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Burhan Altemimi R, Nabil Ibrahim N, Ali Nazar L, Ali Hasan H, Heilo Al-Musawi M, Mortazavi Moghadam F. The Predictive Value of Melatonin Levels for the Development of Diabetic Nephropathy in Men with Type 2 Diabetes Mellitus. Rep Biochem Mol Biol 2024; 13:341-348. [PMID: 40330571 PMCID: PMC12050062 DOI: 10.61186/rbmb.13.3.341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Accepted: 07/14/2024] [Indexed: 05/08/2025]
Abstract
Background Type 2 diabetes mellitus (T2DM) poses a significant public health challenge due to its high prevalence. Diabetic nephropathy (DN) is one of the most severe complications associated with T2DM. Early prediction of DN in patients with T2DM can significantly aid in managing this disease. This study takes an approach by investigating the potential role of melatonin and thyroid hormone levels as predictive biomarkers for the progression of diabetic nephropathy in individuals diagnosed with type 2 diabetes mellitus. Methods Our cross-sectional study involved 120 male participants, divided into two groups: 60 patients with T2DM and 60 with DN. The Cobas technique was used to measure serum thyroid hormone levels and quantified melatonin levels using an enzyme-linked immunosorbent assay (ELISA). A receiver utilizing characteristic (ROC) curve analysis to evaluate the predictive value of serum melatonin for DN was performed. Results No notable disparities in thyroid function tests were observed between diabetic patients with and without DN. However, the average serum melatonin quantity in patients with DN. (177.25 ± 60.48 pg/mL) was drastically lower in those with T2DM without DN (199.9 ± 55.16 pg/mL). The sensitivity and specificity of melatonin in predicting DN were 78% and 76%, respectively, with an optimal cut-off value of 178 pg/mL. Conclusions Serum melatonin levels exhibited a notable reduction. among individuals who were diabetic with DN, suggesting its potential utility as an additional predictive marker for developing DN in patients with T2DM.
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Affiliation(s)
- Refaa Burhan Altemimi
- Department of anesthesia techniques, College of Health and Medical Technology, Middle Technical university, Baghdad, Iraq.
| | - Nabaa Nabil Ibrahim
- Department of Pharmacognosy and Medicinal Plants, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq.
| | - Lara Ali Nazar
- Department of Chemistry, College of Sciences, Mustansiriyah University, Baghdad, Iraq.
| | - Hiba Ali Hasan
- Department of Pharmacognosy and Medicinal Plants, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq.
| | - Mastafa Heilo Al-Musawi
- Department of Clinical Laboratory Sciences, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq.
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Sajjadpour Z, Hoseini Tavassol Z, Aghaei Meybodi HR, Eskandarynasab M, Pejman Sani M, Hasani-Ranjbar S, Larijani B. Evaluating the effectiveness of melatonin in reducing the risk of foot ulcers in diabetic patients. J Diabetes Metab Disord 2023; 22:1073-1082. [PMID: 37975123 PMCID: PMC10638255 DOI: 10.1007/s40200-023-01289-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 08/22/2023] [Indexed: 11/19/2023]
Abstract
Objectives Diabetes and its complications, as a major health concern, are associated with morbidity and mortality around the world. One of these complications is diabetic foot ulcer. Factors such as hyperglycemia, neuropathy, vascular damage and impaired immune system can cause foot ulcers. The present review aims to study the potential effects of melatonin, the main product of pineal glands, on diabetic foot ulcers. Methods A narrative review was performed using present literature in an attempt to identify the different aspects of melatonin's impact on diabetic foot ulcers by searching related keywords in electronic databases without any restriction. Results This review shows that, melatonin has anti-diabetic effects. It is effective in reducing the risk of hyperglycemia, neuropathy, vascular damage and immune system impairment in diabetic patients. By reducing these complications with melatonin, correspondingly, the incidence of diabetic foot ulcers may also decrease in these patients. Conclusions The results of this study indicate promising properties of melatonin while dealing with diabetic foot ulcers and their common underlying conditions, but still, it needs to be investigated more in future studies.
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Affiliation(s)
- Zahra Sajjadpour
- Obesity and Eating Habits Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Hoseini Tavassol
- Obesity and Eating Habits Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamid Reza Aghaei Meybodi
- Evidence Based Medicine Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Eskandarynasab
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahnaz Pejman Sani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Shirin Hasani-Ranjbar
- Obesity and Eating Habits Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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Liu W, Gao Y, Zhou Y, Yu F, Li X, Zhang N. Mechanism of Cordyceps sinensis and its Extracts in the Treatment of Diabetic Kidney Disease: A Review. Front Pharmacol 2022; 13:881835. [PMID: 35645822 PMCID: PMC9136174 DOI: 10.3389/fphar.2022.881835] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 04/27/2022] [Indexed: 11/13/2022] Open
Abstract
Diabetic kidney disease (DKD) is the major reason of chronic kidney disease (CKD)-caused end-stage renal failure (ESRF), and leads to high mortality worldwide. At present, the treatment of DKD is mainly focused on controlling the hyperglycemia, proteinuria, and hypertension, but is insufficient on the effective delay of DKD progression. Cordyceps sinensis is a kind of wild-used precious Chinese herb. Its extracts have effects of nephroprotection, hepatoprotection, neuroprotection, and protection against ischemia/reperfusion-induced injury, as well as anti-inflammatory and anti-oxidant activities. According to the theory of traditional Chinese medicine, Cordyceps sinensis can tonify the lung and the kidney. Several Chinese patent medicines produced from Cordyceps sinensis are often used to treat DKD and achieved considerable efficacy. This review summarized the clinical usage of Cordyceps sinensis, as well as its mainly biological activities including anti-hyperglycemic, anti-inflammatory, immunomodulatory, anti-oxidant, anti-fibrotic activities and regulation of apoptosis.
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Affiliation(s)
- Wu Liu
- Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yiwei Gao
- Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yi Zhou
- Department of Graduate Student, Beijing University of Chinese Medicine, Beijing, China
| | - Fangning Yu
- Department of Graduate Student, Beijing University of Chinese Medicine, Beijing, China
| | - Xinyi Li
- Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ning Zhang
- Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- *Correspondence: Ning Zhang,
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Louis MBP, França DCH, Queiroz AA, Calderon IDMP, França EL, Honorio-França AC. Melatonin Hormone Acts on Cells of Maternal Blood and Placenta From Diabetic Mothers. Front Physiol 2022; 12:765928. [PMID: 35126170 PMCID: PMC8814459 DOI: 10.3389/fphys.2021.765928] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 12/14/2021] [Indexed: 11/13/2022] Open
Abstract
Changes in glucose metabolism of diabetic mothers affect immunological components, proinflammatory factors, and placental hypervascularization that can induce cell death. The hormone melatonin has been identified as a potential modulating agent. The aim of this study was to analyze the oxidative process and the apoptosis in maternal blood and placental cells modulated by melatonin from diabetic mothers. The groups were 40 pregnant women divided into non-diabetic (ND) and type 2 diabetes mellitus (T2DM) groups. Blood and placental cells were obtained by density gradient and maintained in culture treated or not with melatonin (100 ng/mL) for 24 h (37°C, 5% CO2). Oxidative stress was evaluated by superoxide release and CuZn superoxide dismutase (SOD). Apoptosis was assessed by flow cytometry. Maternal hyperglycemia increased superoxide release and apoptosis in MN cells from maternal blood and reduced SOD level and SOD/O2- ratio. Melatonin reduced oxidative stress and apoptosis rates in MN cells in the blood of diabetic mothers. There was a reduction in SOD and SOD/O2- ratio in the placental extravillous layer, and melatonin restored the concentrations of this enzyme. There was greater superoxide release, reduced SOD/O2- ratio, and apoptosis in MN cells placental villous layer. Melatonin increased apoptosis rates in the placental villous layer from hyperglycemic mothers. These data suggest that hyperglycemia altered the processes oxidative in blood and placenta from hyperglycemic mothers. These changes reflected in the mechanisms of induction of apoptosis, especially in the vascularized layers of the placenta, and were modulated by melatonin.
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Affiliation(s)
- Martino B. Pierre Louis
- Institute of Biological and Health Science, Federal University of Mato Grosso, Barra do Garças, Brazil
| | - Danielle Cristina Honorio França
- Institute of Biological and Health Science, Federal University of Mato Grosso, Barra do Garças, Brazil
- Medical Course, State University of Mato Grosso, Cáceres, Brazil
| | - Adriele Athaídes Queiroz
- Institute of Biological and Health Science, Federal University of Mato Grosso, Barra do Garças, Brazil
| | | | - Eduardo Luzía França
- Institute of Biological and Health Science, Federal University of Mato Grosso, Barra do Garças, Brazil
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Patel R, Parmar N, Pramanik Palit S, Rathwa N, Ramachandran AV, Begum R. Diabetes mellitus and melatonin: Where are we? Biochimie 2022; 202:2-14. [PMID: 35007648 DOI: 10.1016/j.biochi.2022.01.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 12/07/2021] [Accepted: 01/04/2022] [Indexed: 12/24/2022]
Abstract
Diabetes mellitus (DM) and diabetes-related complications are amongst the leading causes of mortality worldwide. The international diabetes federation (IDF) has estimated 592 million people to suffer from DM by 2035. Hence, finding a novel biomolecule that can effectively aid diabetes management is vital, as other existing drugs have numerous side effects. Melatonin, a pineal hormone having antioxidative and anti-inflammatory properties, has been implicated in circadian dysrhythmia-linked DM. Reduced levels of melatonin and a functional link between melatonin and insulin are implicated in the pathogenesis of type 2 diabetes (T2D) Additionally, genomic studies revealed that rare variants in melatonin receptor 1b (MTNR1B) are also associated with impaired glucose tolerance and increased risk of T2D. Moreover, exogenous melatonin treatment in cell lines, rodent models, and diabetic patients has shown a potent effect in alleviating diabetes and other related complications. This highlights the role of melatonin in glucose homeostasis. However, there are also contradictory reports on the effects of melatonin supplementation. Thus, it is essential to explore if melatonin can be taken from bench to bedside for diabetes management. This review summarizes the therapeutic potential of melatonin in various diabetic models and whether it can be considered a safe drug for managing diabetic complications and diabetic manifestations like oxidative stress, inflammation, ER stress, mitochondrial dysfunction, metabolic dysregulation, etc.
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Affiliation(s)
- Roma Patel
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, 390 002, Gujarat, India
| | - Nishant Parmar
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, 390 002, Gujarat, India
| | - Sayantani Pramanik Palit
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, 390 002, Gujarat, India
| | - Nirali Rathwa
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, 390 002, Gujarat, India
| | - A V Ramachandran
- Division of Life Science, School of Sciences, Navrachana University, Vadodara, 391 410, Gujarat, India
| | - Rasheedunnisa Begum
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, 390 002, Gujarat, India.
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Sahan A, Akbal C, Tavukcu HH, Cevik O, Cetinel S, Sekerci CA, Sener TE, Sener G, Tanidir Y. Melatonin prevents deterioration of erectile function in streptozotocin-induced diabetic rats via sirtuin-1 expression. Andrologia 2020; 52:e13639. [PMID: 32478903 DOI: 10.1111/and.13639] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 03/29/2020] [Accepted: 04/19/2020] [Indexed: 11/28/2022] Open
Abstract
A review of the literature indicated that sirtuin-1 expression, a regulator of nitric oxide bioavailability in erectile dysfunction (ED) after melatonin therapy, has not yet been investigated. The objective of this study was to evaluate the protective effects of melatonin for erectile function with sirtuin-1 protein expression in type 1 diabetic rat models. Fifty male Sprague Dawley rats were placed into five groups. Except for those in the control group (C), each animal received a single dose (60 mg/kg) of streptozotocin to induce diabetes. The animals were placed into the diabetes (D) group, insulin (I) group (6 U/kg/day), melatonin (Mel) group (10 mg kg-1 day-1 ) and combined treatment (I + Mel) group. Ten weeks later, the serum testosterone levels, intracavernosal pressure (ICP), mean arterial pressure (MAP), malondialdehyde (MDA), cyclic guanosine monophosphate (c-GMP), 8-hydroxydeoxyguanosine (8-OHdG), nitric oxide synthase (NOS), caspase-3 activity, sirtuin-1 and endothelial nitric oxide synthase (eNOS) protein expression and histological findings were assessed. The mean ICP/MAP ratio for the D group was lower than the mean ratios for the other groups. The treatment groups, particularly the I + Mel group, exhibited lower 8-OHdG and MDA levels and caspase-3 activity than the D group. The sirtuin-1 and eNOS expression and cavernosal tissue (CT) histology seemed to have been preserved by the melatonin and/or insulin therapy. These results were indicative of a profound protective effect of melatonin by the activation of sirtuin-1 protein expression against hyperglycemia-induced oxidative CT injury.
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Affiliation(s)
- Ahmet Sahan
- Department of Urology, Kartal Dr. Lutfi Kirdar Training and Research Hospital, Istanbul, Turkey
| | - Cem Akbal
- Department of Urology, School of Medicine, Acibadem University, Istanbul, Turkey
| | - Hasan Huseyin Tavukcu
- Department of Urology, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey
| | - Ozge Cevik
- Department of Biochemistry, School of Medicine, Adnan Menderes University, Aydın, Turkey
| | - Sule Cetinel
- Department of Histology and Embryology, School of Medicine, Marmara University, Istanbul, Turkey
| | - Cagrı Akın Sekerci
- Department of Urology, School of Medicine, Marmara University, Istanbul, Turkey
| | - Tarik Emre Sener
- Department of Urology, School of Medicine, Marmara University, Istanbul, Turkey
| | - Goksel Sener
- Department of Pharmacology, School of Pharmacy, Marmara University, Istanbul, Turkey
| | - Yiloren Tanidir
- Department of Urology, School of Medicine, Marmara University, Istanbul, Turkey
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Espino J, Rodríguez AB, Pariente JA. Melatonin and Oxidative Stress in the Diabetic State: Clinical Implications and Potential Therapeutic Applications. Curr Med Chem 2019; 26:4178-4190. [PMID: 29637854 DOI: 10.2174/0929867325666180410094149] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 12/07/2017] [Accepted: 12/07/2017] [Indexed: 02/07/2023]
Abstract
All living organisms exhibit circadian rhythms, which govern the majority of biological functions, including metabolic processes. Misalignment of these circadian rhythms increases the risk of developing metabolic diseases. Thus, disruption of the circadian system has been proven to affect the onset of type 2 diabetes mellitus (T2DM). In this context, the pineal indoleamine melatonin is a signaling molecule able to entrain circadian rhythms. There is mounting evidence that suggests a link between disturbances in melatonin production and impaired insulin, glucose, lipid metabolism, and antioxidant capacity. Besides, several genetic association studies have causally associated various single nucleotide polymorphysms (SNPs) of the human MT2 receptor with increased risk of developing T2DM. Taken together, these data suggest that endogenous as well as exogenous melatonin may influence diabetes and associated metabolic disturbances not only by regulating insulin secretion but also by providing protection against reactive oxygen species (ROS) since pancreatic β-cells are very susceptible to oxidative stress due to their low antioxidant capacity.
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Affiliation(s)
- Javier Espino
- Department of Physiology (Neuroimmunophysiology and Chrononutrition Research Group), Faculty of Science, University of Extremadura, Badajoz, Spain
| | - Ana B Rodríguez
- Department of Physiology (Neuroimmunophysiology and Chrononutrition Research Group), Faculty of Science, University of Extremadura, Badajoz, Spain
| | - José A Pariente
- Department of Physiology (Neuroimmunophysiology and Chrononutrition Research Group), Faculty of Science, University of Extremadura, Badajoz, Spain
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Sun T, Li J, Xing HL, Tao ZS, Yang M. Melatonin improves the osseointegration of hydroxyapatite-coated titanium implants in senile female rats. Z Gerontol Geriatr 2019; 53:770-777. [PMID: 31654128 DOI: 10.1007/s00391-019-01640-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Accepted: 10/07/2019] [Indexed: 02/03/2023]
Abstract
The aim of this study was to confirm the effect of the systemic administration of melatonin on hydroxyapatite-coated titanium (HA-Ti) implants in senile osteopenic rats. For this study 24-month-old female Sprague-Dawley rats were used. The animals were randomly divided into two groups: a control group and a melatonin group and the bilateral femurs of all the rats received HA-Ti implants. Animals in the melatonin group received treatment with melatonin (30 mg/kg day). After a 12-week healing period, rats in the melatonin group revealed improved osseointegration compared to the control group, with the bone area ratio (BAR) and bone to implant contact (BIC) increased by 1.87-fold and 1.65-fold in histomorphometry, the quantitative results of implant osseointegration and peri-implant trabeculae, such as a higher bone volume per total volume (BV/TV), trabecular number (Tb.N), the mean connective density (Conn.D), trabecular thickness (Tb.Th), and a lower trabecular spacing (Tb.Sp) in micro-computed tomography (CT) evaluation and the maximum push-out force by 1.75-fold in push out tests. Additionally, compared with the control group, melatonin could significantly up-regulate the expression of the runt-related transcription factor 2 (Runx2), osteocalcin (OC) and osteoprotegerin (OPG) genes and down-regulate the expression of the RANKL gene. These findings suggest that systemic administration with melatonin is useful to improve the fixation of HA-coated implants even in osteopenic rats through promoting Runx2, OC and OPG gene expression and inhibiting RANKL gene expression.
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Affiliation(s)
- Tao Sun
- Department of Orthopaedic Surgery, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, No. 289, Kuocang Road, Liandu District, Lishui City, Zhejiang, China
| | - Jian Li
- Department of Orthopaedic Surgery, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, No. 289, Kuocang Road, Liandu District, Lishui City, Zhejiang, China
| | - Hai-Lin Xing
- Department of Orthopaedic Surgery, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, No. 289, Kuocang Road, Liandu District, Lishui City, Zhejiang, China
| | - Zhou-Shan Tao
- Department of Trauma Orthopedics, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, No. 2, Zhe shan Xi Road, 241001, Wuhu, Anhui, China.
| | - Min Yang
- Department of Trauma Orthopedics, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, No. 2, Zhe shan Xi Road, 241001, Wuhu, Anhui, China
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Ghaderi A, Banafshe HR, Mirhosseini N, Motmaen M, Mehrzad F, Bahmani F, Aghadavod E, Mansournia MA, Reiter RJ, Karimi MA, Asemi Z. The effects of melatonin supplementation on mental health, metabolic and genetic profiles in patients under methadone maintenance treatment. Addict Biol 2019; 24:754-764. [PMID: 29949232 DOI: 10.1111/adb.12650] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 04/24/2018] [Accepted: 05/21/2018] [Indexed: 12/11/2022]
Abstract
This investigation was designed to determine the effect of melatonin supplementation on mental health parameters, metabolic and genetic profiles in patients under methadone maintenance treatment (MMT). This randomized, double-blind, placebo-controlled, clinical trial was conducted among 54 patients under MMT. Participants were randomly allocated to receive either 10 mg melatonin (2 melatonin capsules, 5 mg each) (n = 26) or placebo (n = 28) once a day, 1 hour before bedtime for 12 weeks. Melatonin supplementation significantly decreased Pittsburgh Sleep Quality Index (β -4.08; 95 percent CI, -5.51, -2.65; P < 0.001), Beck Depression Inventory index (β -5.46; 95% CI, -8.92, -2.00; P = 0.003) and Beck Anxiety Inventory index (β -3.87; 95% CI, -5.96, -1.77; P = 0.001) and significantly increased International Index of Erectile Functions (β 5.59; 95% CI, 1.76, 9.42; P = 0.005) compared with the placebo. Subjects who received melatonin supplements had significantly lower serum insulin levels (β -2.53; 95% CI, -4.48, -0.59; P = 0.01), homeostasis model of assessment-insulin resistance (β -0.56; 95% CI, -1.03, -0.09; P = 0.01) and higher quantitative insulin sensitivity check index (β 0.01; 95% CI, 0.004, 0.02; P = 0.009) and HDL-cholesterol levels (β 3.71; 95% CI, 1.77, 5.64; P = 0.002) compared to placebo. Additionally, melatonin intake resulted in a significant reduction in serum high sensitivity C-reactive protein (β -0.15; 95% CI, -0.27, -0.02; P = 0.02), malondialdehyde (β -0.31; 95% CI, -0.57, -0.05; P = 0.02) and protein carbonyl (β -0.06; 95% CI, -0.09, -0.04; P < 0.001). This trial indicated that taking melatonin supplements for 12 weeks by patients under MMT had beneficial effects on their mental health metabolic profiles.
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Affiliation(s)
- Amir Ghaderi
- Department of Addiction Studies, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Hamid Reza Banafshe
- Department of Addiction Studies, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Department of Pharmacology, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | | | - Maryam Motmaen
- Department of Psychiatry, School of Medicine, Kashan University of Medical Science, Kashan, Iran
| | - Fatemeh Mehrzad
- Department of Psychiatry, School of Medicine, Kashan University of Medical Science, Kashan, Iran
| | - Fereshteh Bahmani
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Esmat Aghadavod
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Ali Mansournia
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Russel J Reiter
- Department of Cellular and Structural Biology, University of Texas Health Science, Center, San Antonio, TX, USA
| | - Mohammad-Amin Karimi
- Department of Educational Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
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Kandemir YB, Konuk E, Katırcı E, Xxx F, Behram M. Is the effect of melatonin on vascular endothelial growth factor receptor-2 associated with angiogenesis in the rat ovary? Clinics (Sao Paulo) 2019; 74:e658. [PMID: 30864638 PMCID: PMC6438131 DOI: 10.6061/clinics/2019/e658] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 12/19/2018] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVES Vascular endothelial growth factor (VEGF) and its receptors play important roles in angiogenesis. Melatonin plays an important role in gonadal development; thus, its effect on the reproductive system is evident. We investigated the influence of melatonin on the expression of VEGF, vascular endothelial growth factor receptor-1 (VEGFR1) and vascular endothelial growth factor receptor-2 (VEGFR2), as well as on changes in oxidative stress markers and follicle numbers in rat ovaries. METHODS For this purpose, 45 Wistar rats were separated into the following groups: Group 1, control; Group 2, vehicle; and Group 3, melatonin. Rats in Group 3 were treated with melatonin at 50 mg/kg/day for 30 days. The effects of melatonin on the expression of VEGF, VEGFR1 and VEGFR2 were established by immunohistochemistry analysis. The effects of melatonin on antioxidant enzyme activities were demonstrated by spectrophotometric analysis. RESULTS Based on immunohistochemistry analysis, VEGFR2 was predominantly localized to theca cells in the ovary. Our data indicate that melatonin treatment can significantly increase VEGF and VEGFR1 expression in the ovary ( p <0.05). Additionally, the number of degenerated follicles significantly decreased with melatonin treatment ( p <0.05). Melatonin administration also led to significant increases in antioxidant enzyme levels in the ovary. CONCLUSION Melatonin treatment exerts protective effects on follicles against increased lipid peroxidation through modulating tissue antioxidant enzyme levels. These effects may be related to angiogenesis and antioxidant activities.
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Affiliation(s)
- Yasemin Behram Kandemir
- Harran University, Faculty of Medicine, Department of Anatomy, Şanlıurfa, Turkey
- Corresponding author. E-mail:
| | - Esma Konuk
- Akdeniz University, Faculty of Medicine, Department of Histology, Antalya, Turkey
| | - Ertan Katırcı
- Akdeniz University, Faculty of Medicine, Department of Histology, Antalya, Turkey
| | - Feride Xxx
- Akdeniz University, Faculty of Medicine, Department of Histology, Antalya, Turkey
| | - Mustafa Behram
- Kanuni Sultan Süleyman Hospital, Department of Perinatology, Istanbul, Turkey
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Hari AD, Naidu VGM, Das UN. n-6 and n-3 Fatty acids and their metabolites augment inhibitory action of doxorubicin on the proliferation of human neuroblastoma (IMR-32) cells by enhancing lipid peroxidation and suppressingRas, Myc, andFos. Biofactors 2018. [DOI: 10.1002/biof.1436] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- Anasuya Devi Hari
- Bio-Science Research Centre; Gayatri Vidya Parishad College of Engineering Campus, Madhurawada; Visakhapatnam Andhra Pradesh, 530048 India
| | - Vegi G. M. Naidu
- Department of pharmacology and Toxicology; National Institute of Pharmaceutical Education and Research (NIPER), Balanagar; Hyderabad Telangana, 500037 India
| | - Undurti N. Das
- UND Life Sciences, 2221 NW 5th St; Battle Ground WA, 98604 USA
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Gundala NKV, Naidu VGM, Das UN. Arachidonic acid and lipoxin A4 attenuate alloxan-induced cytotoxicity to RIN5F cells in vitro and type 1 diabetes mellitus in vivo. Biofactors 2017; 43:251-271. [PMID: 27862450 DOI: 10.1002/biof.1336] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 09/17/2016] [Accepted: 10/03/2016] [Indexed: 12/27/2022]
Abstract
OBJECTIVE We studied whether polyunsaturated fatty acids (PUFAs) can protect rat insulinoma (RIN5F) cells against alloxan-induced apoptosis in vitro and type 1 diabetes mellitus (type 1 DM) in vivo and if so, mechanism of this beneficial action. MATERIAL AND METHODS In vitro study was conducted using RIN5F cells while in vivo study was performed in Wistar rats. The effect of PUFAs, cyclo-oxygenase and lipoxygenase inhibitors, various eicosanoids and PUFAs metabolites: lipoxin A4 (LXA4), resolvin D2 and protectin against alloxan-induced cytotoxicity to RIN5F cells and type 1 DM was studied. Expression of PDX1, P65 NF-kB and IKB in RIN5F cells and Nrf2, GLUT2, COX2, iNOS protein levels in the pancreatic tissue and plasma glucose, insulin and tumor necrosis factor-α and antioxidants, lipid peroxides and nitric oxide were measured. RESULTS Of all, arachidonic acid (AA) was found to be the most effective against alloxan-induced cytotoxicity to RIN5F cells and preventing type 1 DM. Both cyclo-oxygenase and lipoxygenase inhibitors did not block the beneficial actions of AA in vitro and in vivo. Alloxan inhibited LXA4 production by RIN5F cells and in alloxan-induced type 1 DM Wistar rats. AA-treatment restored LXA4 levels to normal both in vitro and in vivo. LXA4 protected RIN5F cells against alloxan-induced cytotoxicity and prevented type 1 DM and restored expression of Nrf2, Glut2, COX2, and iNOS genes and abnormal antioxidants to near normal. DISCUSSION AA seems to bring about its beneficial actions against alloxan-induced cytotoxicity and type 1 DM by enhancing the production of LXA4. © 2016 BioFactors, 43(2):251-271, 2017.
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Affiliation(s)
- Naveen K V Gundala
- Department of Medicine, BioScience Research Centre, Gayatri Vidya Parishad Hospital, GVP College of Engineering Campus, Visakhapatnam, 530048, India
| | - Vegi G M Naidu
- National Institute of Pharmaceutical Education and Research, Hyderabad, India
| | - Undurti N Das
- Department of Medicine, BioScience Research Centre, Gayatri Vidya Parishad Hospital, GVP College of Engineering Campus, Visakhapatnam, 530048, India
- UND Life Sciences, 2020 S 360th St, # K-202, Federal Way, WA, 98003, USA
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Yildirimturk S, Batu S, Alatli C, Olgac V, Firat D, Sirin Y. The effects of supplemental melatonin administration on the healing of bone defects in streptozotocin-induced diabetic rats. J Appl Oral Sci 2016; 24:239-49. [PMID: 27383705 PMCID: PMC5022211 DOI: 10.1590/1678-775720150570] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 03/15/2016] [Indexed: 12/31/2022] Open
Abstract
Diabetes mellitus (DM) causes an increased production of free radicals that can impair bone healing. Melatonin is a hormone secreted mainly by the pineal gland, which participates in the neutralization process of free radicals.
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Affiliation(s)
- Senem Yildirimturk
- - Istanbul University, Faculty of Dentistry, Department of Oral and Maxillofacial Surgery, Istanbul, Turkey
| | - Sule Batu
- - Istanbul University, Faculty of Dentistry, Department of Biochemistry, Istanbul, Turkey
| | - Canan Alatli
- - Istanbul University, Institute of Oncology, Department of Pathology, Istanbul, Turkey
| | - Vakur Olgac
- - Istanbul University, Institute of Oncology, Department of Pathology, Istanbul, Turkey
| | - Deniz Firat
- - Istanbul University, Faculty of Dentistry, Department of Oral and Maxillofacial Surgery, Istanbul, Turkey
| | - Yigit Sirin
- - Istanbul University, Faculty of Dentistry, Department of Oral and Maxillofacial Surgery, Istanbul, Turkey
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Arachidonic acid and lipoxinA4 attenuate streptozotocin-induced cytotoxicity to RIN5 F cells in vitro and type 1 and type 2 diabetes mellitus in vivo. Nutrition 2016; 35:61-80. [PMID: 28241993 DOI: 10.1016/j.nut.2016.10.004] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 09/21/2016] [Accepted: 10/01/2016] [Indexed: 12/29/2022]
Abstract
OBJECTIVE The aim of this study was to observe whether polyunsaturated fatty acids (PUFAs) can protect rat insulinoma (RIN5 F) cells against streptozotocin (STZ)-induced apoptosis in vitro and type 1 diabetes mellitus (T1DM) and type 2 DM (T2DM) in vivo and if so, what would be the mechanism of this action. METHODS RIN5 F cells were used for the in vitro study, whereas the in vivo study was performed in Wistar rats. STZ was used to induce apoptosis of RIN5 F cells in vitro and T1- and T2DM in vivo. The effect of PUFAs: γ-linolenic acid (GLA), arachidonic acid (AA) of ω-6 series, and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) of ω-3 series; cyclooxygenase (COX) and lipoxygenase (LOX) inhibitors and antiinflammatory metabolite of AA and DHA, lipoxin A4 (LXA4), and resolvin D2 and protectin, respectively against STZ-induced cytotoxicity to RIN5 F cells in vitro and LXA4 against T1- and T2DM in vivo was studied. Changes in the antioxidant content, lipid peroxides, nitric oxide, and expression of PDX1, P65, nuclear factor-κb (NF-κb), and IKB genes in STZ-treated RIN5 F cells in vitro and Nrf2, GLUT2, COX2, iNOS protein levels in the pancreatic tissue of T1- and T2DM and LPCLN2 (lipocalin 2), NF-κb, IKB I in adipose tissue of T2DM after LXA4 treatment were studied. Plasma glucose, insulin, and tumor necrosis factor (TNF)-α levels also were measured in STZ-induced T1- and T2DM Wistar rats. RESULTS Among all PUFAs tested, AA and EPA are the most effective against STZ-induced cytotoxicity to RIN5 F cells in vitro. Neither COX nor LOX inhibitors blocked the cytoprotective action of AA in vitro and T1- and T2DM by STZ. LXA4 production by RIN5 F cells in vitro and plasma LXA4 levels in STZ-induced T1- and T2DM animals were decreased by STZ that reverted to normal after AA treatment. AA prevented both T1- and T2DM induced by STZ. Antiinflammatory metabolite of AA and LXA4 prevented both T1- and T2DM induced by STZ. The expression of Pdx1, NF-κb, IKB genes in the pancreas and plasma TNF-α levels in T1- and T2DM; Nrf2, Glut2, COX2, and iNOS proteins in pancreatic tissue of T1DM and LPCLN2, NF-κb, IKB I in adipose tissue of T2DM reverted to normal in LXA4-treated animals. CONCLUSION Both AA and LXA4 prevented STZ-induced cytotoxicity to RIN5 F cells in vitro and T1- and T2DM in vivo, suggesting that these two bioactive lipids may function as antidiabetic molecules. AA is beneficial against STZ-induced cytotoxicity and T1- and T2DM by enhancing the production of LXA4.
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Bathina S, Srinivas N, Das UN. BDNF protects pancreatic β cells (RIN5F) against cytotoxic action of alloxan, streptozotocin, doxorubicin and benzo(a)pyrene in vitro. Metabolism 2016; 65:667-684. [PMID: 27085775 DOI: 10.1016/j.metabol.2016.01.016] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Revised: 01/26/2016] [Accepted: 01/29/2016] [Indexed: 12/22/2022]
Abstract
OBJECTIVE The study was conducted to observe whether brain-derived neurotrophic factor (BDNF) has cytoprotective actions against alloxan (AL), streptozotocin (STZ), doxorubicin (DB) and benzo(a)pyrene (BP) compounds in vitro that may account for its beneficial action in diabetes mellitus. MATERIALS AND METHODS This in vitro study was performed using rat insulinoma (RIN5F) cells. Possible cytoprotective action of BDNF (using pre-treatment, simultaneous and post-treatment schedules of RIN5F cells with BDNF) against the four chemicals tested was evaluated using MTT and apoptosis assays. Possible mechanism of cytoprotective action of BDNF was assessed by measuring BCl2/IKB-β/Pdx mRNA transcripts and anti-oxidant levels in RIN5F cells. Effect of alloxan, STZ, doxorubicin and BP on the production of BDNF by RIN5F cells was also studied. RESULTS Results of the present study revealed that BDNF in the doses (100ng>50ng>10ng/ml) has significant cytoprotection (P<0.001, P<0.01) on cytotoxic action of AL, STZ, DB and BP against rat insulinoma RIN5F (5×10(4) cells/100μl) cells in vitro. It was observed that AL, STZ, DB and BP inhibited BDNF production significantly (P<0.001) in a dose-dependent manner by RIN5F cells (0.5×10(6) cells/500μl) in vitro, while BDNF not only prevented apoptosis induced by these four chemicals but also significantly increased (P<0.001) BCl2/IKB-β/Pdx mRNA transcripts and restored anti-oxidant levels (P<0.01) in RIN5F cells to normal. DISCUSSION These results suggest that BDNF has potent cytoprotective actions, restores anti-oxidant defenses to normal and thus, prevents apoptosis and preserves insulin secreting capacity of β cells. In addition, BDNF enhanced viability of RIN 5F in vitro. Thus, BDNF not only has anti-diabetic actions but also preserves pancreatic β cells integrity and enhances their viability. These results imply that BDNF functions as an endogenous cytoprotective molecule that may explain its beneficial actions in some neurological conditions as well.
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Affiliation(s)
- Siresha Bathina
- BioScience Research Centre, Department of Medicine, Gayatri Vidya Parishad Hospital, GVP College of Engineering Campus, Visakhapatnam 530048, India
| | - Nanduri Srinivas
- National Institute of Pharmaceutical Education and Research, Hyderabad, India
| | - Undurti N Das
- BioScience Research Centre, Department of Medicine, Gayatri Vidya Parishad Hospital, GVP College of Engineering Campus, Visakhapatnam 530048, India; UND Life Sciences, 2020 S 360th St, #K-202, Federal Way, WA 98003, USA
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Can Melatonin Act as an Antioxidant in Hydrogen Peroxide-Induced Oxidative Stress Model in Human Peripheral Blood Mononuclear Cells? Biochem Res Int 2016; 2016:5857940. [PMID: 26881079 PMCID: PMC4737018 DOI: 10.1155/2016/5857940] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 12/10/2015] [Indexed: 01/14/2023] Open
Abstract
Purpose. We aimed to investigate the possible effects of melatonin on gene expressions and activities of MnSOD and catalase under conditions of oxidative stress induced by hydrogen peroxide (H2O2) in peripheral blood mononuclear cells (PBMCs). Materials and Methods. PBMCs were isolated from healthy subjects and treated as follows: (1) control (only with 0.1% DMSO for 12 h); (2) melatonin (1 mM) for 12 h; (3) H2O2 (250 μM) for 2 h; (4) H2O2 (250 μM) for 2 h following 10 h pretreatment with melatonin (1 mM). The gene expression was evaluated by real-time PCR. MnSOD and catalase activities in PBMCs were determined by colorimetric assays. Results. Pretreatment of PBMCs with melatonin significantly augmented expression and activity of MnSOD which were diminished by H2O2. Melatonin treatment of PBMCs caused a significant upregulation of catalase by almost 2-fold in comparison with untreated cells. However, activity and expression of catalase increased by 1.5-fold in PBMCs under H2O2-induced oxidative stress compared with untreated cell. Moreover, pretreatment of PBMCs with melatonin resulted in a significant 1.8-fold increase in catalase expression compared to PBMCs treated only with H2O2. Conclusion. It seems that melatonin could prevent from undesirable impacts of H2O2-induced oxidative stress on MnSOD downregulation. Moreover, melatonin could promote inductive effect of H2O2 on catalase mRNA expression.
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Wietzycoski CR, Marchesini JCD, Al-Themyat S, Meyer FS, Trindade MRM. IMPROVEMENT IN OXIDATIVE STRESS AFTER DUODENOJEJUNOSTOMY IN AN EXPERIMENTAL MODEL OF TYPE 2 DIABETES MELLITUS. ACTA ACUST UNITED AC 2016; 29Suppl 1:3-7. [PMID: 27683765 PMCID: PMC5064274 DOI: 10.1590/0102-6720201600s10002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 04/05/2016] [Indexed: 01/24/2023]
Abstract
Background: Type 2 Diabetes Mellitus is a multifactorial syndrome with severe complications.
Oxidative stress is accepted as a causal factor of chronic complications Aim: To demonstrate alterations in oxidative stress after metabolic surgery. Methods: Twenty-four 2-day-old Wistar rats were used. In 16, Type 2 Diabetes Mellitus was
induced by 100 mg/kg streptozotocin injection. The development of diabetes was
confirmed after 10 weeks using an oral glucose tolerance test. Eight diabetic rats
composed the diabetic surgical group; the remaining eight composed the diabetic
group. Eight animals in which diabetes was not induced formed the clinical control
group. The Marchesini technique was used in the diabetic surgical group. After 90
days, the rats were sacrificed, and the oxidative stress markers were measured.
Results: Thiobarbituric acid reactive substances, superoxide dismutase and catalase were
significantly reduced in the diabetic surgical group compared to the diabetic
group. Conclusion: The duodenojejunostomy was effective in controlling the exacerbated oxidative
stress present in diabetic rats.
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Affiliation(s)
- Cacio Ricardo Wietzycoski
- Master in Surgical Sciences Program, Federal University of Rio Grande do Sul - UFRGS, Porto Alegre, RS, Brazil
| | | | - Sultan Al-Themyat
- Master in Surgical Sciences Program, Federal University of Rio Grande do Sul - UFRGS, Porto Alegre, RS, Brazil
| | - Fabiola Shons Meyer
- Master in Surgical Sciences Program, Federal University of Rio Grande do Sul - UFRGS, Porto Alegre, RS, Brazil
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Nayki U, Onk D, Balci G, Nayki C, Onk A, Çankaya M, Taskın Kafa AH, Kuzucu M. The effect of melatonin on oxidative stress and apoptosis in experimental diabetes mellitus-related ovarian injury. Gynecol Endocrinol 2016; 32:421-6. [PMID: 26743008 DOI: 10.3109/09513590.2015.1126819] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
We aimed to evaluate the effect of melatonin on oxidative stress and ovarian injury in rats. Twenty-four Sprague-Dawley albino rats were divided into three groups: Group 1 as nondiabetic healthy controls (n = 8), group 2 as nontreated diabetic rats (n = 8) and group 3 as melatonin-treated diabetic rats (n = 8). After overt diabetes was produced by intraperitoneal injection of streptozosin, 20 mg/kg/day of melatonin was given intraperitoneally to group 3 for a week. NF-kB and caspase-3 immunoexpressions, lipid peroxidation, the activities of antioxidative enzymes, total oxidant capacity and total antioxidant capacity were assessed. Immunoexpressions of NF-kB and caspase-3 were significantly lower in group 3 than group 2. There was a significant decrease in superoxide dismutase activity in group 2 than group 1 and a significant increase in group 3 compared with group 2. We observed a nonsignificant decrease in catalase activity between group 1 and group 2 and a nonsignificant increase between group 2 and group 3. There was a nonsignificant increase in the plasma level of total oxidant status in group 2 than group 1, but a significant decrease was observed in group 3 compared to group 2. Total antioxidant status was significantly lower in group 2 compared with group 1 and group 3. In conclusion, melatonin ameliorates the negative effects of oxidative stress on DM-related ovarian injury.
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Affiliation(s)
- Umit Nayki
- a Department of Obstetrics and Gynecology
| | - Didem Onk
- b Department of Anesthesiology and Reanimation
| | | | - Cenk Nayki
- a Department of Obstetrics and Gynecology
| | - Alper Onk
- d Department of Cardiovascular Surgery , and
| | - Murat Çankaya
- e Department of Biochemistry School of Medicine , Erzincan University , Erzincan , Turkey
| | | | - Mehmet Kuzucu
- e Department of Biochemistry School of Medicine , Erzincan University , Erzincan , Turkey
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Yokoi N, Beppu M, Yoshida E, Hoshikawa R, Hidaka S, Matsubara T, Shinohara M, Irino Y, Hatano N, Seino S. Identification of putative biomarkers for prediabetes by metabolome analysis of rat models of type 2 diabetes. Metabolomics 2015; 11:1277-1286. [PMID: 26366137 PMCID: PMC4559098 DOI: 10.1007/s11306-015-0784-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Accepted: 02/05/2015] [Indexed: 10/26/2022]
Abstract
Biomarkers for the development of type 2 diabetes (T2D) are useful for prediction and intervention of the disease at earlier stages. In this study, we performed a longitudinal study of changes in metabolites using an animal model of T2D, the spontaneously diabetic Torii (SDT) rat. Fasting plasma samples of SDT and control Sprague-Dawley (SD) rats were collected from 6 to 24 weeks of age, and subjected to gas chromatography-mass spectrometry-based metabolome analysis. Fifty-nine hydrophilic metabolites were detected in plasma samples, including amino acids, carbohydrates, sugars and organic acids. At 12 weeks of age, just before the onset of diabetes in SDT rats, the amounts of nine of these metabolites (asparagine, glutamine, glycerol, kynurenine, mannose, n-alpha-acetyllysine, taurine, threonine, and tryptophan) in SDT rats were significantly different from those in SD rats. In particular, metabolites in the tryptophan metabolism pathway (tryptophan and kynurenine) were decreased in SDT rats at 12 weeks of age and later. The lower tryptophan and kynurenine levels in the prediabetic state and later were further confirmed by a replication study on SDT rats and by a longitudinal study on another animal model of T2D, the Otsuka Long-Evans Tokushima Fatty rat. Our data indicate that tryptophan and its metabolites are potential biomarkers for prediabetes and that tryptophan metabolism may be a potential target of intervention for treatment of the disease.
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Affiliation(s)
- Norihide Yokoi
- Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017 Japan
| | - Masayuki Beppu
- Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017 Japan
- Division of Cellular and Molecular Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, 650-0017 Japan
| | - Eri Yoshida
- Division of Cellular and Molecular Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, 650-0017 Japan
| | - Ritsuko Hoshikawa
- Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017 Japan
| | - Shihomi Hidaka
- Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017 Japan
| | - Toshiya Matsubara
- Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017 Japan
- Life Science Research Center, Technology Research Laboratory, Shimadzu Corporation, Kyoto, 619-0237 Japan
| | - Masami Shinohara
- Tokyo Animal and Diet Department, CLEA Japan, Inc., Meguro-ku, Tokyo, 153-8533 Japan
| | - Yasuhiro Irino
- The Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, 650-0017 Japan
- Division of Evidenced-based Laboratory Medicine, Kobe University Graduate School of Medicine, Kobe, 650-0017 Japan
| | - Naoya Hatano
- The Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, 650-0017 Japan
| | - Susumu Seino
- Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017 Japan
- Division of Cellular and Molecular Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, 650-0017 Japan
- The Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, 650-0017 Japan
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Polavarapu S, Mani AM, Gundala NKV, Hari AD, Bathina S, Das UN. Effect of polyunsaturated fatty acids and their metabolites on bleomycin-induced cytotoxic action on human neuroblastoma cells in vitro. PLoS One 2014; 9:e114766. [PMID: 25536345 PMCID: PMC4275295 DOI: 10.1371/journal.pone.0114766] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Accepted: 11/13/2014] [Indexed: 12/20/2022] Open
Abstract
In the present study, we noted that bleomycin induced growth inhibitory action was augmented by all the polyunsaturated fatty acids (PUFAs) tested on human neuroblastoma IMR-32 (0.5 × 10(4) cells/100 µl of IMR) cells (EPA > DHA > ALA = GLA = AA > DGLA = LA: ∼ 60, 40, 30, 10-20% respectively) at the maximum doses used. Of all the prostaglandins (PGE1, PGE2, PGF2α, and PGI2) and leukotrienes (LTD4 and LTE4) tested; PGE1, PGE2 and LTD4 inhibited the growth of IMR-32 cells to a significant degree at the highest doses used. Lipoxin A4 (LXA4), 19,20-dihydroxydocosapentaenoate (19, 20 DiHDPA) and 10(S),17(S)-dihydroxy-4Z,7Z,11E,13Z,15E,19Z-docosahexaenoic acid (protectin: 10(S),17(S)DiHDoHE), metabolites of DHA, significantly inhibited the growth of IMR-32 cells. Pre-treatment with AA, GLA, DGLA and EPA and simultaneous treatment with all PUFAs used in the study augmented growth inhibitory action of bleomycin. Surprisingly, both indomethacin and nordihydroguaiaretic acid (NDGA) at 60 and 20 µg/ml respectively enhanced the growth of IMR-32 cells even in the presence of bleomycin. AA enhanced oxidant stress in IMR-32 cells as evidenced by an increase in lipid peroxides, superoxide dismutase levels and glutathione peroxidase activity. These results suggest that PUFAs suppress growth of human neuroblastoma cells, augment growth inhibitory action of bleomycin by enhancing formation of lipid peroxides and altering the status of anti-oxidants and, in all probability, increase the formation of lipoxins, resolvins and protectins from their respective precursors that possess growth inhibitory actions.
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Affiliation(s)
- Sailaja Polavarapu
- Bio-Science Research Centre, Gayatri Vidya Parishad College of Engineering Campus, Madhurawada, Visakhapatnam-530048, Andhra Pradesh, India
| | - Arul M Mani
- Bio-Science Research Centre, Gayatri Vidya Parishad College of Engineering Campus, Madhurawada, Visakhapatnam-530048, Andhra Pradesh, India
| | - Naveen K V Gundala
- Bio-Science Research Centre, Gayatri Vidya Parishad College of Engineering Campus, Madhurawada, Visakhapatnam-530048, Andhra Pradesh, India
| | - Anasuya D Hari
- Bio-Science Research Centre, Gayatri Vidya Parishad College of Engineering Campus, Madhurawada, Visakhapatnam-530048, Andhra Pradesh, India
| | - Siresha Bathina
- Bio-Science Research Centre, Gayatri Vidya Parishad College of Engineering Campus, Madhurawada, Visakhapatnam-530048, Andhra Pradesh, India
| | - Undurti N Das
- UND Life Sciences, 2020 S 360th St, # K-202, Federal Way, Washington, 98003, United States of America
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Abdolsamadi H, Goodarzi MT, Ahmadi Motemayel F, Jazaeri M, Feradmal J, Zarabadi M, Hoseyni M, Torkzaban P. Reduction of Melatonin Level in Patients with Type II Diabetes and Periodontal Diseases. J Dent Res Dent Clin Dent Prospects 2014; 8:160-5. [PMID: 25346835 PMCID: PMC4206758 DOI: 10.5681/joddd.2014.029] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2013] [Accepted: 04/06/2014] [Indexed: 01/01/2023] Open
Abstract
Background and aims. Melatonin is a circulating hormone that is mainly released from the pineal gland. It possesses antioxidant, free-radical scavenging, and immune-enhancing properties. A growing number of studies reveal a complex role for melatonin in influencing various diseases, including diabetes and periodontal diseases. The aim of this study was to examine the possible links between salivary melatonin levels and type II diabetes and periodontal diseases. Materials and methods. A total of 30 type II diabetic patients, 30 patients with periodontal diseases, 30 type II diabetic patients with periodontal disease and 30 age- and BMI-matched controls were studied. The periodontal status was evaluated by the Community Periodontal Index (CPI). Salivary melatonin levels were determined by a commercial enzyme-linked immunosorbent assay (ELISA) kit. Results. The mean of salivary melatonin level was significantly lower in patients with either periodontitis or diabetes compared to healthy subjects (P < 0.05). Salivary melatonin concentration decreased in type II diabetic patients and periodontitis patients, and then decreased reaching the lowest levels in type II diabetic patients with periodontal disease. Conclusion. Based on the results of this study, it can probably be concluded that salivary level of melatonin has an important role in the pathogenesis of diabetes and periodontal diseases. It is also worth noting that this factor could probably be used as a pivotal biological marker in the diagnosis and possible treatment of these diseases, although further research is required to validate this hypothesis.
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Affiliation(s)
- Hamidreza Abdolsamadi
- Professor, Department of Oral Medicine, Dental Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mohammad Taghi Goodarzi
- Professor, Department of Oral Medicine, Dental Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Fatemeh Ahmadi Motemayel
- Professor, Department of Biochemistry and Nutrition, Research Center for Molecular Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mina Jazaeri
- Assistant Professor, Department of Oral Medicine, Faculty of Dentistry, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Javad Feradmal
- Department of Biostatistics and Epidemiology, School of Public Health, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mahdiyeh Zarabadi
- Postgraduate Student, Department of Oral Medicine, Hamadan University of Medical Sciences, Haman, Iran
| | - Mostafa Hoseyni
- Student of Biochemistry and Nutrition, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Parviz Torkzaban
- Associate Professor, Department of Periodontology, Dental Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
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Hepatoprotective effects of melatonin against pronecrotic cellular events in streptozotocin-induced diabetic rats. J Physiol Biochem 2014; 70:441-50. [PMID: 24604251 DOI: 10.1007/s13105-014-0322-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Accepted: 02/04/2014] [Indexed: 12/18/2022]
Abstract
Oxidative stress-mediated damage to liver tissue underlies the pathological alterations in liver morphology and function that are observed in diabetes. We examined the effects of the antioxidant action of melatonin against necrosis-inducing DNA damage in hepatocytes of streptozotocin (STZ)-induced diabetic rats. Daily administration of melatonin (0.2 mg/kg) was initiated 3 days before diabetes induction and maintained for 4 weeks. Melatonin-treated diabetic rats exhibited improved markers of liver injury (P < 0.05), alkaline phosphatase, and alanine and aspartate aminotransferases. Melatonin prevented the diabetes-related morphological deterioration of hepatocytes, DNA damage (P < 0.05), and hepatocellular necrosis. The improvement was due to containment of the pronecrotic oxygen radical load, observed as inhibition (P < 0.05) of the diabetes-induced rise in lipid peroxidation and hydrogen peroxide increase in the liver. This was accompanied by improved necrotic markers of cellular damage: a significant reduction in cleavage of the DNA repair enzyme poly(ADP-ribose) polymerase 1 (PARP-1) into necrotic 55- and 62-kDa fragments, and inhibition of nucleus-to-cytoplasm translocation and accumulation in the serum of the high-mobility group box 1 (HMGB1) protein. We conclude that melatonin is hepatoprotective in diabetes. It reduces extensive DNA damage and resulting necrotic processes. Melatonin application could thus present a viable therapeutic option in the management of diabetes-induced liver injury.
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Morceli G, Honorio-França AC, Fagundes DLG, Calderon IMP, França EL. Antioxidant effect of melatonin on the functional activity of colostral phagocytes in diabetic women. PLoS One 2013; 8:e56915. [PMID: 23437270 PMCID: PMC3577679 DOI: 10.1371/journal.pone.0056915] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2012] [Accepted: 01/16/2013] [Indexed: 01/24/2023] Open
Abstract
Melatonin is involved in a number of physiological and oxidative processes, including functional regulation in human milk. The present study investigated the mechanisms of action of melatonin and its effects on the functional activity of colostral phagocytes in diabetic women. Colostrum samples were collected from normoglycemic (N = 38) and diabetic (N = 38) women. We determined melatonin concentration, superoxide release, bactericidal activity and intracellular Ca(2+) release by colostral phagocytes treated or not with 8-(Diethylamino) octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-8) and incubated with melatonin and its precursor (N-acetyl-serotonin-NAS), antagonist (luzindole) and agonist (chloromelatonin-CMLT). Melatonin concentration was higher in colostrum samples from hyperglycemic than normoglycemic mothers. Melatonin stimulated superoxide release by colostral phagocytes from normoglycemic but not hyperglycemic women. NAS increased superoxide, irrespective of glycemic status, whereas CMTL increased superoxide only in cells from the normoglycemic group. Phagocytic activity in colostrum increased significantly in the presence of melatonin, NAS and CMLT, irrespective of glycemic status. The bactericidal activity of colostral phagocytes against enterophatogenic Escherichia coli (EPEC) increased in the presence of melatonin or NAS in the normoglycemic group, but not in the hyperglycemic group. Luzindole blocked melatonin action on colostrum phagocytes. Phagocytes from the normoglycemic group treated with melatonin exhibited an increase in intracellular Ca(2+) release. Phagocytes treated with TMB-8 (intracellular Ca(2+) inhibitor) decreased superoxide, bactericidal activity and intracellular Ca(2+) release in both groups. The results obtained suggest an interactive effect of glucose metabolism and melatonin on colostral phagocytes. In colostral phagocytes from normoglycemic mothers, melatonin likely increases the ability of colostrum to protect against EPEC and other infections. In diabetic mothers, because maternal hyperglycemia modifies the functional activity of colostrum phagocytes, melatonin effects are likely limited to anti-inflammatory processes, with low superoxide release and bactericidal activity.
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Affiliation(s)
- Gliciane Morceli
- Post Graduate Program in Gynecology, Obstetrics and Mastology of Botucatu Medical School, São Paulo State University/Unesp, Botucatu, São Paulo, Brazil
| | - Adenilda C. Honorio-França
- Institute of Biological and Health Science, Federal University of Mato Grosso, Barra do Garças, Mato Grosso, Brazil
| | - Danny L. G. Fagundes
- Post Graduate Program in Gynecology, Obstetrics and Mastology of Botucatu Medical School, São Paulo State University/Unesp, Botucatu, São Paulo, Brazil
| | - Iracema M. P. Calderon
- Post Graduate Program in Gynecology, Obstetrics and Mastology of Botucatu Medical School, São Paulo State University/Unesp, Botucatu, São Paulo, Brazil
| | - Eduardo L. França
- Institute of Biological and Health Science, Federal University of Mato Grosso, Barra do Garças, Mato Grosso, Brazil
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Shabani M, Zangiabadi N, Asadi-Shekaari M. Evidence for Positive Effects of Date Extract That Attenuates Thermal Hyperalgesia in a Diabetic Rat Model of Neuropathic Pain. ACTA ACUST UNITED AC 2013. [DOI: 10.4236/nm.2013.41003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Taheri E, Djalali M, Saedisomeolia A, Moghadam AM, Djazayeri A, Qorbani M. The relationship between the activates of antioxidant enzymes in red blood cells and body mass index in Iranian type 2 diabetes and healthy subjects. J Diabetes Metab Disord 2012; 11:3. [PMID: 23497678 PMCID: PMC3581104 DOI: 10.1186/2251-6581-11-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2012] [Accepted: 07/18/2012] [Indexed: 11/10/2022]
Abstract
BACKGROUND Diabetes mellitus is a metabolic disorder characterized by increased production of free radicals and oxidative stress. The aim of this study was to evaluate the activity of antioxidant enzymes, superoxide dismutase (SOD), glutathione reductase (GR), and glutathione peroxide (GSH-PX) in type 2 diabetic patients compared with healthy subjects. METHODS This cross-sectional study was conducted on 100 type 2 diabetic patients and 100 healthy controls. Total antioxidant capacity and fasting serum levels of SOD, GR, and GSH-Px were measured. All data were analyzed using SPSS software compatible with Microsoft Windows. RESULTS The activity levels of SOD were lower in diabetic patients (111.93 ± 354.99 U/g Hb) than in healthy controls (1158.53 ± 381.21 U/g Hb), but this was not significant. Activity levels of GSH-PX and GR in diabetics (62.33 ± 36.29 and 7.17 ± 5.51 U/g Hb, respectively) were higher than in controls (24.62 ± 11.2 and 3.16 ± 2.95 U/g Hb, respectively). The statistical difference in enzyme activity of both GSH-Px and GR was significant (P <0.05). CONCLUSION The increasing production of free radicals and changes in activity levels of antioxidant enzymes in order to scavenge free radicals and/or the effect of diabetes on the activity levels of antioxidant enzymes has an important effect on diabetic complications and insulin resistance. Evaluation of the levels of antioxidant enzymes and antioxidant factors in patients at different stages of the disease, and pharmaceutical and nutritional interventions, can be helpful in reducing oxidative stress in type 2 diabetic patients. There were positive relationship between BMI and the activity of antioxidant enzymes including SOD, GR and GPX in both groups.
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Affiliation(s)
- Ehsaneh Taheri
- Department of Nutrition and Biochemistry, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
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Yin H, Miao J, Ma C, Sun G, Zhang Y. β-Casomorphin-7 cause decreasing in oxidative stress and inhibiting NF-κB-iNOS-NO signal pathway in pancreas of diabetes rats. J Food Sci 2012; 77:C278-82. [PMID: 22339544 DOI: 10.1111/j.1750-3841.2011.02577.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
β-Casomorphin-7 (β-CM-7) is a milk biological active peptide. The present study is aimed to investigate the protective effects of β-CM-7, against oxidative stress in pancreas of streptozotocin-induced diabetic rats by assaying malondialdehyde (MDA), nitric oxide (NO) level, the activity of enzymatic antioxidants such as superoxide dismutase (SOD), catalase, glutathione peroxidase (GSH-Px), and NF-κB, inducible nitric oxide synthase (iNOS) gene expression. A significant increase in the level of oxidative stress was observed in pancreas of the diabetic rats when compared to control rats. After 15 d oral administration of β-CM-7 (7.5 × 10(-8) mol/d), the pancreas MDA level was markedly reduced. Oral administration of β-CM-7 to diabetic rats showed an obviously increase in the activity of catalase in pancreas, oral administration of β-CM-7 to the diabetic group of rats also showed a reduction of NF-κB and iNOS gene expression in pancreas. The elevated pancreas NO level was markedly reduced by the oral administration of β-CM-7. Thus, the results of the present study suggest that β-CM-7 may cause protective effects such as pronounced decreasing in oxidative stress and inhibiting NF-κB-iNOS-NO signal pathway in pancreas of diabetes rats.
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Affiliation(s)
- Hong Yin
- Key Laboratory of Animal Physiology and Biochemistry, Nanjing Agricultural Univ, Nanjing 210095, PR China
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Effects of glutamine supplementation on oxidative stress-related gene expression and antioxidant properties in rats with streptozotocin-induced type 2 diabetes. Br J Nutr 2011; 107:1112-8. [PMID: 22129885 DOI: 10.1017/s0007114511004168] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
There are close links among hyperglycaemia, oxidative stress and diabetic complications. Glutamine (GLN) is an amino acid with immunomodulatory properties. The present study investigated the effect of dietary GLN on oxidative stress-relative gene expressions and tissue oxidative damage in diabetes. There were one normal control (NC) and two diabetic groups in the present study. Diabetes was induced by an intraperitoneal injection of nicotinamide followed by streptozotocin (STZ). Rats in the NC group were fed a regular chow diet. In the two diabetic groups, one group (diabetes mellitus, DM) was fed a common semi-purified diet while the other group received a diet in which part of the casein was replaced by GLN (DM-GLN). GLN provided 25% of total amino acid N. The experimental groups were fed the respective diets for 8 weeks, and then the rats were killed for further analysis. The results showed that blood thioredoxin-interacting protein (Txnip) mRNA expression in the diabetic groups was higher than that in the NC group. Compared with the DM group, the DM-GLN group had lower glutamine fructose-6-phosphate transaminase 1, a receptor of advanced glycation end products, and Txnip gene expressions in blood mononuclear cells. The total antioxidant capacity was lower and antioxidant enzyme activities were altered by the diabetic condition. GLN supplementation increased antioxidant capacity and normalised antioxidant enzyme activities. Also, the renal nitrotyrosine level and Txnip mRNA expression were lower when GLN was administered. These results suggest that dietary GLN supplementation decreases oxidative stress-related gene expression, increases the antioxidant potential and may consequently attenuate renal oxidative damage in rats with STZ-induced diabetes.
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Espino J, Pariente JA, Rodríguez AB. Role of melatonin on diabetes-related metabolic disorders. World J Diabetes 2011; 2:82-91. [PMID: 21860691 PMCID: PMC3158876 DOI: 10.4239/wjd.v2.i6.82] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2011] [Revised: 05/20/2011] [Accepted: 05/27/2011] [Indexed: 02/05/2023] Open
Abstract
Melatonin is a circulating hormone that is mainly released from the pineal gland. It is best known as a regulator of seasonal and circadian rhythms, its levels being high during the night and low during the day. Interestingly, insulin levels are also adapted to day/night changes through melatonin-dependent synchronization. This regulation may be explained by the inhibiting action of melatonin on insulin release, which is transmitted through both the pertussis-toxin-sensitive membrane receptors MT1 and MT2 and the second messengers 3’,5’-cyclic adenosine monophosphate, 3’,5’-cyclic guanosine monophosphate and inositol 1,4,5-trisphosphate. Melatonin may influence diabetes and associated metabolic disturbances not only by regulating insulin secretion, but also by providing protection against reactive oxygen species, since pancreatic β-cells are very susceptible to oxidative stress because they possess only low-antioxidative capacity. On the other hand, in several genetic association studies, single nucleotide polymorphysms of the human MT2 receptor have been described as being causally linked to an elevated risk of developing type 2 diabetes. This suggests that these individuals may be more sensitive to the actions of melatonin, thereby leading to impaired insulin secretion. Therefore, blocking the melatonin-induced inhibition of insulin secretion may be a novel therapeutic avenue for type 2 diabetes.
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Affiliation(s)
- Javier Espino
- Javier Espino, José A Pariente, Ana B Rodríguez, Department of Physiology, Neuroimmunophysiology and Chrononutrition Research Group, Faculty of Science, University of Extremadura, Badajoz 06006, Spain
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Modulation of oxidative stress by Chlorella vulgaris in streptozotocin (STZ) induced diabetic Sprague-Dawley rats. Adv Med Sci 2010; 55:281-8. [PMID: 21147697 DOI: 10.2478/v10039-010-0046-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE Chlorella vulgaris (CV), a fresh water alga has been reported to have hypoglycemic effects. However, antioxidant and anti-inflammatory effects of CV in diabetic animals have not been investigated to date. The aim of the present study was to investigate the role of CV in inflammation and oxidative damage in STZ-induced diabetic rats. MATERIALS AND METHODS Male Sprague-Dawley rats (300 - 400g) were divided into 4 groups: control, CV, STZ-induced diabetic rats, and STZ rats treated with CV (150mg/kg body wt). Blood samples were drawn from orbital sinus at 1 and 4 weeks for determination of oxidative cellular damage (DNA damage and lipid peroxidation [malondialdehyde, MDA]), inflammation (tumour necrosis factor alpha, TNF-α) and antioxidant status (catalase, CAT, and superoxide dismutase, SOD). RESULTS CV did not have any effects on glucose levels in diabetic rats, over the 4 weeks of treatment. However, it reduced significantly DNA damage and blood MDA levels in STZ-induced diabetic rats compared to the control group. Plasma levels of TNF-α however did not show any significant changes in STZ-induced diabetic rats fed with CV. Antioxidant enzyme SOD showed no significant changes in all groups but CAT activity was reduced in STZ-induced diabetic rats compared to the control. CONCLUSIONS CV did not have hypoglycaemic effect but it has a protective role in STZ-induced diabetic rats by reducing oxidative DNA damage, and lipid peroxidation.
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Involvement of advanced glycation end products in the pathogenesis of diabetic complications: the protective role of regular physical activity. Eur Rev Aging Phys Act 2008. [DOI: 10.1007/s11556-008-0032-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Abstract
Advanced glycation end products (AGEs) may play an important role in the pathogenesis of chronic diabetic complications and in the natural process of biological aging. In fact, maintained hyperglycaemia favours the formation of AGEs at the tissue level in diabetic patients, which may influence the triggering of different chronic pathologies of diabetes such as retinopathy, nephropathy, neuropathy and macro- and micro-vascular diseases. Moreover, the literature has also demonstrated the involvement of AGEs in biological aging, which may explain the accelerated process of aging in diabetic patients. The practice of regular physical activity appears to positively influence glycaemic control, particularly in type 2 diabetes mellitus patients. This occurs through the diminution of fasting glycaemia, with a consequent reduction of glycation of plasmatic components suggested by the normalisation of HbA1c plasmatic levels. This exercise-induced positive effect is evident in the blood of diabetic patients and may also reach the endothelium and connective tissues of different organs, such as the kidneys and eyes, and systems, such as the cardiovascular and nervous systems, with a local reduction of AGEs production and further deceleration of organ dysfunction. The aim of this paper was to review the literature concerning this topic to coherently describe the harmful effects of AGEs in organ dysfunction induced by diabetes in advanced age as well as the mechanisms behind the apparent protection given by the practice of regular physical activity.
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Gokce G, Haznedaroglu MZ. Evaluation of antidiabetic, antioxidant and vasoprotective effects of Posidonia oceanica extract. JOURNAL OF ETHNOPHARMACOLOGY 2008; 115:122-130. [PMID: 17977678 DOI: 10.1016/j.jep.2007.09.016] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2007] [Revised: 09/13/2007] [Accepted: 09/18/2007] [Indexed: 05/25/2023]
Abstract
The aim of this study is to evaluate antidiabetic, antioxidant and vasoprotective effects of Posidonia oceanica extract (POE) in alloxan diabetic rats. Posidonia oceanica (L) Delile (Posidoniaceae), is a widely allocated phanerogam in Mediterranean and Aegean Sea. Up to date, no published data relevant to use of the plant in traditional medicine are available. However, decoction of the leaves has been quoted to be used as a remedy for diabetes mellitus and hypertension by villagers living by the sea coast of Western Anatolia. Oral administration of extract for 15 days (50, 150, and 250 mg/kg b.wt.) resulted in a dose-dependent decrease in blood glucose. Relaxant responses to acetylcholine (ACh) in diabetic thoracic aorta were restored by POE treatment (50, 150, and 250 mg/kg b.wt.). POE also attenuated the augmented phenylephrine (PE) and serotonin (5-HT) contractions. At concentration levels of 150 and 250 mg/kg b.wt., POE exerted a protective effect on the significantly decreased levels of antioxidants namely, glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase and nitric oxide (NO). POE (50mg/kg b.wt.) produced no effect on alloxan-induced alterations in the antioxidant status while possessing glucose lowering and vasoprotective activities. Furthermore, liver and kidney function markers, leucocyte counts, body weight and liver glycogen content remained unchanged at dose level of 50mg/kg b.wt., when compared with diabetic control group. These results suggest that antidiabetic and vasoprotective effects of POE may be unrelated to its antioxidant properties.
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Affiliation(s)
- Goksel Gokce
- Ege University, Faculty of Pharmacy, Department of Pharmacology, 35100 Bornova, Izmir, Turkey.
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Abstract
Melatonin influences insulin secretion both in vivo and in vitro. (i) The effects are MT(1)-and MT(2)-receptor-mediated. (ii) They are specific, high-affinity, pertussis-toxin-sensitive, G(i)-protein-coupled, leading to inhibition of the cAMP-pathway and decrease of insulin release. [Correction added after online publication 4 December 2007: in the preceding sentence, 'increase of insulin release' was changed to 'decrease of insulin release'.] Furthermore, melatonin inhibits the cGMP-pathway, possibly mediated by MT(2) receptors. In this way, melatonin likely inhibits insulin release. A third system, the IP(3)-pathway, is mediated by G(q)-proteins, phospholipase C and IP(3), which mobilize Ca(2+) from intracellular stores, with a resultant increase in insulin. (iii) Insulin secretion in vivo, as well as from isolated islets, exhibits a circadian rhythm. This rhythm, which is apparently generated within the islets, is influenced by melatonin, which induces a phase shift in insulin secretion. (iv) Observation of the circadian expression of clock genes in the pancreas could possibly be an indication of the generation of circadian rhythms in the pancreatic islets themselves. (v) Melatonin influences diabetes and associated metabolic disturbances. The diabetogens, alloxan and streptozotocin, lead to selective destruction of beta-cells through their accumulation in these cells, where they induce the generation of ROS. Beta-cells are very susceptible to oxidative stress because they possess only low-antioxidative capacity. Results suggest that melatonin in pharmacological doses provides protection against ROS. (vi) Finally, melatonin levels in plasma, as well as the arylalkylamine-N-acetyltransferase (AANAT) activity, are lower in diabetic than in nondiabetic rats and humans. In contrast, in the pineal gland, the AANAT mRNA is increased and the insulin receptor mRNA is decreased, which indicates a close interrelationship between insulin and melatonin.
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Affiliation(s)
- Elmar Peschke
- Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Germany.
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Reyes-Toso CF, Linares LM, Witriw A, Vázquez MB, Ricci CR, Cardinali DP. Antioxidants restore aortic ring relaxation in pancreatectomized rats. Life Sci 2007; 81:1467-72. [DOI: 10.1016/j.lfs.2007.09.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2007] [Revised: 07/31/2007] [Accepted: 09/19/2007] [Indexed: 10/22/2022]
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Sudnikovich EJ, Maksimchik YZ, Zabrodskaya SV, Kubyshin VL, Lapshina EA, Bryszewska M, Reiter RJ, Zavodnik IB. Melatonin attenuates metabolic disorders due to streptozotocin-induced diabetes in rats. Eur J Pharmacol 2007; 569:180-7. [PMID: 17597602 DOI: 10.1016/j.ejphar.2007.05.018] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2007] [Revised: 05/10/2007] [Accepted: 05/15/2007] [Indexed: 12/31/2022]
Abstract
Enhanced oxidative stress and impairments in nitric oxide synthesis and bioavailability are of considerable importance in the pathogenesis of diabetic vascular diseases. The aim of the present work was to evaluate the metabolic effects of pharmacological doses of the melatonin, a known antioxidant, on streptozotocin-induced diabetic damage in rats. We investigated the indolamine's influence on the cellular redox-balance, nitric oxide (NO) level, and the activities of antioxidative defence enzymes, as well as the activities of enzymes involved in phase II detoxication and NADPH-generating pentose phosphate pathway. Blood glucose, glycated hemoglobin, bilirubin, as well as plasma alanine aminotransferase activities increased and body weight was reduced in rats with streptozotocin-induced (60 mg/kg, i.p.) diabetes (25 days). The NO level was markedly increased in diabetic plasma (by 50%) and aortic tissue (by 30%). The hyperglycemia resulted in reduced activities of glutathione peroxidase (by 25%), catalase (by 20%), glucose-6-phosphate dehydrogenase (by 55%) and transketolase (by 40%) in liver tissue of diabetic animals. Melatonin treatment (10 mg/kg, 18 days) did not influence the level of hyperglycemia or glycated hemoglobin and it had little effect on the activities of antioxidative enzymes. However, melatonin markedly reversed the activities of glucose-6-phosphate dehydrogenase and transketolase in liver tissue of diabetic rats. The most pronounced effect of the melatonin administration was the prevention of an increase in nitric oxide levels in blood plasma and aortic tissue during diabetes. In in vitro experiments, nitrosomelatonin formation in the presence of nitrosodonors was observed. This implies that melatonin might operate as an NO scavenger and carrier. Thus, melatonin treatment may have some beneficial effects in controlling diabetic vascular complications.
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Affiliation(s)
- Elena Ju Sudnikovich
- State Research and Innovation Center, Institute for Pharmacology and Biochemistry of the National Academy of Sciences of Belarus, BLK-50, 230017 Grodno, Belarus
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Ates O, Cayli SR, Yucel N, Altinoz E, Kocak A, Durak MA, Turkoz Y, Yologlu S. Central nervous system protection by resveratrol in streptozotocin-induced diabetic rats. J Clin Neurosci 2007; 14:256-60. [PMID: 17258134 DOI: 10.1016/j.jocn.2005.12.010] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2005] [Revised: 12/07/2005] [Accepted: 12/09/2005] [Indexed: 10/23/2022]
Abstract
The objective of the present study was to investigate the possible neuroprotective effect of resveratrol against streptozotocin-induced hyperglycaemia in the rat brain and medulla spinalis. Thirty adult male Wistar rats were divided into three groups as follows: control group, streptozotocin-induced diabetic-untreated group, and streptozotocin-induced diabetic resveratrol-treated group. Diabetes was induced by a single injection of streptozotocin (STZ) (60 mg/kg body weight). Three days after streptozotocin injection, resveratrol (10 mg/kg) was injected intraperiteonally daily over 6 weeks to the rats in the treatment group. Six weeks later, seven rats from each group were killed and the brain stem and cervical spinal cord were removed. The hippocampus, cortex, cerebellum, brain stem and spinal cord were dissected for biochemical studies (lipid peroxidation measuring malondialdehyde [MDA], xanthine oxidase [XO], nitric oxide [NO] and glutathione). MDA, XO and NO levels in hippocampus, cortex, cerebellum, brain stem and spinal cord in the streptozotocin-induced diabetic-untreated group increased significantly. Treatment with resveratrol significantly reduced MDA, XO and NO production and increased glutathione levels when compared to the streptozotocin-induced diabetic-untreated group. This study demonstrates that resveratrol is a potent neuroprotective agent against diabetic oxidative damage.
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Affiliation(s)
- Ozkan Ates
- Inonu University, School of Medicine, Department of Neurosurgery, Turgut Ozal Medical Center, 44069 Malatya, Turkey.
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Lukivskaya O, Patsenker E, Buko VU. Protective effect of ursodeoxycholic acid on liver mitochondrial function in rats with alloxan-induced diabetes: link with oxidative stress. Life Sci 2007; 80:2397-402. [PMID: 17512017 DOI: 10.1016/j.lfs.2007.02.042] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2006] [Revised: 02/17/2007] [Accepted: 02/22/2007] [Indexed: 02/02/2023]
Abstract
We investigated the effects of ursodeoxycholic acid (UDCA) on mitochondrial functions and oxidative stress and evaluated their relationships in the livers of rats with alloxan-induced diabetes. Diabetes was induced in male Wistar rats by a single alloxan injection (150 mg kg(-1) b.w., i.p.). UDCA (40 mg kg(-1) b.w., i.g., 30 days) was administered from the 5th day after the alloxan treatment. Mitochondrial functions were evaluated by oxygen consumption with Clark oxygen electrode using succinate, pyruvate+malate or palmitoyl carnitine as substrates and by determination of succinate dehydrogenase and NADH dehydrogenase activities. Liver mitochondria were used to measure chemiluminiscence enhanced by luminol and lucigenin, reduced liver glutathione and the end-products of lipid peroxidation. The activities of both NADH dehydrogenase and succinate dehydrogenase as well as the respiratory control (RC) value with all the substrates and the ADP/O ratio with pyruvate+malate and succinate as substrates were significantly decreased in diabetic rats. UDCA developed the beneficial effect on the mitochondrial respiration and oxidative phosphorylation parameters in alloxan-treated rats, whereas the activities of mitochondrial enzymes were increased insignificantly after the administration of UDCA. The contents of polar carbonyls and MDA as well as the chemiluminescence with luminol were elevated in liver mitochondria of diabetic rats. The treatment with UDCA normalized all the above parameters measured except the MDA content. UDCA administration prevents mitochondrial dysfunction in rats treated with alloxan and this process is closely connected with inhibition of oxidative stress by this compound.
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Affiliation(s)
- Oxana Lukivskaya
- Department of Experimental Hepatology, Institute of Biochemistry, National Academy of Sciences, BLK-50, Grodno, Belarus
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Li SP, Zhang GH, Zeng Q, Huang ZG, Wang YT, Dong TTX, Tsim KWK. Hypoglycemic activity of polysaccharide, with antioxidation, isolated from cultured Cordyceps mycelia. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2006; 13:428-33. [PMID: 16716913 DOI: 10.1016/j.phymed.2005.02.002] [Citation(s) in RCA: 104] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/22/2004] [Accepted: 02/01/2005] [Indexed: 05/09/2023]
Abstract
Cordyceps sinensis, a well-known traditional Chinese medicine, possesses anti-tumor, immunostimulant and antioxidant activities; however, the identities of active components have not been determined. In our previous study using antioxidant activity-guided fractionation [Li et al., 2003. A polysaccharide isolated from Cordyceps sinensis, a traditional Chinese medicine, protects PC12 cells against hydrogen peroxide-induced injury. Life Sci. 73, 2503-2513], a polysaccharide of molecular weight approximately 210kDa was isolated from cultured Cordyceps mycelia by ion-exchange and sizing chromatography. The isolated polysaccharide, named CSP-1, which has strong anti-oxidation activity, contains glucose, mannose and galactose in the ratio of 1:0.6:0.75. In the present study, we demonstrated the hypoglycemic effect of CSP-1 on normal and alloxan-diabetic mice and streptozotocin (STZ)-diabetic rats. The basal glucose level did not differ significantly among the normal mice. CSP-1 (at 200 and 400mg/kg body wt./day for 7 days, p.o.), however, significantly reduced the blood glucose level by 12.0+/-3.2% and 22.5+/-4.7% in normal mice, respectively (p<0.05). When administered at a dose of higher than 200mg/kg body wt. daily for 7 days, CSP-1 produced a significant drop in blood glucose level in both STZ-induced diabetic rats and alloxan-induced diabetic mice. The serum insulin levels in diabetic animals were also increased by administration of CSP-1 (p<0.05). CSP-1 with hypoglycemic properties increased circulating insulin level in diabetic animals, which suggests that CSP-1 may stimulate pancreatic release of insulin and/or reduce insulin metabolism.
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Affiliation(s)
- S P Li
- Institute of Chinese Medical Sciences, University of Macau, Taipa, China.
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38
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Guven A, Yavuz O, Cam M, Ercan F, Bukan N, Comunoglu C, Gokce F. Effects of melatonin on streptozotocin-induced diabetic liver injury in rats. Acta Histochem 2006; 108:85-93. [PMID: 16714049 DOI: 10.1016/j.acthis.2006.03.005] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2006] [Revised: 03/13/2006] [Accepted: 03/15/2006] [Indexed: 01/29/2023]
Abstract
This study investigated the possible protective effects of melatonin as an antioxidant against streptozotocin (STZ)-induced diabetic liver injury in rats. Wistar rats were divided into four groups: untreated control (UC), melatonin-treated control (MC), untreated diabetic (UD), and melatonin-treated diabetic (MD). Experimental diabetes was induced by a single-dose (60 mg/kg, intraperitoneally (ip)) STZ injection, and melatonin was injected (200 microg/kg/day, ip) for 4 weeks. Upon light and electron microscopic examination, we observed that melatonin improved the morphological and histopathological changes of the liver caused by diabetes. Malondialdehyde levels in the liver homogenates of UD rats were higher than those of controls and were markedly reduced after melatonin treatment. Although no significant difference was observed with respect to antioxidant status, the superoxide dismutase activity tended to be higher in the UD rats than in the treated rats. Our findings showed that melatonin administration partially reduced liver injury in STZ-induced diabetic rats.
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Affiliation(s)
- Aysel Guven
- Department of Histology and Embryology, Abant Izzet Baysal University, Duzce School of Medicine, 81620 Konuralp, Duzce, Turkey.
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39
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Tutuncu NB, Batur MK, Yildirir A, Tutuncu T, Deger A, Koray Z, Erbas B, Kabakci G, Aksoyek S, Erbas T. Melatonin levels decrease in type 2 diabetic patients with cardiac autonomic neuropathy. J Pineal Res 2005; 39:43-9. [PMID: 15978056 DOI: 10.1111/j.1600-079x.2005.00213.x] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The present study has been designed to determine melatonin levels in type 2 diabetic patients and test the relationship between the autonomic nervous system and melatonin dynamics. Thirty-six type 2 diabetic patients and 13 age-matched healthy subjects were recruited for the study. Circadian rhythm of melatonin secretion was assessed by measuring serum melatonin concentrations between 02:00-04:00 and 16:00-18:00 hr. Melatonin dynamics were re-evaluated with respect to autonomic nervous system in diabetic patients with autonomic neuropathy who were diagnosed by the cardiovascular reflex tests, heart rate variability (HRV), and 24-hr blood pressure monitoring. Nocturnal melatonin levels and the nocturnal melatonin surge were low in the diabetic group (P = 0.027 and 0.008 respectively). Patients with autonomic neuropathy revealed decreased melatonin levels both at night and during day when compared with healthy controls (P < 0.001 and 0.004 respectively) while the melatonin dynamics were similar to controls in patients without autonomic neuropathy. Nocturnal melatonin level was positively correlated with nocturnal high and low frequency components of HRV (P = 0.005 and 0.011 respectively) and systolic and diastolic blood pressures at night (P = 0.002 and 0.004 respectively) in patients with autonomic neuropathy. We found a negative correlation between nocturnal melatonin levels and the degree of systolic blood pressure decrease at night (r = -0.478, P = 0.045). As a conclusion this study has shown that circadian rhythm of melatonin secretion is blunted in type 2 diabetic patients and there is a complex relationship between various components of autonomic nervous system and melatonin secretion at night. Among the patients with autonomic neuropathy those with more preserved HRV and the systolic nondippers (<10% reduction in blood pressure during the night relative to daytime values) have more pronounced melatonin surge at night.
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Affiliation(s)
- Neslihan B Tutuncu
- Department of Endocrinology and Metabolism, Hacettepe University Faculty of Medicine, Ankara, Turkey.
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40
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Pawlak J, Singh J, Lea RW, Skwarlo-Sonta K. Effect of melatonin on phagocytic activity and intracellular free calcium concentration in testicular macrophages from normal and streptozotocin-induced diabetic rats. Mol Cell Biochem 2005; 275:207-13. [PMID: 16335800 DOI: 10.1007/s11010-005-1995-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
This study examined the effect of melatonin (MLT) on in vitro phagocytosis of testicular macrophages taken from control and streptozotocin (STZ)-induced diabetic rats and the possible mechanism of its action. The phagocytic activity was measured as a number of latex beads ingested by 100 macrophages (PI, phagocytic index) in consecutive time points of the incubation. Changes in intracellular free calcium level [Ca2+]i in isolated macrophages in vitro were measured with the use of ratio-image fluorescence microscopy (fluorescent dye: Fura2/AM). Phagocytic index in macrophages isolated from healthy rats was 20% higher than in those from diabetic animals. Melatonin in physiological concentration (10(-7) M) significantly (p < 0.05) increased the PI in testicular macrophages from control animals (PI = 68 +/- 5 with MLT compared to PI = 46 +/- 7 without MLT) while no such effect was observed in the cells from diabetic rats (PI = 36 +/- 23 with MLT compared to PI = 31 +/- 11 without MLT). Basal [Ca2+]i was significantly (p < 0.01) higher in macrophages from diabetic rats compared to control. Stimulation of both control and diabetic testicular macrophages with 10(-7) M MLT resulted in a significant (p < 0.05) increase in [Ca2+]i in cells incubated in 2.5 mM calcium solution while no such response was observed in calcium-free Tyrode solution. However, MLT evoked [Ca2+]i response in macrophages isolated from diabetic animals was much lower than in macrophages isolated from age-matched controls and the time needed for maximal response was much longer. Lack of response in calcium-free solution suggests that extracellular calcium may be necessary to trigger MLT response and in its progression.
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Affiliation(s)
- Joanna Pawlak
- Department of Vertebrate Physiology, Faculty of Biology, Warsaw University, ul. Miecznikowa 1, 02-096 Warsaw, Poland.
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41
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Reyes-Toso CF, Linares LM, Ricci CR, Arán M, Pinto JE, Rodríguez RR, Cardinali DP. Effect of melatonin on vascular reactivity in pancreatectomized rats. Life Sci 2004; 74:3085-92. [PMID: 15081574 DOI: 10.1016/j.lfs.2003.10.032] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2003] [Accepted: 10/23/2003] [Indexed: 10/26/2022]
Abstract
The present study was undertaken to assess whether the improvement of contractile performance of aortic rings by melatonin described in streptozotocin diabetic rats also occurs in another model of type I diabetes, the pancreatectomized rats. Adult male Wistar rats submitted to a subtotal pancreatectomy and exhibiting altered levels of fasting glucose and an abnormal tolerance glucose test, were used. Sham-operated laparotomized rats were employed as controls. Dose-response curves for acetylcholine-induced, endothelium-related relaxation of aortic rings (after previous exposure to phenylephrine) and for phenylephrine-induced vasoconstriction were conducted. This protocol was repeated with rings pre-incubated in a high glucose solution (44 mmol/l). Pancreatectomy decreased significantly acetylcholine-induced relaxation of aortic rings, but not phenylephrine-induced vasoconstriction, the effect being amplified by preincubation in high glucose solution. The deleterious effect of a high glucose medium was more pronounced in pancreatectomized rats. Melatonin (10(-5) M) did not modify acetylcholine-induced relaxation in normal glucose concentration but was effective to prevent the impairment of relaxation brought about by exposure to high glucose solution. The contractile response to phenylephrine of aortic rings obtained from pancreatectomized rats was not affected by melatonin. The results further support the improvement by melatonin of endothelial-mediated relaxation in blood vessels of diabetic rats.
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Affiliation(s)
- Carlos F Reyes-Toso
- Department of Physiology, Faculty of Medicine, University of Buenos, Aires, Paraguay 2155, 1121 Buenos Aires, Argentina
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42
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Yavuz O, Cam M, Bukan N, Guven A, Silan F. Protective effect of melatonin on beta-cell damage in streptozotocin-induced diabetes in rats. Acta Histochem 2004; 105:261-6. [PMID: 13677620 DOI: 10.1078/0065-1281-00711] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The aim of the present study was the evaluation of possible protective effects of melatonin against beta-cell damage in streptozotocin-induced diabetes in rats. Malondialdehyde levels and glutathione peroxidase activity were measured in pancreatic homogenates. Pancreatic beta-cells were examined by immunohistochemical methods. Streptozotocin was injected intraperitoneally at a single dose of 60 mg/kg for induction of diabetes. Melatonin (200 microg/kg/day, ip) was injected for 3 days prior to administration of streptozotocin; these injections were continued until the end of the study (4 weeks). Streptozotocin induced a significant increase in malondialdehyde levels (p < 0.01) and a significant decrease in glutathione peroxidase activity (p < 0.05) in pancreatic tissue. Degeneration of islet cells and weak immunohistochemical staining of insulin was observed in diabetic rats. Treatment of diabetic rats with melatonin markedly reduced malondialdehyde production (p < 0.05) and increased glutathione peroxidase activity (p < 0.01) without affecting hyperglycemia. Increased staining of insulin and preservation of islet cells were apparent in the melatonin-treated diabetic rats. These data suggest that melatonin treatment has a therapeutic effect in diabetes by reduction of oxidative stress and preservation of pancreatic beta-cell integrity.
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Affiliation(s)
- Ozlem Yavuz
- Department of Biochemistry, Abant Izzet Baysal University, Faculty of Medicine, Duzce, Turkey.
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43
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Cutando A, Gómez-Moreno G, Villalba J, Ferrera MJ, Escames G, Acuña-Castroviejo D. Relationship between salivary melatonin levels and periodontal status in diabetic patients. J Pineal Res 2003; 35:239-44. [PMID: 14521628 DOI: 10.1034/j.1600-079x.2003.00075.x] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Among other functions, melatonin exerts both antioxidative and immunoregulatory roles. The indoleamine is secreted in the saliva, although its role into the mouth is not known. Diabetic patients frequently display oral cavity pathologies such as periodontal disease (PD), an inflammatory disease coursing with an increase in free radical production. Thus, we compared the degree of PD and interleukin-2 (IL-2) levels with melatonin concentrations in plasma and saliva of diabetic patients. A total of 43 diabetic patients (20 with type I and 23 with type II diabetes) and 20 age- and sex-matched controls were studied. Dental and medical history of all patients was in accordance with the criteria of the WHO. The periodontal status was evaluated by the Community Periodontal Index (CPI). Plasma and salivary melatonin levels were determined by specific commercial radioimmunoassays, and plasma IL-2 was measured using a commercial enzyme-linked immunosorbent assay kit. Diabetic patients had plasma and saliva melatonin levels of 8.98 +/- 7.14 and 2.70 +/- 2.04 pg/mL, respectively. These values were significantly lower (P < 0.001) than those obtained in plasma and saliva of controls (14.91 +/- 4.75 and 4.35 +/- 0.98 pg/mL, respectively). Plasma and salivary melatonin concentrations show a biphasic response in diabetic patients. Melatonin decreased in patients with a CPI index of 2, and then increased reaching highest levels in patients with a CPI index of 4. By contrast, IL-2 levels decreased from CPI index 1 to 4. The results indicate that, in diabetic patients, the presence of a marked impairment of the oral status, as assessed by the CPI index, is accompanied by an increase in plasma and salivary melatonin. The increase in salivary melatonin excretion may have a periodontal protective role.
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Affiliation(s)
- Antonio Cutando
- Departamento de Clínica Odontológica Integral en Pacientes Especiales, Instituto de Biotecnología, Universidad de Granada, Granada, Spain.
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Maritim AC, Sanders RA, Watkins JB. Diabetes, oxidative stress, and antioxidants: a review. J Biochem Mol Toxicol 2003; 17:24-38. [PMID: 12616644 DOI: 10.1002/jbt.10058] [Citation(s) in RCA: 1892] [Impact Index Per Article: 86.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Increasing evidence in both experimental and clinical studies suggests that oxidative stress plays a major role in the pathogenesis of both types of diabetes mellitus. Free radicals are formed disproportionately in diabetes by glucose oxidation, nonenzymatic glycation of proteins, and the subsequent oxidative degradation of glycated proteins. Abnormally high levels of free radicals and the simultaneous decline of antioxidant defense mechanisms can lead to damage of cellular organelles and enzymes, increased lipid peroxidation, and development of insulin resistance. These consequences of oxidative stress can promote the development of complications of diabetes mellitus. Changes in oxidative stress biomarkers, including superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, glutathione levels, vitamins, lipid peroxidation, nitrite concentration, nonenzymatic glycosylated proteins, and hyperglycemia in diabetes, and their consequences, are discussed in this review. In vivo studies of the effects of various conventional and alternative drugs on these biomarkers are surveyed. There is a need to continue to explore the relationship between free radicals, diabetes, and its complications, and to elucidate the mechanisms by which increased oxidative stress accelerates the development of diabetic complications, in an effort to expand treatment options.
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Affiliation(s)
- A C Maritim
- Moi University, College of Health Sciences, Eldoret, Kenya
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45
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Cam M, Yavuz O, Guven A, Ercan F, Bukan N, Ustündag N. Protective effects of chronic melatonin treatment against renal injury in streptozotocin-induced diabetic rats. J Pineal Res 2003; 35:212-20. [PMID: 12932206 DOI: 10.1034/j.1600-079x.2003.00082.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The aim of this study was to investigate the effects of melatonin as an antioxidant, on prevention and treatment of streptozotocin (STZ)-induced diabetic renal injury in rats. Male Wistar rats were divided into four groups: (1) untreated, (2) melatonin-treated, (3) untreated diabetic (UD), (4) melatonin-treated diabetic (MD). Experimental diabetes was induced by single dose (60 mg/kg, i.p.) STZ injection. For 3 days prior to administration of STZ, melatonin was injected (200 microg/kg/day, i.p.); these injections were continued until the end of the study (4 weeks). Malondialdehyde (MDA) levels as a marker of lipid peroxidation were significantly increased in the renal homogenates of UD animals and decreased after melatonin administration. The activity of the antioxidative enzyme glutathione peroxidase (GSH-Px) was significantly reduced in UD rats. Melatonin treatment reversed STZ-induced reduction of GSH-Px activity without having an effect on blood glucose. Upon histopathological examination, it was observed that the melatonin treatment prevented the renal morphological damage caused by diabetes. Upon immunohistochemical investigation, glomerular anti-laminin beta1 staining decreased in MD rats. Additionally, no tubular anti-IGF-1 staining was observed in melatonin-treated rats. In conclusion, chronically administered melatonin reduced renal injury in STZ-induced diabetic rats and thus it may provide a useful therapeutic option in humans to reduce oxidative stress and the associated renal injury in patients with diabetes mellitus.
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Affiliation(s)
- Meryem Cam
- Department of Histology and Embryology, Abant Izzet Baysal University, School of Medicine, Duzce, Turkey
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46
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Aksoy N, Vural H, Sabuncu T, Aksoy S. Effects of melatonin on oxidative-antioxidative status of tissues in streptozotocin-induced diabetic rats. Cell Biochem Funct 2003; 21:121-5. [PMID: 12736900 DOI: 10.1002/cbf.1006] [Citation(s) in RCA: 97] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
In view of the antioxidant properties of melatonin, the effects of melatonin on the oxidative-antioxidative status of tissues affected by diabetes, e.g. liver, heart and kidneys, were investigated in streptozotocin (STZ)-induced diabetic rats in the present study. Concentrations of malondialdehyde (MDA) and reduced glutathione (GSH), and activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the tissues were compared in three groups of 10 rats each (control non-diabetic rats (group I), untreated diabetic rats (group II) and diabetic rats treated with melatonin (group III)). In the study groups, diabetes developed 3 days after intraperitoneal (i.p.) administration of a single 60 mg kg(-1) dose of STZ. Thereafter, while the rats in group II received no treatment, the rats in group III began to receive a 10 mg kg(-1) i.p. dose of melatonin per day. After 6 weeks, the rats in groups II and III had significantly lower body weights and higher blood glucose levels than the rats in group I (p < 0.001 and p < 0.001, respectively). MDA levels in the liver, kidney and heart of group II rats were higher than that of the control group (p < 0.01, p < 0.05, p < 0.01, respectively) and diabetic rats treated with melatonin (p < 0.05). The GSH, GSH-Px and SOD levels increased in diabetic rats. Treatment with melatonin changed them to near control values. Our results confirm that diabetes increases oxidative stress in many organs such as liver, kidney and heart and indicate the role of melatonin in combating the oxidative stress via its free radical-scavenging and antioxidant properties.
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Affiliation(s)
- Nurten Aksoy
- Department of Biochemistry, Harran University, Faculty of Medicine, Sanliurfa, Turkey.
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47
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Sener G, Saçan O, Yanardağ R, Ayanoğlu-Dülger G. Effects of chard (Beta vulgaris L. var. cicla) extract on oxidative injury in the aorta and heart of streptozotocin-diabetic rats. J Med Food 2003; 5:37-42. [PMID: 12511111 DOI: 10.1089/109662002753723205] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
In diabetes mellitus, increased free radical formation raises the incidence of atherosclerosis and cardiovascular diseases. Regardless of the type of diabetes, the objective of the therapy is to achieve normoglycemia and to prevent or delay the complications. Chard (Beta vulgaris L. var. cicla) is used as a hypoglycemic agent by diabetic patients in Turkey. The aim of this study was to investigate the effect of feeding chard on diabetes-induced free radical-mediated injury in rat aorta and heart tissues. Female Swiss albino rats were randomly divided into four groups: control, diabetic, chard, and diabetic + chard. Rats were subjected to intraperitoneal streptozotocin (STZ, 65 mg/kg) to induce diabetes. Chard extract (2 g/kg) was given for 28 days beginning on the 14th day of the study. Aorta and heart tissue lipid peroxidation and glutathione levels as well as blood glucose levels were determined. The results of the present study indicate that lipid peroxidation was increased and glutathione levels were decreased in both aorta and heart tissue of the diabetic rats. However, treatment with chard extract reversed the effects of diabetes on blood glucose and tissue lipid peroxidation and glutathione levels.
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Affiliation(s)
- G Sener
- Department of Pharmacology, Faculty of Pharmacy, Marmara University, 81010, Istanbul, Turkey.
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48
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Abstracts of Original Communications. Proc Nutr Soc 2002. [DOI: 10.1017/s0029665102000253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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49
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Reyes-Toso CF, Rosón MI, Albornoz LE, Damiano PF, Linares LM, Cardinali DP. Vascular reactivity in diabetic rats: effect of melatonin. J Pineal Res 2002; 33:81-6. [PMID: 12153441 DOI: 10.1034/j.1600-079x.2002.01886.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The aim of the present study was to evaluate the in vitro contractile response of rat aorta in mild and severe type I diabetes and the effect of melatonin on it. Aortic rings were obtained from male Wistar rats injected with streptozotocin 8-12 wks earlier. Rats were divided into three groups: non-diabetic rats (NDR), mildly diabetic rats (MDR) and severely diabetic rats (SDR). Dose-response curves for acetylcholine-induced, endothelium-related relaxation of aortic rings (after previous exposure to phenylephrine) and for serotonin-induced vasoconstriction were conducted in the presence or absence of 10-5 mol/L melatonin. This protocol was repeated with rings preincubated in a high glucose solution (44 mmol/L). The contractile response to phenylephrine decreased in SDR, an effect counteracted by preincubation with high glucose. Melatonin decreased phenylephrine-induced vasoconstriction in MDR and counteracted the effect of high glucose in SDR. Acetylcholine-evoked relaxation decreased significantly after exposure to a high glucose in SDR, this effect being counteracted by melatonin. Serotonin-induced vasoconstriction decreased in SDR and augmented in MDR, but only after exposure to high glucose. Melatonin reduced the maximal tension of aortic contraction after serotonin in MDR, both under basal conditions and after preincubation in a high glucose solution. The results support the existence of differences in vasomotor responses as a function of the diabetes state and of an improvement of contractile performance in diabetic rats after exposure to melatonin at a pharmacological concentration (in terms of circulating melatonin levels but not necessarily for some other fluids or tissues).
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Affiliation(s)
- Carlos F Reyes-Toso
- Departmento de Fisiología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
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50
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Görgün FM, Oztürk Z, Gümüştaş MK, Kökogu E. Melatonin administration affects plasma total sialic acid and lipid peroxidation levels in streptozotocin induced diabetic rats. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2002; 65:695-700. [PMID: 12028824 DOI: 10.1080/00984100290071045] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
Administration of streptozotocin (STZ) was used to induce diabetes, as the mechanism involved is believed associated with generation of free radicals. Supplementation with antioxidant molecules such as melatonin may serve as a protection against diabetes. The aim of this study was to determine whether the STZ-induced effects on plasma thiobarbituric acid-reactive substances (TBARS, a marker of lipid peroxidation) and total sialic acid levels could be blocked by melatonin. STZ significantly increased the plasma levels of sialic acid and TBARS. Treatment with melatonin markedly reduced the STZ-induced effects on plasma sialic acid and TBARS and was associated with restoration of hyperglycemia to control blood glucose levels. These data suggest that melatonin protects against oxidative damage, and daily supplementation with melatonin may be beneficial for diabetics.
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Affiliation(s)
- F Murat Görgün
- Department of Biochemistry, Cerrahpaşa Medical Faculty, Istanbul University, Turkey.
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