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Bibha K, Akhigbe TM, Hamed MA, Akhigbe RE. Metabolic Derangement by Arsenic: a Review of the Mechanisms. Biol Trace Elem Res 2024; 202:1972-1982. [PMID: 37670201 DOI: 10.1007/s12011-023-03828-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 08/21/2023] [Indexed: 09/07/2023]
Abstract
Studies have implicated arsenic exposure in various pathological conditions, including metabolic disorders, which have become a global phenomenon, affecting developed, developing, and under-developed nations. Despite the huge risks associated with arsenic exposure, humans remain constantly exposed to it, especially through the consumption of contaminated water and food. This present study provides an in-depth insight into the mechanistic pathways involved in the metabolic derangement by arsenic. Compelling pieces of evidence demonstrate that arsenic induces metabolic disorders via multiple pathways. Apart from the initiation of oxidative stress and inflammation, arsenic prevents the phosphorylation of Akt at Ser473 and Thr308, leading to the inhibition of PDK-1/Akt insulin signaling, thereby reducing GLUT4 translocation through the activation of Nrf2. Also, arsenic downregulates mitochondrial deacetylase Sirt3, decreasing the ability of its associated transcription factor, FOXO3a, to bind to the agents that support the genes for manganese superoxide dismutase and PPARg co-activator (PGC)-1a. In addition, arsenic activates MAPKs, modulates p53/ Bcl-2 signaling, suppresses Mdm-2 and PARP, activates NLRP3 inflammasome and caspase-mediated apoptosis, and induces ER stress, and ox-mtDNA-dependent mitophagy and autophagy. More so, arsenic alters lipid metabolism by decreasing the presence of 3-hydroxy-e-methylglutaryl-CoA synthase 1 and carnitine O-octanoyl transferase (Crot) and increasing the presence of fatty acid-binding protein-3 mRNA. Furthermore, arsenic promotes atherosclerosis by inducing endothelial damage. This cascade of pathophysiological events promotes metabolic derangement. Although the pieces of evidence provided by this study are convincing, future studies evaluating the involvement of other likely mechanisms are important. Also, epidemiological studies might be necessary for the translation of most of the findings in animal models to humans.
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Affiliation(s)
- K Bibha
- Department of Zoology, Magadh Mahila College, Patna University, Patna, India
| | - T M Akhigbe
- Breeding and Plant Genetics Unit, Department of Agronomy, Osun State University, Osogbo, Osun State, Nigeria
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Osun State, Nigeria
| | - M A Hamed
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Osun State, Nigeria
- Department of Medical Laboratory Science, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria
- The Brainwill Laboratory, Osogbo, Osun State, Nigeria
| | - R E Akhigbe
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Osun State, Nigeria.
- Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Ladoke Akintola University of Technology, Ogbomosho, Oyo State, Nigeria.
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Zhang Q, Xiao X, Li M, Yu M, Ping F. Bailing capsule (Cordyceps sinensis) ameliorates renal triglyceride accumulation through the PPARα pathway in diabetic rats. Front Pharmacol 2022; 13:915592. [PMID: 36091833 PMCID: PMC9453879 DOI: 10.3389/fphar.2022.915592] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
Diabetic nephropathy (DN) is a severe diabetic complication of the kidney and is the main cause of end-stage kidney disease worldwide. Cordyceps sinensis (C. sinensis) is not only a traditional Chinese medicine (TCM) but also a healthy food. In China, C. sinensis has been widely used to treat various kidney diseases. Bailing Capsule, which active ingredient is C. sinensis, is approved to treat kidney disease, respiratory disease, and immune disease. However, its underlying mechanism in DN remains unclear. The purpose of the present study was to investigate the underlying mechanism of Bailing Capsule on kidney in diabetic rats. The DN model was established by streptozotocin (STZ) injection. Low and high doses of Bailing Capsule were orally administrated for 12 weeks after diabetes induction. Renal function was evaluated by serum creatinine, blood urea nitrogen, 24-h urinary protein, and urinary albumin. Mesangial matrix expansion and renal fibrosis were measured using histopathology staining. We found that the disorder of renal function and pathology in DN rats was significantly modified by Bailing Capsule treatment. Consistently, Bailing Capsule markedly alleviated DN rat glomerulosclerosis, tubulointerstitial injury and renal fibrosis as shown by pathological staining. Moreover, Bailing Capsule significantly reduced the kidney triglyceride content and renal lipid droplet formation in DN rats. The renal transcriptome revealed that Bailing Capsule-treated kidneys had 498 upregulated genes and 448 downregulated genes. These differentially expressed genes were enriched in the peroxisome proliferator activated receptor (PPAR) pathway and fatty acid metabolism function ontology. mRNA and protein expression analyses revealed substantial enhancement of the lipolysis pathway and inhibition of lipogenesis in Bailing Capsule-treated rat kidneys compared to DN rats. Bailing Capsule activated the expression of PPARα, ACOX1 (acyl-CoA oxidase 1), and SCD (stearoyl-CoA desaturase) in diabetic nephropathy while suppressing the expression of FASN (fatty acid synthase). In conclusion, Bailing Capsule could attenuate renal triglyceride accumulation in diabetic rats by moderating PPARα pathway.
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Makarchikov AF, Kudyrka TG, Luchko TA, Yantsevich AV, Rusina IM, Makar AA, Kolas IK, Usanov SA. Synthesis, physico-chemical properties and effect of adenosine thiamine triphosphate on vitamin B 1 metabolism in the liver of alloxan diabetic rats. Biochim Biophys Acta Gen Subj 2022; 1866:130086. [PMID: 35016976 DOI: 10.1016/j.bbagen.2022.130086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 12/23/2021] [Accepted: 01/05/2022] [Indexed: 10/19/2022]
Abstract
BACKGROUND Adenosine thiamine triphosphate (AThTP) is a nucleotide discovered in bacteria and some other living organisms more than a decade ago. No biochemical function for AThTP has been established yet, however, experimental data available indicate its possible involvement in metabolic regulation or cell signaling. Metabolism of AThTP in mammals, as well as the feasibility of its pharmacological application, is essentially unstudied. METHODS Preparative low-pressure chromatography was employed to purify chemically synthesized AThTP with its further analysis by mass spectrometry, HPLC, UV and fluorescence spectroscopy. Enzyme activity assays along with HPLC were used to examine the effects of AThTP and thiamine on vitamin B1 metabolism in the liver of alloxan-induced diabetic rats. RESULTS An improved procedure for AThTP synthesis and purification is elaborated. Solution stability, optical spectral properties and the molar absorption coefficient for AThTP were determined. The levels of thiamine compounds were found to be increased in the liver of diabetic rats. Neither AThTP nor thiamine treatment affected hepatic vitamin B1 metabolism. Fasting blood glucose concentration was also unchangeable after AThTP or thiamine administration. GENERAL SIGNIFICANCE Contrast to the widespread view about thiamine deficiency in diabetes, our results clearly shows an adaptive increase in the level of B1 vitamers in the liver of alloxan diabetic rats with no further rising after AThTP or thiamine treatment at a moderate dose. Neither AThTP nor thiamine is effective in glycaemic control. These findings are to be considered in future studies dealing with thiamine or its analogues application to correct metabolic disturbances in diabetes.
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Affiliation(s)
- Alexander F Makarchikov
- Grodno State Agrarian University, 28 Tereshkova St., Grodno 230008, Belarus; Institute of Biochemistry of Biologically Active Compounds, National Academy of Sciences of Belarus, 50 BLK, Grodno 230030, Belarus.
| | - Tatsiana G Kudyrka
- Grodno State Agrarian University, 28 Tereshkova St., Grodno 230008, Belarus; Institute of Biochemistry of Biologically Active Compounds, National Academy of Sciences of Belarus, 50 BLK, Grodno 230030, Belarus
| | - Tatyana A Luchko
- Institute of Biochemistry of Biologically Active Compounds, National Academy of Sciences of Belarus, 50 BLK, Grodno 230030, Belarus
| | - Aliaksei V Yantsevich
- Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, 5/2 Kuprevicha St., Minsk 220141, Belarus
| | - Iryna M Rusina
- Grodno State Agrarian University, 28 Tereshkova St., Grodno 230008, Belarus; Institute of Biochemistry of Biologically Active Compounds, National Academy of Sciences of Belarus, 50 BLK, Grodno 230030, Belarus
| | - Alena A Makar
- Institute of Biochemistry of Biologically Active Compounds, National Academy of Sciences of Belarus, 50 BLK, Grodno 230030, Belarus
| | - Iryna K Kolas
- Grodno State Agrarian University, 28 Tereshkova St., Grodno 230008, Belarus; Institute of Biochemistry of Biologically Active Compounds, National Academy of Sciences of Belarus, 50 BLK, Grodno 230030, Belarus
| | - Sergey A Usanov
- Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, 5/2 Kuprevicha St., Minsk 220141, Belarus
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Chakkarwar VA, Kawtikwar P. Fenofibrate Prevents nicotine-induced Acute Kidney Injury: Possible Involvement of Endothelial Nitric Oxide Synthase. Indian J Nephrol 2021; 31:435-441. [PMID: 34880552 PMCID: PMC8597793 DOI: 10.4103/ijn.ijn_380_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 10/06/2020] [Accepted: 10/11/2020] [Indexed: 11/19/2022] Open
Abstract
Objective: The present study investigated the possible effect of fenofibrate (peroxisome proliferator-activated receptors-α agonist) in nicotine-induced acute kidney injury (AKI) in rats. Materials and Methods: Nicotine (2 mg/kg/day, intraperitoneally) was administered for 4 weeks to induce AKI in rats. Lipid profile and renal oxidative stress were measured and expression of mRNA for eNOS was assessed using reverse transcription-polymerase chain reaction along with serum and renal tissue nitrite levels. Serum creatinine, blood urea nitrogen and microproteinuria were estimated along with the kidney histology, as markers of kidney function. Treatment with fenofibrate (30 mg/kg per oral, 4 weeks) was initiated 3 days before the administration of nicotine and continued for 4 weeks from the day of administration of nicotine. Results: Nicotine administered rats developed apparent AKI confirmed by elevated markers of kidney function and noticeable glomerulosclerosis and tubular cell degeneration. Nicotine decreases the expression of mRNA for eNOS, along with serum and renal tissue nitrite levels. In addition, nicotine showed significantly lipid alteration beside decrease oxidative stress, assessed in terms of increase in serum thiobarbituric acid reactive substance and a marked decrease in tissue reduced glutathione. However, fenofibrate significantly prevented the development of nicotine-AKI by reducing serum creatinine, BUN, and urinary protein, normalizing the lipid profile, reducing renal oxidative stress, increases the eNOS expression and concentration of serum and renal nitrate levels. Conclusion: Fenofibrate attenuates nicotine-induced AKI, via its antihyperlipidemic and antioxidant property. Moreover, fenofibrate induced upregulation of eNOS expression additionally play key roles in the improvement of nicotine-induced AKI could be the future alternative.
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Affiliation(s)
- Vishal Arvind Chakkarwar
- Department of Pharmacology, SN Institute of Pharmacy, Pusad, Yavatmal, India.,Senior Editor, Prime Editors, SN 40, Besides Prozone Mall, Golden City Centre, Aurangabad, Maharashtra, India
| | - Pravin Kawtikwar
- Department of Pharmacology, SN Institute of Pharmacy, Pusad, Yavatmal, India
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Medapati JR, Rapaka D, Bitra VR, Ranajit SK, Guntuku GS, Akula A. Role of endocannabinoid CB1 receptors in Streptozotocin-induced uninephrectomised Wistar rats in diabetic nephropathy. BENI-SUEF UNIVERSITY JOURNAL OF BASIC AND APPLIED SCIENCES 2021. [DOI: 10.1186/s43088-021-00121-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Abstract
Background
The endocannabinoid CB1 receptor is known to have protective effects in kidney disease. The aim of the present study is to evaluate the potential agonistic and antagonistic actions and to determine the renoprotective potential of CB1 receptors in diabetic nephropathy. The present work investigates the possible role of CB1 receptors in the pathogenesis of diabetes-induced nephropathy. Streptozotocin (STZ) (55 mg/kg, i.p., once) is administered to uninephrectomised rats for induction of experimental diabetes mellitus. The CB1 agonist (oleamide) and CB1 antagonist (AM6545) treatment were initiated in diabetic rats after 1 week of STZ administration and were given for 24 weeks.
Results
The progress in diabetic nephropathy is estimated biochemically by measuring serum creatinine (1.28±0.03) (p < 0.005), blood urea nitrogen (67.6± 2.10) (p < 0.001), urinary microprotein (74.62± 3.47) (p < 0.005) and urinary albuminuria (28.31±1.17) (p < 0.0001). Renal inflammation was assessed by estimating serum levels of tumor necrosis factor alpha (75.69±1.51) (p < 0.001) and transforming growth factor beta (8.73±0.31) (p < 0.001). Renal morphological changes were assessed by estimating renal hypertrophy (7.38± 0.26) (p < 0.005) and renal collagen content (10.42± 0.48) (p < 0.001).
Conclusions
From the above findings, it can be said that diabetes-induced nephropathy may be associated with overexpression of CB1 receptors and blockade of CB1 receptors might be beneficial in ameliorating the diabetes-induced nephropathy.
Graphical abstract
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Libby AE, Jones B, Lopez-Santiago I, Rowland E, Levi M. Nuclear receptors in the kidney during health and disease. Mol Aspects Med 2020; 78:100935. [PMID: 33272705 DOI: 10.1016/j.mam.2020.100935] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 10/24/2020] [Accepted: 11/16/2020] [Indexed: 02/06/2023]
Abstract
Over the last 30 years, nuclear receptors (NRs) have been increasingly recognized as key modulators of systemic homeostasis and as contributing factors in many diseases. In the kidney, NRs play numerous important roles in maintaining homeostasis-many of which continue to be unraveled. As "master regulators", these important transcription factors integrate and coordinate many renal processes such as circadian responses, lipid metabolism, fatty acid oxidation, glucose handling, and inflammatory responses. The use of recently-developed genetic tools and small molecule modulators have allowed for detailed studies of how renal NRs contribute to kidney homeostasis. Importantly, while NRs are intimately involved in proper kidney function, they are also implicated in a variety of renal diseases such as diabetes, acute kidney injury, and other conditions such as aging. In the last 10 years, our understanding of renal disease etiology and progression has been greatly shaped by knowledge regarding how NRs are dysregulated in these conditions. Importantly, NRs have also become attractive therapeutic targets for attenuation of renal diseases, and their modulation for this purpose has been the subject of intense investigation. Here, we review the role in health and disease of six key renal NRs including the peroxisome proliferator-activated receptors (PPAR), estrogen-related receptors (ERR), the farnesoid X receptors (FXR), estrogen receptors (ER), liver X receptors (LXR), and vitamin D receptors (VDR) with an emphasis on recent findings over the last decade. These NRs have generated a wealth of data over the last 10 years that demonstrate their crucial role in maintaining normal renal homeostasis as well as their capacity to modulate disease progression.
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Affiliation(s)
- Andrew E Libby
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, 3900 Reservoir Rd, Washington, DC, 20007, USA.
| | - Bryce Jones
- Department of Pharmacology and Physiology, Georgetown University, 3900 Reservoir Rd, Washington, DC, 20007, USA.
| | - Isabel Lopez-Santiago
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, 3900 Reservoir Rd, Washington, DC, 20007, USA.
| | - Emma Rowland
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, 3900 Reservoir Rd, Washington, DC, 20007, USA.
| | - Moshe Levi
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, 3900 Reservoir Rd, Washington, DC, 20007, USA.
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Dose and time-dependent toxicological impact of pantoprazole on vascular endothelium and renal tissue. Toxicol Lett 2020; 333:97-104. [PMID: 32763312 DOI: 10.1016/j.toxlet.2020.07.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 06/21/2020] [Accepted: 07/28/2020] [Indexed: 02/07/2023]
Abstract
Proton pump inhibitors (PPIs) have wide pleiotropic action in addition to their therapeutic potential in gastroesophageal reflux diseases. Conversely, recent reports revealed a significant incidence of toxic events of PPIs including nephritis, osteoporosis, and cardiac damage. Thus, the study was designed to reconcile the deceptive contraindications. The present investigation targeted to reveal the toxic impact of sub-acute and sub-chronic administration of pantoprazole (PPZ) with different concentrations (low dose 4 mg/kg, medium-dose 8 mg/kg and high dose 16 mg/kg once a day) on normal vascular endothelium and renal tissue of rats. Vascular endothelial dysfunction (VED) was estimated by the contractility of an isolated aortic ring, nitrite/nitrate concentration, oxidative stress, and integrity of the endothelium layer. Moreover, the renal abnormalities were further confirmed by an increased level of serum creatinine, blood urea nitrogen (BUN), the incidence of microproteinuria, and structural alteration. Sub-acute administration of PPZ treatment did not produce any toxicological impact on endothelium and renal tissue. Whereas, sub-chronic administration of PPZ treatment causes moderate VED and renal dysfunction in a dose-dependent manner. Sub-chronic treatment of PPZ also influences the mitigation of NO and elevation of oxidative stress. Collecting all the evidence, it concludes that decreased nitric oxide availability and increased levels of oxidative stress may be a possible underlying mechanism of causing VED and renal abnormalities from high-dose PPZ treatment.
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Emami F, Hariri A, Matinfar M, Nematbakhsh M. Fenofibrate-induced renal dysfunction, yes or no? JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2020; 25:39. [PMID: 32582345 PMCID: PMC7306240 DOI: 10.4103/jrms.jrms_772_19] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Revised: 12/16/2019] [Accepted: 02/03/2020] [Indexed: 12/16/2022]
Abstract
In the treatment process of hypertriglyceridemia and diabetic nephropathy in type 2 diabetes, fenofibrate (FEN) is a well-known medication. FEN is from fibrate class drugs that using orally; however, as a side effect, it is associated with serum creatinine level increasing. The aim of this review was to determine the real effect of FEN therapy on renal functions based on both experimental and clinical studies. For this review, using the keywords of “fenofibrate” and “renal” and “function,” a variety of sources of information banks, including PubMed, Google Scholar, and Scopus, were used, and the published articles were considered and interpreted. Followed by searching in databases, 45 articles were collected. After screening these articles, based on the study source, they were devided into two parts: 23 articles on animal experiments and 22 articles clinical experiments. Based on this information, it seems that the protective mechanism of FEN is related to vascular endothelial functions. The increased creatinine by FEN is related to different sensitivities to FEN effects caused by a polymorphism in different patients. In patients with normal renal function, follow-up of serum creatinine would be necessary after FEN, but the discontinuation of FEN is not recommended. In addition, in diabetic patients with hypertriglyceridemia, FEN treatment would be suggested for protecting the kidney from diabetes-induced renal injury.
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Affiliation(s)
- Fatemeh Emami
- Water and Electrolytes Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Amirali Hariri
- Water and Electrolytes Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Matinfar
- Isfahan Kidney Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mehdi Nematbakhsh
- Water and Electrolytes Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.,Department of Physiology, Isfahan University of Medical Sciences, Isfahan, Iran.,Isfahan MN Institute of Basic and Applied Sciences Research, Isfahan, Iran
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Yeh PT, Wang LC, Chang SW, Yang WS, Yang CM, Yang CH. Effect of Fenofibrate on the Expression of Inflammatory Mediators in a Diabetic Rat Model. Curr Eye Res 2019; 44:1121-1132. [PMID: 31109206 DOI: 10.1080/02713683.2019.1622020] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Purpose: To investigate the mechanisms of anti-inflammatory and anti-oxidative effects of fenofibrate, a peroxisome proliferator-activated receptors-α agonist, in preventing diabetic retinopathy (DR) progression via a diabetic rat model. Methods: Diabetes was induced by intraperitoneal injection of streptozotocin in 6-week-old female Wistar rats. Diabetic rats were divided into diabetes without treatment (n = 10), diabetes treated with low dose fenofibrate (30 mg/kg/day) (n = 10) and high dose fenofibrate (100 mg/kg/day) (n = 10). Serum aqueous humor (AqH) and ocular tissues were gathered after 3-month treatment. Expressions of NF-κB and inflammatory chemokines (monocyte chemoattractant protein-1, fractalkine, and intercellular adhesion molecule-1) were detected by reverse transcription-polymerase chain reaction, Western blot, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), and electrophoretic mobility shift assay. The levels of oxidative biomarkers, including acrolein, nitrotyrosine, and 8-hydroxy-2'-deoxyguanosin (8-OHdG), were determined by IHC and ELISA. The reactive oxygen species (ROS) levels in serum and AqH were measured by chemiluminescence methods. Results: After 3 months of treatment, the expressions of mRNA and protein of monocyte chemoattractant protein-1, fractalkine, and intercellular adhesion molecule-1 in the retina of diabetic rats were significantly inhibited by fenofibrate in a dose-dependent manner. These effects were mediated by inhibition of NF-κB by fenofibrate. The levels of oxidative markers, including acrolein, nitrotyrosine, and 8-OHdG, decreased in the retina of diabetic rats after fenofibrate treatment. The ROS levels in the AqH of diabetic rats also suppressed by fenofibrate. Conclusions: Fenofibrate significantly inhibited the expressions of NF-κB and inflammatory chemokines and reduced oxidative products within diabetic retina. Treatment of fenofibrate might be beneficial to preventing DR progression.
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Affiliation(s)
- Po-Ting Yeh
- Department of Ophthalmology, National Taiwan University Hospital , Taipei , Taiwan
| | - Lu-Chun Wang
- Department of Ophthalmology, National Taiwan University Hospital, Yun-Lin Branch , Douliou City, Yunlin County , Taiwan
| | - Shu-Wen Chang
- Department of Ophthalmology, Far Eastern Memorial Hospital , NewTaipei City , Taiwan
| | - Wei-Shiung Yang
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University , Taipei , Taiwan.,Department of Internal Medicine, National Taiwan University Hospital , Taipei , Taiwan
| | - Chung-May Yang
- Department of Ophthalmology, National Taiwan University Hospital , Taipei , Taiwan.,Department of Ophthalmology, College of Medicine, National Taiwan University , Taipei , Taiwan
| | - Chang-Hao Yang
- Department of Ophthalmology, National Taiwan University Hospital , Taipei , Taiwan.,Department of Ophthalmology, College of Medicine, National Taiwan University , Taipei , Taiwan
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10
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Iso-α-acids, bitter components of beer, prevent obesity-induced cognitive decline. Sci Rep 2018; 8:4760. [PMID: 29555941 PMCID: PMC5859182 DOI: 10.1038/s41598-018-23213-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 03/07/2018] [Indexed: 12/28/2022] Open
Abstract
Dementia and cognitive decline have become worldwide public health problems, and it was recently reported that life-style related diseases and obesity are key risk factors in dementia. Iso-α-acids, hop-derived bitter components of beer, have been reported to have various physiological functions via activation of peroxisome proliferator-activated receptor γ. In this report, we demonstrated that daily intake of iso-α-acids suppresses inflammations in the hippocampus and improves cognitive decline induced by high fat diet (HFD). Body weight, epididymal fat weight, and plasma triglyceride levels were increased in HFD-fed mice, and significantly decreased in iso-α-acids supplemented HFD-fed mice. HFD feeding enhances the production of inflammatory cytokines and chemokines, such as TNF-α, which was significantly suppressed by iso-α-acids administration. HFD-induced neuroinflammation caused lipid peroxidation, neuronal loss, and atrophy in hippocampus, and those were not observed in iso-α-acids-treated mice. Furthermore, iso-α-acids intake significantly improved cognitive decline induced by HFD-feeding. Iso-α-acids are food derived components that suppressing both lipid accumulation and brain inflammation, thus iso-α-acids might be beneficial for the risk of dementia increased by obesity and lifestyle-related diseases.
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11
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Gargouri M, Hamed H, Akrouti A, Dauvergne X, Magné C, El Feki A. Effects of Spirulina platensis on lipid peroxidation, antioxidant defenses, and tissue damage in kidney of alloxan-induced diabetic rats. Appl Physiol Nutr Metab 2017; 43:345-354. [PMID: 29091744 DOI: 10.1139/apnm-2017-0461] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Chronic hyperglycemia in diabetes causes free radicals overproduction, which contributes to the development of diabetic nephropathy. In modern medicine, no satisfactory therapy is available to cure diabetes mellitus. In that context, we investigated the potential therapeutic action of spirulina-enriched diet on renal impairment and oxidative stress in diabetic rats. Diabetes was induced by a single subcutaneous injection of alloxan (120 mg·kg-1) in rats. Following alloxan treatment, male Wistar rats were fed daily with 5% spirulina-enriched diet or treated with insulin (0.5 IU·rat-1) for 3 weeks. Diabetes was associated with hyperglycemia, increase in renal oxidative parameters (lipid peroxidation, thiobarbituric-acid reactive substances, protein carbonyl and advanced oxidation protein products levels, changes in antioxidant enzyme activities), and nephropathology markers. The renal injury induced by alloxan was confirmed by histological study of the diabetic rat kidney. Treatment with spirulina or insulin significantly ameliorated renal dysfunction by reducing oxidative stress, while rats recovered normal kidney histology. Overall, this study indicates that spirulina is efficient in inhibiting hyperglycemia and oxidative stress induced by diabetes, and suggests that the administration of this alga may be helpful in the prevention of diabetic complications. This amelioration was even more pronounced than that caused by insulin injection.
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Affiliation(s)
- Manel Gargouri
- a Laboratory of animal Ecophysiology, Faculty of Sciences, University of Sfax, BP 3038, Sfax, Tunisia.,b EA 2219 Géoarchitecture, Faculty of Sciences, University of Western Brittany, 6 Avenue V. Le Gorgeu, CS 93837, 29238 Brest Cedex 3, France
| | - Houda Hamed
- a Laboratory of animal Ecophysiology, Faculty of Sciences, University of Sfax, BP 3038, Sfax, Tunisia
| | - Amel Akrouti
- a Laboratory of animal Ecophysiology, Faculty of Sciences, University of Sfax, BP 3038, Sfax, Tunisia
| | - Xavier Dauvergne
- b EA 2219 Géoarchitecture, Faculty of Sciences, University of Western Brittany, 6 Avenue V. Le Gorgeu, CS 93837, 29238 Brest Cedex 3, France
| | - Christian Magné
- b EA 2219 Géoarchitecture, Faculty of Sciences, University of Western Brittany, 6 Avenue V. Le Gorgeu, CS 93837, 29238 Brest Cedex 3, France
| | - Abdelfattah El Feki
- a Laboratory of animal Ecophysiology, Faculty of Sciences, University of Sfax, BP 3038, Sfax, Tunisia
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Ustuner MA, Kaman D, Colakoglu N. Effects of benfotiamine and coenzyme Q10 on kidney damage induced gentamicin. Tissue Cell 2017; 49:691-696. [PMID: 29066103 DOI: 10.1016/j.tice.2017.10.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Revised: 09/14/2017] [Accepted: 10/03/2017] [Indexed: 01/31/2023]
Abstract
OBJECTIVE Gentamicin (GM) is an effective antibiotic against severe infection but has limitations related to nephrotoxicity. In this study, we investigated whether benfotiamine (BFT) and coenzyme Q10 (CoQ10), could ameliorate the nephrotoxic effect of GM in rats. METHODS Rats were divided into five groups. Group 1 and 2 served as control and sham respectively, Group 3 as GM group, Group 4 as GM+CoQ10 and Group 5 as GM+BFT for 8days. At the end of the study, all rats were euthanized by cervical decapitation and then blood samples and kidneys were collected for further analysis. Serum urea, creatinine, cytokine TNF-a, oxidant and antioxidant parameters, as well as histopathological examination of kidney tissues were assessed. RESULTS Gentamicin administration caused a severe nephrotoxicity which was evidenced by an elevated serum creatinine, urea and KIM-1 level as compared with the controls. Moreover, a significant increase in serum malondialdehyde, reduced glutathione. Histopathological examination of renal tissue in gentamisin administered group, there were extremly pronounced necrotic tubules in the renal cortex and hyalen cast accumulation in the medullar tubuli. BFT given to GM rats reduced these nephrotoxicity parameters. Serum creatinine, urea, and KIM-1 were almost normalized in the GM+BFT group. Benfotiamin treatment was significantly decreased necrotic tubuli and hyalen deposition in gentamisin plus benfotiamin group. CoQ10 given to GM rats did not cause any statistically significant alterations in these nephrotoxicity parameters when compared with GM group but histopathological examination of renal tissue in GM+CoQ10 administered group, CoQ10 treatment was decreased necrotic tubuli rate and hyalen accumulation in tubuli. CONCLUSION The results from our study indicate that BFT supplement attenuates gentamicin-induced renal injury via the amelioration of oxidative stress and inflammation of renal tubular cells.
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Affiliation(s)
| | - Dilara Kaman
- Department of Medical Biochemistry, Firat University School of Medicine, Elazığ, Turkey.
| | - Neriman Colakoglu
- Department of Histology and Embryology, Firat University School of Medicine, Elazığ, Turkey
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13
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Al-Rasheed NM, Al-Rasheed NM, Al-Amin MA, Hasan IH, Al-Ajmi HN, Mohammad RA, Attia HA. Fenofibrate attenuates diabetic nephropathy in experimental diabetic rat's model via suppression of augmented TGF-β1/Smad3 signaling pathway. Arch Physiol Biochem 2016; 122:186-194. [PMID: 26959841 DOI: 10.3109/13813455.2016.1164186] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
CONTEXT Fibrates, the ligands of peroxisome profileferator-activated receptor-α have been shown to have a renal protective action in diabetic nephropathy (DN). OBJECTIVE This study aimed to elucidate the effect of fenofibrate on renal transforming growth factor-β1 (TGF-β1) and Smad3 in Streptozotocin (STZ)-induced DN. METHODS Diabetes was induced in rats by a single intraperitoneal injection of streptozotocin (55 mg/kg). Diabetic rats were given fenofibrate (100 mg/kg, p.o.). After 12 weeks, diabetic nephropathy biomarkers were assessed. The mRNA expression of collage I and III, TGF-β1 and Smad3 and were detected by RT-PCR. RESULTS Fenofibrate reduced significantly serum creatinine, kidney/body weight ratio, serum albumin excretion Collage I & III, TGF-β1 and Smad3 mRNA expression. CONCLUSIONS Our results give further insights into the mechanisms underlying the protective role of fenofibrate in DN, suggesting that interference with TGF-β1/Smad3 signaling pathway may be a useful therapeutic approach to prevent DN.
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Affiliation(s)
- Nouf Mohamed Al-Rasheed
- a Pharmacology and Toxicology Department , College of Pharmacy, King Saud University , Riyadh , KSA
| | - Nawal Mohamed Al-Rasheed
- a Pharmacology and Toxicology Department , College of Pharmacy, King Saud University , Riyadh , KSA
- b Pharmacology Department , College of Pharmacy, Princess Nora Bint Abdul Rahman University , KSA
| | - Maha Abdelrahman Al-Amin
- a Pharmacology and Toxicology Department , College of Pharmacy, King Saud University , Riyadh , KSA
| | - Iman Huesein Hasan
- a Pharmacology and Toxicology Department , College of Pharmacy, King Saud University , Riyadh , KSA
| | - Hanaa Najeeb Al-Ajmi
- a Pharmacology and Toxicology Department , College of Pharmacy, King Saud University , Riyadh , KSA
| | - Raeesa Ahmed Mohammad
- c Anatomy Department , Faculty of Medicine, King Saud University , Riyadh , KSA , and
| | - Hala Aboulfotooh Attia
- a Pharmacology and Toxicology Department , College of Pharmacy, King Saud University , Riyadh , KSA
- d Biochemistry Department , College of Pharmacy, Mansours University , Mansoura , Egypt
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14
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Garg M, Khanna D, Kalra S, Balakumar P. Chronic oral administration of low-dose combination of fenofibrate and rosuvastatin protects the rat heart against experimentally induced acute myocardial infarction. Fundam Clin Pharmacol 2016; 30:394-405. [DOI: 10.1111/fcp.12204] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2015] [Revised: 03/26/2016] [Accepted: 04/26/2016] [Indexed: 12/25/2022]
Affiliation(s)
- Monika Garg
- Cardiovascular Pharmacology Division; Department of Pharmacology; Rajendra Institute of Technology and Sciences; Sirsa 125 055 Haryana India
| | - Deepa Khanna
- Cardiovascular Pharmacology Division; Department of Pharmacology; Rajendra Institute of Technology and Sciences; Sirsa 125 055 Haryana India
| | - Sanjeev Kalra
- Cardiovascular Pharmacology Division; Department of Pharmacology; Rajendra Institute of Technology and Sciences; Sirsa 125 055 Haryana India
| | - Pitchai Balakumar
- Pharmacology Unit; Faculty of Pharmacy; AIMST University; Semeling 08100 Bedong Kedah DarulAman Malaysia
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15
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Yaribeygi H, Mohammadi MT. Evaluation of PPAR-α Agonist effect on Kidney Performance Through Increment of Nitric Oxide During Hyperglycemia-Induced Nephropathy in Rat. RAZAVI INTERNATIONAL JOURNAL OF MEDICINE 2016. [DOI: 10.17795/rijm37670] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
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16
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Sharma AK, Kumar A, Taneja G, Nagaich U, Deep A, Rajput SK. Synthesis and preliminary therapeutic evaluation of copper nanoparticles against diabetes mellitus and -induced micro- (renal) and macro-vascular (vascular endothelial and cardiovascular) abnormalities in rats. RSC Adv 2016. [DOI: 10.1039/c6ra03890e] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Current study synthesized and investigated the effect of low-dose copper nanoparticles (CuNPs) against diabetes mellitus and -induced experimental micro- (nephropathy) and macro-vascular (cardio and endothelium) complications.
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Affiliation(s)
- Arun K. Sharma
- Cardiovascular Pharmacology Division
- Department of Pharmacology
- Amity Institute of Pharmacy
- Amity University
- Noida
| | - Ashish Kumar
- Department of Nanomedicine and Pharmaceutics
- Amity University
- Noida
- India
| | - Gaurav Taneja
- Cardiovascular Pharmacology Division
- Department of Pharmacology
- Amity Institute of Pharmacy
- Amity University
- Noida
| | - Upendra Nagaich
- Department of Nanomedicine and Pharmaceutics
- Amity University
- Noida
- India
| | - Aakash Deep
- Department of Pharmaceutical Chemistry
- Chaudhary Bansi Lal University
- Bhiwani 127021
- India
| | - Satyendra K. Rajput
- Cardiovascular Pharmacology Division
- Department of Pharmacology
- Amity Institute of Pharmacy
- Amity University
- Noida
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17
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Toth-Manikowski S, Atta MG. Diabetic Kidney Disease: Pathophysiology and Therapeutic Targets. J Diabetes Res 2015; 2015:697010. [PMID: 26064987 PMCID: PMC4430644 DOI: 10.1155/2015/697010] [Citation(s) in RCA: 107] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 04/17/2015] [Indexed: 12/13/2022] Open
Abstract
Diabetes is a worldwide epidemic that has led to a rise in diabetic kidney disease (DKD). Over the past two decades, there has been significant clarification of the various pathways implicated in the pathogenesis of DKD. Nonetheless, very little has changed in the way clinicians manage patients with this disorder. Indeed, treatment is primarily centered on controlling hyperglycemia and hypertension and inhibiting the renin-angiotensin system. The purpose of this review is to describe the current understanding of how the hemodynamic, metabolic, inflammatory, and alternative pathways are all entangled in pathogenesis of DKD and detail the various therapeutic targets that may one day play a role in quelling this epidemic.
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Affiliation(s)
- Stephanie Toth-Manikowski
- Division of Nephrology, Johns Hopkins University, 1830 E. Monument Street, Suite 416, Baltimore, MD 21287, USA
| | - Mohamed G. Atta
- Division of Nephrology, Johns Hopkins University, 1830 E. Monument Street, Suite 416, Baltimore, MD 21287, USA
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18
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Bhardwaj P, Khanna D, Balakumar P. Catechin averts experimental diabetes mellitus-induced vascular endothelial structural and functional abnormalities. Cardiovasc Toxicol 2014; 14:41-51. [PMID: 24048981 DOI: 10.1007/s12012-013-9226-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Diabetes mellitus is associated with an induction of vascular endothelial dysfunction (VED), an initial event that could lead to the pathogenesis of atherosclerosis and hypertension. Previous studies showed that catechin, a key component of green tea, possesses vascular beneficial effects. We investigated the effect of catechin hydrate in diabetes mellitus-induced experimental vascular endothelial abnormalities (VEA). Streptozotocin (50 mg/kg, i.p., once) administration to rats produced diabetes mellitus, which subsequently induced VEA in 8 weeks by markedly attenuating acetylcholine-induced endothelium-dependent relaxation in the isolated aortic ring preparation, decreasing aortic and serum nitrite/nitrate concentrations and impairing aortic endothelial integrity. These abnormalities in diabetic rats were accompanied with elevated aortic superoxide anion generation and serum lipid peroxidation in addition to hyperglycemia. Catechin hydrate treatment (50 mg/kg/day p.o., 3 weeks) markedly prevented diabetes mellitus-induced VEA and vascular oxidative stress. Intriguingly, in vitro incubation of L-NAME (100 μM), an inhibitor of nitric oxide synthase, or Wortmannin (100 nM), a selective inhibitor of phosphatidylinositol 3-kinase (PI3K), markedly prevented catechin hydrate-induced improvement in acetylcholine-provoked endothelium-dependent relaxation in the diabetic rat aorta. Moreover, catechin hydrate treatment considerably reduced the elevated level of serum glucose in diabetic rats. In conclusion, catechin hydrate treatment prevents diabetes mellitus-induced VED through the activation of endothelial PI3K signal and subsequent activation of eNOS and generation of nitric oxide. In addition, reduction in high glucose, vascular oxidative stress, and lipid peroxidation might additionally contribute to catechin hydrate-associated prevention of diabetic VEA.
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Affiliation(s)
- Pooja Bhardwaj
- Cardiovascular Pharmacology Division, Department of Pharmacology, Institute of Pharmacy, Rajendra Institute of Technology and Sciences (RITS), Sirsa, 125 055, Haryana, India
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Balakumar P, Varatharajan R, Nyo YH, Renushia R, Raaginey D, Oh AN, Akhtar SS, Rupeshkumar M, Sundram K, Dhanaraj SA. Fenofibrate and dipyridamole treatments in low-doses either alone or in combination blunted the development of nephropathy in diabetic rats. Pharmacol Res 2014; 90:36-47. [PMID: 25263930 DOI: 10.1016/j.phrs.2014.08.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2014] [Revised: 08/20/2014] [Accepted: 08/26/2014] [Indexed: 12/19/2022]
Abstract
Low-doses of fenofibrate and dipyridamole have pleiotropic renoprotective actions in diabetic rats. This study investigated their combined effect relative to their individual treatments and lisinopril in rats with diabetic nephropathy. Streptozotocin (55mg/kg, i.p., once)-administered diabetic rats were allowed for 10 weeks to develop nephropathy. Diabetic rats after 10 weeks developed nephropathy with discernible renal structural and functional changes as assessed in terms of increase in kidney weight to body weight ratio (KW/BW), and elevations of serum creatinine, urea and uric acid, which accompanied with elevated serum triglycerides and decreased high-density lipoproteins. Hematoxylin-eosin, periodic acid Schiff and Masson trichrome staining confirmed renal pathological changes in diabetic rats that included glomerular capsular wall distortion, mesangial cell expansion, glomerular microvascular condensation, tubular damage and degeneration and fibrosis. Low-dose fenofibrate (30mg/kg, p.o., 4 weeks) and low-dose dipyridamole (20mg/kg, p.o., 4 weeks) treatment either alone or in combination considerably reduced renal structural and functional abnormalities in diabetic rats, but without affecting the elevated glucose level. Fenofibrate, but not dipyridamole, significantly prevented the lipid alteration and importantly the uric acid elevation in diabetic rats. Lisinopril (5mg/kg, p.o., 4 weeks, reference compound), prevented the hyperglycemia, lipid alteration and development of diabetic nephropathy. Lipid alteration and uric acid elevation, besides hyperglycemia, could play key roles in the development of nephropathy. Low-doses of fenofibrate and dipyridamole treatment either alone or in combination markedly prevented the diabetes-induced nephropathy. Their combination was as effective as to their individual treatment, but not superior in preventing the development of diabetic nephropathy.
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Affiliation(s)
- Pitchai Balakumar
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Malaysia.
| | - Rajavel Varatharajan
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Malaysia
| | - Ying Hui Nyo
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Malaysia
| | - Raja Renushia
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Malaysia
| | - Devarajan Raaginey
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Malaysia
| | - Ann Nah Oh
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Malaysia
| | - Shaikh Sohrab Akhtar
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Malaysia
| | - Mani Rupeshkumar
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Malaysia
| | - Karupiah Sundram
- Pharmaceutical Chemistry Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Malaysia
| | - Sokkalingam A Dhanaraj
- Pharmaceutical Technology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Malaysia
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20
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Lee HJ, Jeong KH, Kim YG, Moon JY, Lee SH, Ihm CG, Sung JY, Lee TW. Febuxostat ameliorates diabetic renal injury in a streptozotocin-induced diabetic rat model. Am J Nephrol 2014; 40:56-63. [PMID: 25034030 DOI: 10.1159/000363421] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Accepted: 05/03/2014] [Indexed: 02/02/2023]
Abstract
BACKGROUND Oxidative stress and inflammation are known to play central roles in the development of diabetic nephropathy (DN). Febuxostat is a novel non-purine xanthine oxidase (XO)-specific inhibitor developed to treat hyperuricemia. In this study, we investigated whether febuxostat could ameliorate DN via renoprotective mechanisms such as alleviation of oxidative stress and anti-inflammatory actions. METHODS Male Sprague-Dawley rats were divided into three groups: a normal group, a diabetes group (DM group), and a febuxostat-treated diabetes group (DM+Fx group). We administered 5 mg/kg of febuxostat to experimental rats for 7 weeks and evaluated clinical and biochemical parameters and XO and xanthine dehydrogenase (XDH) activity in hepatic tissue. The degree of oxidative stress and extent of inflammation were evaluated from urine samples and renal tissue collected from each group. RESULTS Diabetic rats (DM and DM+Fx groups) had higher blood glucose and kidney weight relative to body weight than normal rats. Albuminuria was significantly reduced in febuxostat-treated diabetic rats compared with untreated diabetic rats. Quantitative analysis showed that hepatic XO and XDH activities were higher in the DM groups, but decreased after treatment with febuxostat. Urinary 8-OHdG concentrations and renal cortical nitrotyrosine also indicated reduced oxidative stress in the DM+Fx group relative to the DM group. The number of ED-1-stained cells in the glomerulus and tubule of diabetic renal tissue decreased in febuxostat-treated diabetic rats relative to that of non-treated diabetic rats. Diabetic rats also expressed higher transcript levels of inflammatory genes (E-selectin and VCAM-1), an inflammation-induced enzyme (COX-2), and inflammatory mediators (ED-1 and NF-κB) than control rats; expression of these genes was significantly reduced by treatment with febuxostat. CONCLUSIONS Febuxostat prevents diabetic renal injury such as albuminuria. This renoprotective effect appears to be due to attenuation of the inflammatory and oxidative effects of diabetes-induced renal damage through inhibition of XO and XDH activities.
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Affiliation(s)
- Hong-Joo Lee
- Department of Nephrology, Seoul Red Cross Hospital, Seoul, Korea
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21
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Pácal L, Kuricová K, Kaňková K. Evidence for altered thiamine metabolism in diabetes: Is there a potential to oppose gluco- and lipotoxicity by rational supplementation? World J Diabetes 2014; 5:288-295. [PMID: 24936250 PMCID: PMC4058733 DOI: 10.4239/wjd.v5.i3.288] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 04/14/2014] [Accepted: 05/16/2014] [Indexed: 02/05/2023] Open
Abstract
Growing prevalence of diabetes (type 2 as well as type 1) and its related morbidity due to vascular complications creates a large burden on medical care worldwide. Understanding the molecular pathogenesis of chronic micro-, macro- and avascular complications mediated by hyperglycemia is of crucial importance since novel therapeutic targets can be identified and tested. Thiamine (vitamin B1) is an essential cofactor of several enzymes involved in carbohydrate metabolism and published data suggest that thiamine metabolism in diabetes is deficient. This review aims to point out the physiological role of thiamine in metabolism of glucose and amino acids, to present overview of thiamine metabolism and to describe the consequences of thiamine deficiency (either clinically manifest or latent). Furthermore, we want to explain why thiamine demands are increased in diabetes and to summarise data indicating thiamine mishandling in diabetics (by review of the studies mapping the prevalence and the degree of thiamine deficiency in diabetics). Finally, we would like to summarise the evidence for the beneficial effect of thiamine supplementation in progression of hyperglycemia-related pathology and, therefore, to justify its importance in determining the harmful impact of hyperglycemia in diabetes. Based on the data presented it could be concluded that although experimental studies mostly resulted in beneficial effects, clinical studies of appropriate size and duration focusing on the effect of thiamine supplementation/therapy on hard endpoints are missing at present. Moreover, it is not currently clear which mechanisms contribute to the deficient action of thiamine in diabetes most. Experimental studies on the molecular mechanisms of thiamine deficiency in diabetes are critically needed before clear answer to diabetes community could be given.
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Abstract
Aims/Introduction: In diabetes, increased oxidative stress as a result of damage to the electron transport chain can lead to tissue injury through upregulation of multiple vasoactive factors and extracellular matrix proteins. Benfotiamine, a lipid soluble thiamine derivative, through reducing mitochondrial superoxide production, blocks multiple pathways leading to tissue damage in hyperglycemia. We investigated if treatment with benfotiamine can prevent diabetes‐induced production of vasoactive factors and extracellular matrix proteins, and whether such effects are tissue‐specific. We also examined whether effects of benfotiamine are mediated through a nuclear mechanism. Materials and Methods: Retinal, renal and cardiac tissues from the streptozotocin‐induced diabetic rats were examined after 4 months of follow up. mRNA levels were quantified using real‐time RT‐PCR. Protein levels were quantified using western blot and ELISA. Cellular expressions of 8‐Hydroxy‐2′‐deoxyguanosine, a marker of nuclear DNA damage and Phospho‐H2AX were also examined. Results: Diabetic animals showed hyperglycemia, glucosuria, increased urinary albumin/creatine ratio and loss of bodyweight. In the kidneys, heart and retina, diabetes caused increased production of endothelin‐1, transforming growth factor‐β1, vascular endothelial growth factor and augmented extracellular matrix proteins (collagen, fibronectin [FN] and its splice variant extradomain B containing FN), along with evidence of structural alterations, characteristic of diabetes‐induced tissue damage. Such changes were prevented by benfotiamine. Furthermore, benfotiamine prevented diabetes‐induced oxidative DNA damage and upregulation of p300, a histone acetylator and a transcription coactivator. Conclusions: Data from the present study suggest that benfotiamine is effective in preventing tissue damage in diabetes and at the transcriptional level such effects are mediated through prevention of p300 upregulation. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00077.x, 2010)
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Affiliation(s)
- Rana Chakrabarti
- Department of Pathology, The University of Western Ontario, London, ON, Canada
| | - Megan Chen
- Department of Pathology, The University of Western Ontario, London, ON, Canada
| | - Weihua Liu
- Department of Pathology, The University of Western Ontario, London, ON, Canada
| | - Shali Chen
- Department of Pathology, The University of Western Ontario, London, ON, Canada
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Sharma AK, Khanna D, Balakumar P. Low-dose dipyridamole treatment partially prevents diabetes mellitus-induced vascular endothelial and renal abnormalities in rats. Int J Cardiol 2014; 172:530-2. [DOI: 10.1016/j.ijcard.2014.01.053] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Accepted: 01/12/2014] [Indexed: 10/25/2022]
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Taneja G, Mahadevan N, Balakumar P. Fish oil blunted nicotine-induced vascular endothelial abnormalities possibly via activation of PPARγ-eNOS-NO signals. Cardiovasc Toxicol 2013. [PMID: 23208382 DOI: 10.1007/s12012-012-9190-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Nicotine exposure is associated with an induction of vascular endothelial dysfunction (VED), a hallmark of various cardiovascular disorders. The present study investigated the effect of fish oil in nicotine-induced experimental VED. VED was assessed by employing isolated aortic ring preparation, estimating aortic and serum nitrite/nitrate, aortic superoxide anion generation, and serum TBARS, and carrying out electron microscopic and histological studies of thoracic aorta. Nicotine (2 mg/kg/day, i.p., 4 weeks) administration produced VED in rats by attenuating acetylcholine-induced endothelium-dependent relaxation in the isolated aortic ring preparation, decreasing aortic and serum nitrite/nitrate concentration, impairing endothelial integrity, and inducing vascular oxidative stress. Treatment with fish oil (2 mL/kg/day p.o., 4 weeks) markedly prevented nicotine-induced endothelial functional and structural abnormalities and oxidative stress. However, administration of GW9662, a selective inhibitor of PPARγ, to a significant degree attenuated fish oil-associated anti-oxidant action and vascular endothelial functional and structural improvements. Intriguingly, in vitro incubation of L-NAME (100 μM), an inhibitor of nitric oxide synthase (NOS), markedly attenuated fish oil-induced improvement in endothelium-dependent relaxation in the aorta of nicotine-administered rats. Nicotine administration altered the lipid profile by increasing serum total cholesterol, which was significantly prevented by fish oil treatment. The vascular protective potential of fish oil in preventing nicotine-induced VED may pertain to its additional properties (besides its lipid-lowering effect) such as activation of PPARγ and subsequent possible activation of endothelial NOS and generation of nitric oxide, and consequent reduction in oxidative stress.
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Affiliation(s)
- Gaurav Taneja
- Cardiovascular Pharmacology Division, Department of Pharmacology, Rajendra Institute of Technology and Sciences, Sirsa 125 055, India
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Pappachan JM, Varughese GI, Sriraman R, Arunagirinathan G. Diabetic cardiomyopathy: Pathophysiology, diagnostic evaluation and management. World J Diabetes 2013; 4:177-189. [PMID: 24147202 PMCID: PMC3797883 DOI: 10.4239/wjd.v4.i5.177] [Citation(s) in RCA: 124] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2013] [Revised: 07/02/2013] [Accepted: 08/17/2013] [Indexed: 02/05/2023] Open
Abstract
Diabetes affects every organ in the body and cardiovascular disease accounts for two-thirds of the mortality in the diabetic population. Diabetes-related heart disease occurs in the form of coronary artery disease (CAD), cardiac autonomic neuropathy or diabetic cardiomyopathy (DbCM). The prevalence of cardiac failure is high in the diabetic population and DbCM is a common but underestimated cause of heart failure in diabetes. The pathogenesis of diabetic cardiomyopathy is yet to be clearly defined. Hyperglycemia, dyslipidemia and inflammation are thought to play key roles in the generation of reactive oxygen or nitrogen species which are in turn implicated. The myocardial interstitium undergoes alterations resulting in abnormal contractile function noted in DbCM. In the early stages of the disease diastolic dysfunction is the only abnormality, but systolic dysfunction supervenes in the later stages with impaired left ventricular ejection fraction. Transmitral Doppler echocardiography is usually used to assess diastolic dysfunction, but tissue Doppler Imaging and Cardiac Magnetic Resonance Imaging are being increasingly used recently for early detection of DbCM. The management of DbCM involves improvement in lifestyle, control of glucose and lipid abnormalities, and treatment of hypertension and CAD, if present. The role of vasoactive drugs and antioxidants is being explored. This review discusses the pathophysiology, diagnostic evaluation and management options of DbCM.
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Seok H, Cha BS. Refocusing Peroxisome Proliferator Activated Receptor-α: A New Insight for Therapeutic Roles in Diabetes. Diabetes Metab J 2013; 37:326-32. [PMID: 24199160 PMCID: PMC3816132 DOI: 10.4093/dmj.2013.37.5.326] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Although glucose-lowering treatment shows some risk lowering effects in cardiovascular diseases, risks of macrovascular and microvascular complications have still remained, and development of new therapeutic strategies is needed. Recent data have shown that peroxisome proliferator activated receptor-α (PPAR-α) plays a pivotal role in the regulation of lipid homeostasis, fatty acid oxidation, cellular differentiation, and immune response such as inflammation or vascularization related to diabetic complication. This review will re-examine the metabolic role of PPAR-α, summarize data from clinical studies on the effect of PPAR-α agonist in diabetes, and will discuss the possible therapeutic role of PPAR-α activation.
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Affiliation(s)
- Hannah Seok
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Bong Soo Cha
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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27
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Engelen L, Stehouwer CDA, Schalkwijk CG. Current therapeutic interventions in the glycation pathway: evidence from clinical studies. Diabetes Obes Metab 2013; 15:677-89. [PMID: 23279611 DOI: 10.1111/dom.12058] [Citation(s) in RCA: 88] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2012] [Revised: 07/20/2012] [Accepted: 12/05/2012] [Indexed: 02/06/2023]
Abstract
The increased formation of advanced glycation endproducts (AGEs) constitutes a potential mechanism of hyperglycaemia-induced micro- and macrovascular disease in diabetes. In vitro and animal experiments have shown that various interventions can inhibit formation and/or actions of AGEs, in particular the specific AGE inhibitor aminoguanidine and the AGEs crosslink breaker alagebrium, and the B vitamins pyridoxamine and thiamine, and the latter's synthetic derivative, benfotiamine. The potential clinical value of these interventions, however, remains to be established. The present review provides, from the clinical point of view, an overview of current evidence on interventions in the glycation pathway relating to (i) the clinical benefits of specific AGE inhibitors and AGE breakers and (ii) the potential AGE-inhibiting effects of therapies developed for purposes unrelated to the glycation pathway. We found that safety and/or efficacy in clinical studies with the specific AGE inhibitor, aminoguanidine and the AGE breaker, alagebrium, appeared to be a concern. The clinical evidence on the potential AGE-inhibiting effects of B vitamins is still limited. Finally, current evidence for AGE inhibition by therapies developed for purposes unrelated to glycation is limited due to a large heterogeneity in study designs and/or measurement techniques, which have often been sub-optimal. We conclude that, clinical evidence on interventions to inhibit formation and/or action of AGEs is currently weak and unconvincing.
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Affiliation(s)
- L Engelen
- Department of Internal Medicine, CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands
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Chakkarwar VA. Smoking in diabetic nephropathy: sparks in the fuel tank? World J Diabetes 2012; 3:186-95. [PMID: 23301120 PMCID: PMC3538984 DOI: 10.4239/wjd.v3.i12.186] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2012] [Revised: 11/20/2012] [Accepted: 12/01/2012] [Indexed: 02/05/2023] Open
Abstract
Diabetic nephropathy is associated with high morbidity and mortality and the prevalence of this disease is continuously increasing worldwide. Long-term diabetes increases the likelihood of developing secondary complications like nephropathy, the most common cause of end stage renal disease. Usually, other factors like hypertension, alcoholism and smoking also partly contribute to the progression of diabetic nephropathy. Among this, cigarette smoking in diabetes has been repeatedly confirmed as an independent risk factor for the onset and progression of diabetic nephropathy. Various studies suggest that smoking is a major fuel in the development of high oxidative stress and subsequently hyperlipidemia, accumulation of advanced glycation end products, activation of the renin angiotensin system and Rho-kinase, which are observed to play a pathogenic role in the progression of diabetic nephropathy. Furthermore, cigarette smoking in diabetic patients with vascular complications produces a variety of pathological changes in the kidney, such as thickening of the glomerular basement membrane and mesangial expansion with progression in glomerulosclerosis and interstitial fibrosis, which ultimately results in end stage renal failure. Strong associations are consistently found between chronic cigarette smoking and diabetic microvascular complications. A diverse group of studies unveil potential mechanisms that may explain the role of cigarette smoking in the progression of diabetic nephropathy. Tremendous efforts are being made to control smoking mediated progression of diabetic nephropathy, but no promising therapy is yet available. The present review critically discusses the possible detrimental role of chronic cigarette smoking in the progression of diabetic nephropathy and various possible pharmacological interventions to attenuate the exacerbation of diabetic nephropathy.
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Affiliation(s)
- Vishal Arvind Chakkarwar
- Vishal Arvind Chakkarwar, Department of Pharmacology, Shri Bhagwan College of Pharmacy, Aurangabad 431003, Maharashtra, India
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Król E, Krejpcio Z, Michalak S, Wójciak RW, Bogdański P. Effects of combined dietary chromium(III) propionate complex and thiamine supplementation on insulin sensitivity, blood biochemical indices, and mineral levels in high-fructose-fed rats. Biol Trace Elem Res 2012; 150:350-9. [PMID: 23065486 PMCID: PMC3510416 DOI: 10.1007/s12011-012-9515-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2012] [Accepted: 09/26/2012] [Indexed: 12/22/2022]
Abstract
Insulin resistance is the first step in glucose intolerance and the development of type 2 diabetes mellitus, thus effective prevention strategies should also include dietary interventions to enhance insulin sensitivity. Nutrients, such as microelement chromium(III) and thiamine, play regulatory roles in carbohydrate metabolism. The objective of this study was to evaluate the insulin-sensitizing potential of the combined supplementary chromium(III) propionate complex (CrProp) and thiamine in insulin resistance animal model (rats fed a high-fructose diet). The experiment was carried out on 40 nine-week-old male Wistar rats divided into five groups (eight animals each). Animals were fed ad libitum: the control diet (AIN-93 M) and high-fructose diets with and without a combination of two levels of CrProp (0.1 and 1 mg Cr/kg body mass/day) and two levels of thiamine (0.5 and 10 mg/kg body mass/day) for 8 weeks. At the end of the experiment rats were sacrificed to collect blood and internal organs for analyses of blood biochemical and hematologic indices as well as tissular microelement levels that were measured using appropriate methods. It was found that both supplementary CrProp and thiamine (given alone) have significant insulin-sensitizing and moderate blood-lipid-lowering properties, while the combined supplementation with these agents does not give synergistic effects in insulin-resistant rats. CrProp given separately increased kidney Cu and Cr levels, while thiamine alone increased hepatic Cu contents and decreased renal Zn and Cu contents.
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Affiliation(s)
- Ewelina Król
- Department of Human Nutrition and Hygiene, Poznan University of Life Sciences, 31 Wojska Polskiego, 60-624, Poznan, Poland.
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Al-Attas OS, Al-Daghri NM, Alfadda AA, Abd-Alrahman SH, Sabico S. Blood thiamine and its phosphate esters as measured by high-performance liquid chromatography: levels and associations in diabetes mellitus patients with varying degrees of microalbuminuria. J Endocrinol Invest 2012; 35:951-6. [PMID: 22107884 DOI: 10.3275/8126] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Thiamine deficiency has been linked to microvascular complications in patients with diabetes mellitus (DM). In this study, we aim to assess blood and urine thiamine status by high performance liquid chromatography (HPLC) in patients with DM Type 1 and Type 2 (DMT1, DMT2) and to identify associations with markers of incipient nephropathy and kidney dysfunction. SUBJECTS AND METHODS A total of 205 subjects (43 DMT1 and 162 DMT2) with and without microalbuminuria and 26 non-diabetic controls were included. Fasting blood samples were collected and anthropometric parameters were measured. Fasting blood, lipid and renal profile were determined routinely. Blood thiamine concentration, its phosphate esters and urine thiamine were quantified using HPLC. RESULTS Blood thiamine concentrations (ng 1-1) were decreased by 75.7% and 49.6% in patients with DMT1 and DMT2, respectively [controls (54.8+/-11.4); DMT1 (41.5+/-17.9); DMT2 (27.2+/-12.7), p<0.001]. Among those with normo-albuminuria, urinary excretion of thiamine was significantly increased to 390.1 microg/ml and 1212.4 microg/ml in DMT1 and DMT2 respectively, as compared to controls (326.4 microg/ml). DMT1 and DMT2 patients with micro- albuminuria on the other hand had 2.5- and 3.4-fold increase in urinary excretion of thiamine compared to controls. CONCLUSION Low levels of blood thiamine are present in patients with DMT1 and DMT2, and are associated with increased thiamine clearance.
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Affiliation(s)
- O S Al-Attas
- Center of Excellence in Biotechnology Research, King Saud University, Riyadh, Kingdom of Saudi Arabia
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Chen P, Xia K, Zhao Z, Deng X, Yang T. Atorvastatin modulates the DDAH1/ADMA system in high-fat diet-induced insulin-resistant rats with endothelial dysfunction. Vasc Med 2012. [PMID: 23184902 DOI: 10.1177/1358863x12467492] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Dimethylarginine dimethyl-aminohydrolase 1 (DDAH1) is a metabolic enzyme for asymmetric dimethylarginine (ADMA), both of which are closely related to endothelial function. Endothelial dysfunction, a main risk factor of cardiovascular diseases, can be attributed to insulin resistance. We aimed to determine the effects of atorvastatin, an endothelium-protective drug, on DDAH1/ADMA in insulin-resistant rats. Insulin resistance in male Sprague-Dawley rats was induced with a high-fat diet for 8 weeks. Some rats received atorvastatin (30 mg/kg/day) for an additional 8 weeks. Insulin-resistant rats exhibited not only decreases in the DDAH activity and aortic expression of DDAH1 and sterol regulatory element-binding protein 1 (SREBP1) but also increases in plasma ADMA levels, all of which were inhibited by atorvastatin. Insulin sensitivity and DDAH activity showed a significant positive correlation. In conclusion, our results suggest that atorvastatin may modulate DDAH1/ADMA to improve endothelial function in insulin-resistant rats; SREBP1 may also play a role in this.
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Affiliation(s)
- Po Chen
- Cardiology Department, Xiangya Hospital, Central South University, Changsha, Hunan, PR China
| | - Ke Xia
- Cardiology Department, Xiangya Hospital, Central South University, Changsha, Hunan, PR China
- Institute of Molecular Medicine and Surgery (MMK), Rolf Luft Centrum, Karolinska Hospital, Stockholm, Sweden
| | - Zhenyu Zhao
- Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, PR China
| | - Xu Deng
- Cardiology Department, Xiangya Hospital, Central South University, Changsha, Hunan, PR China
| | - Tianlun Yang
- Cardiology Department, Xiangya Hospital, Central South University, Changsha, Hunan, PR China
- Institute of Hypertension, Central South University, Changsha, Hunan, PR China
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Kadian S, Mahadevan N, Balakumar P. Differential effects of low-dose fenofibrate treatment in diabetic rats with early onset nephropathy and established nephropathy. Eur J Pharmacol 2012; 698:388-96. [PMID: 23085026 DOI: 10.1016/j.ejphar.2012.10.012] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2012] [Revised: 09/28/2012] [Accepted: 10/06/2012] [Indexed: 01/13/2023]
Abstract
We have previously shown that low-dose fenofibrate treatment has an ability to prevent diabetes-induced nephropathy in rats. We investigated here the comparative pre- and post-treatment effects of low-dose fenofibrate (30 mg/kg/day p.o.) in diabetes-induced onset of nephropathy. Rats were made diabetics by single administration of streptozotocin (STZ, 55 mg/kg i.p.). The development of diabetic nephropathy was assessed biochemically and histologically. Moreover, lipid profile and renal oxidative stress were assessed. Diabetic rats after 8 weeks of STZ-administration developed apparent nephropathy by elevating serum creatinine, blood urea nitrogen and microproteinuria, and inducing glomerular-capsular wall distortion, mesangial expansion and tubular damage and renal oxidative stress. Fenofibrate (30 mg/kg/day p.o., 4 weeks) pretreatment (4 weeks after STZ-administration) markedly prevented diabetes-induced onset of diabetic nephropathy, while the fenofibrate (30 mg/kg/day p.o., 4 weeks) post-treatment (8 weeks after STZ-administration) was less-effective. However, both pre-and post fenofibrate treatments were effective in preventing diabetes-induced renal oxidative stress and lipid alteration in diabetic rats though the pretreatment was slightly more effective. Conversely, both pre-and post fenofibrate treatments did not alter elevated glucose levels in diabetic rats. It may be concluded that diabetes-induced oxidative stress and lipid alteration, in addition to a marked glucose elevation, play a detrimental role in the onset of nephropathy in diabetic rats. The pretreatment with low-dose fenofibrate might be a potential therapeutic approach in preventing the onset of nephropathy in diabetic subjects under the risk of renal disease induction. However, low-dose fenofibrate treatment might not be effective in treating the established nephropathy in diabetic subjects.
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Affiliation(s)
- Supriya Kadian
- Cardiovascular Pharmacology Division, Department of Pharmacology, Rajendra Institute of Technology and Sciences, Sirsa 125 055, India
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Morsy MA. Protective effect of lisinopril on hepatic ischemia/reperfusion injury in rats. Indian J Pharmacol 2012; 43:652-5. [PMID: 22144768 PMCID: PMC3229779 DOI: 10.4103/0253-7613.89820] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2011] [Revised: 05/11/2011] [Accepted: 08/31/2011] [Indexed: 01/24/2023] Open
Abstract
Objective: Ischemia/reperfusion (I/R) injury plays a key role in the pathogenesis of hepatic failure in several clinical settings such as liver resection or transplantation. Lisinopril, a widely prescribed drug for various cardiovascular conditions, has been reported to have diverse pharmacological properties. The aim of this study, therefore, was to evaluate a potential protective effect of lisinopril on hepatic I/R injury in rats. Materials and Methods: In anesthetized rats, partial hepatic ischemia was applied for one hour followed by two hours reperfusion. Biochemical analysis of serum and hepatic tissue was done. Hepatic tissue was also subjected to electron microscopy. Results: Pre-ischemic treatment with lisinopril (10 mg/kg) exerted protection against I/R-induced hepatocellular injury as evident by significant decrease in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin levels, along with hepatic lipid peroxidation, expressed as malondialdehyde content, with a concurrent increase in hepatic nitric oxide content as compared to I/R group. The electron microscopic examination indicated that lisinopril can effectively protect against hepatic I/R injury. Conclusion: Lisinopril provides a protection against hepatic I/R injury in rats. The protective effect is associated with reduction of oxidative stress-induced lipid peroxidation level and enhancement of nitric oxide availability.
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Affiliation(s)
- M A Morsy
- Department of Pharmacology, Faculty of Medicine, El-Minia University, El-Minia, Egypt
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Benfotiamine prevents increased β-amyloid production in HEK cells induced by high glucose. Neurosci Bull 2012; 28:561-6. [PMID: 22961478 DOI: 10.1007/s12264-012-1264-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2012] [Accepted: 04/13/2012] [Indexed: 01/21/2023] Open
Abstract
OBJECTIVE To determine whether high glucose enhances β-amyloid (Aβ) production in HEK293 Swedish mutant (APPsw) cells with Aβ precursor protein (APP) overexpression, and whether under this condition benfotiamine reduces the increased Aβ production. METHODS HEK293 APPsw cells were cultured with different concentrations of glucose for different times. The Aβ content in the supernatant was determined by ELISA. To investigate the mechanism by which benfotiamine reduced Aβ production, glycogen synthase kinase-3 (GSK-3) activity and expression were measured after the cells were cultured with 5.5 g/L glucose for 12 h. RESULTS With 1.0, 3.0, 4.5, 5.5, 6.5, 7.5, 8.5, or 10.5 g/L glucose, Aβ production by HEK293 APPsw cells was highest in the presence of 5.5 g/L glucose for 6 and 12 h. The difference in Aβ content between 5.5 and 1.0 g/L was most marked after incubation for 12 h. Benfotiamine at 20 and 40 μg/mL significantly reduced Aβ production in cells incubated with 5.5 g/L glucose for 12 h. Moreover, 40 μg/mL benfotiamine significantly enhanced the ratio of phosphorylated GSK-3 to total GSK-3, together with consistent down-regulation of GSK-3 activity. CONCLUSION High glucose increases Aβ production by HEK293 APPsw cells while benfotiamine prevents this increase. This is correlated with the modulation of GSK-3 activity.
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Zhang M, Chen L. Berberine in type 2 diabetes therapy: a new perspective for an old antidiarrheal drug? Acta Pharm Sin B 2012. [DOI: 10.1016/j.apsb.2012.06.004] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
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Jagadeesh G, Balakumar P, Stockbridge N. How well do aliskiren's purported mechanisms track its effects on cardiovascular and renal disorders? Cell Signal 2012; 24:1583-91. [DOI: 10.1016/j.cellsig.2012.04.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2012] [Accepted: 04/04/2012] [Indexed: 01/27/2023]
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Balakumar P, Taneja G. Fish oil and vascular endothelial protection: bench to bedside. Free Radic Biol Med 2012; 53:271-9. [PMID: 22584102 DOI: 10.1016/j.freeradbiomed.2012.05.005] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2011] [Revised: 03/16/2012] [Accepted: 05/03/2012] [Indexed: 02/07/2023]
Abstract
Fish oil is recommended for the management of hypertriglyceridemia and to prevent secondary cardiovascular disorders. Fish oil is a major source of ω-3-polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Clinical studies suggest that fish oil not only prevents the incidence of detrimental cardiovascular events, but also lowers the cardiovascular mortality rate. In addition to a classic lipid-lowering action, ω-3-PUFAs in fish oil could regulate blood pressure and enhance vascular integrity and compliance. Additionally, ω-3-PUFAs have the ability to protect vascular endothelial cells by decreasing oxidative stress, halting atherosclerotic events, and preventing vascular inflammatory and adhesion cascades. Intriguingly, recent studies have demonstrated that ω-3-PUFAs improve the function of vascular endothelium by enhancing the generation and bioavailability of endothelium-derived relaxing factor (nitric oxide) through upregulation and activation of endothelial nitric oxide synthase (eNOS). This certainly opens up a new area of research identifying potential mechanisms influencing fish oil-mediated functional regulatory action on vascular endothelium. We address in this review the potential of fish oil to prevent vascular endothelial dysfunction and associated cardiovascular disorders. Moreover, the mechanisms pertaining to fish oil-mediated eNOS activation and nitric oxide generation in improving endothelial function are delineated. We finally suggest the importance of further studies to determine the dose adjustment of fish oil with an optimal ratio of EPA and DHA for achieving consistent cardiovascular protection.
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Affiliation(s)
- Pitchai Balakumar
- Cardiovascular Pharmacology Division, Department of Pharmacology, Institute of Pharmacy, Rajendra Institute of Technology and Sciences, Sirsa 125 055, India.
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Kouroumichakis I, Papanas N, Zarogoulidis P, Liakopoulos V, Maltezos E, Mikhailidis DP. Fibrates: therapeutic potential for diabetic nephropathy? Eur J Intern Med 2012; 23:309-16. [PMID: 22560376 DOI: 10.1016/j.ejim.2011.12.007] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2011] [Revised: 12/04/2011] [Accepted: 12/18/2011] [Indexed: 12/30/2022]
Abstract
Despite intensive glucose-lowering treatment and advanced therapies for cardiovascular risk factors, such as hypertension and dyslipidaemia, diabetes mellitus with its macro- and microvascular complications remains a major health problem. Especially diabetic nephropathy is a leading cause of morbidity and mortality, and its prevalence is increasing. Peroxisome proliferator-activated receptor-α (PPAR-α), a member of a large nuclear receptor superfamily, is expressed in several tissues including the kidney. Recently, experimental data have suggested that PPAR-α activation plays a pivotal role in the regulation of fatty acid oxidation, lipid metabolism, inflammatory and vascular responses, and might regulate various metabolic and intracellular signalling pathways that lead to diabetic microvascular complications. This review examines the role of PPAR-α activation in diabetic nephropathy and summarises data from experimental and clinical studies on the emerging therapeutic potential of fibrates in diabetic nephropathy.
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Affiliation(s)
- I Kouroumichakis
- Outpatient Clinic of Obesity, Diabetes and Metabolism, Second Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece
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Artemisia campestris leaf extract alleviates early diabetic nephropathy in rats by inhibiting protein oxidation and nitric oxide end products. Pathol Res Pract 2012; 208:157-62. [DOI: 10.1016/j.prp.2012.01.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Revised: 12/12/2011] [Accepted: 01/11/2012] [Indexed: 02/02/2023]
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Are PPAR alpha agonists a rational therapeutic strategy for preventing abnormalities of the diabetic kidney? Pharmacol Res 2012; 65:430-6. [PMID: 22285932 DOI: 10.1016/j.phrs.2012.01.004] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2011] [Revised: 01/12/2012] [Accepted: 01/12/2012] [Indexed: 12/14/2022]
Abstract
The uncontrolled diabetes mellitus may result in the induction of diabetic nephropathy, one of the detrimental microvascular complications of diabetes mellitus. Diabetic nephropathy is associated with glomerular hypertrophy, glomerulosclerosis, tubulointerstitial fibrosis, mesangial cell expansion, followed by albuminuria and reduction in glomerular filtration rate. Indeed, no promising therapeutic options are available in the present clinical scenario to manage efficiently the diabetic nephropathy. Nevertheless, angiotensin converting enzyme inhibitors and angiotensin-II-AT(1) receptor blockers are currently employed to improve structural and functional status of the diabetic kidney. These interventions, however, are not optimal in improving overall outcomes of diabetic nephropathy. Hence, there is a continuing need of developing promising therapeutic interventions to manage this insidious condition adequately. Recent bench and clinical studies strongly suggest the potentials of peroxisome proliferator-activated receptor alpha (PPARα) agonists in the management of diabetic nephropathy by keeping the view that renal lipid accumulation-induced lipotoxicity is one of risk factors for nephropathy during chronic diabetes mellitus. As inflammation, oxidative stress and dyslipidemia are common consequences of renal dysfunction, PPARα agonists could serve as promising therapeutic agents for controlling the progression of diabetic nephropathy. In fact, fenofibrate, a hypolipidemic agent acts as a PPARα agonist, reduced renal lipotoxicity, inflammation, fibrosis and oxidative stress, and subsequently prevented the symptoms of diabetic nephropathy. However, fenofibrate has been shown to cause renal dysfunction in established renal disorders. The present review addressed the rationale of employing PPARα agonists in the management of diabetic nephropathy.
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El-Seweidy MM, Mohamed HE, Asker ME, Atteia HH. Nicotine and vascular endothelial dysfunction in female ovariectomized rats: role of estrogen replacement therapy. J Pharm Pharmacol 2012; 64:108-119. [PMID: 22150678 DOI: 10.1111/j.2042-7158.2011.01377.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVES The protective effects of estrogen replacement therapy (ERT) against oxidative injury and endothelial dysfunction in the aortic tissues induced with nicotine in ovariectomized (OVX) rats were investigated. METHODS Female rats were divided into a sham-operated group (n = 8) and four groups in which OVX rats received either vehicle (0.1 ml sesame oil, i.m., n = 8), or nicotine (0.1 mg/kg, s.c., n = 8), or estradiol benzoate (0.1 mg/kg, i.m., n = 8), or both nicotine and estradiol benzoate (n = 8) starting at week 5 after the surgery and continuing for the following 6 weeks. KEY FINDINGS ERT was effective in preventing the rise in plasma lipid profile, atherogenic index and the level of induced endothelin-1 (ET-1) in nicotine-treated OVX rats. It also reduced aortic malondialdehyde, hydroxyproline levels, calcium content and caspase-3 expression induced in nicotine-treated OVX rats. ERT increased serum estradiol, high-density lipoprotein cholesterol and nitric oxide levels in nicotine-treated OVX rats. Furthermore, ERT was effective in restoring reduced glutathione and cyclic guanosine monophosphate contents and endothelial nitric oxide synthase expression in aortic tissues of nicotine-treated OVX rats. CONCLUSIONS Short-term ERT could be a promising therapeutic strategy to minimize nicotine-induced oxidative stress and vascular endothelial dysfunction in menopausal women subjected to environmental smoke.
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Affiliation(s)
- Mohamed M El-Seweidy
- Department of Biochemistry, Faculty of Pharmacy, University of Zagazig, Zagazig, Egypt
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Chakkarwar VA. Fenofibrate attenuates nicotine-induced vascular endothelial dysfunction in the rat. Vascul Pharmacol 2011; 55:163-8. [PMID: 21864717 DOI: 10.1016/j.vph.2011.08.215] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2010] [Revised: 07/31/2011] [Accepted: 08/08/2011] [Indexed: 12/23/2022]
Abstract
The study has been designed to investigate the effect of fenofibrate on nicotine-induced vascular endothelial dysfunction (VED) in rats. Nicotine (2 mg/kg/day, i.p., 4 weeks) was administered to produce VED in rats. The development of VED was assessed by employing isolated aortic ring preparation and estimating serum and aortic concentration of nitrite/nitrate. Further, the integrity of vascular endothelium was assessed using the scanning electron microscopy of thoracic aorta. The expression of mRNA for p22phox and eNOS was assessed by using reverse transcriptase-polymerase chain reaction. Serum thiobarbituric acid reactive substances concentration (TBARS) and aortic superoxide anion concentration were estimated to assess oxidative stress. Moreover, the serum lipid profile was assessed by estimating serum cholesterol, triglycerides and high density lipoprotein. The administration of nicotine induces VED by increased oxidative stress, altered lipid profile and impaired the integrity of vascular endothelium as assessed in terms of decrease in expression of mRNA for endothelial nitric oxide synthase (eNOS), impairing the integrity of vascular endothelium and subsequently decreasing serum and aortic nitrite/nitrate and attenuating acetylcholine-induced endothelium dependent relaxation. Further, nicotine produced oxidative stress, assessed in terms of increase in serum TBARS and aortic superoxide anion generation and increase in expression of mRNA for p22phox. Nicotine altered the lipid profile by increasing the serum cholesterol, triglycerides and decreasing the high density lipoprotein. However, treatment with fenofibrate (32 mg/kg, p.o.) markedly prevented nicotine-induced VED by decreasing oxidative stress and improving integrity of vascular endothelium, normalising the altered lipid profile, increasing the concentration of serum and aortic nitrite/nitrate, enhancing the acetylcholine-induced endothelium dependent relaxation and decreasing serum TBARS and aortic superoxide anion generation. Thus, it may be concluded that fenofibrate has vascular protecting potential, by improving the integrity and function of vascular endothelium.
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Affiliation(s)
- Vishal Arvind Chakkarwar
- Cardiovascular Pharmacology Division, I.S.F. Institute of Pharmaceutical Sciences and Drug Research, Moga 142 001, India.
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Rabbani N, Thornalley PJ. Emerging role of thiamine therapy for prevention and treatment of early-stage diabetic nephropathy. Diabetes Obes Metab 2011; 13:577-83. [PMID: 21342411 DOI: 10.1111/j.1463-1326.2011.01384.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Thiamine supplementation may prevent and reverse early-stage diabetic nephropathy. This probably occurs by correcting diabetes-linked increased clearance of thiamine, maintaining activity and expression of thiamine pyrophosphate-dependent enzymes that help counter the adverse effects of high glucose concentrations-particularly transketolase. Evidence from experimental and clinical studies suggests that metabolism and clearance of thiamine is disturbed in diabetes leading to tissue-specific thiamine deficiency in the kidney and other sites of development of vascular complications. Thiamine supplementation prevented the development of early-stage nephropathy in diabetic rats and reversed increased urinary albumin excretion in patients with type 2 diabetes and microalbuminuria in two recent clinical trials. The thiamine monophosphate prodrug, Benfotiamine, whilst preventing early-stage development of diabetic nephropathy experimentally, has failed to produce similar clinical effect. The probable explanations for this are discussed. Further definitive trials for prevention of progression of early-stage diabetic nephropathy by thiamine are now required.
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Affiliation(s)
- N Rabbani
- Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, University Hospital, Coventry, UK.
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Page GLJ, Laight D, Cummings MH. Thiamine deficiency in diabetes mellitus and the impact of thiamine replacement on glucose metabolism and vascular disease. Int J Clin Pract 2011; 65:684-90. [PMID: 21564442 DOI: 10.1111/j.1742-1241.2011.02680.x] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Despite the targeting of traditional risk factors for cardiovascular disease, disease burden has not been completely eliminated. Thiamine is an essential cofactor in carbohydrate metabolism and individuals with diabetes are thiamine deficient. The pathophysiology of recognised complications of thiamine deficiency is similar to that underlying atherosclerosis and the metabolic syndrome, namely oxidative stress, inflammation and endothelial dysfunction. This review examines the mechanisms by which thiamine deficiency occurs in individuals with diabetes, how this deficiency leads to hyperglycaemic-induced damage, and the effect of thiamine replacement on vascular disease, endothelial function and oxidative stress. Thiamine administration can prevent the formation of harmful by-products of glucose metabolism, reduce oxidative stress and improve endothelial function. The potential benefit of long-term replacement in those with diabetes is not yet known but may reduce cardiovascular risk and angiopathic complications.
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Affiliation(s)
- G L J Page
- Academic Department of Diabetes and Endocrinology, Queen Alexandra Hospital, Portsmouth, UK.
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Kihm LP, Müller-Krebs S, Klein J, Ehrlich G, Mertes L, Gross ML, Adaikalakoteswari A, Thornalley PJ, Hammes HP, Nawroth PP, Zeier M, Schwenger V. Benfotiamine protects against peritoneal and kidney damage in peritoneal dialysis. J Am Soc Nephrol 2011; 22:914-26. [PMID: 21511829 DOI: 10.1681/asn.2010070750] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Residual renal function and the integrity of the peritoneal membrane contribute to morbidity and mortality among patients treated with peritoneal dialysis. Glucose and its degradation products likely contribute to the deterioration of the remnant kidney and damage to the peritoneum. Benfotiamine decreases glucose-induced tissue damage, suggesting the potential for benefit in peritoneal dialysis. Here, in a model of peritoneal dialysis in uremic rats, treatment with benfotiamine decreased peritoneal fibrosis, markers of inflammation, and neovascularization, resulting in improved characteristics of peritoneal transport. Furthermore, rats treated with benfotiamine exhibited lower expression of advanced glycation endproducts and their receptor in the peritoneum and the kidney, reduced glomerular and tubulointerstitial damage, and less albuminuria. Increased activity of transketolase in tissue and blood contributed to the protective effects of benfotiamine. In primary human peritoneal mesothelial cells, the addition of benfotiamine led to enhanced transketolase activity and decreased expression of advanced glycation endproducts and their receptor. Taken together, these data suggest that benfotiamine protects the peritoneal membrane and remnant kidney in a rat model of peritoneal dialysis and uremia.
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Affiliation(s)
- Lars P Kihm
- Department of Nephrology, University of Heidelberg, Im Neuenheimer Feld 162, 69120 Heidelberg, Germany.
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Levi M. Nuclear receptors in renal disease. Biochim Biophys Acta Mol Basis Dis 2011; 1812:1061-7. [PMID: 21511032 DOI: 10.1016/j.bbadis.2011.04.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2011] [Revised: 03/21/2011] [Accepted: 04/06/2011] [Indexed: 02/07/2023]
Abstract
Diabetes is the leading cause of end-stage renal disease in developed countries. In spite of excellent glucose and blood pressure control, including administration of angiotensin converting enzyme inhibitors and/or angiotensin II receptor blockers, diabetic nephropathy still develops and progresses. The development of additional protective therapeutic interventions is, therefore, a major priority. Nuclear hormone receptors regulate carbohydrate metabolism, lipid metabolism, the immune response, and inflammation. These receptors also modulate the development of fibrosis. As a result of their diverse biological effects, nuclear hormone receptors have become major pharmaceutical targets for the treatment of metabolic diseases. The increasing prevalence of diabetic nephropathy has led intense investigation into the role that nuclear hormone receptors may have in slowing or preventing the progression of renal disease. This role of nuclear hormone receptors would be associated with improvements in metabolism, the immune response, and inflammation. Several nuclear receptor activating ligands (agonists) have been shown to have a renal protective effect in the context of diabetic nephropathy. This review will discuss the evidence regarding the beneficial effects of the activation of several nuclear, especially the vitamin D receptor (VDR), farnesoid X receptor (FXR), and peroxisome-proliferator-associated receptors (PPARs) in preventing the progression of diabetic nephropathy and describe how the discovery and development of compounds that modulate the activity of nuclear hormone receptors may provide potential additional therapeutic approaches in the management of diabetic nephropathy. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.
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Affiliation(s)
- Moshe Levi
- Department of Medicine, Division of Nephrology and Hypertension, University of Colorado Denver,CO 80045, USA.
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Asanuma H, Kitakaze M. Does the treatment of both hypertension and cardiac hypertrophy not only prevent but also treat acute myocardial infarction? Circ J 2011; 75:1061-2. [PMID: 21467665 DOI: 10.1253/circj.cj-11-0292] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Alcázar-Leyva S, Alvarado-Vásquez N. Could thiamine pyrophosphate be a regulator of the nitric oxide synthesis in the endothelial cell of diabetic patients? Med Hypotheses 2011; 76:629-31. [PMID: 21288652 DOI: 10.1016/j.mehy.2011.01.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2010] [Accepted: 01/09/2011] [Indexed: 12/12/2022]
Abstract
Thiamine (Vitamin B1) is considered an essential micronutrient for humans; its deficient intake brings about the Wernicke-Korsakoff syndrome (encephalopathy and psychosis) or beriberi (a neurological and cardiovascular disease). Once thiamine enters the cells it is phosphorylated by thiamine pyrophosphokinase (TPPK), and converted into the coenzyme thiamine pyrophosphate (TPP), the active form of thiamine. TPP is a relevant cofactor for transketolase (TK), α-ketoglutarate dehydrogenase (αKDH), and pyruvate dehydrogenase (PDH), all these enzymes are fundamental for glucose metabolism. Diabetes mellitus (DM), however, is considered both a deficient thiamine and deficient energy state, as a consequence of the limited TPP synthesis. Recent evidences have shown that the administration of thiamine or lipid-soluble derivatives, such as benfotiamine (developed to improve the bioavailability of thiamine), has positive effects in the diabetic patient (after thiamine is transformed into TPP). For this reason, administration of supplements with TPP in the diabetic patients is recommended to avoid complications, like neuropathy and nephropathy. It has been suggested that these beneficial effects are a consequence of the activation of TK (pentose pathway) or the PDH complex in mitochondria. Nitric oxide (NO) is synthesized by the endothelial cell and is also an important element for the viability and functionality of this cell type. However, in the DM patient, a deficient synthesis of NO has been reported. It is relevant to mention that recent evidences have led to propose mitochondrial activity as an important regulator of nitric oxide synthesis (ON). We consider that the exogenous administration of TPP facilitates the utilization of this molecule, regulating some metabolic processes such as phosphorylation of thiamine by TPPK, energy consumption (ATP), as well as mitochondrial activity, inducing eventually NO synthesis. If this is confirmed, the administration of TPP to the diabetic patient would provide additional protection to endothelial cells, reducing the risk of vascular damage, to which the diabetic patient is highly susceptible.
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Fenofibrate treatment enhances antioxidant status and attenuates endothelial dysfunction in streptozotocin-induced diabetic rats. EXPERIMENTAL DIABETES RESEARCH 2010; 2010:828531. [PMID: 21234421 PMCID: PMC3014714 DOI: 10.1155/2010/828531] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2010] [Revised: 11/21/2010] [Accepted: 11/24/2010] [Indexed: 01/11/2023]
Abstract
Diabetic endothelial dysfunction is accompanied by increased oxidative stress and upregulated proinflammatory and inflammatory mediators in the vasculature. Activation of peroxisome proliferator-activated receptor-alpha (PPAR-α) results in antioxidant and anti-inflammatory effects. This study was designed to investigate the effect of fenofibrate, a PPAR-α activator, on the endothelial dysfunction, oxidative stress, and inflammation in streptozotocin diabetic rats. Diabetic rats received fenofibrate (150 mg kg−1 day−1) for 4 weeks. Fenofibrate treatment restored the impaired endothelium-dependent relaxation and increased basal nitric oxide availability in diabetic aorta, enhanced erythrocyte/liver superoxide dismutase and catalase levels, ameliorated the abnormal serum/aortic thiobarbituric acid reactive substances, and prevented the increased aortic myeloperoxidase without a significant change in serum total cholesterol and triglyceride levels. It did not affect the decreased total homocysteine level and the increased tumor necrosis factor-α level in the serum of diabetic rats. Fenofibrate-induced prevention of the endothelial function seems to be related to its potential antioxidant and antiinflammatory activity.
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Hiukka A, Maranghi M, Matikainen N, Taskinen MR. PPARalpha: an emerging therapeutic target in diabetic microvascular damage. Nat Rev Endocrinol 2010; 6:454-63. [PMID: 20567246 DOI: 10.1038/nrendo.2010.89] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The global pandemic of diabetes mellitus portends an alarming rise in the prevalence of microvascular complications, despite advanced therapies for hyperglycemia, hypertension and dyslipidemia. Peroxisome proliferator-activated receptor alpha (PPARalpha) is expressed in organs affected by diabetic microvascular disease (retina, kidney and nerves), and its expression is regulated specifically in these tissues. Experimental evidence suggests that PPARalpha activation attenuates or inhibits several mediators of vascular damage, including lipotoxicity, inflammation, reactive oxygen species generation, endothelial dysfunction, angiogenesis and thrombosis, and thus might influence intracellular signaling pathways that lead to microvascular complications. PPARalpha has emerged as a novel target to prevent microvascular disease, via both its lipid-related and lipid-unrelated actions. Despite strong experimental evidence of the potential benefits of PPARalpha agonists in the prevention of vascular damage, the evidence from clinical studies in patients with diabetes mellitus remains limited. Promising findings from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study on microvascular outcomes are countered by elevations in participants' homocysteine and creatinine levels that might potentially attenuate the benefits of PPARalpha activation. This Review focuses on the role of PPARalpha activation in diabetic microvascular disease and highlights the available experimental and clinical evidence from studies of PPARalpha agonists.
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Affiliation(s)
- Anne Hiukka
- Division of Cardiology, Department of Medicine, Helsinki University Central Hospital and Biomedicum, Haartmaninkatu 8, 00029 Helsinki, Finland
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