Abdülhadi Cihangir Uğuz

Melatonin potentiates chemotherapy-induced cytotoxicity and apoptosis in rat pancreatic tumor cells

Abstract:  Melatonin has antitumor activity via several mechanisms including its antiproliferative and proapoptotic effects in addition to its potent antioxidant action. Thus, melatonin has proven useful in the treatment of tumors in association with chemotherapeutic drugs. This study was performed to evaluate the effect of melatonin on the cytotoxicity and apoptosis induced by three different chemotherapeutic agents, namely 5‐fluorouracil (5‐FU), cisplatin, and doxorubicin in the rat pancreatic tumor cell line AR42J. We found that both melatonin and the three chemotherapeutic drugs induce a time‐dependent decrease in AR42J cell viability, reaching the highest cytotoxic effect after 48 hr of incubation. Furthermore, melatonin significantly augmented the cytotoxicity of the chemotherapeutic agents. Consistently, cotreatment of AR42J cells with each of the chemotherapeutic agents in the presence of melatonin increased the population of apoptotic cells, elevated mitochondrial membrane depolarization, and augmented intracellular reactive oxygen species (ROS) production compared to treatment with each chemotherapeutic agent alone. These results provide evidence that in vitro melatonin enhances chemotherapy‐induced cytotoxicity and apoptosis in rat pancreatic tumor AR42J cells and, therefore, melatonin may be potentially applied to pancreatic tumor treatment as a powerful synergistic agent in combination with chemotherapeutic drugs.

Oral vitamin C and E combination modulates blood lipid peroxidation and antioxidant vitamin levels in maximal exercising basketball players

Oxidative stress occurs during maximal exercise, perhaps as a result of increased consumption of oxygen. Vitamins C and E can overcome the effects of antioxidants in exercise. We investigated the effects of supplementation with a combination of vitamin C and E (VCE) on blood lipid peroxidation (LP) and antioxidant levels following maximal training in basketball players.

2.45-Gz wireless devices induce oxidative stress and proliferation through cytosolic Ca2+ influx in human leukemia cancer cells

Purpose: Electromagnetic radiation from wireless devices may affect biological systems by increasing free radicals. The present study was designed to determine the effects of 2.45 GHz radiation on the antioxidant redox system, calcium ion signaling, cell count and viability in human leukemia 60 cells. Materials and methods: Twelve cell cultures were equally divided into two main groups as controls (n = 6) and irradiated (n = 6) and then subdivided into four different subgroups depending on the duration of exposure, namely 1, 2, 12 and 24 hours. The samples were analyzed immediately after the experimental period. Results: The extent of lipid peroxidation, cytosolic free Ca2+ and cell numbers were higher in 2.45 GHz groups than in the controls. The increase of cytosolic free Ca2+ concentrations was radiation time-dependent and was highest at 24-h exposure. The reduced glutathione, glutathione peroxidase, vitamin C and cell viability values did not show any changes in any of the experimental groups. 2-aminoethyl diphenylborinate inhibits Ca2+ ions influx by blockage of the transient receptor potential melastatin 2. Conclusions: 2.45 GHz electromagnetic radiation appears to induce proliferative effects through oxidative stress and Ca2+ influx although blocking of transient receptor potential melastatin 2 channels by 2-aminoethyl diphenylborinate seems to counteract the effects on Ca2+ ions influx.

Effects of pentoxifylline and alpha lipoic acid on methotrexate-induced damage in liver and kidney of rats.

The aim of the current study was to investigate the probable protective effects of Pentoxifylline (PTX) and Alpha Lipoic Acid (ALA), which display anti-oxidative efficacy against hepatotoxicity and nephrotoxicity, those being the major side effects of Methotrexate (MTX). Rats were divided into four groups: a control group; MTX (20mg/kg/day) group; MTX+PTX (20mg/kg/day+50mg/kg/day) group; and an MTX+ALA (20mg/kg/day+100mg/kg/day) group. At the end of the experiment, biochemical, histochemical and immunohistochemical analyses were performed on liver and kidney tissues of rats. We determined Glutathione Peroxidase (GSH-Px), Superoxide Dismutase (SOD), Catalase (CAT), Malondialdehyde (MDA), Nitric Oxide (NO) and Xanthine Oxidase (XO) levels in the liver and kidney. Moreover, Gamma Glutamyl Transferase (GGT), Direct Bilirubin (DBil), Blood Urea Nitrogen (BUN), and urea levels were measured in the serum. The histochemical evaluation revealed a significant decrease in MTX caused damage in the PTX- and ALA-treated groups (especially in ALA group). On the other hand, the immune staining of iNOS and TNF-α were observed most densely in the MTX group, while the density decreased in the PTX- and ALA-administered groups. We determined increased GGT, BUN, urea and levels of CAT, MDA, NO, and XO values in both groups, while GSH-Px (an increase in liver tissue) and DBil levels were decreased in the group that received MTX. However, we determined decreased SOD levels in liver tissue. In the PTX and ALA groups, the levels of GGT, BUN and urea as well as the levels of CAT, MDA, NO and XO decreased (SOD increased in the liver tissue), and the levels of GSH-Px and DBil increased. In conclusion, it can be stated that, although ALA is more effective in preventing the toxic effects of MTX on the liver and kidney, PTX also has a preventive effect. As a result, we can readily suggest that ALA and PTX can have protective effects by decreasing MDA, NO, BUN and urea values as antioxidants against MTX-induced damage in liver and kidney of rats.

Riboflavin and Vitamin E Increase Brain Calcium and Antioxidants, and Microsomal Calcium-ATP-ase Values in Rat Headache Models Induced by Glyceryl Trinitrate

The essential use of riboflavin is the prevention of migraine headaches, although its effect on migraines is considered to be associated with the increased mitochondrial energy metabolism. Oxidative stress is also important in migraine pathophysiology. Vitamin E is a strong antioxidant in nature and its analgesic effect is not completely clear in migraines. The current study aimed to investigate the effects of glyceryl trinitrate (GTN)-sourced exogen nitric oxide (NO), in particular, and also riboflavin and/or vitamin E on involved in the headache model induced via GTN-sourced exogen NO on oxidative stress, total brain calcium levels, and microsomal membrane Ca2+-ATPase levels. GTN infusion is a reliable method to provoke migraine-like headaches in experimental animals and humans. GTN resulted in a significant increase in brain cortex and microsomal lipid peroxidation levels although brain calcium, vitamin A, vitamin C, and vitamin E, and brain microsomal-reduced glutathione (GSH), glutathione peroxidase (GSH-Px), and plasma-membrane Ca2+-ATPase values decreased through GTN. The lipid peroxidation, GSH, vitamin A, β-carotene, vitamin C, and vitamin E, and calcium concentrations, GSH-Px, and the Ca2+-ATPase activities were increased both by riboflavin and vitamin E treatments. Brain calcium and vitamin A concentrations increased through riboflavin only. In conclusion, riboflavin and vitamin E had a protective effect on the GTN-induced brain injury by inhibiting free radical production, regulation of calcium-dependent processes, and supporting the antioxidant redox system. However, the effects of vitamin E on the values seem more important than in riboflavin.

Role of TRPM2 cation channels in dorsal root ganglion of rats after experimental spinal cord injury.

Introduction: We sought to determine the contribution of oxidative stress–dependent activation of TRPM2 and L‐type voltage‐gated Ca2+ channels (VGCC) in dorsal root ganglion (DRG) neurons of rats after spinal cord injury (SCI). Methods: The rats were divided into 4 groups: control; sham control; SCI; and SCI+nimodipine groups. The neurons of the SCI groups were also incubated with non‐specific TRPM2 channel blockers, 2‐aminoethoxydiphenylborate (2‐APB) and N‐(p‐amylcinnamoyl)anthranilic acid (ACA), before H2O2 stimulation. Results:The [Ca2+]i concentrations were higher in the SCI group than in the control groups, although their concentrations were decreased by nimodipine and 2‐APB. The H2O2‐induced TRPM2 current densities in patch‐clamp experiments were decreased by ACA and 2‐APB incubation. In the nimodipine group, the TRPM2 channels of neurons were not activated by H2O2 or cumene hydroperoxide. Conclusions: Increased Ca2+ influx and currents in DRG neurons after spinal injury indicated TRPM2 and voltage‐gated Ca2+ channel activation. Muscle Nerve 48: 945–950, 2013

Curcumin inhibits apoptosis by regulating intracellular calcium release, reactive oxygen species and mitochondrial depolarization levels in SH-SY5Y neuronal cells

Abstract Neurological diseases such as Alzheimer’s and Parkinson’s diseases are incurable progressive neurological disorders caused by the degeneration of neuronal cells and characterized by motor and non-motor symptoms. Curcumin, a turmeric product, is an anti-inflammatory agent and an effective reactive oxygen and nitrogen species scavenging molecule. Hydrogen peroxide (H2O2) is the main source of oxidative stress, which is claimed to be the major source of neurological disorders. Hence, in this study we aimed to investigate the effect of curcumin on Ca2+ signaling, oxidative stress parameters, mitochondrial depolarization levels and caspase-3 and -9 activities that are induced by the H2O2 model of oxidative stress in SH-SY5Y neuronal cells. SH-SY5Y neuronal cells were divided into four groups namely, the control, curcumin, H2O2, and curcumin + H2O2 groups. The dose and duration of curcumin and H2O2 were determined from published data. The cells in the curcumin, H2O2, and curcumin + H2O2 groups were incubated for 24 h with 5 µM curcumin and 100 µM H2O2. Lipid peroxidation and cytosolic free Ca2+ concentrations were higher in the H2O2 group than in the control group; however, their levels were lower in the curcumin and curcumin + H2O2 groups than in the H2O2 group alone. Reduced glutathione (GSH) and glutathione peroxidase (GSH-Px) values were lower in the H2O2 group although they were higher in the curcumin and curcumin + H2O2 groups than in the H2O2 group. Caspase-3 activity was lower in the curcumin group than in the H2O2 group. In conclusion, curcumin strongly induced modulator effects on oxidative stress, intracellular Ca2+ levels, and the caspase-3 and -9 values in an experimental oxidative stress model in SH-SY5Y cells.

Elevated hydrostatic pressures induce apoptosis and oxidative stress through mitochondrial membrane depolarization in PC12 neuronal cells: A cell culture model of glaucoma

Abstract Background: Despite the importance of oxidative stress and apoptosis through mitochondrial depolarization in neurodegenerative diseases, their roles in etiology of glaucoma are poorly understood. We aimed to investigate whether oxidative stress and apoptosis formation are altered in rat pheochromocytoma-derived cell line-12 (PC12) neuronal cell cultures exposed to elevated different hydrostatic pressures as a cell culture model of glaucoma. Materials: Cultured PC12 cells were subjected to 0, 15 and 70 mmHg hydrostatic pressure for 1 and 24 h. Then, the following values were analyzed: (a) cell viability; (b) lipid peroxidation and intracellular reactive oxygen species production; (c) mitochondrial membrane depolarization; (d) cell apoptosis; (e) caspase-3 and caspase-9 activities; (f) reduced glutathione (GSH) and glutathione peroxidase (GSH-Px). Results: The hydrostatic pressures (15 and 70 mmHg) increased oxidative cell damage through a decrease of GSH and GSH-Px values, and increasing mitochondrial membrane potential. Additionally, 70 mmHg hydrostatic pressure for 24 h indicated highest apoptotic effects, as demonstrated by plate reader analyses of apoptosis, caspase-3 and -9 values. Conclusion: The present data indicated oxidative stress, apoptosis and mitochondrial changes in PC12 cell line during different hydrostatic pressure as a cell culture model of glaucoma. This findings support the view that mitochondrial oxidative injury contributes early to glaucomatous optic neuropathy.

Intracellular Ca2+ and antioxidant values induced positive effect on fertilisation ratio and oocyte quality of granulosa cells in patients undergoing in vitro fertilisation

Oxidative stress is important for promoting oocyte maturation and ovulation within the follicle through calcium ion (Ca(2+)) influx. The relationship between antioxidant and cytosolic Ca(2+) levels and oocyte quality and fertilisation rate in the granulosa cells of patients undergoing in vitro fertilisation was investigated. Granulosa cells were collected from 33 patients. Cytosolic free Ca(2+) ([Ca(2+)]i) concentration, lipid peroxidation, reduced glutathione, glutathione peroxidase and oocyte quality were measured in the granulosa cells. The relationship between two drug protocols was also examined (gonadotrophin-releasing hormone antagonist and agonist protocols) and the same parameters investigated. The [Ca(2+)]i concentration (P<0.001), glutathione (P<0.05) and oocyte quality (P<0.001) values were significantly higher in the fertilised group than in the non-fertilised group, although glutathione peroxidase activity was significantly (P<0.05) higher in the non-fertilised group than in the fertilised group. The [Ca(2+)]i concentrations were also higher (P<0.001) in the good-quality oocyte groups than in the poor-quality oocyte group. There was no correlation between the two drug protocols and investigated parameters. In conclusion, it was observed that high glutathione and cytosolic Ca(2+) concentrations in granulosa cells of patients undergoing in vitro fertilisation tended to increase the fertilisation potential of oocytes.

The Importance of Melatonin and Mitochondria Interaction in Mood Disorders and Schizophrenia: A Current Assessment.

Mitochondria play a critical role in regulating cellular functions, such as redox signaling, calcium homeostasis, and apoptosis. Also, mitochondria are crucial for neurogenesis and neuronal functions. Melatonin is an indole analog hormone, which is generally produced by the pineal gland. It plays a vital role in circadian rhythm and act as a powerful antioxidant by scavenging free radicals, immunomodulators, and anticancer agents. Schizophrenia and mood disorders are the two major psychiatric disorders. Disturbances of sleep and circadian rhythms are well-known symptoms of schizophrenia and mood disorders (bipolar disorder, major depression). Since melatonin has a regulator effect on circadian rhythm and sleep quality, it has a close interaction with schizophrenia and mood disorders. Herein, we aimed to summarize the effects of melatonin on mitochondrial activity in schizophrenia and mood disorders.