high glucose-induced inflammatory process is characterised by the cooperation of a complex network of inflammatory molecules such as cytokines, adhesion molecules, growth factors, and chemokines. Among the chemokine family, monocyte chemoattractant protein (MCP-1) is a potent chemotactic factor, which is upregulated at sites of inflammation being in control of leukocytes trafficking. Here, we review the current knowledge on MCP-1 and its regulation by high glucose level in vascular cells involved in diabetes-induced accelerated atherosclerosis. The signalling pathways involved in MCP-1 modulation by high glucose, the proximal signalling events that stimulate downstream effects and the role of this chemokine in the pathophysiology of diabetes and its complications, are discussed.
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Affiliation(s)
- Elena Dragomir
- Institute of Cellular Biology and Pathology Nicolae Simionescu, Bucharest, Romania.
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Yousif MHM. Signal transduction through Ras-GTPase and Ca2+/ calmodulin-dependent protein kinase II contributes to development of diabetes-induced renal vascular dysfunction. Cell Biochem Funct 2006; 24:299-305. [PMID: 16287213 DOI: 10.1002/cbf.1301] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
This study examined the role of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and Ras-GTPase in the development of abnormal reactivity to vasoactive agents in the renal artery of diabetic rats. The vasoconstrictor response induced by norepinephrine (NE), endothelin-1 (ET-1) or angiotensin II (Ang II) was significantly increased whereas vasodilator response to carbachol, histamine or sodium nitroprusside (SNP) was not altered in the renal artery segments of the streptozotocin (STZ)-diabetic rats. Chronic intraperitoneal administration of KN-93 (5 mg/kg/ alt diem), an inhibitor of CaMKII or FPTIII (1.5 mg/kg/ alt diem), an inhibitor of Ras-GTPase, produced significant normalization of the altered agonist-induced vasoconstrictor responses without affecting blood glucose levels. All the inhibitors were administered for four weeks starting from day one of diabetes induction. Inhibition of Ras-GTPase or CaMKII did not affect the agonist-induced vasoconstrictor and vasodilator responses in the non-diabetic control animals. These data suggest that inhibition of signal transduction involving CaMKII and Ras-GTPase can prevent development of diabetes-induced abnormal vascular reactivity in the renal artery.
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Affiliation(s)
- Mariam H M Yousif
- Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, P. O. Box: 24923, Safat 13110, Kuwait.
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Balducci S, Iacobellis G, Parisi L, Di Biase N, Calandriello E, Leonetti F, Fallucca F. Exercise training can modify the natural history of diabetic peripheral neuropathy. J Diabetes Complications 2006; 20:216-23. [PMID: 16798472 DOI: 10.1016/j.jdiacomp.2005.07.005] [Citation(s) in RCA: 255] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2004] [Revised: 02/25/2005] [Accepted: 07/05/2005] [Indexed: 12/11/2022]
Abstract
BACKGROUND Diabetes is the most important cause of peripheral neuropathy (DPN). No definitive treatment for DPN has been established, and very few data on the role of exercise training on DPN have been reported. AIM OF THE STUDY We sought to examine the effects of long-term exercise training on the development of DPN in both Types 1 and 2 diabetic patients. PARTICIPANTS AND METHODS Seventy-eight diabetic patients without signs and symptoms of peripheral DPN were enrolled, randomized, and subdivided in two groups: 31 diabetic participants [15 f, 16 m; 49+/-15.5 years old; body mass index (BMI)=27.9+/-4.7], who performed a prescribed and supervised 4 h/week brisk walking on a treadmill at 50% to 85% of the heart rate reserve (exercise group: EXE), and a control group of 47 diabetic participants (CON; 24 f, 23 m; 52.9+/-13.4 years old; BMI=30.9+/-8.4). Vibration perception threshold (VPT), nerve distal latency (DL), nerve conduction velocity (NCV), and nerve action potential amplitude (NAPA) in the lower limbs were measured. RESULTS We found significant differences on Delta (delta) in NCV for both peroneal and sural motor nerve between the EXE and CON groups during the study period (P<.001, for both). The percentage of diabetic patients that developed motor neuropathy and sensory neuropathy during the 4 years of the study was significantly higher in the CON than the EXE group (17% vs. 0.0%, P<.05, and 29.8% vs. 6.45%, P<.05, respectively). In addition, the percentage of diabetic patients who developed increased VPT (25 V) during the study was significantly higher in the CON than the EXE group (21.3% vs. 12.9%, P<.05). Change on Hallux VPT from baseline to the end of the study was significantly different between the EXE and CON groups (P<.05); no significant change in Malleolus VPT between the two groups occurred. CONCLUSIONS This study suggests, for the first time, that long-term aerobic exercise training can prevent the onset or modify the natural history of DPN.
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Affiliation(s)
- Stefano Balducci
- Health Care Team, Metabolic Fitness Association, Monterotondo, Rome, Italy
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West MB, Hill BG, Xuan YT, Bhatnagar A. Protein glutathiolation by nitric oxide: an intracellular mechanism regulating redox protein modification. FASEB J 2006; 20:1715-7. [PMID: 16809435 DOI: 10.1096/fj.06-5843fje] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
This study was designed to examine whether NO regulates protein glutathiolation. Exposure to NO donors increased protein glutathiolation in COS-7 or rat aortic smooth muscle cells as detected by anti-protein glutathione (GSH) antibodies. This process was reversible and saturable. Stimulation with acetylcholine (ACh) increased protein glutathiolation in isolated rat aortic rings. This was prevented by inhibiting endothelial NO synthase (eNOS). In ACh-treated rings, proteins showing positive immunoreactivity with the anti-PSSG antibody (Ab) were identified by matrix assisted laser desorption-time-of-flight mass spectrometry to be actin, vimentin, and heat shock protein 70. Purified actin was more readily glutathiolated by S-nitrosoglutathione than by oxidized GSH as determined by electrospray-ionization mass spectrometry, and nitrosylated actin was glutathiolated by reduced GSH. Relative to wild-type (WT) mice, increased protein glutathiolation was observed in hearts of mice with cardiac-specific expression of inducible NO synthase (iNOS). Proteins immunoprecipitated from transgenic hearts revealed GSH-adducted peptides corresponding to adenine nucleotide translocator and the alpha-subunit of F1F0ATPase. These data suggest that exogenous NO or NO generated by eNOS or iNOS regulates protein adduction with GSH. This could be due to a direct reaction of proteins with S-nitrosoglutathione or denitrosylation of S-nitrosylated proteins by reduced GSH. Glutathiolation of cytoskeletal and mitochondrial proteins may be a significant feature of NO bioreactivity.
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Affiliation(s)
- Matthew B West
- Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, Kentucky 40202, USA
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Kaiserova K, Srivastava S, Hoetker JD, Awe SO, Tang XL, Cai J, Bhatnagar A. Redox Activation of Aldose Reductase in the Ischemic Heart. J Biol Chem 2006; 281:15110-20. [PMID: 16567803 DOI: 10.1074/jbc.m600837200] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Aldose reductase (AR) reduces cytotoxic aldehydes and glutathione conjugates of aldehydes derived from lipid peroxidation. Its inhibition has been shown to increase oxidative injury and abolish the late phase of ischemic preconditioning. However, the mechanisms by which ischemia regulates AR activity remain unclear. Herein, we report that rat hearts subjected to ischemia, in situ or ex vivo, display a 2-4-fold increase in AR activity. The AR activity was not further enhanced by reperfusion. Activation increased Vmax of the enzyme without affecting the Km and decreased the sensitivity of the enzyme to inhibition by sorbinil. Enzyme activation could be prevented by pretreating the hearts with the radical scavenging thiol, N-(2-mercaptoproprionyl)glycine or the superoxide dismutase mimetic, Tiron, or by treating homogenates with dithiothreitol. In vitro, the recombinant enzyme was activated upon treatment with H2O2 and the activated, but not the native enzyme, formed a covalent adduct with the sulfenic acid-specific reagent dimedone. The enzyme activity in the ischemic, but not the nonischemic heart homogenates was inhibited by dimedone. Separation of proteins from hearts subjected to coronary occlusion by two-dimensional electrophoresis and subsequent matrix-assisted laser desorption ionization time-of-flight/mass spectrometry analysis revealed the formation of sulfenic acids at Cys-298 and Cys-303. These data indicate that reactive oxygen species formed in the ischemic heart activate AR by modifying its cysteine residues to sulfenic acids.
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Affiliation(s)
- Karin Kaiserova
- Institute of Molecular Cardiology, Department of Physiology and Biophysics, University of Louisville, Louisville, Kentucky 40202, USA
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Jay D, Hitomi H, Griendling KK. Oxidative stress and diabetic cardiovascular complications. Free Radic Biol Med 2006; 40:183-92. [PMID: 16413400 DOI: 10.1016/j.freeradbiomed.2005.06.018] [Citation(s) in RCA: 332] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2005] [Accepted: 06/15/2005] [Indexed: 02/07/2023]
Abstract
Diabetes diagnoses are increasing at an alarming rate worldwide. The majority of diabetes-related deaths arise from cardiovascular complications such as myocardial infarction, stroke, and peripheral vascular disease. Oxidative stress has been demonstrated to be present in animal models as well as in patients with diabetes and has been suggested as a possible contributor to the accelerated atherosclerosis seen in diabetics. The generation of reactive oxygen species in diabetes occurs via several mechanisms and is initiated not only by glucose, but also by other substances that are found at elevated levels in diabetic patients. The resulting oxidative stress leads to a number of proatherogenic events. The elucidation of the mechanisms of oxidative stress in diabetes and their relationship with atherosclerosis could potentially identify molecular targets of therapy for this condition and its cardiovascular consequences.
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Affiliation(s)
- Desmond Jay
- Department of Medicine, Division of Cardiology, Emory University, Atlanta, GA 30322, USA
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