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Hyun MK, Kim DH, Park CH, Noh SG, Choi S, Lee JY, Choi JH, Park D, Choi YJ, Chung HY. Protective mechanisms of loquat leaf extract and ursolic acid against diabetic pro-inflammation. J Mol Med (Berl) 2022; 100:1455-1464. [PMID: 35962799 DOI: 10.1007/s00109-022-02243-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 07/14/2022] [Accepted: 08/04/2022] [Indexed: 10/15/2022]
Abstract
The pharmacological effectiveness of loquat leaf extract (LE) and its important component, ursolic acid (UA), in the treatment of diabetes mellitus, has been well established in traditional medicine; however, the mechanism underlying their action is still unclear. We evaluated the protective effects of LE and UA against hyperglycemia-induced advanced glycation end product (AGE) formations and hepatic pro-inflammation. Oral administration of UA and LE at a dose of 50 mg/kg/day for 15 days yielded no significant hypoglycemic effect in diabetic db/db mice. UA and LE suppressed hepatic oxidative stress and AGE formation in diabetic mice, and this was followed by the downregulated mitogen-activated protein kinase signaling and nuclear factor κ B (NF-κB) activity. To identify the molecular target of LE and UA, a docking simulation was performed, and this predicted UA to bind to liver kinase B1 (LKB1), an upstream of AMP-activated protein kinase (AMPK)/transcription factor forkhead box O3 (FOXO3) axis. UA reversed the high-glucose-induced downregulation of LKB1-AMPK1-FOXO3 activation and antioxidant gene transcription. These findings demonstrated the antioxidant and anti-inflammatory effects of UA and LE against hyperglycemia-induced hepatic inflammation. Furthermore, we speculate that the LKB1/AMPK/FOXO3 pathway is a potential target responsible for these beneficial effects of LE and UA.
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Affiliation(s)
- Min Kyung Hyun
- Department of Pharmacy, College of Pharmacy, Pusan National University, 2 Busandaehak-ro, 63 Beon-gil, Geumjeong-gu, Busan, 46241, Republic of Korea.,Department of Medicinal Crop Research, National Institute of Horticultural and Herbal Science, Rural Development Administration, Eumseong, 369-873, Republic of Korea
| | - Dae Hyun Kim
- Department of Pharmacy, College of Pharmacy, Pusan National University, 2 Busandaehak-ro, 63 Beon-gil, Geumjeong-gu, Busan, 46241, Republic of Korea
| | - Chan Hum Park
- Department of Medicinal Crop Research, National Institute of Horticultural and Herbal Science, Rural Development Administration, Eumseong, 369-873, Republic of Korea
| | - Sang Gyun Noh
- Department of Pharmacy, College of Pharmacy, Pusan National University, 2 Busandaehak-ro, 63 Beon-gil, Geumjeong-gu, Busan, 46241, Republic of Korea
| | - Sihyun Choi
- Department of Biopharmaceutical Engineering, College of Science and Technology, Dongguk University Gyeongju, 123 Dongdaero, Gyeongju, 38066, Gyeongbuk, Republic of Korea
| | - Jae Yong Lee
- Department of Biopharmaceutical Engineering, College of Science and Technology, Dongguk University Gyeongju, 123 Dongdaero, Gyeongju, 38066, Gyeongbuk, Republic of Korea
| | - Ji Hye Choi
- Department of Biopharmaceutical Engineering, College of Science and Technology, Dongguk University Gyeongju, 123 Dongdaero, Gyeongju, 38066, Gyeongbuk, Republic of Korea
| | - Duhyeon Park
- Department of Biopharmaceutical Engineering, College of Science and Technology, Dongguk University Gyeongju, 123 Dongdaero, Gyeongju, 38066, Gyeongbuk, Republic of Korea
| | - Yeon Ja Choi
- Department of Biopharmaceutical Engineering, College of Science and Technology, Dongguk University Gyeongju, 123 Dongdaero, Gyeongju, 38066, Gyeongbuk, Republic of Korea.
| | - Hae Young Chung
- Department of Pharmacy, College of Pharmacy, Pusan National University, 2 Busandaehak-ro, 63 Beon-gil, Geumjeong-gu, Busan, 46241, Republic of Korea.
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Simvastatin Improves Microcirculatory Function in Nonalcoholic Fatty Liver Disease and Downregulates Oxidative and ALE-RAGE Stress. Nutrients 2022; 14:nu14030716. [PMID: 35277075 PMCID: PMC8838100 DOI: 10.3390/nu14030716] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 01/11/2022] [Accepted: 01/14/2022] [Indexed: 12/12/2022] Open
Abstract
Increased reactive oxidative stress, lipid peroxidation, inflammation, and fibrosis, which contribute to tissue damage and development and progression of nonalcoholic liver disease (NAFLD), play important roles in microcirculatory disorders. We investigated the effect of the modulatory properties of simvastatin (SV) on the liver and adipose tissue microcirculation as well as metabolic and oxidative stress parameters, including the advanced lipoxidation end product–receptors of advanced glycation end products (ALE-RAGE) pathway. SV was administered to an NAFLD model constructed using a high-fat–high-carbohydrate diet (HFHC). HFHC caused metabolic changes indicative of nonalcoholic steatohepatitis; treatment with SV protected the mice from developing NAFLD. SV prevented microcirculatory dysfunction in HFHC-fed mice, as evidenced by decreased leukocyte recruitment to hepatic and fat microcirculation, decreased hepatic stellate cell activation, and improved hepatic capillary network architecture and density. SV restored basal microvascular blood flow in the liver and adipose tissue and restored the endothelium-dependent vasodilatory response of adipose tissue to acetylcholine. SV treatment restored antioxidant enzyme activity and decreased lipid peroxidation, ALE-RAGE pathway activation, steatosis, fibrosis, and inflammatory parameters. Thus, SV may improve microcirculatory function in NAFLD by downregulating oxidative and ALE-RAGE stress and improving steatosis, fibrosis, and inflammatory parameters.
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Lino Rodrigues K, Vieira Dias Da Silva V, Nunes Goulart da Silva Pereira E, Rangel Silvares R, Peres de Araujo B, Eduardo Ilaquita Flores E, Ramos IP, Pereira Borges J, Fernandes-Santos C, Daliry A. Aerobic Exercise Training Improves Microvascular Function and Oxidative Stress Parameters in Diet-Induced Type 2 Diabetic Mice. Diabetes Metab Syndr Obes 2022; 15:2991-3005. [PMID: 36200064 PMCID: PMC9527816 DOI: 10.2147/dmso.s365496] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 06/30/2022] [Indexed: 11/29/2022] Open
Abstract
PURPOSE Type 2 diabetic (T2D) patients have liver and adipose tissue microcirculation disturbances associated with metabolic dysfunction and disease progression. However, the potential role of aerobic training on hepatic and white adipose tissue (WAT) microcirculation and the underlying mechanisms have not been elucidated to date. Therefore, we investigated the role of aerobic training on liver and WAT microcirculation and AGE-RAGE modulation in T2D mice. METHODS The control group (CTL) was fed standard chow, and T2D was induced by feeding male C57BL/6 a high-fat, high-carbohydrate diet for 24 weeks. In the following 12 weeks, mice underwent aerobic training (CTL EX and T2D EX groups), or were kept sedentary (CTL and T2D groups). We assessed metabolic parameters, biochemical markers, oxidative damage, the AGE-RAGE axis, hepatic steatosis, hepatic stellate cells activation (HSC) and liver and WAT microcirculation. RESULTS Hepatic microcirculation was improved in T2D EX mice which were associated with improvements in body, liver and fat mass, blood pressure, hepatic steatosis and fibrosis, and decreased HSC and AGE-RAGE activation. In contrast, improvement in WAT microcirculation, that is, decreased leukocyte recruitment and increased perfusion, was associated with increased catalase antioxidant activity. CONCLUSION Physical training improves hepatic and adipose tissue microcirculatory dysfunction associated with T2D, likely due to downregulation of AGE-RAGE axis, decreased HSC activation and increased antioxidant activity.
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Affiliation(s)
- Karine Lino Rodrigues
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, RJ, Brazil
| | | | | | - Raquel Rangel Silvares
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, RJ, Brazil
| | - Beatriz Peres de Araujo
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, RJ, Brazil
| | | | - Isalira Peroba Ramos
- National Center of Structural Biology and Bio-imaging, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Juliana Pereira Borges
- Laboratory of Physical Activity and Health Promotion, University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Caroline Fernandes-Santos
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, RJ, Brazil
- Department of Basic Sciences, Federal Fluminense University, Nova Friburgo, RJ, Brazil
| | - Anissa Daliry
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, RJ, Brazil
- Correspondence: Anissa Daliry, Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, FIOCRUZ, Pavilhão Ozorio de Almeida Av. Brasil, 4365 (Room 14), Manguinhos, Rio de Janeiro, RJ, CEP: 21040-900, Brazil, Tel +55 212562-1312, Email
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Pereira ENGDS, Paula DP, Araujo BPD, Fonseca MDJMD, Diniz MDFHS, Daliry A, Griep RH. Advanced glycation end product: A potential biomarker for risk stratification of non-alcoholic fatty liver disease in ELSA-Brasil study. World J Gastroenterol 2021; 27:4913-4928. [PMID: 34447235 PMCID: PMC8371502 DOI: 10.3748/wjg.v27.i29.4913] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 03/18/2021] [Accepted: 04/26/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Liver diseases are associated with the excess formation of advanced glycation end products (AGEs), which induce tissue inflammation and oxidative damage. However, the trend of oxidative marker levels according to the steatosis grade in non-alcoholic fatty liver disease (NAFLD) is unclear.
AIM To compare serum AGE levels between participants with NAFLD accordingly to steatosis severity in the baseline ELSA-Brasil population.
METHODS In 305 individuals at baseline ELSA-Brasil, NAFLD-associated steatosis was classified by ultrasound hepatic attenuation. The participants were grouped according to the severity of steatosis: mild and moderate/severe pooled. The measurement of serum fluorescent AGE concentrations was based on spectrofluorimetric detection. Serum AGE content and clinical and laboratory characteristics of the participants were compared between groups. The correlation between serum AGE levels and the grade of steatosis was analyzed. Logistic regression analysis was used to investigate the relationship between serum AGE levels and steatosis severity. A P value < 0.05 was considered statistically significant.
RESULTS According to the steatosis severity spectrum in NAFLD, from mild to moderate/severe, individuals with the most severe steatosis grade had a higher incidence of metabolic syndrome (63% vs 34%, P ≤ 0.001), diabetes mellitus (37% vs 14%, P ≤ 0.001), and high cholesterol levels (51% vs 33%, P < 0.001). Moreover, individuals with increasing severity of steatosis presented increasing waist circumference, body mass index, systolic and diastolic blood pressure, fasting blood glucose, glycated hemoglobin, insulin, triglycerides, alanine aminotransferase, gamma-glutamyl transferase, C-reactive protein, and uric acid levels and lower high-density lipoprotein. Higher serum AGE content was present in the moderate/severe group of individuals than in the mild group (P = 0.008). In addition, the serum AGE levels were correlated with the steatosis grade in the overall sample (rho = 0.146, P = 0.010). Logistic regression analysis, after adjusting for confounding variables, showed that subjects with higher serum AGE content had a 4.6-fold increased chance of having moderate or severe steatosis when compared to low levels of serum AGEs. According to the results of the receiver operator characteristic curves analyses (areas under the curve, AUC = 0.83), AGEs could be a good marker of steatosis severity in patients with NAFLD and might be a potential biomarker in predicting NAFLD progression, strengthening the involvement of AGE in NAFLD pathogenesis.
CONCLUSION NAFLD-associated steatosis was associated with serum AGE levels; therefore, plasmatic fluorescent AGE quantification by spectroscopy could be a promising alternative method to monitor progression from mild to severe NAFLD accordingly to steatosis grade.
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Affiliation(s)
| | - Daniela Polessa Paula
- National School of Statistical Sciences, Brazilian Institute of Geography and Statistics, Rio de Janeiro 20231-050, Brazil
| | - Beatriz Peres de Araujo
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Foundation, Rio de Janeiro 21040-360, Brazil
| | | | | | - Anissa Daliry
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Foundation, Rio de Janeiro 21040-360, Brazil
| | - Rosane Harter Griep
- Laboratory of Health and Environment Education, Oswaldo Cruz Foundation, Rio de Janeiro 21040-360, Brazil
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8C-glycosylflavone from the Piper auritum suppressed glycoxidation process in vitro and in streptozotocin-induced diabetic mice. ADVANCES IN TRADITIONAL MEDICINE 2021. [DOI: 10.1007/s13596-021-00577-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Ni Z, Lin X, Wen Q, Kintoko, Zhang S, Huang J, Xu X, Huang R. WITHDRAWN: Effect of 2-dodecyl-6-methoxycyclohexa-2, 5-diene-1, 4-dione, isolated from Averrhoa carambola L. (Oxalidaceae) roots, on advanced glycation end-product-mediated renal injury in type 2 diabetic KKAy mice. Toxicol Lett 2021; 339:88-96. [PMID: 33423876 DOI: 10.1016/j.toxlet.2020.11.022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
The Publisher regrets that this article is an accidental duplication of an article that has already been published in [Toxicology Letters, 339C (2021) 88–96], https://doi.org/10.1016/j.toxlet.2020.11.022. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal
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Affiliation(s)
- Zheng Ni
- Department of Pharmacology, Guangxi Medical University, Nanning 530021, PR China
| | - Xing Lin
- Department of Pharmacology, Guangxi Medical University, Nanning 530021, PR China
| | - Qingwei Wen
- Department of Pharmacology, Guangxi Medical University, Nanning 530021, PR China
| | - Kintoko
- Department of Pharmacology, Guangxi Medical University, Nanning 530021, PR China
| | - Shijun Zhang
- Department of Pharmacology, Guangxi Medical University, Nanning 530021, PR China
| | - Jianchun Huang
- Department of Pharmacology, Guangxi Medical University, Nanning 530021, PR China
| | - Xiaohui Xu
- Department of Pharmacology, Guangxi Medical University, Nanning 530021, PR China
| | - Renbin Huang
- Department of Pharmacology, Guangxi Medical University, Nanning 530021, PR China.
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Effect of Berberine on Glycation, Aldose Reductase Activity, and Oxidative Stress in the Lenses of Streptozotocin-Induced Diabetic Rats In Vivo-A Preliminary Study. Int J Mol Sci 2020; 21:ijms21124278. [PMID: 32560082 PMCID: PMC7349706 DOI: 10.3390/ijms21124278] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 06/10/2020] [Accepted: 06/12/2020] [Indexed: 12/13/2022] Open
Abstract
Diabetes mellitus affects the eye lens, leading to cataract formation by glycation, osmotic stress, and oxidative stress. Berberine, an isoquinoline alkaloid, is a natural compound that has been reported to counteract all these pathological processes in various tissues and organs. The goal of this study was to evaluate whether berberine administered at a dose of 50 mg/kg by oral gavage for 28 days to rats with streptozotocin-induced diabetes reveals such effects on the biochemical parameters in the lenses. For this purpose, the following lenticular parameters were studied: concentrations of soluble protein, non-protein sulfhydryl groups (NPSH), advanced oxidation protein products (AOPP), advanced glycation end-products (AGEs), thiobarbituric acid reactive substances (TBARS), and activities of aldose reductase (AR), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Diabetes induced unfavorable changes in the majority of the examined parameters. The administration of berberine resulted in an increased soluble protein level, decreased activity of AR, and lowered AOPP and AGEs levels. The results suggest that berberine administered orally positively affects the lenses of diabetic rats, and should be further examined with regard to its anticataract potential.
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Rashid G, Luzon AA, Korzets Z, Klein O, Zeltzer E, Bernheim J. The Effect of Advanced Glycation End-Products and Aminoguanidine on Tnfα Production by Rat Peritoneal Macrophages. Perit Dial Int 2020. [DOI: 10.1177/089686080102100203] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
ObjectiveTo evaluate the effect of advanced glycation end-products (AGEs) and the inhibitor of their formation, aminoguanidine, on tumor necrosis factor-α (TNFα) production (as a functional marker) by rat peritoneal macrophages (PMΦ).DesignCharles River rats underwent a daily intraperitoneal injection of peritoneal dialysis solution [(PDS), 4.25 g/dL dextrose; Dialine, Travenol, Ashdod, Israel] for a 2-month period (group E). Another group of rats was subjected to the same protocol with the addition of 25 mg/kg aminoguanidine (group A). Three control groups were utilized: ( 1 ) rats that were injected daily with aminoguanidine only (group AO), ( 2 ) rats that were injected with Dulbecco's phosphate-buffered saline (group D), and ( 3 ) rats in which no intervention was carried out (group C). After 2 months, PMΦ were isolated from rat peritoneal effluent and their TNFα production measured by ELISA in cell-free culture supernatants, in both the basal state and after 24-hour stimulation with lipopolysaccharide (LPS). The concentrations of AGEs in peritoneal effluent were assayed and correlated to TNFα levels. PMΦ obtained from normal rats were then incubated for 24 hours with ( 1 ) the peritoneal effluent of each of the above respective groups, with or without LPS; ( 2 ) increasing concentrations of AGEs (0 - 250 μg/mL); and ( 3 ) increasing concentrations of aminoguanidine (0 - 7.5 mg/mL), and TNFα secretion again determined.ResultsAfter 2 months of daily intraperitoneal injection of PDS, in the basal state, TNFα production was significantly higher in PMΦ isolated from the peritoneal effluent groups (groups E, A, and AO) compared to controls (group C). Following LPS stimulation, a further increase in TNFα secretion was seen, with a significantly greater response in group AO versus groups E, A, and D. Effluent AGEs were markedly elevated only in group E. No correlation was found between TNFα secretion by these PMΦ and the concentration of AGEs. On incubation with the respective peritoneal effluents (groups E, A, and AO), in both the basal and stimulated state, TNFα production by PMΦ from normal rats was significantly enhanced compared to group C. Incubation with increasing concentrations of AGEs or aminoguanidine resulted in an increase of TNFα secretion by these PMΦ.ConclusionsFollowing intermittent intraperitoneal administration of glucose-based PDS, rat PMΦ are chronically activated, as evidenced by increased basal TNFα secretion. The peritoneal effluent of such treated animals is capable of stimulating TNFα production by normal rat PMΦ. These data suggest that glucose-based PDS acts as a primer of PMΦ, which retain their ability to further stimulation by LPS. Although, in vitro, AGEs promote TNFα secretion by normal rat PMΦ, in vivo, their influence is probably modulated by other factors. Aminoguanidine has a specific inducing effect on rat PMΦ, independent of glucose-based PDS.
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Affiliation(s)
- Gloria Rashid
- Department of Nephrology and Hypertension, Sapir Medical Center, Kfar-Saba, and The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ami-Ad Luzon
- Department of Nephrology and Hypertension, Sapir Medical Center, Kfar-Saba, and The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ze'ev Korzets
- Department of Nephrology and Hypertension, Sapir Medical Center, Kfar-Saba, and The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Osnat Klein
- Department of Nephrology and Hypertension, Sapir Medical Center, Kfar-Saba, and The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ella Zeltzer
- Department of Nephrology and Hypertension, Sapir Medical Center, Kfar-Saba, and The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Jacques Bernheim
- Department of Nephrology and Hypertension, Sapir Medical Center, Kfar-Saba, and The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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Zeltzer E, Klein O, Rashid G, Katz D, Korzets Z, Bernheim J. Intraperitoneal Infusion of Glucose-Based Dialysate in the Rat—An Animal Model for the Study of Peritoneal Advanced Glycation End-Products Formation and Effect on Peritoneal Transport. Perit Dial Int 2020. [DOI: 10.1177/089686080002000613] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
ObjectiveGlucose-based dialysate induces non enzymatic glycation within the peritoneal cavity. To evaluate the relationship between the formation of advanced glycation end-products (AGEs) and peritoneal transfer for small solutes and macromolecules, we developed a model of simulated peritoneal dialysis (PD) in normal rats.MethodsMale albino rats of the Charles River strain were divided into two sets of 3 groups (15 – 25 rats in each group). In the experimental (E) group, the rats were intra-peritoneally (IP) injected daily with a commercially available 4.25% dextrose solution. In the control puncture (CP) group, the peritoneum was punctured daily, but no PD solution infused. In an age-matched control (CC) group, no intervention was given. Two study protocols were used. Protocol A (duration 20 weeks) consisted of a daily IP injection of 10 mL PD solution per 100 g body weight. In protocol B, a double volume of PD solution was introduced (20 mL per 100 g body weight). At 9, 16, and 20 weeks in protocol A, and at 9 weeks in protocol B, urea, creatinine, microalbumin [(MAL) measured using specific anti-rat albumin monoclonal antibody], and AGEs (measured by fluorescent assay with excitation at 370 nm and emission at 440 nm) were measured in peritoneal effluent and serum.ResultsAt no time during the study were AGEs detected in serum from any group in either protocol. In both protocols, no differences were found between the control groups (CP, CC) with respect to all parameters. In protocol A, the dialysate-to-plasma ratio (D/P) of urea was significantly higher in the experimental group as compared with the control groups at 9, 16, and 20 weeks [9 weeks: 0.59 ± 0.03 (E) vs 0.39 ± 0.02 (CP) vs 0.46 ± 0.02 (CC), p < 0.0004 and p < 0.002, respectively; 16 weeks: 0.71 ± 0.08 (E) vs 0.42 ± 0.01 (CP) vs 0.46 ± 0.01 (CC), p < 0.0001 and p < 0.02, respectively; 20 weeks: 0.57 ± 0.03 (E) vs 0.39 ± 0.01 (CP) vs 0.41 ± 0.02 (CC), p < 0.002 and p < 0.004, respectively]. At 16 and 20 weeks, dialysate MAL levels were significantly increased in group E [16 weeks: 354.00 ± 80.35 μg/mL (E) vs 134.75 ± 14.36 μg/mL (CP) vs 110.69 ± 7.83 μg/mL (CC), p < 0.04 and p < 0.03, respectively; 20 weeks: 283.17 ± 14.71 μg/mL (E) vs 105.14 ± 12.11 μg/mL (CP) vs 135.50 ± 19.03 μg/mL (CC), p < 0.00001 and p < 0.0001, respectively]. In protocol B, at completion of the study (week 9), D/P urea, effluent MAL, and AGEs were significantly higher in the experimental group as compared with the control groups [D/P: 0.67 ± 0.04 (E) vs 0.46 ± 0.07 (CP) vs 0.41 ± 0.02 (CC), p < 0.0002 and p < 00001, respectively; MAL: 336.8 ± 63.30 μg/mL (E) vs 125.71 ± 16.77 μg/mL (CP) vs 119.00 ± 39.75 μg/mL (CC), p < 0.008 and p < 0.007, respectively; AGEs: 265.77 ± 33.49 U/mg creatinine (E) vs 163.10 ± 21.99 U/mg creatinine (CP) vs 83.17 ± 22.66 U/mg creatinine (CC), p < 0.02 and p < 0.001, respectively]. Peritoneal effluent AGEs were found to be significantly correlated with D/P urea and dialysate MAL ( r = 0.42, p < 0.04, and r = 0.7, p = 0.00001, respectively).ConclusionsIn situ generation of AGEs constitutes the chief origin of peritoneal AGEs. Advanced glycation end-products affect peritoneal permselectivity for both small and large solutes. The rat model of simulated peritoneal dialysis developed in this experiment provides a reliable method for studying peritoneal AGE formation and effect on peritoneal transfer of small solutes and macro-molecules.
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Affiliation(s)
- Ella Zeltzer
- Department of Nephrology and Department of Biochemistry, Meir Hospital, Kfar–Saba and the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Osnat Klein
- Department of Nephrology and Department of Biochemistry, Meir Hospital, Kfar–Saba and the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Gloria Rashid
- Department of Nephrology and Department of Biochemistry, Meir Hospital, Kfar–Saba and the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Dov Katz
- Department of Nephrology and Department of Biochemistry, Meir Hospital, Kfar–Saba and the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ze'ev Korzets
- Department of Nephrology and Department of Biochemistry, Meir Hospital, Kfar–Saba and the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Jacques Bernheim
- Department of Nephrology and Department of Biochemistry, Meir Hospital, Kfar–Saba and the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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Pereira ENGDS, Silvares RR, Flores EEI, Rodrigues KL, Daliry A. Pyridoxamine improves metabolic and microcirculatory complications associated with nonalcoholic fatty liver disease. Microcirculation 2020; 27:e12603. [PMID: 31876010 DOI: 10.1111/micc.12603] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 12/19/2019] [Indexed: 02/06/2023]
Abstract
OBJECTIVE We investigated the protective effects of pyridoxamine against metabolic and microcirculatory complications in nonalcoholic fatty liver disease. METHODS Nonalcoholic fatty liver disease was established by a high-fat diet administration over 28 weeks. Pyridoxamine was administered between weeks 20 and 28. The recruitment of leukocytes and the number of vitamin A-positive hepatic stellate cells were examined by in vivo microscopy. Laser speckle contrast imaging was used to evaluate microcirculatory hepatic perfusion. Thiobarbituric acid reactive substances measurement and RT-PCR were used for oxidative stress and inflammatory parameters. advanced glycation end products were evaluated by fluorescence spectroscopy. RESULTS The increase in body, liver, and fat weights, together with steatosis and impairment in glucose metabolism observed in the nonalcoholic fatty liver disease group were attenuated by pyridoxamine treatment. Regarding the hepatic microcirculatory parameters, rats with high-fat diet-induced nonalcoholic fatty liver disease showed increased rolling and adhesion of leukocytes, increased hepatic stellate cells activation, and decreased tissue perfusion, which were reverted by pyridoxamine. Pyridoxamine protected against the increased hepatic lipid peroxidation observed in the nonalcoholic fatty liver disease group. Pyridoxamine treatment was associated with increased levels of tumor necrosis factor alpha (TNF-α) mRNA transcripts in the liver. CONCLUSION Pyridoxamine modulates oxidative stress, advanced glycation end products, TNF-α transcripts levels, and metabolic disturbances, being a potential treatment for nonalcoholic fatty liver disease-associated microcirculatory and metabolic complications.
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Affiliation(s)
| | - Raquel Rangel Silvares
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | | | - Karine Lino Rodrigues
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Anissa Daliry
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
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Ohno RI, Ichimaru K, Tanaka S, Sugawa H, Katsuta N, Sakake S, Tominaga YK, Ban I, Shirakawa JI, Yamaguchi Y, Ito E, Taniguchi N, Nagai R. Glucoselysine is derived from fructose and accumulates in the eye lens of diabetic rats. J Biol Chem 2019; 294:17326-17338. [PMID: 31594865 DOI: 10.1074/jbc.ra119.010744] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 10/04/2019] [Indexed: 12/12/2022] Open
Abstract
Prolonged hyperglycemia generates advanced glycation end-products (AGEs), which are believed to be involved in the pathogenesis of diabetic complications. In the present study, we developed a polyclonal antibody against fructose-modified proteins (Fru-P antibody) and identified its epitope as glucoselysine (GL) by NMR and LC-electrospray ionization (ESI)- quadrupole TOF (QTOF) analyses and evaluated its potential role in diabetes sequelae. Although the molecular weight of GL was identical to that of fructoselysine (FL), GL was distinguishable from FL because GL was resistant to acid hydrolysis, which converted all of the FLs to furosine. We also detected GL in vitro when reduced BSA was incubated with fructose for 1 day. However, when we incubated reduced BSA with glucose, galactose, or mannose for 14 days, we did not detect GL, suggesting that GL is dominantly generated from fructose. LC-ESI-MS/MS experiments with synthesized [13C6]GL indicated that the GL levels in the rat eye lens time-dependently increase after streptozotocin-induced diabetes. We observed a 31.3-fold increase in GL 8 weeks after the induction compared with nondiabetic rats, and Nϵ-(carboxymethyl)lysine and furosine increased by 1.7- and 21.5-fold, respectively, under the same condition. In contrast, sorbitol in the lens levelled off at 2 weeks after diabetes induction. We conclude that GL may be a useful biological marker to monitor and elucidate the mechanism of protein degeneration during progression of diabetes.
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Affiliation(s)
- Rei-Ichi Ohno
- Laboratory of Food and Regulation Biology, Graduate School of Bioscience, Tokai University, 9-1-1 Toroku, Kumamoto, Higashi-ku, Kumamoto 862-0970, Japan
| | - Kenta Ichimaru
- Laboratory of Food and Regulation Biology, Graduate School of Agriculture, Tokai University, 9-1-1 Toroku, Kumamoto, Higashi-ku, Kumamoto 862-0970, Japan
| | - Seitaro Tanaka
- Laboratory of Food and Regulation Biology, Graduate School of Agriculture, Tokai University, 9-1-1 Toroku, Kumamoto, Higashi-ku, Kumamoto 862-0970, Japan
| | - Hikari Sugawa
- Laboratory of Food and Regulation Biology, Graduate School of Bioscience, Tokai University, 9-1-1 Toroku, Kumamoto, Higashi-ku, Kumamoto 862-0970, Japan
| | - Nana Katsuta
- Laboratory of Food and Regulation Biology, Graduate School of Agriculture, Tokai University, 9-1-1 Toroku, Kumamoto, Higashi-ku, Kumamoto 862-0970, Japan
| | - Shiori Sakake
- Laboratory of Food and Regulation Biology, Graduate School of Agriculture, Tokai University, 9-1-1 Toroku, Kumamoto, Higashi-ku, Kumamoto 862-0970, Japan
| | - Yu-Ki Tominaga
- Laboratory of Food and Regulation Biology, Graduate School of Agriculture, Tokai University, 9-1-1 Toroku, Kumamoto, Higashi-ku, Kumamoto 862-0970, Japan
| | - Ikuho Ban
- Laboratory of Food and Regulation Biology, Department of Bioscience, School of Agriculture, Tokai University, 9-1-1 Toroku, Kumamoto, Higashi-ku, Kumamoto 862-0970, Japan
| | - Jun-Ichi Shirakawa
- Laboratory of Food and Regulation Biology, Department of Bioscience, School of Agriculture, Tokai University, 9-1-1 Toroku, Kumamoto, Higashi-ku, Kumamoto 862-0970, Japan
| | - Yoshiki Yamaguchi
- Laboratory of Pharmaceutical Physical Chemistry, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558, Japan
| | - Emi Ito
- Department of Diabetic Complications, Diabetes Research Center, Research Institute National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Naoyuki Taniguchi
- Department of Glyco-Oncology and Medical Biochemistry, Osaka International Cancer Institute 3-1-69 Otemae, Chuoku, Osaka, 541-8567, Japan
| | - Ryoji Nagai
- Laboratory of Food and Regulation Biology, Graduate School of Bioscience, Tokai University, 9-1-1 Toroku, Kumamoto, Higashi-ku, Kumamoto 862-0970, Japan .,Laboratory of Food and Regulation Biology, Graduate School of Agriculture, Tokai University, 9-1-1 Toroku, Kumamoto, Higashi-ku, Kumamoto 862-0970, Japan.,Laboratory of Food and Regulation Biology, Department of Bioscience, School of Agriculture, Tokai University, 9-1-1 Toroku, Kumamoto, Higashi-ku, Kumamoto 862-0970, Japan
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Yeh PT, Wang LC, Chang SW, Yang WS, Yang CM, Yang CH. Effect of Fenofibrate on the Expression of Inflammatory Mediators in a Diabetic Rat Model. Curr Eye Res 2019; 44:1121-1132. [PMID: 31109206 DOI: 10.1080/02713683.2019.1622020] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Purpose: To investigate the mechanisms of anti-inflammatory and anti-oxidative effects of fenofibrate, a peroxisome proliferator-activated receptors-α agonist, in preventing diabetic retinopathy (DR) progression via a diabetic rat model. Methods: Diabetes was induced by intraperitoneal injection of streptozotocin in 6-week-old female Wistar rats. Diabetic rats were divided into diabetes without treatment (n = 10), diabetes treated with low dose fenofibrate (30 mg/kg/day) (n = 10) and high dose fenofibrate (100 mg/kg/day) (n = 10). Serum aqueous humor (AqH) and ocular tissues were gathered after 3-month treatment. Expressions of NF-κB and inflammatory chemokines (monocyte chemoattractant protein-1, fractalkine, and intercellular adhesion molecule-1) were detected by reverse transcription-polymerase chain reaction, Western blot, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), and electrophoretic mobility shift assay. The levels of oxidative biomarkers, including acrolein, nitrotyrosine, and 8-hydroxy-2'-deoxyguanosin (8-OHdG), were determined by IHC and ELISA. The reactive oxygen species (ROS) levels in serum and AqH were measured by chemiluminescence methods. Results: After 3 months of treatment, the expressions of mRNA and protein of monocyte chemoattractant protein-1, fractalkine, and intercellular adhesion molecule-1 in the retina of diabetic rats were significantly inhibited by fenofibrate in a dose-dependent manner. These effects were mediated by inhibition of NF-κB by fenofibrate. The levels of oxidative markers, including acrolein, nitrotyrosine, and 8-OHdG, decreased in the retina of diabetic rats after fenofibrate treatment. The ROS levels in the AqH of diabetic rats also suppressed by fenofibrate. Conclusions: Fenofibrate significantly inhibited the expressions of NF-κB and inflammatory chemokines and reduced oxidative products within diabetic retina. Treatment of fenofibrate might be beneficial to preventing DR progression.
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Affiliation(s)
- Po-Ting Yeh
- Department of Ophthalmology, National Taiwan University Hospital , Taipei , Taiwan
| | - Lu-Chun Wang
- Department of Ophthalmology, National Taiwan University Hospital, Yun-Lin Branch , Douliou City, Yunlin County , Taiwan
| | - Shu-Wen Chang
- Department of Ophthalmology, Far Eastern Memorial Hospital , NewTaipei City , Taiwan
| | - Wei-Shiung Yang
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University , Taipei , Taiwan.,Department of Internal Medicine, National Taiwan University Hospital , Taipei , Taiwan
| | - Chung-May Yang
- Department of Ophthalmology, National Taiwan University Hospital , Taipei , Taiwan.,Department of Ophthalmology, College of Medicine, National Taiwan University , Taipei , Taiwan
| | - Chang-Hao Yang
- Department of Ophthalmology, National Taiwan University Hospital , Taipei , Taiwan.,Department of Ophthalmology, College of Medicine, National Taiwan University , Taipei , Taiwan
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Rangel Silvares R, Nunes Goulart da Silva Pereira E, Eduardo Ilaquita Flores E, Lino Rodrigues K, Ribeiro Silva A, Gonçalves-de-Albuquerque CF, Daliry A. High-fat diet-induced kidney alterations in rats with metabolic syndrome: endothelial dysfunction and decreased antioxidant defense. Diabetes Metab Syndr Obes 2019; 12:1773-1781. [PMID: 31564943 PMCID: PMC6735540 DOI: 10.2147/dmso.s211253] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 06/11/2019] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION This study aimed to investigate changes in renal function and the AGE-RAGE axis in the kidney of a non-genetic animal model of metabolic syndrome (MetS) induced by high-fat diet (HFD). Additionally, we evaluated the protective effect of pyridoxamine (PM), a vitamin B6 analog with anti-AGE effects, in the context of diet-related renal endothelial dysfunction. METHODOLOGY In Wistar rats, the MetS animal model was induced by 20 or 28 weeks of HFD feeding. When indicated, a subgroup of animals was treated daily with PM (60 mg/kg) for 2 months. Tissue perfusion in renal microcirculation was examined by laser speckle contrast imaging. Oxidative stress was analyzed by thiobarbituric acid reactive species and the inflammatory markers by ELISA (TNF-α and IL-1β). Reverse transcription polymerase chain reaction was used to analyze eNOs, IL-6, vascular cell adhesion molecule (VCAM), NADPH oxidase subunit 47 (N47), catalase, and receptor for AGE (RAGE) gene expression. RESULTS Wistar rats fed a HFD showed negligible alteration in renal function, decrease in catalase mRNA transcripts and catalase enzyme activity compared to control (CTL) animals. Increased levels of IL-1β were observed in the kidney of MetS-induced rats. HFD-fed rats exhibited kidney endothelial dysfunction, with no significant differences in basal microvascular blood flow. PM significantly improved kidney vasorelaxation in HFD-fed rats. eNOS, VCAM, and RAGE gene expression and AGE content were not altered in kidneys of HFD-induced MetS rats in comparison to CTLs. CONCLUSIONS Our findings suggest that HFD-induced microvascular dysfunction precedes the decline in renal function, and could be related to antioxidant machinery defects and inflammation activation in the kidney. PM showed a vasoprotective effect, and thus, could be an important contributory factor in ameliorating diet-induced renal damage.
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Affiliation(s)
- Raquel Rangel Silvares
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
| | | | - Edgar Eduardo Ilaquita Flores
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
| | - Karine Lino Rodrigues
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
| | - Adriana Ribeiro Silva
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
| | - Cassiano Felipe Gonçalves-de-Albuquerque
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
- Laboratory of Immunopharmacology, Federal University of the State of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Anissa Daliry
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
- Correspondence: Anissa DaliryInstituto Oswaldo Cruz, Fiocruz, Pavilhão Ozório de Almeida, Manguinhos, Rio de Janeiro, CEP: 21.040-360, RJ, BrazilEmail
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Pereira ENGDS, Silvares RR, Flores EEI, Rodrigues KL, Ramos IP, da Silva IJ, Machado MP, Miranda RA, Pazos-Moura CC, Gonçalves-de-Albuquerque CF, Faria-Neto HCDC, Tibiriça E, Daliry A. Hepatic microvascular dysfunction and increased advanced glycation end products are components of non-alcoholic fatty liver disease. PLoS One 2017. [PMID: 28628674 PMCID: PMC5476253 DOI: 10.1371/journal.pone.0179654] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND This study aimed to investigate the pathophysiology of hepatic microcirculatory dysfunction in non-alcoholic fatty liver disease (NAFLD). METHODS In Wistar rats, NAFLD model was induced by 20 weeks of high-fat diet (HFD) feeding. Rolling and adhesion of leukocytes and tissue perfusion in hepatic microcirculation were examined using in vivo microscopic and laser speckle contrast imaging (LSCI), respectively. Oxidative stress and inflamatory parameters were analysed by TBARs, catalase enzyme activity, RT-PCR and ELISA. The participation of advanced glycation end-products (AGE) and its receptor RAGE was evaluated by the measurement of gene and protein expression of RAGE by RT-PCR and Western-blot, respectively and by liver and serum quantification of fluorescent AGEs. RESULTS Wistar rats fed high-fat diet (HFD) showed increase in epididymal and abdominal fat content, systolic arterial blood pressure, fasting blood glucose levels, hepatic triglycerides and cholesterol, and impairment of glucose and insulin metabolisms. Liver histology confirmed the presence of steatosis and ultrasound analysis revealed increased liver size and parenchymal echogenicity in HFD-fed rats. HFD causes significant increases in leukocyte rolling and adhesion on hepatic microcirculation and decrease in liver microvascular blood flow. Liver tissue presented increase in oxidative stress and inflammtion. At 20 weeks, there was a significantly increase in AGE content in the liver and serum of HFD-fed rats and an increase in RAGE gene expression in the liver. CONCLUSION The increase in liver AGE levels and microcirculatory disturbances could play a role in the pathogenesis of liver injury and are key components of NAFLD.
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Affiliation(s)
| | - Raquel Rangel Silvares
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Rio de Janeiro, RJ, Brazil
| | | | - Karine Lino Rodrigues
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Rio de Janeiro, RJ, Brazil
| | - Isalira Peroba Ramos
- Laboratory of Celular and Molecular Cardiology, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- National Center of Structural Biology and Bio-imaging, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Igor José da Silva
- Laboratory of Pathology, Oswaldo Cruz Institute, Rio de Janeiro, RJ, Brazil
| | | | - Rosiane Aparecida Miranda
- Laboratory of Molecular Endocrinology, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | | | | | | | - Eduardo Tibiriça
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Rio de Janeiro, RJ, Brazil
| | - Anissa Daliry
- Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, Rio de Janeiro, RJ, Brazil
- * E-mail:
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15
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Silvares RR, Pereira ENGDS, Flores EEI, Estato V, Reis PA, Silva IJD, Machado MP, Neto HCDCF, Tibiriça E, Daliry A. Combined therapy with metformin and insulin attenuates systemic and hepatic alterations in a model of high-fat diet-/streptozotocin-induced diabetes. Int J Exp Pathol 2016; 97:266-77. [PMID: 27381700 DOI: 10.1111/iep.12184] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 03/16/2016] [Indexed: 12/22/2022] Open
Abstract
In this study we have explored the pathogenesis of the hepatic alterations which occur in diabetes and the modulation of these complications by the combination of metformin adjunct treatment and insulin monotherapy. For this purpose, diabetic rats were treated with insulin (DM + Ins) or metformin plus insulin (DM + Met + Ins). Biochemical and cardiometabolic parameters were analysed by spectrophotometry. Intravital microscopy was used to study the hepatic microcirculation. In the liver tissue, real-time PCR was used to analyse oxidative stress enzymes, inflammatory markers and receptors for advanced glycation end products (AGE) (RAGE) gene expression. Lipid peroxidation was assessed by thiobarbituric acid reactive species (TBARs) analyses. AGE deposition and RAGE protein expression were studied by fluorescence spectrophotometry and Western blot respectively. Body weight, %HbA1c , urea, total proteins and oxidative stress parameters were found to be similarly improved by insulin or Met + Ins treatments. On the other hand, Met + Ins treatment showed a more pronounced effect on fasting blood glucose level than insulin monotherapy. Fructosamine, uric acid, creatinine, albumin and amylase levels and daily insulin dose requirements were found to be only improved by the combined Met + Ins treatment. Liver, renal and pancreatic dysfunction markers were found to be more positively affected by metformin adjunct therapy when compared to insulin treatment. Liver microcirculation damage was found to be completely protected by Met + Ins treatment, while insulin monotherapy showed no effect. Our results suggest that oxidative stress, microcirculatory damage and glycated proteins could be involved in the aetiology of liver disease due to diabetes. Additionally, metformin adjunct treatment improved systemic and liver injury in induced diabetes and showed a more pronounced effect than insulin monotherapy.
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Affiliation(s)
- Raquel Rangel Silvares
- Laboratório de Investigação Cardiovascular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | | | - Edgar Eduardo Ilaquita Flores
- Laboratório de Investigação Cardiovascular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - Vanessa Estato
- Laboratório de Investigação Cardiovascular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - Patrícia Alves Reis
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - Igor José da Silva
- Laboratório de Patologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - Marcelo Pelajo Machado
- Laboratório de Patologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | | | - Eduardo Tibiriça
- Laboratório de Investigação Cardiovascular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - Anissa Daliry
- Laboratório de Investigação Cardiovascular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
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Sil R, Ray D, Chakraborti AS. Glycyrrhizin ameliorates metabolic syndrome-induced liver damage in experimental rat model. Mol Cell Biochem 2015; 409:177-89. [PMID: 26400710 DOI: 10.1007/s11010-015-2523-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Accepted: 08/06/2015] [Indexed: 12/29/2022]
Abstract
Glycyrrhizin, a major constituent of licorice (Glycyrrhiza glabra) root, has been reported to ameliorate insulin resistance, hyperglycemia, dyslipidemia, and obesity in rats with metabolic syndrome. Liver dysfunction is associated with this syndrome. The objective of this study is to investigate the effect of glycyrrhizin treatment on metabolic syndrome-induced liver damage. After induction of metabolic syndrome in rats by high fructose (60%) diet for 6 weeks, the rats were treated with glycyrrhizin (50 mg/kg body weight, single intra-peritoneal injection). After 2 weeks of treatment, rats were sacrificed to collect blood samples and liver tissues. Compared to normal, elevated activities of serum alanine transaminase, alkaline phosphatase and aspartate transaminase, increased levels of liver advanced glycation end products, reactive oxygen species, lipid peroxidation, protein carbonyl, protein kinase Cα, NADPH oxidase-2, and decreased glutathione cycle components established liver damage and oxidative stress in fructose-fed rats. Activation of nuclear factor κB, mitogen-activated protein kinase pathways as well as signals from mitochondria were found to be involved in liver cell apoptosis. Increased levels of cyclooxygenase-2, tumor necrosis factor, and interleukin-12 proteins suggested hepatic inflammation. Metabolic syndrome caused hepatic DNA damage and poly-ADP ribose polymerase cleavage. Fluorescence-activated cell sorting using annexin V/propidium iodide staining confirmed the apoptotic hepatic cell death. Histology of liver tissue also supported the experimental findings. Treatment with glycyrrhizin reduced oxidative stress, hepatic inflammation, and apoptotic cell death in fructose-fed rats. The results suggest that glycyrrhizin possesses therapeutic potential against hepatocellular damage in metabolic syndrome.
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Affiliation(s)
- Rajarshi Sil
- Department of Biophysics, Molecular Biology and Bioinformatics, University College of Science, University of Calcutta, 92 Acharyya Prafulla Chandra Road, Kolkata, West Bengal, 700009, India
| | - Doel Ray
- Department of Biophysics, Molecular Biology and Bioinformatics, University College of Science, University of Calcutta, 92 Acharyya Prafulla Chandra Road, Kolkata, West Bengal, 700009, India.,School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Abhay Sankar Chakraborti
- Department of Biophysics, Molecular Biology and Bioinformatics, University College of Science, University of Calcutta, 92 Acharyya Prafulla Chandra Road, Kolkata, West Bengal, 700009, India.
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Perez Gutierrez RM, de Jesus Martinez Ortiz M. Beneficial effect of Azadirachta indica on advanced glycation end-product in streptozotocin-diabetic rat. PHARMACEUTICAL BIOLOGY 2014; 52:1435-1444. [PMID: 25026338 DOI: 10.3109/13880209.2014.895389] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
CONTEXT Both oxidation and hyperglycemia cause increased glycation and the formation of advanced glycation end-products (AGEs) which underlie the complications of diabetes. OBJECTIVE The goal of this article is to determine the effect of the chloroform extract from leaves of Azadirachta indica A. Juss; (Meliaceae) (AI) on the formation of glycated protein. MATERIALS AND METHODS Chloroform extract was subjected to in vitro bioassays to evaluate advanced glycation end-products formation. Bovine serum albumin (BSA)-glucose, BSA-methylglyoxal, Amadori-rich protein, glycated hemoglobin, oxidation, and glycation of LDL were determined. Doses of AI of 200 mg/kg/d by oral gavage were administered once daily for 30 d, at streptozotocin-induced diabetic rats. After this period, renal damage (TBARS), glucose, methylglyoxal, glycolaldehyde, and tail tendon collagen were investigated. RESULTS AND DISCUSSION AI exhibits protective action in BSA against glycation formation, GHb, protein levels, and LDL against glycation and oxidation. The renal glucose level decreases a 3.9 mg/g wet tissue. TBA-reactive substance showed a significant decrease to 1.82 mmol/mg protein. In addition, AI showed inhibitory activity against AGEs formation, methylglyoxal, and glycolaldehyde levels in kidney. Treatment with AI in rat tail tendon produced a reduction in cross-linking of collagen proteins. The antiglycation activities of A. indica were attributed in part to their antioxidant activity. AI alleviated oxidative stress under diabetic conditions through the inhibition of lipid peroxidation prevents the onset renal damage. CONCLUSION We found that A. indica is an inhibitor AGE formation, and oxidative stress with a renoprotective effect, which are considered to play important roles in diabetic kidney disease.
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Affiliation(s)
- Rosa Martha Perez Gutierrez
- Laboratorio de Investigación de Productos Naturales. Escuela Superior de Ingenieria Quimica e Industrias extractivas IPN. Av. Instituto Politécnico Nacional S/N , Unidad Profesional Adolfo Lopez Mateos cp 07708, Mexico D.F. , Mexico
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Kim YS, Kim J, Kim KM, Jung DH, Choi S, Kim CS, Kim JS. Myricetin inhibits advanced glycation end product (AGE)-induced migration of retinal pericytes through phosphorylation of ERK1/2, FAK-1, and paxillin in vitro and in vivo. Biochem Pharmacol 2014; 93:496-505. [PMID: 25450667 DOI: 10.1016/j.bcp.2014.09.022] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Revised: 09/30/2014] [Accepted: 09/30/2014] [Indexed: 01/24/2023]
Abstract
Advanced glycation end products (AGE) have been implicated in the development of diabetic retinopathy. Characterization of the early stages of diabetic retinopathy is retinal pericytes loss, which is the result of pericytes migration. In this study, we investigated the pathological mechanisms of AGE on the migration of retinal pericytes and confirmed the inhibitory effect of myricetin on migration in vitro and in vivo. Migration assays of bovine retinal pericytes (BRP) were induced using AGE-BSA and phosphorylation of Src, ERK1/2, focal adhesion kinase (FAK-1) and paxillin were determined using immunoblot analysis. Sprague-Dawley rats (6 weeks old) were injected intravitreally with AGE-BSA and morphological and immunohistochemical analysis of p-FAK-1 and p-paxillin were performed in the rat retina. Immunoblot analysis and siRNA transfection were used to study the molecular mechanism of myricetin on BRP migration. AGE-BSA increased BRP migration in a dose-dependent manner via receptor for AGEs (RAGE)-dependent activation of the Src kinase-ERK1/2 pathway. AGE-BSA-induced migration was inhibited by an ERK1/2 specific inhibitor (PD98059), but not by p38 and Jun N-terminal kinase inhibitors. AGE-BSA increased FAK-1 and paxillin phosphorylation in a dose- and time-dependent manner. These increases were attenuated by PD98059 and ERK1/2 siRNA. Phosphorylation of FAK-1 and paxillin was increased in response to AGE-BSA-induced migration of rat retinal pericytes. Myricetin strongly inhibited ERK1/2 phosphorylation and significantly suppressed pericytes migration in AGE-BSA-injected rats. Our results demonstrate that AGE-BSA participated in the pathophysiology of retinal pericytes migration likely through the RAGE-Src-ERK1/2-FAK-1-paxillin signaling pathway. Furthermore, myricetin suppressed phosphorylation of ERK 1/2-FAK-1-paxillin and inhibited pericytes migration.
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Affiliation(s)
- Young Sook Kim
- Korean Medicine-Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseongdae-ro, Yuseong-gu, Daejeon, South Korea.
| | - Junghyun Kim
- Korean Medicine-Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseongdae-ro, Yuseong-gu, Daejeon, South Korea
| | - Ki Mo Kim
- Korean Medicine-Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseongdae-ro, Yuseong-gu, Daejeon, South Korea
| | - Dong Ho Jung
- Korean Medicine-Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseongdae-ro, Yuseong-gu, Daejeon, South Korea
| | - Sojin Choi
- Korean Medicine-Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseongdae-ro, Yuseong-gu, Daejeon, South Korea
| | - Chan-Sik Kim
- Korean Medicine-Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseongdae-ro, Yuseong-gu, Daejeon, South Korea
| | - Jin Sook Kim
- Korean Medicine-Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseongdae-ro, Yuseong-gu, Daejeon, South Korea.
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Gonzalez AMN, Gutierrez RMP, Cotera LBF. Antidiabetic activity of Piper auritum leaves in streptozotocin-induced diabetic rat, beneficial effect on advanced glycation endproduct. Chin J Integr Med 2014. [PMID: 25141815 DOI: 10.1007/s11655-014-1753-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2011] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To investigate the effect of hypoglycaemic, hypolipidemic, oxidative stress, insulin resistance and advanced glycation endproducts (AGEs) formation of hexane extract from Piper auritum. METHODS The streptozotocin (STZ)-induced diabetic Wistar rats were treated with the hexane extract from Piper auritum leaves for 28 days and a set of biochemical parameters were studied including glucose level, total cholesterol, triglycerides, lipid peroxidation, liver and muscle glycogen, superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase. The liver function was observed by determining glucose-6-phosphatase, glucokinase and hexokinase activities, and the effect of the hexane extract on insulin level and protein glycation. RESULTS There was a significant increase in blood glucose level (P<0.05) in diabetic rats after 24 h of STZ injection. There was a significantly decreased in blood glucose in diabetic rats with hexane extract treatment (P<0.05). The serum biochemical parameters, hepatic enzymes, thiobarbituric acid reactive substances, glycosylated hemoglobin, AGEs, and insulin level (P<0.01 or P<0.05) were restored to normal levels in STZ-diabetic rats treated with hexane extract. CONCLUSION The hexane extract from Piper auritum leaves can efficiently inhibit insulin resistance, AGEs formation, improvement of renal function, lipid abnormalities and oxidative stress, indicating that its therapeutic properties may be due to the interaction of hexane extract components with multiple targets involved in diabetes pathogenesis.
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Affiliation(s)
- Adriana María Neira Gonzalez
- Laboratory of Microbial Secondary Metabolites, Department of Biotechnology and Biengineering, Cinvestav, México DF, 07360, México
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Park CH, Noh JS, Tanaka T, Roh SS, Lee JC, Yokozawa T. Polyphenol isolated from Corni Fructus, 7-O-galloyl-D-sedoheptulose, modulates advanced glycation endproduct-related pathway in type 2 diabetic db/db mice. Arch Pharm Res 2014; 38:1270-80. [PMID: 25079767 DOI: 10.1007/s12272-014-0457-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Accepted: 07/16/2014] [Indexed: 12/27/2022]
Abstract
7-O-Galloyl-D-sedoheptulose (GS) is the bioactive polyphenol isolated from the low-molecular-weight fraction of Corni Fructus (Cornus officinalis Sieb. et Zucc.). The present study was conducted to examine whether GS has an ameliorative effect on the liver of type 2 diabetic db/db mice. GS (20 or 100 mg/kg body weight/day, per os) was administered every day for 6 weeks to db/db mice, and its effect was compared with vehicle-treated db/db and m/m mice. The administration of GS decreased the elevated serum glucose, leptin, insulin, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), resistin, and hepatic functional parameters, and reduced the increased fluorescent advanced glycation endproducts (AGEs) and reactive oxygen species in the liver. The db/db mice exhibited the up-regulation of receptor for AGEs (RAGE) and AGE-related proteins; however, GS treatment significantly reduced those expressions. Moreover, the augmented expressions of oxidative stress- and inflammation-related proteins, phospho-extracellular-signal regulated kinase 1/2, phospho-c-Jun N-terminal kinase, nuclear factor-kappa B, activator protein-1, monocyte chemotactic protein-1, intracellular adhesion molecule-1, TNF-α, and IL-6, were down-regulated by GS administration. Hematoxylin-eosin staining showed that the increased hepatocellular damage in the liver of db/db mice improved with GS administration. The present results support the evidence for GS ameliorating hepatic damage through the RAGE-mediated inflammation pathway.
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Affiliation(s)
- Chan Hum Park
- College of Korean Medicine, Daegu Haany University, Daegu, 706-060, Korea
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21
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Gutierrez RMP, Baez EG. Evaluation of antidiabetic, antioxidant and antiglycating activities of the Eysenhardtia polystachya. Pharmacogn Mag 2014; 10:S404-18. [PMID: 24991120 PMCID: PMC4078337 DOI: 10.4103/0973-1296.133295] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2013] [Revised: 11/20/2013] [Accepted: 05/28/2014] [Indexed: 12/20/2022] Open
Abstract
Background: Many diseases are associated with oxidative stress caused by free radicals. The aim of the present study was to evaluate the antidiabetic, antioxidant and antiglycation properties of Eysenhardtia polystachya (EP) bark methanol-water extract. Materials and Methods : The antioxidant capacities were evaluated by studying in vitro the scavenging of DPPH and ABTS free radical, reactive oxygen species such as RO2, O2·-, H2O2, OH., H2O2, ONOO-, NO, HOCl,1 O2, chelating ability, ORAC, β-carotene-bleaching and lipid peroxidation. The antiglycation activities of EP were evaluated by haemoglobin, bovine serum albumin (BSA)-glucose, BSA-methylglyoxal and BSA-glucose assays. Oral administration of EP at the doses of 100 mg/kg, 200 mg/kg and 400 mg/g was studied in normal, glucose-loaded and antidiabetic effects on streptozotocin-induced mildly diabetic (MD) and severely diabetic (SD) mice. Results: EP showed Hdonor activity, free radical scavenging activity, metal chelating ability and lipid peroxidation Antioxidant activity may be attributed to the presence of phenolic and flavonoid compounds. EP is an inhibitor of fluorescent AGE, methylglyoxal and the glycation of haemoglobin. In STZ-induced diabetic mice, EP reduced the blood glucose, increased serum insulin, body weight, marker enzymes of hepatic function, glycogen, HDL, GK and HK while there was reduction in the levels of triglyceride, cholesterol, TBARS, LDL and G6Pase. Conclusions: Eysenhardtia polystachya possesses considerable antioxidant activity with reactive oxygen species (ROS) scavenging activity and demonstrated an anti-AGEs and hepatoprotective role, inhibits hyperglycemic, hyperlipidemic and oxidative stress indicating that these effects may be mediated by interacting with multiple targets operating in diabetes mellitus.
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Affiliation(s)
- Rosa Martha Perez Gutierrez
- Laboratory of Research on Natural Products, School of Chemical Engineering and Extractive Industries, Av. Instituto Politécnico Nacional S/N, Unidad Profesional Adolfo Lopez Mateos, Zacatenco, Mexico D.F
| | - Efren Garcia Baez
- Laboratory of Research Organic Chemistry. UPIBI-IPN, Col. San Pedro Zacatenco, Mexico D.F
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Cahn F, Burd J, Ignotz K, Mishra S. Measurement of Lens Autofluorescence Can Distinguish Subjects With Diabetes From Those Without. J Diabetes Sci Technol 2014; 8:43-49. [PMID: 24876536 PMCID: PMC4454118 DOI: 10.1177/1932296813516955] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Lens autofluorescence is increased in patients with diabetes mellitus, but clinical application has been limited by the lack of an instrument suitable for routine clinical use. We investigate possible uses of a new scanning confocal biomicroscope (1) to identify subjects with undiagnosed type 2 diabetes and (2) as a marker for the progression of diabetes. One hundred seventy-eight subjects self-reported as normal and 53 subjects physician-diagnosed with diabetes or prediabetes were recruited. Measurements were collected using a ClearPath DS-120 Lens Fluorescence Biomicroscope calibrated with standards traceable to National Institute of Standards and Technology (NIST). Fluorescence intensities were corrected for age by subtracting the value expected from a regression of intensity versus age for normal subjects. This "fluorescence deviation" showed progressively higher values for normal, prediabetes, type 2 diabetes, and type 1 diabetes and a high degree of predictability of diabetes diagnosis. A receiver operating characteristics curve was used to determine sensitivity and specificity for prediction of diabetes type 2. At a fluorescence deviation of 2500, a sensitivity of 67% at 94% specificity was observed detection of type 2 diabetes. The progressively higher fluorescence deviations are consistent with the physiological mechanisms of accumulation of fluorescent advanced glycation end products as the subject ages. The sensitivity and specificity performance of the lens autofluorescence test for type 2 diabetes is comparable to the performance of glucose threshold tests. The statistically significant difference between fluorescence deviations of normal and type 2 diabetes supports the feasibility of lens autofluorescence to screen subjects for undiagnosed type 2 diabetes. Ophthalmic practices are points of care at which there may be a public health benefit for screening patients for undiagnosed diabetes.
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Affiliation(s)
| | - John Burd
- Freedom Meditech Inc, San Diego, CA, USA
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Yin D, Yin J, Yang Y, Chen S, Gao X. Renoprotection of Danshen Injection on streptozotocin-induced diabetic rats, associated with tubular function and structure. JOURNAL OF ETHNOPHARMACOLOGY 2013; 151:667-674. [PMID: 24269771 DOI: 10.1016/j.jep.2013.11.025] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Revised: 11/11/2013] [Accepted: 11/13/2013] [Indexed: 06/02/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Danshen Injection, the aqueous extracts of Radix Salvia miltiorrhiza (S. miltiorrhiza), is one of the most commonly used traditional Chinese herbs in chronic renal failure treatment. In present study, the mechanism of the renoprotective effect of Danshen Injection was analyzed on streptozocin (STZ)-induced diabetic rats. MATERIALS AND METHODS Diabetic experimental model was established in male Sprague-Dawley (SD) rats by intraperitoneal injection of STZ. Rats with blood glucose concentration of higher than 300 mg/dl were intraperitoneally administered with Danshen Injection at a dose of 0.78 ml/kgday. The blood glucose, 24h urinary protein excretion, serum creatinine (sCr), blood urea nitrogen (BUN), advanced glycation end products (AGEs), lipid peroxide (LPO), antioxidant enzyme of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), transforming growth factor-β1 (TGF-β1), and histomorphological changes in kidney of diabetic rats were analyzed during the course of Danshen Injection administration, as well as the tubular function index of albumin reabsorption of fluorescein isothiocyanate labeled bovine serum albumin (FITC-BSA). RESULTS The intraperitoneal administration of Danshen Injection could ameliorate the physiological dysfunctions of increased 24h urinary protein excretion((48.21 ± 8.04)%), sCr((39.4 ± 3.7)%), and BUN((43.37 ± 6.74)%), alleviate the ultrastructural abnormalities of hypertrophy, matrix expansion, and fibrosis in glomerulus, decrease the TGF-β1 expression, AGEs and LPO accumulation, and increase the activity of SOD and GSH-Px in kidney of diabetic rats, but did not significantly influence the blood glucose. Besides these, the Danshen Injection administration also partly restored the decrease of megalin expression in tubules and reabsorptive function of FITC-BSA, in diabetic rats. CONCLUSION The renoprotection of Danshen Injection on diabetic rats was associated with the preservation of tubular function and structure from the hyperglycemia induced toxicities of inappropriate cytokines secretion, oxidative stress, advanced glycation stress, and megalin expression deletion.
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Affiliation(s)
- Dengke Yin
- School of Pharmacy, Anhui University of Traditional Chinese Medicine, Hefei, Anhui 230031, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, China; Anhui Provincial key laboratory for Chinese Medicine Research and Development, Hefei, Anhui 230038, China
| | - Juanjuan Yin
- School of Pharmacy, Anhui University of Traditional Chinese Medicine, Hefei, Anhui 230031, China; Anhui Provincial key laboratory for Chinese Medicine Research and Development, Hefei, Anhui 230038, China
| | - Ye Yang
- School of Pharmacy, Anhui University of Traditional Chinese Medicine, Hefei, Anhui 230031, China; Anhui Provincial key laboratory for Chinese Medicine Research and Development, Hefei, Anhui 230038, China.
| | - Song Chen
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, China
| | - Xiangdong Gao
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
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Burd J, Lum S, Cahn F, Ignotz K. Simultaneous noninvasive clinical measurement of lens autofluorescence and rayleigh scattering using a fluorescence biomicroscope. J Diabetes Sci Technol 2012; 6:1251-9. [PMID: 23294769 PMCID: PMC3570864 DOI: 10.1177/193229681200600603] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Lens autofluorescence increases with the age of the subject, and the fluorophores responsible are associated with cataract, retinopathy, and other complications of diabetes. We built a scanning confocal lens fluorescence biomicroscope suitable for routine clinical measurement of lens autofluorescence and light scattering and report data from 127 healthy subjects. METHOD The fluorescence biomicroscope focuses a beam of light from a blue light-emitting diode on the lens and measures fluorescent green light and blue scattered light using a sensitive silicon photomultiplier. The system includes a target fixation light and a video camera for alignment and automatic pupil tracking. Under software control, a volume of measurement is scanned from behind the posterior lens capsule, through the lens to the aqueous humor, and then back again. Software computes the average ratio of lens autofluorescence to scattered light in the central portion of the lens. Self-reported healthy nondiabetic subjects were examined by an optometrist; if their eyes were healthy and without significant cataract, they were entered into the study. RESULTS Valid lens autofluorescence data were collected from 127 subjects between 21 and 70 years of age. A linear model for lens autofluorescence intensity with age was highly statistically significant, and the improvement in fit for higher-order polynomial models was not statistically significant. The ratio of lens autofluorescence to light scatter was also calculated; regression analysis showed significant curvature for the relationship of the fluorescence ratio to age, so a nonlinear model was used to estimate the mean ratio of autofluorescence to scatter and its prediction intervals as a function of age. CONCLUSIONS Our observation of a strongly significant linear regression of fluorescence intensity with age of the subjects agrees with the results from previous studies, as does a nonlinear model for the fluorescence ratio. The fluorescence biomicroscope enables the clinician to identify patients with fluorescence ratio significantly higher than expected for their age.
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Affiliation(s)
- John Burd
- Freedom Meditech, San Diego, California
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25
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Perez Gutierrez RM, Flores Cotera LB, Gonzalez AMN. Evaluation of the antioxidant and anti-glication effects of the hexane extract from Piper auritum leaves in vitro and beneficial activity on oxidative stress and advanced glycation end-product-mediated renal injury in streptozotocin-treated diabetic rats. Molecules 2012; 17:11897-919. [PMID: 23047487 PMCID: PMC6268794 DOI: 10.3390/molecules171011897] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2012] [Revised: 09/21/2012] [Accepted: 10/07/2012] [Indexed: 11/16/2022] Open
Abstract
The aim of this study was to investigate the antioxidant activity of hexane extracts from leaves of Piper auritum (HS). Eight complementary in vitro test methods were used, including inhibition of DPPH· radicals, nitric oxide, superoxide anion, ion-chelating, ABTS, oxygen radical absorbance capacity, β-carotene bleaching and peroxy radical scavenging. The results indicated that HS possesses high antioxidant activity. To add to these finding we tested the effect against oxidative stress in liver, pancreas and kidney in diabetic rats. Low levels of SOD, CAT, GPx and GSH in diabetic rats were reverted to near normal values after treatment with HS. These results suggest that P. auritum prevents oxidative stress, acting as a suppressor of liver cell damage. Given the link between glycation and oxidation, we proposed that HS might possess significant in vitro antiglycation activity. Our data confirmed the inhibitory effect of HS on bovine serum albumin, serum glycosylated protein, glycation of LDL, and glycation hemoglobin. The effect of HS on diabetic renal damage was investigated using streptozotocin-induced diabetic rats. The oral administration of HS at a dose of 200 and 400 mg/kg body weight/day for 28 days significantly reduced advanced glycation endproduct (AGE) formation, elevated renal glucose and thiobarbituric acid-reactive substance levels in the kidneys of diabetic rats. This implies that HS would alleviate the oxidative stress under diabetes through the inhibition of lipid peroxidation. These findings indicate that oxidative stress is increased in the diabetic rat kidney and that HS can prevent renal damage associated with diabetes by attenuating the oxidative stress.
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Affiliation(s)
- Rosa Martha Perez Gutierrez
- Laboratorio de Investigación de Productos Naturales, Escuela Superior de Ingenieria Quimica e Industrias Extractivas IPN, Av. Instituto Politécnico Nacional S/N, Unidad Profesional Adolfo Lopez Mateos, cp. 07708, Mexico D.F., Mexico.
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26
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Horiuchi S. Advanced Glycation End Products (AGE)-Modified Proteins and Their Potential Relevance to Atherosclerosis. Trends Cardiovasc Med 2012; 6:163-8. [PMID: 21232291 DOI: 10.1016/1050-1738(96)00050-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
Modification of proteins by long-term incubation with glucose leads, through the formation of early products such as Schiff base and Amadori rearrangement products, to the formation of advanced glycation end products (AGE). AGE-modified proteins are characterized physicochemically by fluorescence, brown coloration, and intramolecular or intermolecular cross-linking. Biologically, they are specifically recognized by the AGE receptors of the cell surface membrane. Recent studies have provided evidence for the involvement of AGE proteins in atherosclerosis. First, in vitro experiments using Chinese hamster ovary cells overexpressing the macrophage scavenger receptor (MSR) and peritoneal macrophages from MSR-knockout mice demonstrated that MSR plays a major role as the AGE receptor in the endocytotic uptake of AGE by macrophages. Second, immunohistochemical studies using anti-AGE antibody and anti-MSR antibody revealed the presence of AGE proteins in human atherosclerotic lesions in arterial walls. Because MSR is closely associated with the formation of early atherosclerotic lesions, these results suggest a potential role played by AGE proteins or their interaction with MSR in the atherosclerotic process. (Trends Cardiovasc Med 1996;6:163-168).
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Affiliation(s)
- S Horiuchi
- Department of Biochemistry, Kumamoto University School of Medicine,Kumamoto 860,Japan
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27
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Inhibition of Advanced Glycation End-Product Formation by Origanum majorana L. In Vitro and in Streptozotocin-Induced Diabetic Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2012; 2012:598638. [PMID: 23008741 PMCID: PMC3447365 DOI: 10.1155/2012/598638] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/13/2012] [Revised: 08/07/2012] [Accepted: 08/10/2012] [Indexed: 11/18/2022]
Abstract
The development of AGE inhibitors is considered to have therapeutic potential in patients with diabetes diseases. The aim of the present study was investigate the effect of methanolic extract of the leaves of Origanum majorana (OM) used as spice in many countries on AGEs formation. In vitro studies indicated a significant inhibitory effects on the formation of AGEs. Their antiglycation activities were not only brought about by their antioxidant activities but also related to their trapping abilities of reactive carbonyl species such as methylglyoxal, an intermediate reactive carbonyl of AGE formation. The results demonstrate that OM have significant effects on in vitro AGE formation, and the glycation inhibitory activity was more effectively than those obtained using as standard antiglycation agent aminoguanidine. OM is a potent agent for protecting LDL against oxidation and glycation. Treatment of streptozotocin-diabetic mice with OM and glibenclamide for 28 days had beneficial effects on renal metabolic abnormalities including glucose level and AGEs formation. Diabetic mice showed increase in tail tendon collagen, glycated collagen linked fluorescence and reduction in pepsin digestion. Treatment with OM improved these parameters when compared to diabetic control and glibenclamide.
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Sayed AAR. Ferulsinaic Acid Modulates SOD, GSH, and Antioxidant Enzymes in Diabetic Kidney. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2012; 2012:580104. [PMID: 22991571 PMCID: PMC3443615 DOI: 10.1155/2012/580104] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/28/2012] [Revised: 05/09/2012] [Accepted: 05/10/2012] [Indexed: 12/17/2022]
Abstract
The efficacy of Ferulsinaic acid (FA) to modulate the antioxidant enzymes and to reduce oxidative stress induced-diabetic nephropathy (DN) was studied. Rats were fed diets enriched with sucrose (50%, wt/wt), lard (30%, wt/wt), and cholesterol (2.5%, wt/wt) for 8 weeks to induce insulin resistance. After a DN model was induced by streptozotocin; 5, 50 and 500 mg/kg of FA were administrated by oral intragastric intubation for 12 weeks. In FA-treated diabetic rats, glucose, kidney/body weight ratio, creatinine, BUN, albuminurea, and creatinine clearance were significantly decreased compared with non treated diabetic rats. Diabetic rats showed decreased activities of SOD and GSH; increased concentrations of malondialdehyde and IL-6 in the serum and kidney, and increased levels of 8-hydroxy-2'-deoxyguanosine in urine and renal cortex. FA-treatment restored the altered parameters in a dose-dependent manner. The ultra morphologic abnormalities in the kidney of diabetic rats were markedly ameliorated by FA treatment. Furthermore, FA acid was found to attenuate chronic inflammation induced by both Carrageenan and dextran in rats. We conclude that FA confers protection against injuries in the kidneys of diabetic rats by increasing activities of antioxidant enzymes and inhibiting accumulation of oxidized DNA in the kidney, suggesting a potential drug for the prevention and therapy of DN.
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Affiliation(s)
- Ahmed Amir Radwan Sayed
- Biochemistry Department, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia
- Chemistry Department, Faculty of Science, Minia University, El-Minia 61519, Egypt
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Heise EA, Fort PE. Impact of diabetes on alpha-crystallins and other heat shock proteins in the eye. J Ocul Biol Dis Infor 2011; 4:62-9. [PMID: 23264844 DOI: 10.1007/s12177-011-9073-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2011] [Accepted: 12/05/2011] [Indexed: 12/25/2022] Open
Abstract
Diabetes and its related complications represent a major growing health concern and economic burden worldwide. Ocular manifestations of diabetes include cataractogenesis and retinopathy, the latter being the leading cause of blindness in the working-age population. Despite numerous studies and recent progress, the exact pathophysiology of the disease remains to be fully elucidated and development of new and improved therapeutic strategies for this chronic condition are greatly needed. Heat shock proteins (Hsps) are highly conserved families of proteins, which are generally regarded as protective molecules that play a wide variety of roles and can be expressed in response to different types of cellular stresses. In recent years, numerous studies have reported their implication in various ocular diseases including diabetic retinopathy. The present review focuses on the potential implication of Hsps in ocular diabetic complications and discusses their specific mechanisms of regulation with respect to their expression, functions and alteration during diabetes. The review will conclude by examining the potential of Hsps as therapeutic agents or targets for the treatment of diabetic retinopathy.
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Affiliation(s)
- Erich A Heise
- Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI USA
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30
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Beneficial effect of traditional chinese medicinal formula danggui-shaoyao-san on advanced glycation end-product-mediated renal injury in streptozotocin-diabetic rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2011; 2012:140103. [PMID: 21837246 PMCID: PMC3151508 DOI: 10.1155/2012/140103] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/02/2011] [Revised: 04/11/2011] [Accepted: 05/10/2011] [Indexed: 01/15/2023]
Abstract
The present study was undertaken to characterize the effects of Danggui-Shaoyao-San (DSS), a famous traditional Chinese medicine formula consisting of six herbal medicines, on diabetic nephropathy. Streptozotocin-induced diabetic rats were orally administrated DSS (2.8 g kg−1 per day) for 12 consecutive weeks. DSS partially decreased the high plasma glucose level in diabetic rats. Diabetic-dependent alterations in urinary albumin, 24-hour urinary albumin excretion rate, and creatinine clearance as well as the kidney hypertrophy (kidney weight/body weight ratio) and glomerular mesangial matrix expansion were ameliorated after 12 weeks of DSS treatment. The increased expression of nuclear factor-κB as well as transforming growth factor-β1 and the progressive accumulation of type IV collagen in kidney of diabetic rats were also attenuated by DSS. Not only the elevated levels of advanced glycation end products (AGEs) and Nε-(carboxymethyl)lysine but also the higher levels of lipid peroxidation products in kidney of diabetic rats were ameliorated by DSS. Decreased activity of superoxide diamutase and glutathione peroxidase in kidney of diabetic rats was enhanced by DSS. These data demonstrated that the renoprotective effects of DSS in STZ-diabetic rats not only were attributable to regulate plasma glucose to attenuate AGEs expression in diabetic glomeruli but also likely reflected its antioxidant activity.
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31
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Sell DR, Monnier VM. Aging of Long‐Lived Proteins: Extracellular Matrix (Collagens, Elastins, Proteoglycans) and Lens Crystallins. Compr Physiol 2011. [DOI: 10.1002/cphy.cp110110] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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32
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Kim JM, Lee EK, Kim DH, Yu BP, Chung HY. Kaempferol modulates pro-inflammatory NF-kappaB activation by suppressing advanced glycation endproducts-induced NADPH oxidase. AGE (DORDRECHT, NETHERLANDS) 2010; 32:197-208. [PMID: 20431987 PMCID: PMC2861750 DOI: 10.1007/s11357-009-9124-1] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2009] [Accepted: 11/30/2009] [Indexed: 05/26/2023]
Abstract
Advanced glycation endproducts (AGE) are oxidative products formed from the reaction between carbohydrates and a free amino group of proteins that are provoked by reactive species (RS). It is also known that AGE enhance the generation of RS and that the binding of AGE to a specific AGE receptor (RAGE) induces the activation of the redox-sensitive, pro-inflammatory transcription factor, nuclear factor-kappa B (NF-kB). In this current study, we investigated the anti-oxidative effects of short-term kaempferol supplementation on the age-related formation of AGE and the binding activity of RAGE in aged rat kidney. We further investigated the suppressive action of kaempferol against AGE's ability to stimulate activation of pro-inflammatory NF-kB and its molecular mechanisms. For this study, we utilized young (6 months old), old (24 months old), and kaempferol-fed (2 and 4 mg/kg/day for 10 days) old rats. In addition, for the molecular work, the rat endothelial cell line, YPEN-1 was used. The results show that AGE and RAGE were increased during aging and that these increases were blunted by kaempferol. In addition, dietary kaempferol reduced age-related increases in NF-kappaB activity and NF-kB-dependant pro-inflammatory gene activity. The most significant new finding from this study is that kaempferol supplementation prevented age-related NF-kappaB activation by suppressing AGE-induced nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase). Taken together, our results demonstrated that dietary kaempferol exerts its anti-oxidative and anti-inflammatory actions by modulating the age-related NF-kappaB signaling cascade and its pro-inflammatory genes by suppressing AGE-induced NADPH oxidase activation. Based on these data, dietary kaempferol is proposed as a possible anti-AGE agent that may have the potential for use in anti-inflammation therapies.
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Affiliation(s)
- Ji Min Kim
- Department of Pharmacy, College of Pharmacy, Pusan National University, San 30, Jangjun-dong, Gumjung-gu, Busan, 609-735 Korea
| | - Eun Kyeong Lee
- Department of Pharmacy, College of Pharmacy, Pusan National University, San 30, Jangjun-dong, Gumjung-gu, Busan, 609-735 Korea
| | - Dae Hyun Kim
- Department of Pharmacy, College of Pharmacy, Pusan National University, San 30, Jangjun-dong, Gumjung-gu, Busan, 609-735 Korea
| | - Byung Pal Yu
- Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Busan, South Korea
- Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900 USA
| | - Hae Young Chung
- Department of Pharmacy, College of Pharmacy, Pusan National University, San 30, Jangjun-dong, Gumjung-gu, Busan, 609-735 Korea
- Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Busan, South Korea
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Abstract
Diabetes mellitus is associated with a 5-fold higher prevalence of cataracts, which remains a major cause of blindness in the world. Typical diabetic cataracts contain cortical and/or posterior subcapsular opacities. Adult onset diabetic cataracts also often contain nuclear opacities. Mechanisms of diabetic cataractogenesis have been studied in less detail than those of other diabetic complications. Both animal and human studies support important contribution of increased aldose reductase activity. Surgical extraction is the only cure of diabetic cataract today. An improved understanding of pathogenetic mechanisms, together with finding effective therapeutic agents, remain highest priority for diabetic cataract-related research and pharmaceutical development.
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Affiliation(s)
- Irina G Obrosova
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA.
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Kamata K, Ozawa Y, Kobayashi T, Matsumoto T. Effect of N-epsilon-(carboxymethyl)lysine on coronary vasoconstriction in isolated perfused hearts from control and streptozotocin-induced diabetic rats. J Smooth Muscle Res 2009; 45:125-37. [PMID: 19602856 DOI: 10.1540/jsmr.45.125] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Advanced glycation end products (AGEs) derived from glucose are implicated in the pathogenesis of diabetic vascular disease. However, their direct modulatory effects on coronary vascular tone remain unclear. We previously reported that coronary vasoconstriction was induced by acetylcholine (ACh) infusion of the isolated perfused rat heart and that sensitivity was greater in perfused hearts from streptozotocin (STZ)-induced diabetic rats than in those from age-matched controls (Kamata et al., 2008). Here, we investigated the effect of N(epsilon)-(carboxymethyl)lysine (CML), which has one of the main AGE structures, on ACh-induced vasoconstriction in perfused hearts isolated from control and diabetic rats. ACh-induced vasoconstriction was significantly greater in the STZ-induced diabetic group than in the age-matched controls. CML enhanced the ACh-induced vasoconstriction in coronary arteries from control rats, but not in those from STZ-induced diabetic rats. In the controls, the vasoconstriction induced by the calcium-channel activator Bay K 8644 was also enhanced by CML. These CML-mediated enhancements of the vasoconstrictions induced by ACh and Bay K 8644 were significantly suppressed by tempol, a superoxide dismutase mimetic. The plasma CML and glucose levels were each significantly elevated in STZ-induced diabetic rats. These findings suggest (a) that CML augments ACh-induced coronary vasoconstriction, an effect that may be attributable to increased superoxide and to activation of voltage-gated Ca(2+) channels and (b) that this modulating effect may be desensitized in the STZ-induced diabetic heart.
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Affiliation(s)
- Katsuo Kamata
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan.
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35
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Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer's disease. Biochim Biophys Acta Mol Basis Dis 2008; 1792:482-96. [PMID: 19026743 DOI: 10.1016/j.bbadis.2008.10.014] [Citation(s) in RCA: 238] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2008] [Revised: 10/18/2008] [Accepted: 10/21/2008] [Indexed: 12/22/2022]
Abstract
Characterized as a peripheral metabolic disorder and a degenerative disease of the central nervous system respectively, it is now widely recognized that type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) share several common abnormalities including impaired glucose metabolism, increased oxidative stress, insulin resistance and amyloidogenesis. Several recent studies suggest that this is not an epiphenomenon, but rather these two diseases disrupt common molecular pathways and each disease compounds the progression of the other. For instance, in AD the accumulation of the amyloid-beta peptide (Abeta), which characterizes the disease and is thought to participate in the neurodegenerative process, may also induce neuronal insulin resistance. Conversely, disrupting normal glucose metabolism in transgenic animal models of AD that over-express the human amyloid precursor protein (hAPP) promotes amyloid-peptide aggregation and accelerates the disease progression. Studying these processes at a cellular level suggests that insulin resistance and Abeta aggregation may not only be the consequence of excitotoxicity, aberrant Ca(2+) signals, and proinflammatory cytokines such as TNF-alpha, but may also promote these pathological effectors. At the molecular level, insulin resistance and Abeta disrupt common signal transduction cascades including the insulin receptor family/PI3 kinase/Akt/GSK3 pathway. Thus both disease processes contribute to overlapping pathology, thereby compounding disease symptoms and progression.
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36
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Kang KS, Yamabe N, Kim HY, Yokozawa T. Role of maltol in advanced glycation end products and free radicals: in-vitro and in-vivo studies. J Pharm Pharmacol 2008; 60:445-52. [PMID: 18380916 DOI: 10.1211/jpp.60.4.0006] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Inhibitors of advanced glycation end products (AGEs) have potential as preventive agents against diabetic complications. In-vitro AGE inhibitory activity, transition metal chelating, and free radical scavenging activity tests have been used to screen for and identify effective AGE inhibitors. In an ongoing project to elucidate AGE inhibiting active components of heat-processed ginseng, maltol was selected for more detailed investigation. Although there are several lines of evidence concerning the antioxidant activity of maltol, the in-vitro and in-vivo inhibitory effects of maltol on AGE generation have not been evaluated. In the present study, the in-vitro AGE inhibitory effects and free radical scavenging activity of maltol were investigated. In addition, the in-vivo therapeutic potential of maltol against diabetic renal damage was tested using streptozotocin (STZ)-diabetic rats. Maltol showed a stronger AGE inhibitory effect than aminoguanidine, a well known AGE inhibitor. In addition, the hydroxyl radical scavenging activity of maltol on electron spin resonance (ESR) spectrometry was slightly stronger than that of aminoguanidine. Therefore, maltol was found to have stronger in-vitro AGE inhibiting activity compared with aminoguanidine. The administration of 50 mgkg(-1) per day of maltol suppressed the elevated serum levels of glycosylated protein, renal fluorescent AGEs, carboxymethyllysine, receptors for AGEs, and nuclear factor-kappaB p65 in diabetic control rats. These beneficial effects of maltol against STZ-diabetic renal damage were thought to result from its free radical scavenging and AGE inhibitory effects.
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Affiliation(s)
- Ki Sung Kang
- Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
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37
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Dai Z, Wang B, Sun G, Fan X, Anderson VE, Monnier VM. Identification of glucose-derived cross-linking sites in ribonuclease A. J Proteome Res 2008; 7:2756-68. [PMID: 18500835 DOI: 10.1021/pr700874a] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The accumulation of glycation derived cross-links has been widely implicated in extracellular matrix damage in aging and diabetes, yet little information is available on the cross-linking sites in proteins and the intra- versus intermolecular character of cross-linking. Recently, glucosepane, a 7-membered heterocycle formed between lysine and arginine residues, has been found to be the single major cross-link known so far to accumulate during aging. As an approach toward identification of glucose derived cross-linking sites, we have preglycated ribonuclease A first for for 14 days with 500 mM glucose, followed by a 4-week incubation in absence of glucose. MALDI-TOF analysis of tryptic digests revealed the presence of Amadori products (Delta m/ z = 162) at K1, K7, K37 and K41, in accordance with previous studies. In addition, K66, K98 and K104 were also modified by Amadori products. Intramolecular glucosepane cross-links were observed at K41-R39 and K98-R85. Surprisingly, the only intermolecular cross-link observed was the 3-deoxyglucosone-derived DODIC at K1-R39. The identity of cross-linked peptides was confirmed by sequencing with tandem mass spectrometry. Recombinant ribonuclease A mutants R39A, R85A, and K91A were produced, purified, and glycated to further confirm the importance of these sites on protein cross-linking. These data provide the first documentation that both intramolecular and intermolecular cross-links form in glucose-incubated proteins.
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Affiliation(s)
- Zhenyu Dai
- Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106, USA
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38
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Yamabe N, Kang KS, Goto E, Tanaka T, Yokozawa T. Beneficial effect of Corni Fructus, a constituent of Hachimi-jio-gan, on advanced glycation end-product-mediated renal injury in Streptozotocin-treated diabetic rats. Biol Pharm Bull 2007; 30:520-6. [PMID: 17329849 DOI: 10.1248/bpb.30.520] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Previous investigations have demonstrated that Hachimi-jio-gan, a Chinese prescription consisting of eight crude drugs, has a therapeutic potential in diabetes and diabetic nephropathy, using these model rats. To add to these findings, we performed this study to assess whether one of the crude drugs, Corni Fructus (Cornus officinalis SIEB. et ZUCC.), had an effect on streptozotocin-induced diabetic rats as a major active constituent, compared with an inhibitor of advanced glycation end-product (AGE) formation, aminoguanidine. Diabetic rats were orally administrated Corni Fructus extract (50, 100, 200 mg/kg body weight/d) or aminoguanidine (100 mg/kg body weight/d). Treatment with Corni Fructus for 10 d suppressed hyperglycemia, proteinuria, renal AGE formation, and related protein expressions, i.e., receptor for AGEs, nuclear factor-kappaB, transforming growth factor-beta1, and Nepsilon-(carboxymethyl)lysine, in the same way as with aminoguanidine. However, improvement of renal function, shown via serum creatinine (Cr) and Cr clearance, was superior to aminoguanidine treatment. In conclusion, the present study supported the hypothesis that Corni Fructus plays an important role against diabetic pathogenesis, i.e., reducing glucose toxicities, up-regulating renal function, and consequently ameliorating glycation-associated renal damage; thus, this study may provide a new recognition of crude drugs to clarify the mechanisms of Chinese prescriptions.
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MESH Headings
- Administration, Oral
- Animals
- Blood Glucose/analysis
- Blotting, Western
- Cornus/chemistry
- Creatinine/blood
- Diabetes Mellitus, Experimental/blood
- Diabetes Mellitus, Experimental/physiopathology
- Diabetes Mellitus, Experimental/prevention & control
- Dose-Response Relationship, Drug
- Down-Regulation
- Drugs, Chinese Herbal/administration & dosage
- Drugs, Chinese Herbal/chemistry
- Drugs, Chinese Herbal/pharmacology
- Enzyme Inhibitors/administration & dosage
- Enzyme Inhibitors/pharmacology
- Glycation End Products, Advanced/metabolism
- Guanidines/administration & dosage
- Guanidines/pharmacology
- Kidney/drug effects
- Kidney/metabolism
- Kidney/pathology
- Kidney Cortex/drug effects
- Kidney Cortex/metabolism
- Kidney Cortex/pathology
- Mitochondria/drug effects
- Mitochondria/metabolism
- NF-kappa B/metabolism
- Nitrates/blood
- Nitrites/blood
- Proteinuria/metabolism
- Proteinuria/prevention & control
- Rats
- Thiobarbituric Acid Reactive Substances/metabolism
- Transforming Growth Factor beta1/metabolism
- Weight Loss/drug effects
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39
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Yamabe N, Kang KS, Matsuo Y, Tanaka T, Yokozawa T. Identification of Antidiabetic Effect of Iridoid Glycosides and Low Molecular Weight Polyphenol Fractions of Corni Fructus, a Constituent of Hachimi-jio-gan, in Streptozotocin-Induced Diabetic Rats. Biol Pharm Bull 2007; 30:1289-96. [PMID: 17603169 DOI: 10.1248/bpb.30.1289] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
In our previous study, Corni Fructus (Cornus officinalis SIEB. et ZUCC.), a component crude drug of the Chinese prescription Hachimi-jio-gan, was reported to reduce glucotoxicities, up-regulate renal function, and consequently ameliorate glycation-associated renal damage as well as Hachimi-jio-gan. Based upon these facts, we prepared Corni Fructus fractions and evaluated which fraction contained the effective components against diabetes, using one iridoid glycoside and three polyphenol fractions, which were expected to possess stronger activities than Corni Fructus, administered orally at a dose of 20 mg/kg body weight/d for 10 d, respectively. As a result, iridoid glycosides and low molecular weight polyphenol fractions could reduce the pathogenesis of diabetic renal damage, each having different mechanisms, i.e., iridoid glycosides successfully decreased the hyperglycemic state and affected renal advanced glycation end-product (AGE) accumulation, such as N(epsilon)-(carboxyethyl)lysine and N(epsilon)-(carboxymethyl)lysine, while low molecular weight polyphenol fractions could reduce renal lipid peroxidation, the receptor for AGE, and inducible nitric oxide synthase. Overall, these data suggest that iridoid glycosides and low molecular weight polyphenols purified from Corni Fructus improve metabolic parameters associated with the development of diabetic renal damage. The main active components of these fractions are discussed.
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Affiliation(s)
- Noriko Yamabe
- Institute of Natural Medicine, University of Toyama, Sugitani, Toyama, Japan
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40
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Baidoshvili A, Krijnen PAJ, Kupreishvili K, Ciurana C, Bleeker W, Nijmeijer R, Visser CA, Visser FC, Meijer CJLM, Stooker W, Eijsman L, van Hinsbergh VWM, Hack CE, Niessen HWM, Schalkwijk CG. N
ε
-(Carboxymethyl)lysine Depositions in Intramyocardial Blood Vessels in Human and Rat Acute Myocardial Infarction. Arterioscler Thromb Vasc Biol 2006; 26:2497-503. [PMID: 16973974 DOI: 10.1161/01.atv.0000245794.45804.ab] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Objective—
Advanced glycation end products (AGEs), such as N
ε
-(carboxymethyl)lysine (CML), are implicated in vascular disease. We previously reported increased CML accumulation in small intramyocardial blood vessels in diabetes patients. Diabetes patients have an increased risk for acute myocardial infarction (AMI). Here, we examined a putative relationship between CML and AMI.
Methods and Results—
Heart tissue was stained for CML, myeloperoxidase, and E-selectin in AMI patients (n=26), myocarditis patients (n=17), and control patients (n=15). In AMI patients, CML depositions were 3-fold increased compared with controls in the small intramyocardial blood vessels and predominantly colocalized with activated endothelium (E-selectin–positive) both in infarction and noninfarction areas. A trend of increased CML positivity of the intima of epicardial coronary arteries did not reach significance in AMI patients. In the rat heart AMI model, CML depositions were undetectable after 24 hours of reperfusion, but became clearly visible after 5 days of reperfusion. In line with an inflammatory contribution, human myocarditis was also accompanied by accumulation of CML on the endothelium of intramyocardial blood vessels.
Conclusions—
CML, present predominantly on activated endothelium in small intramyocardial blood vessels in patients with AMI, might reflect an increased risk for AMI rather than being a result of AMI.
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Affiliation(s)
- A Baidoshvili
- VU University Medical Center, Department of Pathology, De Boelelaan 1117, 1007 MB Amsterdam, The Netherlands
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41
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Yamabe N, Yokozawa T, Oya T, Kim M. Therapeutic potential of (-)-epigallocatechin 3-O-gallate on renal damage in diabetic nephropathy model rats. J Pharmacol Exp Ther 2006; 319:228-36. [PMID: 16835369 DOI: 10.1124/jpet.106.107029] [Citation(s) in RCA: 115] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Previous investigations have demonstrated that green tea polyphenols and partially hydrolyzed guar gum as dietary fiber have antioxidative and hypolipidemic activity, respectively, supporting their reduction of risk factors in the course of diabetic nephropathy via a hypoglycemic effect and ameliorating the decline of renal function through their combined administration to rats with subtotal nephrectomy plus streptozotocin (STZ) injection. As a further study, we examined whether (-)-epigallocatechin 3-O-gallate (EGCg), the main polyphenolic compound, could ameliorate the development of diabetic nephropathy. Rats with subtotal nephrectomy plus STZ injection were orally administrated EGCg at doses of 25, 50, and 100 mg/kg body weight/day. After a 50-day administration period, EGCg-treated groups showed suppressed hyperglycemia, proteinuria, and lipid peroxidation, although there were only weak effects on the levels of serum creatinine and glycosylated protein. Furthermore, EGCg reduced renal advanced glycation end-product accumulation and its related protein expression in the kidney cortex as well as associated pathological conditions. These results suggest that EGCg ameliorates glucose toxicity and renal injury, thus alleviating renal damage caused by abnormal glucose metabolism-associated oxidative stress involved in renal lesions of diabetic nephropathy.
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Affiliation(s)
- Noriko Yamabe
- Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
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42
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Yokozawa T, Satoh A, Nakagawa T, Yamabe N. Attenuating effects of wen-pi-tang treatment in rats with diabetic nephropathy. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2006; 34:307-21. [PMID: 16552841 DOI: 10.1142/s0192415x06003850] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Wen-pi-tang is a Chinese prescription used traditionally as a medicine to treat moderate renal failure. In this study, we used rats subjected to subtotal nephrectomy and streptozotocin injection to examine the effects of wen-pi-tang on diabetic nephropathy. Wen-pi-tang was administered at a dose of 50, 100 or 200 mg/kg body weight/day for 15 weeks. Diabetic nephropathy is one of the most serious chronic complications of diabetes mellitus, and renal dysfunction is reflected by proteinuria, decreased creatinine clearance (Ccr) and increased serum urea nitrogen and creatinine (Cr) levels. Wen-pi-tang treatment for 15 weeks resulted in significant reductions of blood glucose and serum urea nitrogen levels, while proteinuria, Ccr and serum Cr levels did not change significantly. Wen-pi-tang also lowered serum triglyceride and thiobarbituric acid-reactive substance levels in a dose-dependent manner. Furthermore, the disorders of the glucose-dependent metabolic pathway due to this pathological condition were normalized by the administration of wen-pi-tang through decreased formation of advanced glycation end-products in the kidney. Wen-pi-tang protected against the development of renal lesions, glomerular sclerosis and mesangial matrix expansion, assessed by histopathological evaluation and scoring. This study suggests that wen-pi-tang treatment could be beneficial in reducing the risk of developing diabetic nephropathy.
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Affiliation(s)
- Takako Yokozawa
- Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan.
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43
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Yamabe N, Yokozawa T. Activity of the Chinese prescription Hachimi-jio-gan against renal damage in the Otsuka Long-Evans Tokushima fatty rat: a model of human type 2 diabetes mellitus. J Pharm Pharmacol 2006; 58:535-45. [PMID: 16597372 DOI: 10.1211/jpp.58.4.0014] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Currently, in Japan, approximately 95% of patients with diabetes mellitus have non-insulin-dependent (type 2) diabetes mellitus (NIDDM), and diabetic nephropathy is a major cause of patients requiring chronic haemodialysis. A previous study showed that Hachimi-jio-gan has a protective effect in rats subjected to subtotal nephrectomy plus streptozotocin injection, a model of insulin-dependent (type 1) diabetic nephropathy. In this study, we used the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of human NIDDM, to investigate whether long-term administration of Hachimi-jio-gan affects glycaemic control and renal function in NIDDM. Male OLETF rats, aged 22 weeks, were divided into 4 groups of 10 and given Hachimi-jio-gan (50, 100 or 200 mg kg(-1) daily) orally or no treatment for 32 weeks. Male Long-Evans Tokushima Otsuka (LETO) rats (n = 6) were used as non-diabetic normal controls. Hachimi-jio-gan reduced hyperglycaemia dose-dependently from 16 weeks of the administration period. Urinary protein excretion decreased significantly from an early stage, and creatinine clearance levels improved at 32 weeks. In addition, the levels of serum glycosylated protein and renal advanced glycation end-products were effectively reduced. Hachimi-jio-gan also significantly reduced the levels of thiobarbituric acid-reactive substances in renal mitochondria, although it showed only a tendency to reduce these in serum. Furthermore, long-term administration of Hachimi-jio-gan reduced renal cortical expression of proteins, such as transforming growth factor-beta1 (TGF-beta1), fibronectin, inducible nitric oxide synthase and cyclooxygenase-2. The 100- and 200-mg kg(-1) daily doses of Hachimi-jio-gan significantly reduced TGF-beta1 and fibronectin protein expression to levels below those of LETO rats. These data suggest that Hachimi-jio-gan may have a beneficial effect on the progression of diabetic nephropathy in OLETF rats by attenuating glucose toxicity and renal damage.
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Affiliation(s)
- Noriko Yamabe
- Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan
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44
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Nakano N, Fukuhara-Takaki K, Jono T, Nakajou K, Eto N, Horiuchi S, Takeya M, Nagai R. Association of Advanced Glycation End Products with A549 Cells, a Human Pulmonary Epithelial Cell Line, Is Mediated by a Receptor Distinct from the Scavenger Receptor Family and RAGE. ACTA ACUST UNITED AC 2006; 139:821-9. [PMID: 16751589 DOI: 10.1093/jb/mvj092] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Cellular interactions with advanced glycation end products (AGE)-modified proteins are known to induce several biological responses, not only endocytic uptake and degradation, but also the induction of cytokines and growth factors, combined responses that may be linked to the development of diabetic vascular complications. In this study we demonstrate that A549 cells, a human pulmonary epithelial cell line, possess a specific binding site for AGE-modified bovine serum albumin (AGE-BSA) (K(d) = 27.8 nM), and additionally for EN-RAGE (extracellular newly identified RAGE binding protein) (K(d) = 118 nM). Western blot and RT-PCR analysis showed that RAGE (receptor for AGE) is highly expressed on A549 cells, while the expression of other known AGE-receptors such as galectin-3 and SR-A (class A scavenger receptor), are below the level of detection. The binding of (125)I-AGE-BSA to these cells is inhibited by unlabeled AGE-BSA, but not by EN-RAGE. In contrast, the binding of (125)I-EN-RAGE is significantly inhibited by unlabeled EN-RAGE and soluble RAGE, but not by AGE-BSA. Our results indicate that A549 cells possess at least two binding sites, one specific for EN-RAGE and the other specific for AGE-BSA. The latter receptor on A549 cells is distinct from the scavenger receptor family and RAGE.
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MESH Headings
- Animals
- Cattle
- Cells, Cultured
- Epithelial Cells/metabolism
- Glycation End Products, Advanced/metabolism
- Glycation End Products, Advanced/pharmacokinetics
- Humans
- Lung/metabolism
- Protein Binding
- Receptor for Advanced Glycation End Products
- Receptors, Immunologic/agonists
- Receptors, Immunologic/classification
- Receptors, Scavenger/agonists
- Receptors, Scavenger/classification
- Receptors, Scavenger/metabolism
- Recombinant Proteins/metabolism
- Serum Albumin, Bovine/metabolism
- Serum Albumin, Bovine/pharmacokinetics
- Signal Transduction
- Substrate Specificity
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Affiliation(s)
- Nahoko Nakano
- Departments of Medical Biochemistry, Psychiatry, and Cell Pathology, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Honjo 1-1-1, Kumamoto 860-8556
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45
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Kang KS, Kim HY, Yamabe N, Nagai R, Yokozawa T. Protective Effect of Sun Ginseng against Diabetic Renal Damage. Biol Pharm Bull 2006; 29:1678-84. [PMID: 16880625 DOI: 10.1248/bpb.29.1678] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The effect of sun ginseng (SG, heat-processed Panax ginseng C. A. MEYER at 120 degrees C) on diabetic renal damage was investigated using streptozotocin-induced diabetic rats. The diabetic rats showed loss of body weight gain, and increases in food and water intake and urine volume, while the oral administration of SG at a dose of 50 or 100 mg/kg body weight/d for 15 d attenuated water intake and urine excretion induced by diabetes. In addition, the diabetic rats given SG at a dose of 100 mg/kg body weight showed significant decreases in serum glucose, serum glycosylated protein and urinary protein levels, suggesting that SG improves the abnormal conditions that lead to oxidative stress. Furthermore, SG significantly reduced advanced glycation endproduct (AGE) formation and thiobarbituric acid-reactive substance levels elevated in the kidneys of diabetic rats. This implies that SG would alleviate the oxidative stress under diabetes through the inhibition of lipid peroxidation. SG also reduced the overexpression of cyclooxygenase-2 and inducible nitric oxide synthase in the kidney induced by hyperglycemia via deactivation the activation of nuclear factor-kappa B. Furthermore, treatment with SG decreased the levels of 3-nitrotyrosine, carboxymethyllysine and receptors for AGE which increase under diabetes. These findings indicate that oxidative stress is increased in the diabetic rat kidney and that SG can prevent renal damage associated with diabetes by attenuating the oxidative stress.
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Affiliation(s)
- Ki Sung Kang
- Institute of Natural Medicine, University of Toyama, Japan
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46
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Nakagawa T, Yokozawa T, Terasawa K, Nakanishi K. Therapeutic usefulness of Keishi-bukuryo-gan for diabetic nephropathy. J Pharm Pharmacol 2003; 55:219-27. [PMID: 12631415 DOI: 10.1211/002235702450] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Keishi-bukuryo-gan is a traditional herbal medicine, which is used clinically as a vascular system disorder-eliminating drug. In this study, its effect on the progression of diabetic nephropathy in experimental rats was investigated. The diabetic nephropathy model used in this study shows functional and morphological changes of the kidney resembling those seen in patients with diabetic nephropathy. Increased proteinuria and serum urea nitrogen and creatinine levels and decreased creatinine clearance, which are important parameters of renal function, were observed in rats with diabetic nephropathy. Pathological examination of the kidney revealed diffuse, nodular and exudative lesions and arteriolar hyalinosis. The deterioration of renal function was ameliorated in rats treated with Keishi-bukuryo-gan for 15 weeks and these results agreed with the renal histological findings. In addition, metabolic abnormalities mediated by persistent hyperglycaemia (the glycation reaction, excessive polyol pathway activity, oxidative stress and lipid metabolic abnormalities) were also observed. However, Keishi-bukuryo-gan reduced accumulation of advanced glycation end products, determined by measuring fluorescence, and serum lipid peroxidation, triglyceride and total cholesterol levels dose-dependently. Thus, this study indicates the potential therapeutic usefulness of Keishi-bukuryo-gan for retarding the progression of renal damage and suggests that its beneficial effects were due to its ability to improve metabolic abnormalities associated with diabetes.
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Affiliation(s)
- Takako Nakagawa
- Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan
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47
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Jono T, Kimura T, Takamatsu J, Nagai R, Miyazaki K, Yuzuriha T, Kitamura T, Horiuchi S. Accumulation of imidazolone, pentosidine and N(epsilon)-(carboxymethyl)lysine in hippocampal CA4 pyramidal neurons of aged human brain. Pathol Int 2002; 52:563-71. [PMID: 12406185 DOI: 10.1046/j.1320-5463.2002.01390.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Previous studies from our laboratory demonstrated that N(epsilon)-(carboxymethyl)lysine (CML), one of the major advanced glycation end products (AGE), was accumulated in human pyramidal neurons in the hippocampus in an age-dependent manner. This suggests a potential link between AGE-accumulation and the aging process in neurons. The purpose of the present study was to examine whether this notion could be extended to other AGE structures, such as imidazolone and pentosidine. This was done using 19 human brains that were not affected by dementia. The immunohistochemical survey on distribution in brain tissues of imidazolone and pentosidine was carried out with monoclonal antibodies specific for imidazolone and pentosidine. A parallel control experiment was carried out with anti-CML antibody. The results showed that pentosidine and imidazolone were localized in neurons in different areas of human brain tissue, especially in neurons of CA4 in the hippocampus. The characteristic distribution of pentosidine and imidazolone is very similar to that of CML. Furthermore, when the accumulation of these AGE structures was compared with the age of individual brains it was found that accumulation of imidazolone, pentosidine and CML in the CA4 region increased with age. These findings taken together support the notion that the accumulation of AGE structures in the CA4 region might be closely related to the aging process in neurons.
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Affiliation(s)
- Tadashi Jono
- Department of Biochemistry, Kumamoto University School of Medicine, Japan
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Okamoto T, Tanaka S, Stan AC, Koike T, Kase M, Makita Z, Sawa H, Nagashima K. Advanced glycation end products induce angiogenesis in vivo. Microvasc Res 2002; 63:186-95. [PMID: 11866542 DOI: 10.1006/mvre.2001.2371] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Advanced glycation end products (AGEs) have been thought to participate in diabetic microangiopathy. However, the effects of AGEs on angiogenesis have so far been mainly examined either in vitro or by using cultured cells. In the present study, we have analyzed whether AGEs induce angiogenesis in vivo by using the chorioallantoic membrane (CAM) assay. The CAM assay was carried out in embryonated hen eggs to determine the effects of AGEs. Following generation of AGEs based on bovine serum albumin (BSA), either AGE-BSA or nonglycated BSA was administered to the CAM and their effects on angiogenesis were assessed, together with an inhibitory effect of an anti-AGE antibody against AGE-BSA-induced angiogenesis. The histological features of AGE-induced vascular lumens were examined by immunohistochemical analysis for Factor VIII and smooth muscle alpha-actin. AGE-BSA induced angiogenesis in CAM in a dose- and time-dependent manner. AGE-induced angiogenesis on CAM was neutralized by the anti-AGE antibody. Immunohistochemical analysis demonstrated that AGE-induced vascular lumens were devoid of pericytes. Our data demonstrated that AGEs are an angiogenetic factor and that our system of AGE-induced abnormal vessels in CAMs is useful in further investigations of the mechanism of diabetic retinal angiogenesis and can also be used to provide a therapeutic model for diabetic angiopathy.
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Affiliation(s)
- Tamami Okamoto
- Laboratory of Molecular & Cellular Pathology, Hokkaido University School of Medicine, N 15, W7, Kita-ku, Sapporo, 060-8638, Japan
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Ling X, Nagai R, Sakashita N, Takeya M, Horiuchi S, Takahashi K. Immunohistochemical distribution and quantitative biochemical detection of advanced glycation end products in fetal to adult rats and in rats with streptozotocin-induced diabetes. J Transl Med 2001; 81:845-61. [PMID: 11406646 DOI: 10.1038/labinvest.3780294] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
SUMMARY We used immunohistochemical methods and four monoclonal antibodies for specific molecular structures of advanced glycation end products (AGE)-6D12, KNH-30, 1F6, and 2A2-to examine localization of AGE in fetal, young, and adult rats, and rats with streptozotocin-induced diabetes. 6D12 recognized N(epsilon)-(carboxymethyl)lysine (CML); KNH-30, N(epsilon)-(carboxyethyl)lysine (CEL); and 1F6, fluorolink. The epitope of 2A2 is as yet unknown. Immunoreactivities for these monoclonal antibodies were found in various organs and tissues in postnatal and adult rats, and accumulation increased with aging. In the fetuses, AGE structures were detected at 10 fetal days, and their accumulation increased during ontogeny. Reversed-phase high-performance liquid chromatography revealed CML in fetuses at 13 fetal days and in lungs of 28-week-old rats. In various organs and tissues of fetal, young, and adult rats, CML, CEL, 2A2-positive AGE, and fluorolink accumulated, in that order, which suggests that the accumulation of CML, a nonfluorescent/noncross-linked AGE, occurs earlier than accumulation of fluorolink, a fluorescent/cross-linked AGE. In diabetic rats, hepatocytes, splenic macrophages, renal glomerular endothelial and mesangial cells, testicular Leydig cells, and erythrocytes showed excessive accumulation of AGE, leading to the pathologic changes characteristic of diabetes mellitus. For the induction of these changes, persistent hyperglycemia and hyperketonemia might be important for acceleration of intracellular AGE accumulation in diabetic rats. Thus, AGE accumulation in tissues and cells occurs not only during aging and in diabetes mellitus but also from an early stage of ontogeny.
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Affiliation(s)
- X Ling
- Second Department of Pathology, Kumamoto University School of Medicine, Kumamoto, Japan.
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Zhu W, Sano H, Nagai R, Fukuhara K, Miyazaki A, Horiuchi S. The role of galectin-3 in endocytosis of advanced glycation end products and modified low density lipoproteins. Biochem Biophys Res Commun 2001; 280:1183-8. [PMID: 11162652 DOI: 10.1006/bbrc.2001.4256] [Citation(s) in RCA: 65] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Galectin-3, a member of beta-galactoside-binding lectin family, is suggested to be an AGE-receptor. To examine this possibility, we prepared CHO cells overexpressing human galectin-3 (galectin-3-CHO cells). Galectin-3-CHO cells showed a specific and saturable binding to (125)I-AGE-BSA with Kd of 3.1 microg/ml. (125)I-AGE-BSA was endocytosed by galectin-3-CHO cells and underwent lysosomal degradation. The endocytosis of (125)I-AGE-BSA was inhibited not only by unlabeled AGE-BSA but also by acetylated LDL and oxidized LDL, ligands for the scavenger receptor family. Furthermore, (125)I-oxidized LDL and (125)I-acetylated LDL were actively endocytosed by galectin-3-CHO cells and the incubation with acetyl-LDL led to intracellular accumulation of cholesteryl esters, indicating the role of galectin-3 in endocytosis of AGE-proteins and modified LDLs. Since galectin-3 was localized and up-regulated in foam cells at human atherosclerotic lesions, the present results suggest that galectin-3 plays an important role in formation of atherosclerotic lesions in vivo, by modulating endocytic uptake of AGE-proteins and modified LDLs.
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Affiliation(s)
- W Zhu
- Department of Biochemistry, Kumamoto University School of Medicine, Honjo 2-2-1, Kumamoto, 860-0811, Japan
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