|
1
|
Darkwah E, Aryal P, Zhang C, Musgrave CB, Goddard WA, Reddy VP. Instantaneous Hydrolysis of Methyl Paraoxon Nerve Agent Simulant Is Catalyzed by Nontoxic Aminoguanidine Imines. ACS OMEGA 2025; 10:12294-12305. [PMID: 40191310 PMCID: PMC11966261 DOI: 10.1021/acsomega.4c09946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 02/11/2025] [Accepted: 02/14/2025] [Indexed: 04/09/2025]
Abstract
Exposure to organophosphate-based nerve agents and pesticides poses health and security threats to civilians, soldiers, and first responders. Thus, there is a need to develop effective decontamination agents that are nonhazardous to human health. To address this, we demonstrate that instantaneous hydrolysis of methyl paraoxon (Me-POX), a nerve agent simulant, can be achieved in the presence of aminoguanidine imines at pH 10: ● the pyridine-4-aldehyde aminoguanidine-imine (1) and ● the 2,3-butanedione aminoguanidine-imine (2). The hydrolysis of Me-POX under these conditions is substantially faster than that of the state-of-the-art decontaminating agent, Dekon-139 (2,3-butanedione oxime, potassium salt). Furthermore, Dekon-139 shows adverse effects when applied on skin surfaces, making it of great interest to develop safer but effective decontaminating agents for neutralizing nerve agents and pesticides exposed to skin-surface areas. Our pharmaceutically relevant aminoguanidine derivatives serve as rather nontoxic and safe decontaminating agents for organophosphate-based nerve agents and pesticides. The hydrolytic degradation products of Me-POX by our aminoguanidine-based imines and Dekon-139 are pH dependent. At pH > 10, Me-POX is hydrolyzed to give dimethyl phosphate as the exclusive product, whereas at pH < 9, the major product of hydrolysis is methyl 4-nitrophenyl phosphate (M4NP). We applied Quantum Mechanics calculations to investigate the mechanism of this dramatically accelerated decontamination process. We predict that in the rate-determining transition state, both 1 and 2 stabilize the reaction center through hydrogen bonding. Compared to Dekon-139, the rate constants of the rate-determine steps (RDS) are predicted to be over 9,000 times larger for 1 and over 600 times larger for 2, explaining the improvement. Quantum Mechanics calculations rationalize the pH-dependent hydrolysis products of the Me-POX in the gas phase, and gauge-including atomic orbital (GIAO)-31P NMR chemical shift calculations confirm the experimental values.
Collapse
Affiliation(s)
- Emmanuel
Kingsley Darkwah
- Department
of Chemistry, Missouri University of Science
and Technology, Rolla, Missouri 65409, United States
| | - Puspa Aryal
- Department
of Chemistry, Missouri University of Science
and Technology, Rolla, Missouri 65409, United States
| | - Chi Zhang
- Materials
and Process Simulation Center (MSC), California
Institute of Technology, Pasadena, California 91125, United States
| | - Charles B. Musgrave
- Materials
and Process Simulation Center (MSC), California
Institute of Technology, Pasadena, California 91125, United States
| | - William A. Goddard
- Materials
and Process Simulation Center (MSC), California
Institute of Technology, Pasadena, California 91125, United States
| | - V. Prakash Reddy
- Department
of Chemistry, Missouri University of Science
and Technology, Rolla, Missouri 65409, United States
- Materials
and Process Simulation Center (MSC), California
Institute of Technology, Pasadena, California 91125, United States
| |
Collapse
|
|
2
|
Zhang P, Liu Z, Ma G, Wang J, Shao J, Ma C, Wang L, Ma C. Huaiqihuang (HQH) protects podocytes from high glucose-induced apoptosis and inflammation response by regulating PI3K/AKT/mTOR pathway. Arch Physiol Biochem 2025; 131:285-292. [PMID: 39329410 DOI: 10.1080/13813455.2024.2407552] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 08/03/2024] [Accepted: 09/16/2024] [Indexed: 09/28/2024]
Abstract
Diabetic kidney disease (DKD) is one of the common microvascular complications of diabetes, and there are still lack of effective treatments. Huaiqihuang (HQH) is a kind of traditional Chinese medicine mixed preparation, which is mainly made of Trametes robiniophila Murr, Fructus Lycii, and Polygonatum sibiricumhas. It has been shown to be effective in the treatment of DKD, but the specific mechanism has not been fully elucidated. Our results showed that HQH increased the protein expressions of synaptopodin, podocin, WT-1, and Bcl-2, decreased the protein expressions of Bax and cleaved-casepase-3, and activated the NF-ĸB and PI3K/AKT/mTOR pathway in MPC5 cells exposed to high-glucose (HG). Real-time PCR results showed that HQH reduced the mRNA expression of TNF-α, IL-1β, MCP-1, and IL-6. In conclusion, our results showed that HQH may attenuate podocyte injury by inhibiting MPC5 cell apoptosis induced by HG and NF-κB-mediated inflammation response through activation of the PI3K/AKT/mTOR pathway.
Collapse
Affiliation(s)
- Peipei Zhang
- Department of Nephrology, The Fifth Clinical Medical College of Shanxi Medical University, Fifth Hospital of Shanxi Medical University, Taiyuan, PR China
- Shanxi Provincial Key Laboratory of Kidney Disease, Shanxi Provincial People's Hospital, Taiyuan, PR China
| | - Zhilong Liu
- Hebei Key Laboratory of Integrated Traditional and Western Medicine in Osteoarthrosis Research (Preparing), Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Cangzhou, China
| | - Guiqiao Ma
- Shanxi Provincial Key Laboratory of Kidney Disease, Shanxi Provincial People's Hospital, Taiyuan, PR China
- The Third Clinical College, Shanxi University of Chinese Medicine, Jinzhong, PR China
| | - Junwei Wang
- Shanxi Provincial Key Laboratory of Kidney Disease, Shanxi Provincial People's Hospital, Taiyuan, PR China
- The Third Clinical College, Shanxi University of Chinese Medicine, Jinzhong, PR China
| | - Jing Shao
- Department of Nephrology, The Fifth Clinical Medical College of Shanxi Medical University, Fifth Hospital of Shanxi Medical University, Taiyuan, PR China
- Shanxi Provincial Key Laboratory of Kidney Disease, Shanxi Provincial People's Hospital, Taiyuan, PR China
| | - Chaojing Ma
- Department of Nephrology, The Fifth Clinical Medical College of Shanxi Medical University, Fifth Hospital of Shanxi Medical University, Taiyuan, PR China
- Shanxi Provincial Key Laboratory of Kidney Disease, Shanxi Provincial People's Hospital, Taiyuan, PR China
| | - Liping Wang
- Department of Nephrology, The Fifth Clinical Medical College of Shanxi Medical University, Fifth Hospital of Shanxi Medical University, Taiyuan, PR China
- Shanxi Provincial Key Laboratory of Kidney Disease, Shanxi Provincial People's Hospital, Taiyuan, PR China
| | - Chanjuan Ma
- Department of Nephrology, The Fifth Clinical Medical College of Shanxi Medical University, Fifth Hospital of Shanxi Medical University, Taiyuan, PR China
- Shanxi Provincial Key Laboratory of Kidney Disease, Shanxi Provincial People's Hospital, Taiyuan, PR China
- The Third Clinical College, Shanxi University of Chinese Medicine, Jinzhong, PR China
- Department of Nephrology, Shanxi Provincial People's Hospital, Taiyuan, PR China
| |
Collapse
|
|
3
|
Mirani M, Bahmanpour S, Masjedi F, Derakhshan Z, Dara M, Nasr-Esfahani MH, Tabei SMB. Pyridoxamine protects human granulosa cells against advanced glycation end-products-induced steroidogenesis disturbances. Mol Biol Rep 2023; 50:8537-8549. [PMID: 37642758 DOI: 10.1007/s11033-023-08723-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 07/31/2023] [Indexed: 08/31/2023]
Abstract
BACKGROUND Ovarian advanced glycation end-products (AGEs) accumulation is associated with ovarian granulosa cells (GCs) dysfunction. Vitamin B6 derivatives positively affected reproduction. The current study was conducted to elucidate the AGEs effects on human luteinized mural GCs steroidogenesis in the presence or absence of pyridoxamine (PM). METHODS AND RESULTS Isolated GCs of 50 healthy women were divided into four parts and treated with media alone (Control), PM alone, or human glycated albumin (HGA) with/without PM. Main steroidogenic enzymes and hormones were assessed by qRT-PCR and ELISA. The AGE receptor (RAGE) protein was also determined using Western blotting. The non-toxic concentration of HGA increased the expression of RAGE, StAR, 3β-HSD, and 17β-HSD (P < 0.0001 for all) but decreased the expression of CYP19A1 at mRNA levels. The increased RAGE protein expression was also confirmed by western blot analysis. These effects resulted in declined estradiol (E2), slightly, and a sharp rise in progesterone (P4) and testosterone (T) levels, respectively. PM, on its own, ameliorated the HGA-altered enzyme expression and, thereby, corrected the aberrant levels of E2, P4, and T. These effects are likely mediated by regulating the RAGE gene and protein expression. CONCLUSION This study indicates that hormonal dysfunctions induced by the AGEs-RAGE axis in luteinized GCs are likely rectified by PM treatment. This effect is likely acquired by reduced expression of RAGE. A better understanding of how AGEs and PM interact in ovarian physiology and pathology may lead to more targeted therapy for treating ovarian dysfunction.
Collapse
Affiliation(s)
- Maryam Mirani
- Department of Reproductive Biology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Soghra Bahmanpour
- Department of Reproductive Biology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Anatomical Sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fatemeh Masjedi
- Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Derakhshan
- Department of Reproductive Biology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahintaj Dara
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Hossein Nasr-Esfahani
- Department of Animal Biotechnology, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.
| | - Seyed Mohammad Bagher Tabei
- Department of Reproductive Biology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.
- Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, 7134845794, Iran.
| |
Collapse
|
|
4
|
Jaafarinia A, Kafami B, Sahebnasagh A, Saghafi F. Evaluation of therapeutic effects of crocin in attenuating the progression of diabetic nephropathy: a preliminary randomized triple-blind placebo-controlled trial. BMC Complement Med Ther 2022; 22:262. [PMID: 36209091 PMCID: PMC9548209 DOI: 10.1186/s12906-022-03744-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 09/29/2022] [Indexed: 11/30/2022] Open
Abstract
Background Diabetic nephropathy (DN) is one of the most important complications of type 2 diabetes (T2DM). Oxidative stress and inflammatory cytokines play an essential role in the development and progression of DN. Despite adopting appropriate therapies, many patients with DN progress to end-stage renal disease (ESRD). Therefore, exploring innovative strategies for better management of DN is crucial. Crocin, a natural compound found in saffron, has profound antioxidant, antifibrotic and anti-inflammatory properties. This study aimed to evaluate the therapeutic effects of crocin in attenuation of the progression of DN. Methods In this randomized, triple-blind, placebo-controlled clinical trial, 44 patients with T2DM and microalbuminuria were randomly assigned to receive either crocin (15 mg/day) or a placebo for 90 days. Eventually, 40 patients completed the study: 21 patients in the crocin group and 19 in the placebo group. The primary outcome was a change in urine Albumin-to-Creatinine Ratio (uACR) from baseline to the end of the treatment period. We also evaluated metabolic, anthropometric, and biochemical parameters as the secondary outcomes. Results The results of the present study showed that uACR increased in both groups, but the increment was not significantly higher in the crocin group compared with the placebo. Serum levels of transforming growth factor-β (TGF-β) decreased in the crocin group and increased in the placebo group, but none of these changes was significant. Crocin significantly reduced triglyceride (TG) as an important metabolic parameter (P-Value = 0.03). Conclusion This study has shown that crocin may be a safe and potential adjunct to conventional therapies for DN patients but because of our limitations such as short duration of the treatment period, and prescribing low doses of crocin, we could not achieve the significant level.
Collapse
Affiliation(s)
- Asma Jaafarinia
- grid.412505.70000 0004 0612 5912Department of nephrology, Shahid Rahnemoon hospital, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran ,grid.412505.70000 0004 0612 5912Diabetes Research Center, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
| | - Behzad Kafami
- grid.412505.70000 0004 0612 5912Pharmaceutical Sciences Research Center, School of Pharmacy, Student Research Committee, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
| | - Adeleh Sahebnasagh
- grid.464653.60000 0004 0459 3173Department of Internal Medicine, Clinical Research Center, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Fatemeh Saghafi
- grid.412505.70000 0004 0612 5912Department of Clinical Pharmacy, School of Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
| |
Collapse
|
|
5
|
Advanced Glycation End Products in Health and Disease. Microorganisms 2022; 10:microorganisms10091848. [PMID: 36144449 PMCID: PMC9501837 DOI: 10.3390/microorganisms10091848] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/07/2022] [Accepted: 09/09/2022] [Indexed: 11/18/2022] Open
Abstract
Advanced glycation end products (AGEs), formed through the nonenzymatic reaction of reducing sugars with the side-chain amino groups of lysine or arginine of proteins, followed by further glycoxidation reactions under oxidative stress conditions, are involved in the onset and exacerbation of a variety of diseases, including diabetes, atherosclerosis, and Alzheimer’s disease (AD) as well as in the secondary stages of traumatic brain injury (TBI). AGEs, in the form of intra- and interprotein crosslinks, deactivate various enzymes, exacerbating disease progression. The interactions of AGEs with the receptors for the AGEs (RAGE) also result in further downstream inflammatory cascade events. The overexpression of RAGE and the AGE-RAGE interactions are especially involved in cases of Alzheimer’s disease and other neurodegenerative diseases, including TBI and amyotrophic lateral sclerosis (ALS). Maillard reactions are also observed in the gut bacterial species. The protein aggregates found in the bacterial species resemble those of AD and Parkinson’s disease (PD), and AGE inhibitors increase the life span of the bacteria. Dietary AGEs alter the gut microbiota composition and elevate plasma glycosylation, thereby leading to systemic proinflammatory effects and endothelial dysfunction. There is emerging interest in developing AGE inhibitor and AGE breaker compounds to treat AGE-mediated pathologies, including diabetes and neurodegenerative diseases. Gut-microbiota-derived enzymes may also function as AGE-breaker biocatalysts. Thus, AGEs have a prominent role in the pathogenesis of various diseases, and the AGE inhibitor and AGE breaker approach may lead to novel therapeutic candidates.
Collapse
|
|
6
|
Dehnad A, Fan W, Jiang JX, Fish SR, Li Y, Das S, Mozes G, Wong KA, Olson KA, Charville GW, Ali M, Török NJ. AGER1 downregulation associates with fibrosis in nonalcoholic steatohepatitis and type 2 diabetes. J Clin Invest 2021; 130:4320-4330. [PMID: 32657776 DOI: 10.1172/jci133051] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 05/05/2020] [Indexed: 12/25/2022] Open
Abstract
Type 2 diabetes is clinically associated with progressive necroinflammation and fibrosis in nonalcoholic steatohepatitis (NASH). Advanced glycation end-products (AGEs) accumulate during prolonged hyperglycemia, but the mechanistic pathways that lead to accelerated liver fibrosis have not been well defined. In this study, we show that the AGEs clearance receptor AGER1 was downregulated in patients with NASH and diabetes and in our NASH models, whereas the proinflammatory receptor RAGE was induced. These findings were associated with necroinflammatory, fibrogenic, and pro-oxidant activity via the NADPH oxidase 4. Inhibition of AGEs or RAGE deletion in hepatocytes in vivo reversed these effects. We demonstrate that dysregulation of NRF2 by neddylation of cullin 3 was linked to AGER1 downregulation and that induction of NRF2 using an adeno-associated virus-mediated approach in hepatocytes in vivo reversed AGER1 downregulation, lowered the level of AGEs, and improved proinflammatory and fibrogenic responses in mice on a high AGEs diet. In patients with NASH and diabetes or insulin resistance, low AGER1 levels were associated with hepatocyte ballooning degeneration and ductular reaction. Collectively, prolonged exposure to AGEs in the liver promotes an AGER1/RAGE imbalance and consequent redox, inflammatory, and fibrogenic activity in NASH.
Collapse
Affiliation(s)
- Ali Dehnad
- Gastroenterology and Hepatology, Stanford University, Stanford, and VA Palo Alto, California, USA
| | - Weiguo Fan
- Gastroenterology and Hepatology, Stanford University, Stanford, and VA Palo Alto, California, USA
| | | | | | - Yuan Li
- Gastroenterology and Hepatology, Stanford University, Stanford, and VA Palo Alto, California, USA
| | - Suvarthi Das
- Gastroenterology and Hepatology, Stanford University, Stanford, and VA Palo Alto, California, USA
| | - Gergely Mozes
- Gastroenterology and Hepatology, Stanford University, Stanford, and VA Palo Alto, California, USA
| | | | - Kristin A Olson
- Department of Pathology, UC Davis Medical Center, Sacramento, California, USA
| | | | - Mohammed Ali
- Department of Surgery, UC Davis Medical Center, Sacramento, California, USA
| | - Natalie J Török
- Gastroenterology and Hepatology, Stanford University, Stanford, and VA Palo Alto, California, USA
| |
Collapse
|
|
7
|
Zhang L, Xue S, Hou J, Chen G, Xu ZG. Endothelin receptor antagonists for the treatment of diabetic nephropathy: A meta-analysis and systematic review. World J Diabetes 2020; 11:553-566. [PMID: 33269066 PMCID: PMC7672789 DOI: 10.4239/wjd.v11.i11.553] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 08/22/2020] [Accepted: 10/15/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Diabetic nephropathy (DN) is the main cause of chronic kidney disease and end-stage renal disease worldwide. Although available clinical trials have shown that endothelin receptor (ER) antagonists may be a novel and beneficial drug for DN, no consistent conclusions regarding their sufficient effectiveness and safety for patients with DN have been presented. AIM To assess the effectiveness and safety of ER antagonists among patients with DN. METHODS The EMBASE, PubMed, MEDLINE, Cochrane, and ClinicalTrials.gov databases were searched without any language restrictions. Relative risks with 95% confidence intervals (CIs) for dichotomous data and mean differences or standardized mean difference with 95%CIs for continuous data were calculated using Review Manager 5.3 software. Publication bias was assessed using Egger's test with Stata/SE software. RESULTS We enrolled seven studies with six data sets and 5271 participants. The ER antagonists group showed a significantly greater reduction in albuminuria and more patients with 40% reduction in urinary albumin-to-creatinine ratio than the control group (P < 0.0001 and P = 0.02, respectively). Subgroup analysis for reductions in estimated glomerular filtration rate (eGFR) showed that for the middle-dosage subgroup, the ER antagonists group exhibited lower eGFR reduction than the control group (P < 0.00001; mean difference, 0.70 95%CI: 0.66, 0.74). Moreover, significant reductions in systolic and diastolic blood pressure were observed in the invention group. CONCLUSION ER blockades combined with angiotensin converting enzyme inhibitor /angiotensin II type 1 receptor blockers may be an effective treatment to lower blood pressure and reduce proteinuria in DN with declined eGFR. However, attention should be given to adverse events, including cardiac failure, anemia, and hypoglycemia, as well as serious adverse events.
Collapse
Affiliation(s)
- Li Zhang
- Department of Nephrology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Shuai Xue
- Department of Thyroid Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Jie Hou
- Department of Nephrology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Guang Chen
- Department of Thyroid Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Zhong-Gao Xu
- Department of Nephrology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| |
Collapse
|
|
8
|
Kharazmkia A, Ziaie S, Ahmadpoor P, Moradi O, Khoshdel A, Pour-Reza-Gholi F, Samavat S, Samadian F, Nafar M. A Triple-Blind Randomized Controlled Trial on Impacts of Pioglitazone on Oxidative Stress Markers in Diabetic Kidney Transplant Recipients. SHIRAZ E-MEDICAL JOURNAL 2020; 21. [DOI: 10.5812/semj.98656] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Background: Oxidative stress as a major mediator of adverse outcomes in kidney transplant recipients who are prone to oxidative stress-mediated injury by pre-transplant and post-transplant conditions. Objectives: The purpose of this study was to assess the effects of Pioglitazone on oxidative stress biomarkers and blood glucose control in diabetic patients receiving insulin after kidney transplantation. Methods: In a triple-blind randomized placebo-controlled trial, sixty-two kidney transplanted diabetic patients (40 men and 24 women) were followed for 4 months after randomly assigned to the placebo group and Pioglitazone group (30 mg/d). All of the patients continued their insulin therapy irrespective of the group that they were assigned to evaluate the effects of the addition of pioglitazone on blood glucose and oxidative stress biomarkers, Malondialdehyde (MDA) and total protein carbonyls (TPC) serum levels. Results: At baseline, there were no statistically significant differences in glycemic control levels and oxidative markers between the two groups. After 4 months of intervention, a significant improvement occurred in Hemoglobin A1c (HBA1c) in the Pioglitazone group. The changes of HBA1c during 4 months of follow up in the Pioglitazone group show improvement in glucose control were as HBA1c in the placebo group increased by 0.3% (P = 0.0001). Moreover, at the end of the study, the MDA level was significantly lower in the Pioglitazone group (P < 0.0001, 1.22 - 3.90). Regarding the serum level of TPC, the changes were not statistically different at baseline and also at the end of the study between two groups. Conclusions: Administration of Pioglitazone in addition to insulin in diabetic kidney transplant patients not only improved glycemic control (evidenced by HBA1c) but also significantly decreased oxidative stress markers such as MDA.
Collapse
|
|
9
|
Li H, Rong P, Ma X, Nie W, Chen Y, Zhang J, Dong Q, Yang M, Wang W. Mouse Umbilical Cord Mesenchymal Stem Cell Paracrine Alleviates Renal Fibrosis in Diabetic Nephropathy by Reducing Myofibroblast Transdifferentiation and Cell Proliferation and Upregulating MMPs in Mesangial Cells. J Diabetes Res 2020; 2020:3847171. [PMID: 32455132 PMCID: PMC7222483 DOI: 10.1155/2020/3847171] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 03/23/2020] [Accepted: 04/06/2020] [Indexed: 12/19/2022] Open
Abstract
Transplantation of umbilical cord mesenchymal stem cells (UC-MSCs) is currently considered a novel therapeutic strategy for diabetic nephropathy (DN). However, the mechanisms by which UC-MSCs ameliorate renal fibrosis in DN are not well understood. Herein, we firstly investigated the therapeutic effects of mouse UC-MSC infusion on kidney structural and functional impairment in streptozotocin- (STZ-) induced diabetic mice. We found that the repeated injection with mUC-MSCs alleviates albuminuria, glomerulus injury, and fibrosis in DN mouse models. Next, mesangial cells were exposed to 5.6 mM glucose, 30 mM glucose, or mUC-MSC-conditioned medium, and then we performed western blotting, immunofluorescence, wound healing assay, and cell proliferation assay to measure extracellular matrix (ECM) proteins and matrix metalloproteinases (MMPs), myofibroblast transdifferentiation (MFT), and cell proliferation. We demonstrated that mUC-MSC paracrine decreased the deposition of fibronectin and collagen I by inhibiting TGF-β1-triggered MFT and cell proliferation mediated by PI3K/Akt and MAPK signaling pathways, and elevating the levels of MMP2 and MMP9. Importantly, we provided evidence that the antifibrosis role of mUC-MSC paracrine in DN might be determined by exosomes shed by MSCs. Together, these findings reveal the mechanisms underlying the therapeutic effects of UC-MSCs on renal fibrosis in DN and provide the evidence for DN cell-free therapy based on UC-MSCs in the future.
Collapse
Affiliation(s)
- Hongde Li
- Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
- Postdoctoral Research Station of Special Medicine, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Pengfei Rong
- Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
- Postdoctoral Research Station of Special Medicine, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Xiaoqian Ma
- Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Wei Nie
- Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Yan Chen
- Department of Pathology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Juan Zhang
- Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Qiong Dong
- Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Min Yang
- Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Wei Wang
- Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
- Postdoctoral Research Station of Special Medicine, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
- Engineering and Technology Research Center for Xenotransplantation of Hunan Province, Changsha, China
| |
Collapse
|
|
10
|
Zhang X, Yang Y, Zhao Y. Macrophage phenotype and its relationship with renal function in human diabetic nephropathy. PLoS One 2019; 14:e0221991. [PMID: 31509552 PMCID: PMC6738594 DOI: 10.1371/journal.pone.0221991] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 05/30/2019] [Indexed: 12/30/2022] Open
Abstract
This study aimed to examine the macrophage phenotype and its relationship to renal function and histological changes in human DN and the effect of TREM-1 on high-glucose-induced macrophage activation. We observed that in renal tissue biopsies, the expression of CD68 and M1 was apparent in the glomeruli and interstitium, while accumulation of M2 and TREM-1 was primarily observed in the interstitium. The numbers of CD68, M1, and M2 macrophages infiltrating in the DN group were increased in a process-dependent manner compared with the control group, and the intensities of the infiltrates were proportional to the rate of subsequent decline in renal function. M1 macrophages were recruited into the kidney at an early stage (I+IIa) of DN. The M1-to-M2 macrophage ratio peaked at this time, whereas M2 macrophages predominated at later time points (III) when the percentage of M1/M2 macrophages was at its lowest level. In an in vitro study, we showed that under high glucose conditions, macrophages began to up-regulate their expression of TREM-1, M1, and marker iNOS and decreased the M2 marker MR. However, the above effects of high-glucose were abolished when TREM-1 expression was inhibited by TREM-1 siRNA. In conclusion, our study demonstrated that there was a positive correlation between the M1/M2 activation state and the progress of DN, and TREM-1 played an important role in high-glucose-induced macrophage phenotype transformation.
Collapse
Affiliation(s)
- Xiaoliang Zhang
- Institute of Nephrology, Zhong Da Hospital, Southeast University, School of Medicine, Nanjing, Jiangsu, China
- * E-mail:
| | - Ying Yang
- Institute of Nephrology, Zhong Da Hospital, Southeast University, School of Medicine, Nanjing, Jiangsu, China
| | - Yu Zhao
- Institute of Nephrology, Zhong Da Hospital, Southeast University, School of Medicine, Nanjing, Jiangsu, China
| |
Collapse
|
|
11
|
Yang F, Chen E, Yang Y, Han F, Han S, Wu G, Zhang M, Zhang J, Han J, Su L, Hu D. The Akt/FoxO/p27 Kip1 axis contributes to the anti-proliferation of pentoxifylline in hypertrophic scars. J Cell Mol Med 2019; 23:6164-6172. [PMID: 31270945 PMCID: PMC6714140 DOI: 10.1111/jcmm.14498] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Revised: 05/21/2019] [Accepted: 05/29/2019] [Indexed: 12/28/2022] Open
Abstract
Hypertrophic scars (HS) are characterized by the excessive production and deposition of extracellular matrix (ECM) proteins. Pentoxifylline (PTX), a xanthine derived antioxidant, inhibits the proliferation, inflammation and ECM accumulation of HS. In this study, we aimed to explore the effect of PTX on HS and further clarify the mechanism of PTX‐induced anti‐proliferation. We found that PTX could significantly attenuate proliferation of HS fibroblasts and fibrosis in an animal HS model. PTX inhibited the proliferation of HSFs in a dose‐ and time‐dependent manner, and this growth inhibition was mainly mediated by cell cycle arrest. Transcriptome sequencing showed that PTX affects HS formation through the PI3K/Akt/FoxO1 signalling pathway to activate p27Kip1. PTX down‐regulated p‐Akt and up‐regulated p‐FoxO1 in TGF‐β1 stimulated fibroblasts at the protein level, and simultaneously, the expression of p27Kip1 was activated. In a mouse model of HS, PTX treatment resulted in the ordering of collagen fibres. The results revealed that PTX regulates TGFβ1‐induced fibroblast activation and inhibits excessive scar formation. Therefore, PTX is a promising agent for the treatment of HS formation.
Collapse
Affiliation(s)
- Fangfang Yang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Erfei Chen
- Institute of Preventive Genomic Medicine, School of Life Sciences, Northwest University, Xi'an, China
| | - Yunshu Yang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Fu Han
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Shichao Han
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Gaofeng Wu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Min Zhang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Jian Zhang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Juntao Han
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Linlin Su
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Dahai Hu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| |
Collapse
|
|
12
|
Anderson EJ, Vistoli G, Katunga LA, Funai K, Regazzoni L, Monroe TB, Gilardoni E, Cannizzaro L, Colzani M, De Maddis D, Rossoni G, Canevotti R, Gagliardi S, Carini M, Aldini G. A carnosine analog mitigates metabolic disorders of obesity by reducing carbonyl stress. J Clin Invest 2018; 128:5280-5293. [PMID: 30226473 DOI: 10.1172/jci94307] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Accepted: 09/11/2018] [Indexed: 12/15/2022] Open
Abstract
Sugar- and lipid-derived aldehydes are reactive carbonyl species (RCS) frequently used as surrogate markers of oxidative stress in obesity. A pathogenic role for RCS in metabolic diseases of obesity remains controversial, however, partly because of their highly diffuse and broad reactivity and the lack of specific RCS-scavenging therapies. Naturally occurring histidine dipeptides (e.g., anserine and carnosine) show RCS reactivity, but their therapeutic potential in humans is limited by serum carnosinases. Here, we present the rational design, characterization, and pharmacological evaluation of carnosinol, i.e., (2S)-2-(3-amino propanoylamino)-3-(1H-imidazol-5-yl)propanol, a derivative of carnosine with high oral bioavailability that is resistant to carnosinases. Carnosinol displayed a suitable ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile and was determined to have the greatest potency and selectivity toward α,β-unsaturated aldehydes (e.g., 4-hydroxynonenal, HNE, ACR) among all others reported thus far. In rodent models of diet-induced obesity and metabolic syndrome, carnosinol dose-dependently attenuated HNE adduct formation in liver and skeletal muscle, while simultaneously mitigating inflammation, dyslipidemia, insulin resistance, and steatohepatitis. These improvements in metabolic parameters with carnosinol were not due to changes in energy expenditure, physical activity, adiposity, or body weight. Collectively, our findings illustrate a pathogenic role for RCS in obesity-related metabolic disorders and provide validation for a promising new class of carbonyl-scavenging therapeutic compounds rationally derived from carnosine.
Collapse
Affiliation(s)
- Ethan J Anderson
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, USA.,Department of Pharmacology and Toxicology, East Carolina University, Greenville, North Carolina, USA
| | - Giulio Vistoli
- Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
| | - Lalage A Katunga
- Department of Pharmacology and Toxicology, East Carolina University, Greenville, North Carolina, USA
| | - Katsuhiko Funai
- Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, Utah, USA
| | - Luca Regazzoni
- Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
| | - T Blake Monroe
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, USA.,Department of Pharmacology and Toxicology, East Carolina University, Greenville, North Carolina, USA
| | - Ettore Gilardoni
- Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
| | - Luca Cannizzaro
- Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
| | - Mara Colzani
- Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
| | - Danilo De Maddis
- Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
| | - Giuseppe Rossoni
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | | | | | - Marina Carini
- Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
| | - Giancarlo Aldini
- Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
| |
Collapse
|
|
13
|
Han WQ, Xu L, Tang XF, Chen WD, Wu YJ, Gao PJ. Membrane rafts-redox signalling pathway contributes to renal fibrosis via modulation of the renal tubular epithelial-mesenchymal transition. J Physiol 2018; 596:3603-3616. [PMID: 29863758 DOI: 10.1113/jp275952] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 05/25/2018] [Indexed: 01/27/2023] Open
Abstract
KEY POINTS Membrane rafts (MRs)-redox signalling pathway is activated in response to transforming growth factor-β1 (TGF-β1) stimulation in renal tubular cells. This pathway contributes to TGF-1β-induced epithelial-mesenchymal transition (EMT) in renal tubular cells. The the MRs-redox signalling pathway is activated in renal tubular cells isolated from angiotensin II (AngII)-induced hypertensive rats. Inhibition of this pathway attenuated renal inflammation and fibrosis in AngII-induced hypertension. ABSTRACT The membrane rafts (MRs)-redox pathway is characterized by NADPH oxidase subunit clustering and activation through lysosome fusion, V-type proton ATPase subunit E2 (encoded by the Atp6v1e2 gene) translocation and sphingomyelin phosphodiesterase 1 (SMPD1, encoded by the SMPD1 gene) activation. In the present study, we hypothesized that the MRs-redox-derived reactive oxygen species (ROS) are involved in renal inflammation and fibrosis by promoting renal tubular epithelial-mesenchymal transition (EMT). Results show that transforming growth factor-β1 (TGF-β1) acutely induced MR formation and ROS production in NRK-52E cells, a rat renal tubular cell line. In addition, transfection of Atp6v1e2 small hairpin RNAs (shRNA) and SMPD1 shRNA attenuated TGF-β1-induced changes in EMT markers, including E-cadherin, α-smooth muscle actin (α-SMA) and fibroblast-specific protein-1 (FSP-1) in NRK-52E cells. Moreover, Erk1/2 activation may be a downstream regulator of the MRs-redox-derived ROS, because both shRNAs significantly inhibited TGF-β1-induced Erk1/2 phosphorylation. Further in vivo study shows that the renal tubular the MRs-redox signalling pathway was activated in angiotensin II (AngII)-induced hypertension, as indicated by the increased NADPH oxidase subunit Nox4 fraction in the MR domain, SMPD1 activation and increased ROS content in isolated renal tubular cells. Finally, renal transfection of Atp6v1e2 shRNA and SMPD1 shRNA significantly prevented renal fibrosis and inflammation, as indicated by the decrease of α-SMA, fibronectin, collagen I, monocyte chemoattractant protein-1 (MCP-1), intercellular cell adhesion molecule-1 (ICAM-1) and tumour necrosis factor-α (TNF-α) in kidneys from AngII-infused rats. It was concluded that the the MRs-redox signalling pathway is involved in TGF-β1-induced renal tubular EMT and renal inflammation/fibrosis in AngII-induced hypertension.
Collapse
Affiliation(s)
- Wei-Qing Han
- Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,Shanghai Institute of Hypertension, Shanghai, China
| | - Lian Xu
- Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Xiao-Feng Tang
- Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Institute of Hypertension, Shanghai, China
| | - Wen-Dong Chen
- Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Institute of Hypertension, Shanghai, China
| | - Yong-Jie Wu
- Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Institute of Hypertension, Shanghai, China
| | - Ping-Jin Gao
- Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,Shanghai Institute of Hypertension, Shanghai, China
| |
Collapse
|
|
14
|
Song G, Han P, Sun H, Shao M, Yu X, Wang W, Wang D, Yi W, Ge N, Li S, Yi T. Astragaloside IV ameliorates early diabetic nephropathy by inhibition of MEK1/2-ERK1/2-RSK2 signaling in streptozotocin-induced diabetic mice. J Int Med Res 2018; 46:2883-2897. [PMID: 29896981 PMCID: PMC6124299 DOI: 10.1177/0300060518778711] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Objective The aim of this study was to investigate the renoprotective effects and molecular mechanisms of astragaloside IV (AS-IV) in streptozotocin (STZ)-induced diabetic mice. Methods Male C57BL/6 mice were injected intraperitoneally with STZ at 200 mg/kg body weight. AS-IV was administered for 8 consecutive weeks, beginning 1 week after STZ injection. Body weight, 24-hour urinary albumin excretion, and fasting blood glucose were measured. Kidney tissues were examined by histopathological analyses. Total levels and phosphorylation of mitogen-activated protein kinase 1/2 (MEK1/2), extracellular signal-regulated kinases 1 and 2 (ERK1/2), and ribosomal S6 kinase 2 (RSK2) were determined by Western blotting analysis. Results AS-IV treatment significantly reduced albuminuria and serum creatinine levels, ameliorated mesangial matrix expansion and greater foot process width, and decreased the levels of urinary N-acetyl-beta-D-glucosaminidase, neutrophil gelatinase-associated lipocalin, and transforming growth factor-beta 1 in STZ-induced diabetic mice. AS-IV also inhibited renal cortical phosphorylation of MEK1/2, ERK1/2 and RSK2. Conclusion Our results suggest that AS-IV attenuates renal injury in STZ-induced diabetic mice. This effect might be partially associated with inhibition of the activation of the MEK1/2-ERK1/2-RSK2 signaling pathway.
Collapse
Affiliation(s)
- Gaofeng Song
- 1 Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Pengxun Han
- 1 Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Huili Sun
- 1 Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Mumin Shao
- 2 Department of Pathology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Xuewen Yu
- 2 Department of Pathology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Wenjing Wang
- 1 Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Dongtao Wang
- 1 Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Wuyong Yi
- 1 Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Na Ge
- 1 Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Shunmin Li
- 1 Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Tiegang Yi
- 1 Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| |
Collapse
|
|
15
|
Protective Effects of Pyridoxamine Supplementation in the Early Stages of Diet-Induced Kidney Dysfunction. BIOMED RESEARCH INTERNATIONAL 2017; 2017:2682861. [PMID: 29214163 PMCID: PMC5682048 DOI: 10.1155/2017/2682861] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Accepted: 10/03/2017] [Indexed: 12/24/2022]
Abstract
Pyridoxamine, a structural analog of vitamin B6 that exerts antiglycative effects, has been proposed as supplementary approach in patients with initial diabetic nephropathy. However, the molecular mechanism(s) underlying its protective role has been so far slightly examined. C57Bl/6J mice were fed with a standard diet (SD) or a diet enriched in fat and fructose (HD) for 12 weeks. After 3 weeks, two subgroups of SD and HD mice started pyridoxamine supplementation (150 mg/kg/day) in the drinking water. HD fed mice showed increased body weight and impaired glucose tolerance, whereas pyridoxamine administration significantly improved insulin sensitivity, but not body weight, and reduced diet-induced increase in serum creatinine and urine albumin. Kidney morphology of HD fed mice showed strong vacuolar degeneration and loss of tubule brush border, associated with a drastic increase in both advanced glycation end products (AGEs) and AGEs receptor (RAGE). These effects were significantly counteracted by pyridoxamine, with consequent reduction of the diet-induced overactivation of NF-kB and Rho/ROCK pathways. Overall, the present study demonstrates for the first time that the administration of the antiglycative compound pyridoxamine can reduce the early stages of diet-dependent kidney injury and dysfunction by interfering at many levels with the profibrotic signaling and inflammatory cascades.
Collapse
|
|
16
|
Kim CS, Park S, Kim J. The role of glycation in the pathogenesis of aging and its prevention through herbal products and physical exercise. J Exerc Nutrition Biochem 2017; 21:55-61. [PMID: 29036767 PMCID: PMC5643203 DOI: 10.20463/jenb.2017.0027] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Accepted: 08/09/2017] [Indexed: 01/12/2023] Open
Abstract
[Purpose] Advanced glycation end products (AGEs) are non-enzymatic modifications of proteins or lipids after exposure to sugars. In this review, the glycation process and AGEs are introduced, and the harmful effects of AGEs in the aging process are discussed. [Methods] Results from human and animal studies examining the mechanisms and effects of AGEs are considered. In addition, publications addressing means to attenuate glycation stress through AGE inhibitors or physical exercise are reviewed. [Results] AGEs form in hyperglycemic conditions and/or the natural process of aging. Numerous publications have demonstrated acceleration of the aging process by AGEs. Exogenous AGEs in dietary foods also trigger organ dysfunction and tissue aging. Various herbal supplements or regular physical exercise have beneficial effects on glycemic control and oxidative stress with a consequent reduction of AGE accumulation during aging. [Conclusion] The inhibition of AGE formation and accumulation in tissues can lead to an increase in lifespan.
Collapse
Affiliation(s)
- Chan-Sik Kim
- Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea
| | - Sok Park
- Department of Sports Leadership, Kwangwoon University, Seoul, Republic of Korea
| | - Junghyun Kim
- Department of Oral Pathology, School of Dentistry, Chonbuk National University, Jeonju, Republic of Korea
| |
Collapse
|
|
17
|
Spasov AA, Solov’eva OA, Kuznetsova VA. Protein Glycation During Diabetes Mellitus and the Possibility of its Pharmacological Correction (Review). Pharm Chem J 2017. [DOI: 10.1007/s11094-017-1627-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
|
|
18
|
Kidney, heart and brain: three organs targeted by ageing and glycation. Clin Sci (Lond) 2017; 131:1069-1092. [PMID: 28515343 DOI: 10.1042/cs20160823] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Revised: 02/01/2017] [Accepted: 02/06/2017] [Indexed: 12/20/2022]
Abstract
Advanced glycation end-product (AGE) is the generic term for a heterogeneous group of derivatives arising from a non-enzymatic reaction between reducing sugars and proteins. In recent years, evidence has accumulated that incriminates AGEs in pathogenic processes associated with both chronic hyperglycaemia and age-related diseases. Regardless of their exogenous or endogenous origin, the accumulation of AGEs and their derivatives could promote accelerated ageing by leading to protein modifications and activating several inflammatory signalling pathways via AGE-specific receptors. However, it remains to be demonstrated whether preventing the accumulation of AGEs and their effects is an important therapeutic option for successful ageing. The present review gives an overview of the current knowledge on the pathogenic role of AGEs by focusing on three AGE target organs: kidney, heart and brain. For each of these organs we concentrate on an age-related disease, each of which is a major public health issue: chronic kidney disease, heart dysfunction and neurodegenerative diseases. Even though strong connections have been highlighted between glycation and age-related pathogenesis, causal links still need to be validated. In each case, we report evidence and uncertainties suggested by animal or epidemiological studies on the possible link between pathogenesis and glycation in a chronic hyperglycaemic state, in the absence of diabetes, and with exogenous AGEs alone. Finally, we present some promising anti-AGE strategies that are currently being studied.
Collapse
|
|
19
|
Kim CS, Jo K, Pyo MK, Kim JS, Kim J. Pectin lyase-modified red ginseng extract exhibits potent anti-glycation effects in vitro and in vivo. J Exerc Nutrition Biochem 2017; 21:56-62. [PMID: 28715887 PMCID: PMC5545198 DOI: 10.20463/jenb.2017.0011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 05/18/2017] [Indexed: 12/22/2022] Open
Abstract
PURPOSE GS-E3D is a newly developed pectin lyase-modified red ginseng extract. The purpose of this study was to evaluate the inhibitory effects of GS-E3D against advanced glycation end products. METHODS In this study, we evaluated the inhibitory effects of GS-E3D on the formation of advanced glycation end products (AGEs) and their cross-linking with collagen in vitro and in streptozotocin-induced diabetic rats. RESULTS An in vitro assay for the glycation of bovine serum albumin by methylglyoxal showed that GS-E3D inhibited AGE formation at an IC50 value of 19.65 ± 4.35 μg/mL. In addition, GS-E3D showed a potent inhibitory effect (IC50 = 0.42 ± 0.08 mg/mL) on the cross-linking of AGEs with collagen. However, GS-E3D showed no effect on preformed AGEs cross-linked with collagen in the breakdown assay. To determine whether GS-E3D inhibits AGE formation and their cross-linking with proteins in vivo, streptozotocin induced diabetic rats were treated with GS-E3D (25, 50, and 100 mg/kg/day) for 6 weeks. The administration of GS-E3D decreased serum levels of AGEs and their cross linking with proteins in diabetic rats. CONCLUSION The inhibitory effects of this agent on advanced glycation in vitro and in vivo suggested that it may have a potential therapeutic role in controlling diabetes-induced AGE burden in various tissues.
Collapse
Affiliation(s)
- Chan-Sik Kim
- Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea
| | - Kyuhyung Jo
- Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea
| | - Mi-Kyung Pyo
- International Ginseng and Herb Research Institute, Geumsan, Republic of Korea
| | - Jin Sook Kim
- Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea
| | - Junghyun Kim
- Department of Oral Pathology, School of Dentistry, Chonbuk National University, Jeonju, Republic of Korea
| |
Collapse
|
|
20
|
Targeting endothelial metaflammation to counteract diabesity cardiovascular risk: Current and perspective therapeutic options. Pharmacol Res 2017; 120:226-241. [PMID: 28408314 DOI: 10.1016/j.phrs.2017.04.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 03/21/2017] [Accepted: 04/07/2017] [Indexed: 02/08/2023]
Abstract
The association of obesity and diabetes, termed "diabesity", defines a combination of primarily metabolic disorders with insulin resistance as the underlying common pathophysiology. Cardiovascular disorders associated with diabesity represent the leading cause of morbidity and mortality in the Western world. This makes diabesity, with its rising impacts on both health and economics, one of the most challenging biomedical and social threats of present century. The emerging comprehension of the genes whose alteration confers inter-individual differences on risk factors for diabetes or obesity, together with the potential role of genetically determined variants on mechanisms controlling responsiveness, effectiveness and safety of anti-diabetic therapy underlines the need of additional knowledge on molecular mechanisms involved in the pathophysiology of diabesity. Endothelial cell dysfunction, resulting from the unbalanced production of endothelial-derived vascular mediators, is known to be present at the earliest stages of insulin resistance and obesity, and may precede the clinical diagnosis of diabetes by several years. Once considered as a mere consequence of metabolic abnormalities, it is now clear that endothelial dysfunctional activity may play a pivotal role in the progression of diabesity. In the vicious circle where vascular defects and metabolic disturbances worsen and reinforce each other, a low-grade, chronic, and 'cold' inflammation (metaflammation) has been suggested to serve as the pathophysiological link that binds endothelial and metabolic dysfunctions. In this paradigm, it is important to consider how traditional antidiabetic treatments (specifically addressing metabolic dysregulation) may directly impact on inflammatory processes or cardiovascular function. Indeed, not all drugs currently available to treat diabetes possess the same anti-inflammatory potential, or target endothelial cell function equally. Perspective strategies pointing at reducing metaflammation or directly addressing endothelial dysfunction may disclose beneficial consequences on metabolic regulation. This review focuses on existing and potential new approaches ameliorating endothelial dysfunction and vascular inflammation in the context of diabesity.
Collapse
|
|
21
|
Lacava V, Pellicanò V, Ferrajolo C, Cernaro V, Visconti L, Conti G, Buemi M, Santoro D. Novel avenues for treating diabetic nephropathy: new investigational drugs. Expert Opin Investig Drugs 2017; 26:445-462. [PMID: 28277032 DOI: 10.1080/13543784.2017.1293039] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 02/06/2017] [Indexed: 01/01/2023]
Abstract
At present, treatment of diabetic kidney disease (DKD) is still mainly based on drugs acting on glycemic and blood pressure control, as there is no validated therapy able to halt the progression of renal failure. Because of the high incidence of DKD, due to the increase of diabetes mellitus in general population, new therapeutic strategies are needed. Areas covered: We analysed ongoing and already completed clinical trials, from clinicaltrials.gov and PubMed, dealing with new therapies for DKD. Expert opinion: Among the drugs currently being explored, the most promising molecules are those that interfere with glucose-dependent pathways, in particular polyol, protein kinase, hexosamine and AGEs metabolic pathways, and impaired renal vascular regulation. One of the recent goals achieved by molecular biology is the development of monoclonal antibodies able to interfere with extracellular matrix accumulation and fibrosis. Other interesting therapies are under investigation and further studies with a greater number of patients will establish a better approach for diabetic nephropathy.
Collapse
Affiliation(s)
- Viviana Lacava
- a Unit of Nephrology and Dialysis , University of Messina , Messina , Italy
| | - Vincenzo Pellicanò
- a Unit of Nephrology and Dialysis , University of Messina , Messina , Italy
| | - Carmen Ferrajolo
- b Department of Experimental Medicine , Second University of Naples , Napoli , Italy
| | - Valeria Cernaro
- a Unit of Nephrology and Dialysis , University of Messina , Messina , Italy
| | - Luca Visconti
- a Unit of Nephrology and Dialysis , University of Messina , Messina , Italy
| | - Giovanni Conti
- c Unit of Pediatric Nephrology and Rheumatology , University of Messina , Messina , Italy
| | - Michele Buemi
- a Unit of Nephrology and Dialysis , University of Messina , Messina , Italy
| | - Domenico Santoro
- a Unit of Nephrology and Dialysis , University of Messina , Messina , Italy
| |
Collapse
|
|
22
|
Xu ZJ, Shu S, Li ZJ, Liu YM, Zhang RY, Zhang Y. Liuwei Dihuang pill treats diabetic nephropathy in rats by inhibiting of TGF-β/SMADS, MAPK, and NF-kB and upregulating expression of cytoglobin in renal tissues. Medicine (Baltimore) 2017; 96:e5879. [PMID: 28099346 PMCID: PMC5279091 DOI: 10.1097/md.0000000000005879] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Liuwei Dihuang pill (LDP) was assessed for its effects on renal deficiency.90 STZ induced DN rats were divided into groups (n = 22) without treatment (STZ) and LDP treated (STZ-L) (n = 23), Zhenwu decoction treated (STZ-Z) (n = 22), and valsartan treated (STZ-V) (n = 23) groups, with 16 normal control rats. Total urine protein (TP), blood urea nitrogen (BUN), and serum creatinine (Cr) were measured. Superoxide dismutase (SOD), nitric oxide synthase (NOS), and malondialdehyde (MDA) concentrations as well as expression/phosphorylation of SMAD3, SMAD2, and α-SMA, TGF-β, RI /II, P38, ERK, and NF-kB in renal tissues were determined. In vitro experiments analyzed the effect of enhanced TGF-β containing rat serums of the STZ groups on mesangial cells with and without transient transfection with a cytoglobin-containing plasmid.LDP treatment reduced the kidney coefficient, serum creatinine, blood urea nitrogen, and urine protein and prevented pathological changes. Expression of SOD and NOS in kidney tissue was increased but MDA expression reduced. LDP modulated multiple pathways, and its administration inhibited the phosphorylation of SMADS, ERK, p38, and the expression of NF-kB, α-SMA, and TGF-β RI/II, and upregulated the expression of cytoglobin. In vitro studies revealed that overexpression of cytoglobin suppressed phosphorylation of Smad2, ERK, and p38 induced by TGF-β and expression of NF-kB, α-SMA, and TGF-β RI.LDP prevented renal fibrosis and protected glomerular mesangial cells by upregulation of cytoglobin and suppression of multiple pathways involving TGF-β/SMADS, MAPK, NF-kB signaling.
Collapse
Affiliation(s)
- Zhong Ju Xu
- School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine
- Department of Traditional Chinese Medicine, Shanghai Punan Hospital of Pudong New District
| | - Shi Shu
- Department of Traditional Chinese Medicine, Shanghai Punan Hospital of Pudong New District
| | - Zhi Jie Li
- Science and Technology Center, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yu Min Liu
- School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine
| | - Rui Yi Zhang
- School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine
| | - Yue Zhang
- School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine
| |
Collapse
|
|
23
|
Kim J, Kim CS, Kim YS, Lee IS, Kim JS. Jakyakgamcho-tang and Its Major Component, Paeonia Lactiflora, Exhibit Potent Anti-glycation Properties. J Exerc Nutrition Biochem 2016; 20:60-64. [PMID: 28150470 PMCID: PMC5545203 DOI: 10.20463/jenb.2016.0049] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
[Purpose] Advanced glycation end products (AGEs) have been implicated in the pathogenesis of diabetes and other age-related diseases. AGE inhibitors or breakers, such as aminoguanidine and alagebrium, have been proposed as therapeutic agents for AGE-related disorders. Jakyakgamcho-tang (JGT) is a well-known traditional herbal formula, which consists of the radix of Paeonia lactiflora Pallas (PR) and the radix and rhizome of Glycyrrhiza uralensis Fisch (GR). The purpose of this study was to evaluate the inhibitory and breaking activities of JGT, PR, and GR against AGEs. [Methods] JGT, PR, and GR extracts were prepared in hot water. We performed in vitro assays to evaluate their inhibitory activity against glycation of bovine serum albumin (BSA) by high glucose and their ability to break the already formed AGEs. [Results] In the in vitro AGE formation assay, JGT and PR dose-dependently inhibited AGE-BSA formation (half-maximal inhibitory concentration, IC50, = 41.41 ± 0.36 and 6.84 ± 0.09 μg/mL, respectively). In the breakdown assay of the preformed AGE-BSA-collagen complexes, JGT and PR exhibited potent breaking activities (IC50 = 6.72 ± 1.86 and 7.45 ± 0.47 μg/mL, respectively). However, GR showed a weaker inhibitory activity and no breaking activity against AGEs. [Conclusion] This study suggests that JGT and PR could be valuable drug candidates for treatment of AGE-related diseases by reducing AGE burden.
Collapse
Affiliation(s)
- Junghyun Kim
- Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon Republic of Korea
| | - Chan-Sik Kim
- Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon Republic of Korea
| | - Young Sook Kim
- Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon Republic of Korea
| | - Ik Soo Lee
- Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon Republic of Korea
| | - Jin Sook Kim
- Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon Republic of Korea
| |
Collapse
|
|
24
|
Pereira-Simon S, Rubio GA, Xia X, Cai W, Choi R, Striker GE, Elliot SJ. Inhibition of Advanced Glycation End Products (AGEs) Accumulation by Pyridoxamine Modulates Glomerular and Mesangial Cell Estrogen Receptor α Expression in Aged Female Mice. PLoS One 2016; 11:e0159666. [PMID: 27428057 PMCID: PMC4948910 DOI: 10.1371/journal.pone.0159666] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Accepted: 07/05/2016] [Indexed: 12/31/2022] Open
Abstract
Age-related increases in oxidant stress (OS) play a role in regulation of estrogen receptor (ER) expression in the kidneys. In this study, we establish that in vivo 17β-estradiol (E2) replacement can no longer upregulate glomerular ER expression by 21 months of age in female mice (anestrous). We hypothesized that advanced glycation end product (AGE) accumulation, an important source of oxidant stress, contributes to these glomerular ER expression alterations. We treated 19-month old ovariectomized female mice with pyridoxamine (Pyr), a potent AGE inhibitor, in the presence or absence of E2 replacement. Glomerular ERα mRNA expression was upregulated in mice treated with both Pyr and E2 replacement and TGFβ mRNA expression decreased compared to controls. Histological sections of kidneys demonstrated decreased type IV collagen deposition in mice receiving Pyr and E2 compared to placebo control mice. In addition, anti-AGE defenses Sirtuin1 (SIRT1) and advanced glycation receptor 1 (AGER1) were also upregulated in glomeruli following treatment with Pyr and E2. Mesangial cells isolated from all groups of mice demonstrated similar ERα, SIRT1, and AGER1 expression changes to those of whole glomeruli. To demonstrate that AGE accumulation contributes to the observed age-related changes in the glomeruli of aged female mice, we treated mesangial cells from young female mice with AGE-BSA and found similar downregulation of ERα, SIRT1, and AGER1 expression. These results suggest that inhibition of intracellular AGE accumulation with pyridoxamine may protect glomeruli against age-related oxidant stress by preventing an increase of TGFβ production and by regulation of the estrogen receptor.
Collapse
Affiliation(s)
- Simone Pereira-Simon
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Gustavo A. Rubio
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Xiaomei Xia
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Weijing Cai
- Division of Experimental Diabetes and Aging, Department of Geriatrics and Palliative Care, Mount Sinai School of Medicine, 1 Gustave Levy Place, New York, New York, United States of America
| | - Rhea Choi
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Gary E. Striker
- Division of Experimental Diabetes and Aging, Department of Geriatrics and Palliative Care, Mount Sinai School of Medicine, 1 Gustave Levy Place, New York, New York, United States of America
| | - Sharon J. Elliot
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, United States of America
- * E-mail:
| |
Collapse
|
|
25
|
Corosolic acid inhibits the proliferation of glomerular mesangial cells and protects against diabetic renal damage. Sci Rep 2016; 6:26854. [PMID: 27229751 PMCID: PMC4882506 DOI: 10.1038/srep26854] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 05/10/2016] [Indexed: 12/21/2022] Open
Abstract
Diabetic nephropathy (DN) is one of the major complications of diabetes mellitus (DM). This study aimed to explore the effects of corosolic acid (CA) on the renal damage of DM and the mechanisms behind these effects. The renoprotective effect of CA was investigated in type 1 diabetic rats and db/db mice. The kidneys and glomerular mesangial cells (GMCs) were used to study the proliferation of GMCs by immunostaining and MTT assay. Further immunoblotting, siRNA, qPCR analysis, and detecting of NADPH oxidase activity and reactive oxygen species (ROS) generation were performed to explore relevant molecular mechanisms. In CA-treated diabetic animals, diabetes-induced albuminuria, increased serum creatinine and blood urea nitrogen were significantly attenuated, and glomerular hypertrophy, mesangial expansion and fibrosis were ameliorated. Furthermore, CA significantly inhibited proliferation of GMCs and phosphorylation of ERK1/2 and p38 MAPK in both diabetic animals and high glucose (HG)-induced GMCs. CA also normalized Δψm and inhibited HG-induced NADPH oxidase activity, ROS generation and NOX4, NOX2, p22(phox) and p47(phox) expression. More importantly, CA inhibited GMC proliferation mediated by NADPH/ERK1/2 and p38 MAPK signaling pathways. These findings suggest that CA exert the protective effect on DN by anti-proliferation resulted from inhibition of p38 MAPK- and NADPH-mediated inactivation of ERK1/2.
Collapse
|
|
26
|
Hu C, Sun L, Xiao L, Han Y, Fu X, Xiong X, Xu X, Liu Y, Yang S, Liu F, Kanwar YS. Insights into the Mechanisms Involved in the Expression and Regulation of Extracellular Matrix Proteins in Diabetic Nephropathy. Curr Med Chem 2016; 22:2858-70. [PMID: 26119175 DOI: 10.2174/0929867322666150625095407] [Citation(s) in RCA: 156] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Revised: 06/15/2015] [Accepted: 06/24/2015] [Indexed: 02/06/2023]
Abstract
Diabetic Nephropathy (DN) is believed to be a major microvascular complication of diabetes. The hallmark of DN includes deposition of Extracellular Matrix (ECM) proteins, such as, collagen, laminin and fibronectin in the mesangium and renal tubulo-interstitium of the glomerulus and basement membranes. Such an increased expression of ECM leads to glomerular and tubular basement membranes thickening and increase of mesangial matrix, ultimately resulting in glomerulosclerosis and tubulointerstitial fibrosis. The characteristic morphologic glomerular mesangial lesion has been described as Kimmelstiel-Wilson nodule, and the process at times is referred to as diabetic nodular glomerulosclerosis. Thus, the accumulation of ECM proteins plays a critical role in the development of DN. The relevant mechanism(s) involved in the increased ECM expression and their regulation in the kidney in diabetic state has been extensively investigated and documented in the literature. Nevertheless, there are certain other mechanisms that may yet be conclusively defined. Recent studies demonstrated that some of the new signaling pathways or molecules including, Notch, Wnt, mTOR, TLRs and small GTPase may play a pivotal role in the modulation of ECM regulation and expression in DN. Such modulation could be operational for instance Notch through Notch1/Jagged1 signaling, Wnt by Wnt/β- catenin pathway and mTOR via PI3-K/Akt/mTOR signaling pathways. All these pathways may be critical in the modulation of ECM expression and tubulo-interstitial fibrosis. In addition, TLRs, mainly the TLR2 and TLR4, by TLR2- dependent and TGF-β-dependent conduits, may modulate ECM expression and generate a fibrogenic response. Small GTPase like Rho, Ras and Rab family by targeting relevant genes may also influence the accumulation of ECM proteins and renal fibrosis in hyperglycemic states. This review summarizes the recent information about the role and mechanisms by which these molecules and signaling pathways regulate ECM synthesis and its expression in high glucose ambience in vitro and in vivo states. The understanding of such signaling pathways and the molecules that influence expression, secretion and amassing of ECM may aid in developing strategies for the amelioration of diabetic nephropathy.
Collapse
Affiliation(s)
| | - L Sun
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
27
|
Ren X, Sun H, Zhang C, Li C, Wang J, Shen J, Yu D, Kong L. Protective function of pyridoxamine on retinal photoreceptor cells via activation of the p‑Erk1/2/Nrf2/Trx/ASK1 signalling pathway in diabetic mice. Mol Med Rep 2016; 14:420-4. [PMID: 27177199 DOI: 10.3892/mmr.2016.5270] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 03/17/2016] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to investigate the mechanisms that mediate the protective effects of pyridoxamine (PM) on light‑damaged retinal photoreceptor cells in diabetic mice. A high‑fat diet and streptozotocin were used to induce a mouse model of type II diabetes. During the experiment, mice were divided the mice into three types of group, as follows: Control groups (negative control and light‑damaged groups); experimental groups (diabetic and diabetic light‑damaged groups); and treatment groups (25, 50 and 100 mg/kg PM‑treated groups). Using hematoxylin‑eosin staining, the number of nuclear layer cells were counted. Western blotting and immunohistochemistry were performed to measure the levels of thioredoxin (Trx), phospho‑extracellular signal‑regulated kinase 1/2 (p‑Erk1/2), nuclear factor erythroid 2‑related factor 2 (Nrf2) and apoptosis signal‑regulating kinase 1 (ASK1). The photoreceptor cell count in the outer nuclear layer of the light‑damaged, diabetic control and diabetic light‑damaged groups were significantly reduced compared with the negative control group (P<0.001). The cell counts in the PM‑treated groups were significantly increased compared with the diabetic group (P<0.001). Compared with the negative control group, the light‑damaged, diabetic and diabetic light‑damaged groups exhibited significantly decreased Trx, p‑Erk1/2 and Nrf2 expression levels (P<0.001), and significantly increased ASK1 expression levels (P<0.001). However, in the PM‑treated groups, Trx, p‑Erk1/2 and Nrf2 expression levels were significantly increased (P<0.001), and ASK1 expression was significantly decreased (P<0.001). The results of the present study demonstrate that PM protects retinal photoreceptor cells against light damage in diabetic mice, and that its mechanism may be associated with the upregulation of Trx, p‑Erk1/2 and Nrf2 expression, and the downregulation of ASK1 expression.
Collapse
Affiliation(s)
- Xiang Ren
- Department of Histology and Embryology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Hong Sun
- Department of Histology and Embryology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Chenghong Zhang
- Department of Histology and Embryology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Chen Li
- Department of Histology and Embryology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Jinlei Wang
- Department of Histology and Embryology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Jie Shen
- Department of Histology and Embryology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Dong Yu
- Department of Histology and Embryology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Li Kong
- Department of Histology and Embryology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| |
Collapse
|
|
28
|
Niu HS, Liu IM, Niu CS, Ku PM, Hsu CT, Cheng JT. Eucommia bark (Du-Zhong) improves diabetic nephropathy without altering blood glucose in type 1-like diabetic rats. DRUG DESIGN DEVELOPMENT AND THERAPY 2016; 10:971-8. [PMID: 27041999 PMCID: PMC4780717 DOI: 10.2147/dddt.s98558] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Background Eucommia bark, Eucommia ulmoides Oliver barks (Du-Zhong in Mandarin), is an herb used for renal dysfunction in Chinese traditional medicine. In an attempt to develop this herb as a treatment for diabetic nephropathy (DN), we investigated the effects of Du-Zhong on renal dysfunction in type 1-like diabetic rats. Methods Streptozotocin (STZ) was used to induce type 1-like diabetes in rats (STZ-diabetic rats). In addition to hyperglycemia, STZ-diabetic rats showed significant nephropathy, including higher plasma levels of blood urea nitrogen, creatinine, and renal fibrosis. Western blot analysis of renal cortical tissue was applied to characterize the changes in potential signals related to nephropathy. Results Oral administration of Du-Zhong (1 g/kg/day) to STZ-diabetic rats for 20 days not only decreased the plasma levels of blood urea nitrogen and creatinine but also improved renal fibrosis, whereas the plasma glucose level was not changed. The higher expressions of protein levels of transforming growth factor-beta (TGF-β) and connective tissue growth factor in diabetic rats were markedly attenuated by Du-Zhong. The increased phosphorylation of Smad2/3 in STZ-diabetic rats was also reduced by Du-Zhong. However, Du-Zhong cannot reverse the hyperglycemia-induced overproduction of signal transducers and activators of transcription 3 in the diabetic kidney. Conclusion Oral administration of Du-Zhong improves STZ-induced DN in rats by inhibiting TGF-β/Smad signaling and suppressing TGF-β/connective tissue growth factor expression. Therefore, active principle from Du-Zhong is suitable to develop as new agent for DN in the future.
Collapse
Affiliation(s)
- Ho-Shan Niu
- Department of Nursing, Tzu Chi University of Science and Technology, Hualien City, Taiwan
| | - I-Min Liu
- Department of Pharmacy & Graduate Institute of Pharmaceutical Technology, Tajen University, Pingtung County, Taiwan
| | - Chiang-Shan Niu
- Department of Nursing, Tzu Chi University of Science and Technology, Hualien City, Taiwan
| | - Po-Ming Ku
- Department of Cardiology, Chi-Mei Medical Center, Yong Kang, Tainan City, Taiwan; Department of Medical Research, Chi-Mei Medical Center, Yong Kang, Tainan City, Taiwan
| | - Chao-Tien Hsu
- Department of Pathology, E-DA Hospital, I-Shou University, Kaohsiung City, Taiwan
| | - Juei-Tang Cheng
- Department of Medical Research, Chi-Mei Medical Center, Yong Kang, Tainan City, Taiwan; Institute of Medical Science, College of Health Science, Chang Jung Christian University, Guei-Ren, Tainan City, Taiwan
| |
Collapse
|
|
29
|
Sönmez MF, Dündar M. Ameliorative effects of pentoxifylline on NOS induced by diabetes in rat kidney. Ren Fail 2016; 38:605-13. [PMID: 26905686 DOI: 10.3109/0886022x.2016.1149688] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. The NO system has been implicated in the pathogenesis of DN. In this study, we aimed to evaluate the healing effect of pentoxifylline on NOS in STZ-induced diabetic rat's kidney. MATERIAL AND METHODS In this study, 50 Wistar albino male rats were used. The rats were divided into five groups; Group C control; Group D only diabetes; Group D + PI and D + PII diabetes + pentoxifylline; Group P only pentoxifylline. Group DPI rats received just pentoxifylline from the beginning of the experiments. However, Group DPII rats received saline in the first month and 50 mg/kg/day of pentoxifylline for the following month. At the end of two months, NOS expressions in kidney tissue were assessed using qRT-PCR and immunohistochemistry analysis. RESULTS At the end of the experiments, desquamation of the epithelial cells of the tubules, clear glycogen-filled distal tubules and increased number of apoptotic cells were seen in Group D. Diabetic rats' nNOS immunoreactivity had increased and eNOS and iNOS immunoreactivity had decreased; nNOS, iNOS and eNOS mRNA levels tended to decrease compared to the control group. PTX ameliorated eNOS, iNOS and nNOS protein levels and apoptotic cells, but did not affect mRNA levels. CONCLUSION In conclusion, PTX has a healing effect on this damage by affecting NOS expression.
Collapse
Affiliation(s)
- Mehmet Fatih Sönmez
- a Department of Histology and Embryology, Faculty of Medicine , Erciyes University , Kayseri , Turkey
| | - Munis Dündar
- b Department of Medical Genetics, Faculty of Medicine , Erciyes University , Kayseri , Turkey
| |
Collapse
|
|
30
|
Huang JS, Lee YH, Chuang LY, Guh JY, Hwang JY. Cinnamaldehyde and nitric oxide attenuate advanced glycation end products-induced the Jak/STAT signaling in human renal tubular cells. J Cell Biochem 2016; 116:1028-38. [PMID: 25561392 DOI: 10.1002/jcb.25058] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2014] [Accepted: 12/18/2014] [Indexed: 01/28/2023]
Abstract
Cinnamaldehyde is a major and a bioactive compound isolated from the leaves of Cinnamomum osmophloeum kaneh. It possesses anti-diabetic properties in vitro and in vivo and has anti-inflammatory and anti-cancer effects. To explore whether cinnamaldehyde was linked to altered advanced glycation end products (AGE)-mediated diabetic nephropathy, the molecular mechanisms of cinnamaldehyde responsible for inhibition of AGE-reduced nitric oxide (NO) bioactivity in human renal proximal tubular cells were examined. We found that raising the ambient AGE concentration causes a dose-dependent decrease in NO generation. Cinnamaldehyde significantly reverses AGE-inhibited NO generation and induces high levels of cGMP synthesis and PKG activation. Treatments with cinnamaldehyde, the NO donor S-nitroso-N-acetylpenicillamine, and the JAK2 inhibitor AG490 markedly attenuated AGE-inhibited NOS protein levels and NO generation. Moreover, AGE-induced the JAK2-STAT1/STAT3 activation, RAGE/p27(Kip1) /collagen IV protein levels, and cellular hypertrophy were reversed by cinnamaldehyde. The ability of cinnamaldehyde to suppress STAT activation was also verified by the observation that it significantly increased SCOS-3 protein level. These findings indicate for the first time that in the presence of cinnamaldehyde, the suppression of AGE-induced biological responses is probably mediated by inactivating the JAK2-STAT1/STAT3 cascade or activating the NO pathway.
Collapse
Affiliation(s)
- Jau-Shyang Huang
- Department of Biological Science and Technology, Chung Hwa University of Medical Technology, Tainan, Taiwan
| | | | | | | | | |
Collapse
|
|
31
|
Nasri H, Rafieian-Kopaei M. Diabetes mellitus and renal failure: Prevention and management. JOURNAL OF RESEARCH IN MEDICAL SCIENCES : THE OFFICIAL JOURNAL OF ISFAHAN UNIVERSITY OF MEDICAL SCIENCES 2015; 20:1112-20. [PMID: 26941817 PMCID: PMC4755100 DOI: 10.4103/1735-1995.172845] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Revised: 09/14/2015] [Accepted: 11/20/2015] [Indexed: 01/10/2023]
Abstract
Nowadays, diabetes mellitus (DM) and hypertension are considered as the most common causes of end-stage renal disease (ESRD). In this paper, other than presenting the role of DM in ESRD, glucose metabolism and the management of hyperglycemia in these patients are reviewed. Although in several large studies there was no significant relationship found between tight glycemic control and the survival of ESRD patients, it is recommended that glycemic control be considered as the main therapeutic goal in the treatment of these patients to prevent damage to other organs. Glycemic control is perfect when fasting blood sugar is less than 140 mg/dL, 1-h postprandial blood glucose is less than 200 mg/dL, and glycosylated hemoglobin (HbA1c) is 6-7 in patients with type 1 diabetes and 7-8 in patients with type 2 diabetes. Administration of metformin should be avoided in chronic renal failure (CRF) because of lactic acidosis, the potentially fatal complication of metformin, but glipizide and repaglinide seem to be good choices.
Collapse
Affiliation(s)
- Hamid Nasri
- Department of Internal Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | | |
Collapse
|
|
32
|
Lee YM, Kim J, Kim CS, Jo K, Yoo NH, Sohn E, Kim JS. Anti-glycation and anti-angiogenic activities of 5'-methoxybiphenyl-3,4,3'-triol, a novel phytochemical component of Osteomeles schwerinae. Eur J Pharmacol 2015; 760:172-8. [PMID: 25917323 DOI: 10.1016/j.ejphar.2015.04.022] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Revised: 03/09/2015] [Accepted: 04/15/2015] [Indexed: 11/29/2022]
Abstract
Advanced glycation end products (AGEs) are involved in the development of diabetic complications such as diabetic retinopathy. 5'-methoxybiphenyl-3,4,3'-triol (referred to as K24) was isolated using bioactivity-guided fractionation of Osteomeles schwerinae C. K. Schneid. and identified as a potent AGE inhibitor. To identify the protective effect of K24 on disruption of the blood-retinal barrier, AGE-RSA was intravitreally injected into rat eyes. K24 had an inhibitory effect on AGE-RSA-induced retinal vascular leakage by suppressing the expression of vascular endothelial growth factor (VEGF) and decreasing the loss of occludin. In addition, we examined whether K24 has a preventive effect against retinal pathogenic angiogenesis in an oxygen-induced retinopathy (OIR) mouse model. K24 significantly reduced the retinal non-perfused area and neovascular tufts in the OIR mice. These data indicate that K24 could serve as an innovative pharmaceutical agent to prevent blood-retinal barrier breakage and retinal pathogenic angiogenesis through an anti-VEGF mechanism.
Collapse
Affiliation(s)
- Yun Mi Lee
- Korean Medicine Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, South Korea
| | - Junghyun Kim
- Korean Medicine Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, South Korea
| | - Chan-Sik Kim
- Korean Medicine Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, South Korea
| | - Kyuhyung Jo
- Korean Medicine Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, South Korea
| | - Nam Hee Yoo
- International Ginseng & Herb Research Institute, Geumsan, South Korea
| | - Eunjin Sohn
- Korean Medicine Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, South Korea
| | - Jin Sook Kim
- Korean Medicine Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, South Korea.
| |
Collapse
|
|
33
|
Blumenthal SS. Evolution of Treatment for Diabetic Nephropathy: Historical Progression from RAAS Inhibition and Onward. Postgrad Med 2015; 123:166-79. [DOI: 10.3810/pgm.2011.11.2506] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
|
|
34
|
Kim J, Kim CS, Moon MK, Kim JS. Epicatechin breaks preformed glycated serum albumin and reverses the retinal accumulation of advanced glycation end products. Eur J Pharmacol 2015; 748:108-14. [DOI: 10.1016/j.ejphar.2014.12.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Revised: 11/21/2014] [Accepted: 12/07/2014] [Indexed: 12/26/2022]
|
|
35
|
Maile LA, Busby WH, Gollahon KA, Flowers W, Garbacik N, Garbacik S, Stewart K, Nichols T, Bellinger D, Patel A, Dunbar P, Medlin M, Clemmons D. Blocking ligand occupancy of the αVβ3 integrin inhibits the development of nephropathy in diabetic pigs. Endocrinology 2014; 155:4665-75. [PMID: 25171599 PMCID: PMC4239428 DOI: 10.1210/en.2014-1318] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hyperglycemia stimulates secretion of αVβ3 ligands from vascular cells, including endothelial cells, resulting in activation of the αVβ3 integrin. This study determined whether blocking ligand occupancy of αVβ3 would inhibit the development of diabetic nephropathy. Ten diabetic pigs received an F(ab)2 fragment of an antibody directed against the extracellular domain of the β3-subunit, and 10 received a control IgG F(ab)2 for 18 weeks. Nondiabetic pigs excreted 115 ± 50 μg of protein/mg creatinine compared with control F(ab)2-treated diabetic animals (218 ± 57 μg/mg), whereas diabetic animals treated with the anti-β3 F(ab)2 excreted 119 ± 55 μg/mg (P < .05). Mesangial volume/glomerular volume increased to 21 ± 2.4% in control-treated diabetic animals compared with 14 ± 2.8% (P < .01) in animals treated with active antibody. Diabetic animals treated with control F(ab)2 had significantly less glomerular podocin staining compared with nondiabetic animals, and this decrease was attenuated by treatment with anti-β3 F(ab)2. Glomerular basement membrane thickness was increased in the control, F(ab)2-treated diabetic animals (212 ± 14 nm) compared with nondiabetic animals (170 ± 8.8 nm), but it was unchanged (159.9 ± 16.4 nm) in animals receiving anti-β3 F(ab)2. Podocyte foot process width was greater in control, F(ab)2-treated, animals (502 ± 34 nm) compared with animals treated with the anti-β3 F(ab)2 (357 ± 47 nm, P < .05). Renal β3 tyrosine phosphorylation decreased from 13 934 ± 6437 to 6730 ± 1524 (P < .01) scanning units in the anti-β3-treated group. We conclude that administration of an antibody that inhibits activation of the β3-subunit of αVβ3 that is induced by hyperglycemia attenuates proteinuria and early histologic changes of diabetic nephropathy, suggesting that it may have utility in preventing the progression of this disease complication.
Collapse
Affiliation(s)
- Laura A Maile
- Department of Medicine (L.A.M., W.H.B., K.A.G., T.N., D.B., A.P., P.D., M.M., D.C.), University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599; and Department of Animal Science (W.F., N.G., S.G., K.S.), North Carolina State University, Raleigh, North Carolina 27695
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Wu Y, Wang Y, Qi X, Zhang P, Zhang C, Zhang W. Increased macrophage activation inhibited by tacrolimus in the kidney of diabetic rats. Nephron Clin Pract 2014; 128:46-56. [PMID: 25376933 DOI: 10.1159/000366446] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Accepted: 08/06/2014] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/AIMS Accumulating evidence suggests that macrophage-induced inflammation may be the mechanism of development and progression of diabetic nephropathy. A previous study by our group has shown that tacrolimus, like cyclosporin A, has a renoprotective effect in diabetic rats. The present study aimed to elucidate the underlying molecular events. METHODS Diabetic rats were induced by using streptozotocin. Diabetic rats were subjected to oral tacrolimus treatment at a dose of 0.5 or 1.0 mg/kg daily for 4 weeks. Body weight, blood glucose, hemoglobin A(1c) (HbA(1c)) and renal pathology were assessed, followed by analyses of renal calcineurin (CaN) expression, changes in renal macrophage infiltration, proliferation and activation, and detection of renal TLR2+ and TLR4+ as well as NF-κB-p-p65+ in macrophages. RESULTS Diabetic rats had a reduced body weight and increased blood glucose and HbA(1c) levels, whereas tacrolimus treatment did not affect body weight or blood glucose and HbA(1c). Increased relative kidney weight was only significantly reduced by tacrolimus treatment at a dose of 1.0 mg/kg, while the elevated albumin excretion rate was markedly attenuated after treatment with tacrolimus (0.5 and 1.0 mg/kg) in diabetic rats. Elevated glomerular volume was significantly attenuated by tacrolimus treatment with 0.5 and 1.0 mg/kg, and increased indices for tubulointerstitial injury were only ameliorated by tacrolimus treatment with 1.0 mg/kg. Western blot data showed that expression of CaN protein was induced 2.4-fold in the kidneys of positive control diabetic rats, whereas tacrolimus treatment at 0.5 and 1.0 mg/kg doses reduced the increased expression of CaN protein by 38.0 and 73.2%, respectively. Histologically there was a marked accumulation of ED-1+ cells (macrophages) in diabetic kidneys and tacrolimus treatment failed to inhibit it. In contrast, tacrolimus treatment at 0.5 and 1.0 mg/kg doses significantly inhibited the elevated ED-1+/PCNA+ cells and ED-1+/iNOS+ cells in the kidneys of diabetic rats, while tacrolimus treatment at a dose of 0.5 or 1.0 mg/kg significantly suppressed the increased ED-1+/TLR2+ cells, ED-1+/TLR4+ cells and ED-1+/NF-κB-p-p65+ cells in the kidneys of diabetic rats. CONCLUSION The data from the current study demonstrated that tacrolimus could ameliorate early renal injury through a mechanism to suppress macrophage activation.
Collapse
Affiliation(s)
- Yonggui Wu
- Department of Nephrology, The First Affiliated Hospital of Anhui Medical University, Hefei, PR China
| | | | | | | | | | | |
Collapse
|
|
37
|
Ahmad S, Khan MS, Akhter F, Khan MS, Khan A, Ashraf JM, Pandey RP, Shahab U. Glycoxidation of biological macromolecules: a critical approach to halt the menace of glycation. Glycobiology 2014; 24:979-990. [PMID: 24946787 DOI: 10.1093/glycob/cwu057] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2025] Open
Abstract
Glycation is the result of covalent bonding of a free amino group of biological macromolecules with a reducing sugar, which results in the formation of a Schiff base that undergoes rearrangement, dehydration and cyclization to form a more stable Amadori product. The final products of nonenzymatic glycation of biomacromolecules like DNA, proteins and lipids are known as advanced glycation end products (AGEs). AGEs may be generated rapidly or over long times stimulated by distinct triggering mechanisms, thereby accounting for their roles in multiple settings and disease states. Both Schiff base and Amadori glycation products generate free radicals resulting in decline of antioxidant defense mechanisms and can damage cellular organelles and enzymes. This critical review primarily focuses on the mechanistic insight of glycation and the most probable route for the formation of glycation products and their therapeutic interventions. Furthermore, the prevention of glycation reaction using therapeutic drugs such as metformin, pyridoxamine and aminoguanidine (AG) are discussed with special emphasis on the novel concept of the bioconjugation of these drugs like, AG with gold nanoparticles (GNPs). At or above 10 mM concentration, AG is found to be toxic and therefore has serious health concerns, and the study warrants doing this novel bioconjugation of AG with GNPs. This approach might increase the efficacy of the AG at a reduced concentration with low or no toxicity. Using the concept of synthesis of GNPs with abovementioned drugs, it is assumed that toxicity of various drugs which are used at high doses can be minimized more effectively.
Collapse
Affiliation(s)
- Saheem Ahmad
- Department of Biosciences, Integral University, Lucknow, India
| | - M Salman Khan
- Department of Biosciences, Integral University, Lucknow, India
| | - Firoz Akhter
- Department of Biosciences, Integral University, Lucknow, India
| | - Mohd Sajid Khan
- Department of Biosciences, Integral University, Lucknow, India
| | - Amir Khan
- Glocal School of Life Sciences, Glocal University, Saharanpur, Uttar Pradesh, India
| | - J M Ashraf
- Department of Biotechnology, School of Biotechnology, Yeungnam University, Yeungnam, Republic of Korea
| | - Ramendra Pati Pandey
- Nano-Biotech Lab, Department of Zoology, Kirorimal College, University of Delhi, Delhi, India
| | - Uzma Shahab
- Department of Biochemistry, Central Drug Research Institute, Lucknow, India
| |
Collapse
|
|
38
|
Jung E, Kim J, Kim SH, Kim S, Cho MH. Gemigliptin, a novel dipeptidyl peptidase-4 inhibitor, exhibits potent anti-glycation properties in vitro and in vivo. Eur J Pharmacol 2014; 744:98-102. [PMID: 25448307 DOI: 10.1016/j.ejphar.2014.10.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2014] [Revised: 09/27/2014] [Accepted: 10/03/2014] [Indexed: 11/30/2022]
Abstract
This study evaluated the inhibitory effects of gemigliptin, a highly selective dipeptidyl peptidase-4 inhibitor, on the formation of advanced glycation end products (AGEs) and AGE cross-links with proteins in in vitro as well as in type 2 diabetic db/db mice. In in vitro assay, gemigliptin dose-dependently inhibited methylglyoxal-modified AGE-bovine serum albumin (BSA) formation (IC50=11.69 mM). AGE-collagen cross-linking assays showed that gemigliptin had a potent inhibitory effect (IC50=1.39 mM) on AGE-BSA cross-links to rat tail tendon collagen, and its activity was stronger than aminoguanidine (IC50=26.4 mM). In addition, gemigliptin directly trapped methylglyoxal in a concentration-dependent manner in vitro. To determine whether gemigliptin inhibits the in vivo glycation processes, gemigliptin (100 mg/kg/day) was orally administered into type 2 diabetic db/db mice for 12 weeks. Elevated serum levels of AGEs in db/db mice were suppressed by the administration of gemigliptin. These inhibitory effects of gemigliptin on the glycation process in both in vitro and in vivo suggest its therapeutic potential for ameliorating AGE-related diabetic complications.
Collapse
Affiliation(s)
- Eunsoo Jung
- Laboratory of Toxicology, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea; LG Life Sciences Ltd., R&D Park, Daejeon 305-343, Republic of Korea
| | - Junghyun Kim
- Korean Medicine Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 305-811, Republic of Korea
| | - Sung Ho Kim
- LG Life Sciences Ltd., R&D Park, Daejeon 305-343, Republic of Korea
| | - Sanghwa Kim
- Laboratory of Toxicology, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea
| | - Myung-Haing Cho
- Laboratory of Toxicology, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea; Graduate School of Convergence Science and Technology, Seoul National University, Suwon 443-270, Republic of Korea; Graduate Group of Tumor Biology, Seoul National University, Seoul 151-742, Republic of Korea; Advanced Institute of Convergence Technology, Seoul National University, Suwon 443-270, Republic of Korea.
| |
Collapse
|
|
39
|
Tessari P. Nitric oxide in the normal kidney and in patients with diabetic nephropathy. J Nephrol 2014; 28:257-68. [PMID: 25216787 DOI: 10.1007/s40620-014-0136-2] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Accepted: 08/26/2014] [Indexed: 01/06/2023]
Abstract
Nitric oxide (NO) is a gas with biological and regulatory properties, produced from arginine by the way of nitric oxide synthases (NOS), and with a very short half-life (few seconds). A "coupled" NOS activity leads to NO generation, whereas its uncoupling produces the reactive oxygen species peroxynitrite (ONOO(-)). Uncoupling is usually due to inflammation, oxidative stress, decreased cofactor availability, or excessive NO production. Competitive inhibitors of NO production are post-translationally methylated arginine residues in proteins, which are constantly released into the circulation. NO availability is altered in many clinical conditions associated with vascular dysfunction, such as diabetes mellitus. The kidney plays an important role in body NO homeostasis. This article provides an overview of current literature, on NO production/availability, with a focus on diabetic nephropathy. In diabetes, NO availability is usually decreased (with exception of the early, hyper filtration phase of nephropathy in Type 1 diabetes), and it could constitute a factor of the generalized vasculopathy present in diabetic nephropathy. NO generation in Type 2 diabetes with nephropathy is inversely associated with the dimethyl-arginine concentrations, which are therefore important modulators of NO synthesis independently from the classic stimulatory pathways (such as the insulin effect). A disturbed NO metabolism is present in diabetes associated with nephropathy. Although modulation of NO production is not yet a common therapeutical strategy, a number of yet experimental compounds need to be tested as potential interventions to treat the vascular dysfunction and nephropathy in diabetes, as well as in other diseased states. Finally, in diabetic nephropathy NO deficiency may be associated to that of hydrogen sulfide, another interesting gaseous mediator which is increasingly investigated.
Collapse
Affiliation(s)
- Paolo Tessari
- Metabolism Division, Department of Medicine, University of Padova, via Giustiniani 2, 35128, Padua, Italy,
| |
Collapse
|
|
40
|
Effect of sulodexide in patients with non-proliferative diabetic retinopathy: diabetic retinopathy sulodexide study (DRESS). Graefes Arch Clin Exp Ophthalmol 2014; 253:829-37. [PMID: 25112845 PMCID: PMC4445329 DOI: 10.1007/s00417-014-2746-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2014] [Revised: 07/01/2014] [Accepted: 07/08/2014] [Indexed: 11/13/2022] Open
Abstract
Purpose To evaluate the effectiveness of sulodexide for the treatment of hard exudates (HE) in non-proliferative diabetic retinopathy (NPDR). Methods This was a randomized, placebo-controlled, multicenter trial involving 130 patients (65 for each group) who had mild-to-moderate NPDR with macular HE. Participants were given a daily dose of either 50 mg sulodexide or a matching dose of placebo orally for 12 months. Main outcome measure was an improvement in HE defined as a decrease in severity by at least two grades on a 10-grade severity scale. This was evaluated by fundus photography over 12-month period. Results The sulodexide group showed significantly greater improvement in HE severity than that shown by the placebo group (39.0 % vs. 19.3 %; chi square, P = 0.005). Logistic regression analysis yielded an odds ratio of 2.790 (95 % confidence interval, 1.155-6.743; P = 0.023) for the effect of treatment once adjustments were made for demographic, prognostic and disease confounders. Intention to treat and per-protocol analysis yielded similar results. Sulodexide’s safety was comparable to that of the placebo. Conclusions Oral sulodexide therapy over 12 months improved macular HE in patients with mild-to-moderate NPDR, without leading to detectable adverse events. The study protocol was registered on clinicaltrial.gov under identifier NCT01295775.
Collapse
|
|
41
|
Abstract
Diabetic nephropathy is currently the most common cause of end stage renal disease not only in the Western hemisphere but also in the developing nations. While the available therapeutic options remain not very effective, there is a strong ongoing effort to understand the pathogenesis better and develop more useful biomarkers. As the pathogenic mediators and signaling pathways get better defined, the scope of novel pharmaceutical agents to address such mediating factors as therapeutic targets is advancing. This review provides, in addition to a brief synopsis of currently used strategies, a comprehensive review of potential therapies that have been evolving in the past decade with a specific focus on the promising agents.
Collapse
Affiliation(s)
- Harneet Kaur
- Department of Medicine, New York Medical College, Valhalla, NY, USA
| | - Sharma Prabhakar
- Department of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| |
Collapse
|
|
42
|
Alicic RZ, Tuttle KR. Novel therapies for diabetic kidney disease. Adv Chronic Kidney Dis 2014; 21:121-33. [PMID: 24602462 DOI: 10.1053/j.ackd.2014.01.007] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Revised: 01/13/2014] [Accepted: 01/15/2014] [Indexed: 02/07/2023]
Abstract
The number of people diagnosed with diabetes is rising throughout the world, which in turn drives upward the global frequency of diabetic kidney disease (DKD). Individuals with DKD are at an increased risk for premature death, cardiovascular disease, and other severe illnesses that result in frequent hospitalizations and increased health-care utilization. Current treatments concentrate on controlling hyperglycemia and hypertension with the specific use of renin-angiotensin system inhibitors. Although such measures reduce the risk of progressive kidney disease, DKD remains the leading cause of ESRD and the major risk amplifier for death in this population. Therefore, novel therapeutic approaches are urgently needed. Ideas for novel targets for therapy are founded on recent advances in understanding DKD mechanisms that are based on experimental models and human observations. The purpose of this review is to describe the epidemiology and present knowledge of DKD pathophysiology as the basis for novel therapies including inhibitors of Janus kinases (JAK), protein kinase C, fibrosis, advanced glycation end products treatments, and endothelin.
Collapse
|
|
43
|
Hajhosseiny R, Khavandi K, Jivraj N, Mashayekhi S, Goldsmith DJ, Malik RA. Have we reached the limits for the treatment of diabetic nephropathy? Expert Opin Investig Drugs 2014; 23:511-22. [DOI: 10.1517/13543784.2014.892580] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
|
|
44
|
Maile LA, Gollahon K, Wai C, Dunbar P, Busby W, Clemmons D. Blocking αVβ3 integrin ligand occupancy inhibits the progression of albuminuria in diabetic rats. J Diabetes Res 2014; 2014:421827. [PMID: 25389530 PMCID: PMC4217341 DOI: 10.1155/2014/421827] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Accepted: 10/07/2014] [Indexed: 12/18/2022] Open
Abstract
This study determined if blocking ligand occupancy of the αVβ3 integrin could inhibit the pathophysiologic changes that occur in the early stages of diabetic nephropathy (DN). Diabetic rats were treated with either vehicle or a monoclonal antibody that binds the β3 subunit of the αVβ3 integrin. After 4 weeks of diabetes the urinary albumin to creatinine ratio (UACR) increased in both diabetic animals that subsequently received vehicle and in the animals that subsequently received the anti-β3 antibody compared with control nondiabetic rats. After 8 weeks of treatment the UACR continued to rise in the vehicle-treated rats; however it returned to levels comparable to control nondiabetic rats in rats treated with the anti-β3 antibody. Treatment with the antibody prevented the increase of several profibrotic proteins that have been implicated in the development of DN. Diabetes was associated with an increase in phosphorylation of the β3 subunit in kidney homogenates from diabetic animals, but this was prevented by the antibody treatment. This study demonstrates that, when administered after establishment of early pathophysiologic changes in renal function, the anti-β3 antibody reversed the effects of diabetes normalizing albuminuria and profibrotic proteins in the kidney to the levels observed in nondiabetic control animals.
Collapse
Affiliation(s)
- Laura A. Maile
- Department of Medicine, UNC School of Medicine, Chapel Hill, NC 27599, USA
- Vascular Pharmaceuticals, Inc., 510 Meadowmont Village Circle, Suite 283, Chapel Hill, NC 27517, USA
- *Laura A. Maile:
| | - Katherine Gollahon
- Department of Medicine, UNC School of Medicine, Chapel Hill, NC 27599, USA
| | - Christine Wai
- Department of Medicine, UNC School of Medicine, Chapel Hill, NC 27599, USA
| | - Paul Dunbar
- Department of Medicine, UNC School of Medicine, Chapel Hill, NC 27599, USA
| | - Walker Busby
- Department of Medicine, UNC School of Medicine, Chapel Hill, NC 27599, USA
| | - David Clemmons
- Department of Medicine, UNC School of Medicine, Chapel Hill, NC 27599, USA
| |
Collapse
|
|
45
|
Badri S, Dashti-Khavidaki S, Ahmadi F, Mahdavi-Mazdeh M, Abbasi MR, Khalili H. Effect of add-on pentoxifylline on proteinuria in membranous glomerulonephritis: a 6-month placebo-controlled trial. Clin Drug Investig 2013; 33:215-22. [PMID: 23392759 DOI: 10.1007/s40261-013-0057-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND Membranous glomerulonephritis (MGN) may cause proteinuria as the main complication and is a strong risk factor for end-stage renal disease. Current therapeutic regimens provide only partial renoprotection. Data derived from both animal and human studies provide a scientific basis for the use of pentoxifylline as an antiproteinuric agent. OBJECTIVE This study was designed to evaluate the antiproteinuric effect of add-on pentoxifylline therapy in non-diabetic patients with MGN. STUDY DESIGN This was a double-blind, placebo-controlled trial. SETTING Non-diabetic patients with histologically proven MGN and urinary protein excretion (UPE) > 500 mg/24 h, entered a 6-month study period. Enrolled patients were selected from a university and three private clinics. INTERVENTION Patients were assigned to one of the two treatment groups: pentoxifylline 400 mg two or three times a day, or matching placebo. MAIN OUTCOME MEASURES Baseline and follow-up assessments included estimated glomerular filtration rate (eGFR) and UPE. Differences in the changes in variables within the placebo and pentoxifylline treatment groups during the study period were assessed using Friedman's test. RESULTS Treatment with pentoxifylline for 6 months resulted in a significant reduction of mean UPE (p < 0.001) along with a slight, non-significant increase of eGFR, in comparison to the mean UPE and eGFR increase in the placebo group. CONCLUSION This study showed that add-on therapy of pentoxifylline in MGN was beneficial, and could be considered as a potential new therapeutic indication for the drug in such kidney diseases.
Collapse
Affiliation(s)
- Shirinsadat Badri
- Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, 1417614411, Tehran, Iran
| | | | | | | | | | | |
Collapse
|
|
46
|
Kim T, Spiegel DA. The unique reactivity of N-phenacyl-derived thiazolium salts toward α-dicarbonyl compounds. Rejuvenation Res 2013. [PMID: 23186164 DOI: 10.1089/rej.2012.1370] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Advanced glycation end products (AGEs), a heterogeneous mixture of compounds formed by non-enzymatic chemical reactions between sugars and the nucleophilic residues of proteins, have been implicated in the pathogenesis of a number of diseases. ALT-711 is an N-phenacyl-derived thiazolium carbene developed as a therapeutic agent for cardiovascular diseases that is proposed to function through cleaving preformed AGE-protein crosslinks. However, despite promising results in animal models and clinical trials, its mechanism of action still remains controversial. Herein, we report the first systematic investigations into dicarbonyl cleavage by ALT-711. We demonstrate that it is capable of cleaving α-diketones more efficiently and likely via a distinct mechanism compared with other N-heterocyclic carbene precursors. We also show that ALT-711 reacts rapidly with α-keto aldehydes to form cyclic diol products, and it can efficiently scavenge methylglyoxal under physiological conditions to protect Escherichia coli from lethal concentrations of this reactive α-keto aldehyde. This work suggests ALT-711 may be especially suited for α-dicarbonyl clearance in vivo and supports a mode of action similar to that originally proposed. To this end, our findings may provide insights into the development of next-generation crosslink breakers.
Collapse
Affiliation(s)
- Taehan Kim
- Department of Chemistry, Yale University, New Haven, Connecticut 06511, USA
| | | |
Collapse
|
|
47
|
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.
Collapse
Affiliation(s)
- L Engelen
- Department of Internal Medicine, CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands
| | | | | |
Collapse
|
|
48
|
Xu XX, Zhang W, Zhang P, Qi XM, Wu YG, Shen JJ. Superior renoprotective effects of the combination of breviscapine with enalapril and its mechanism in diabetic rats. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2013; 20:820-827. [PMID: 23664882 DOI: 10.1016/j.phymed.2013.03.027] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2013] [Accepted: 03/28/2013] [Indexed: 06/02/2023]
Abstract
Breviscapine is a flavonoid extracted from a Chinese herb Erigeron breviscapus, previously it was shown that treatment with breviscapine attenuated renal injury in the diabetic rats. The purpose of this study was to investigate whether breviscapine combined with enalapril (an ACE inhibitor) have superior renoprotective effects against diabetic nephropathy. Rats were randomly separated into five groups: control, diabetes, diabetes treated with enalapril, diabetes treated with breviscapine, or diabetes treated with combined enalapril with breviscapine. Twenty-four hours urinary AER and the levels of 3-NT in renal tissue and MDA in renal tissue and urine as well as activities and expression of PKC in renal tissue were determined, and renal tissue morphology were observed by light microscopy after 8 weeks. Expression of TGFβ1 protein was performed by immunohistochemistry method. Increased AER and kidney pathologic injury were attenuated by treatment with either enalapril or breviscapine and further reduced by the combination of the two. Elevated 3-NT in renal tissue and MDA levels in renal tissue and urine were reduced by enalapril or breviscapine and, more effectively, by combined enalapril with breviscapine. PKC activities and expression were higher in renal tissue in diabetic rats than those of the control group, which were reduced by both monotherapies, and further abrogated by combination therapy in both cases. Overexpression of TGFβ1 protein observed in the glomeruli and tubulointerstitium of diabetic rats was attenuated by enalapril or breviscapine to a similar lever and further reduced by the combination of the two. The combination of enalapril and breviscapine confers superiority over monotherapies on renoprotection, which mechanism may be at least partly correlated with synergetic suppression on increased oxidative stress and PKC activities as well as overexpression of TGFβ1 in renal tissue.
Collapse
Affiliation(s)
- Xing-Xin Xu
- Department of Nephrology, The First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, PR China
| | | | | | | | | | | |
Collapse
|
|
49
|
Mima A, Qi W, King GL. Implications of treatment that target protective mechanisms against diabetic nephropathy. Semin Nephrol 2013; 32:471-8. [PMID: 23062988 DOI: 10.1016/j.semnephrol.2012.07.010] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Diabetes results in vascular changes and dysfunction, and vascular complications are the leading cause of morbidity and mortality in diabetic patients. There has been a continual increase in the number of diabetic nephropathy patients and epidemic increases in the number of patients progressing to end-stage renal diseases. To identify targets for therapeutic intervention, most studies have focused on understanding how abnormal levels of glucose metabolites cause diabetic nephropathy, which is of paramount importance in devising strategies to combat the development and progression of diabetic nephropathy. However, less studied than the systemic toxic mechanisms, hyperglycemia and dyslipidemia might inhibit the endogenous vascular protective factors such as insulin, vascular endothelial growth factor, and platelet-derived growth factor. In this review, we highlight the importance of enhancing endogenous protective factors to prevent or delay diabetic nephropathy.
Collapse
Affiliation(s)
- Akira Mima
- Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
| | | | | |
Collapse
|
|
50
|
Kania DS, Smith CT, Nash CL, Gonzalvo JD, Bittner A, Shepler BM. Potential new treatments for diabetic kidney disease. Med Clin North Am 2013; 97:115-34. [PMID: 23290734 DOI: 10.1016/j.mcna.2012.10.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Antifibrotic agents, antioxidant agents, ET-a receptor antagonists, and a few other agents with nonspecific or multifaceted mechanisms of action have been evaluated and progressed to small clinical studies in human subjects. Although there are limited data at the present time, these early evaluations have produced some favorable results that at least warrant further investigation. There is certainly not enough compelling evidence to justify the routine use of any of these products specifically for DKD at the moment; however, more well-controlled and adequately powered studies in several hundred patients will help determine which of these may have a place in the DKD treatment armamentarium of the future.
Collapse
Affiliation(s)
- Deanna S Kania
- Purdue University College of Pharmacy, West Lafayette, IN 47907-2091, USA
| | | | | | | | | | | |
Collapse
|