The association between PD-1 gene polymorphisms and susceptibility to multiple sclerosis.

Programmed cell death 1 (PD-1) is an immune checkpoint and has been reported to be associated with several autoimmune diseases. We aimed to investigate the association between human PD-1 gene (PDCD1) polymorphisms and multiple sclerosis (MS). This case-control study was conducted on 229 MS patients and 246 healthy controls. Genotyping of rs36084323 (PD-1.1 G/A), rs11568821 (PD-1.3 G/A) and rs2227981 (PD-1.5 C/T) polymorphisms was performed by PCR-RFLP technique. The frequency difference of PD-1.1 genotypes and alleles (-536 G/A) between patients and healthy controls was not significant. Regarding PD-1.3, the AA + AG genotype was found to be relatively higher in the control group. Concerning PD-1.5 (+7785 C/T), the frequency of T allele carriers (TT + CT) was relatively higher in MS patients, which was marginally insignificant (p = .07). PD-1 gene polymorphisms may be associated with MS; however, accurate conclusions require further studies with a larger number of samples.

Association of serum kynurenine/tryptophan ratio with poor glycemic control in patients with type2 diabetes.

PURPOSE: The role of indoleamine 2,3-dioxygenase (IDO) has been shown in insulin resistance and metabolic syndrome. The present study aimed to measure serum IDO activity in patients with type 2 diabetes (T2DM) and to determine its association with glycemic control, oxidative stress, and insulin resistance. METHODS: Seventy-four patients with T2DM and 74 healthy subjects were selected to participate in this study. Fasting serum biochemical parameters including fasting blood sugar (FBS), HbA1c, insulin, uric acid, albumin, tryptophan, kynurenine, and total antioxidant capacity (TAC) were measured. HOMA-IR, QUICKI, and HOMA-B were calculated using serum FBS and insulin values. IDO activity was estimated using kynurenine/tryptophan ratio (KTR). Data were analyzed using SPSS software (Version 15) and p < 0.05 was considered as a significant difference. RESULTS: The findings showed higher levels of FBS, HbA1c, HOMA-IR, and KTR in the patients compared to the controls. TAC and HOMA-B were significantly lowered in the T2DM patients compared to controls. KTR was significantly correlated with the level of HbA1c, and T2DM patients with poor glycemic control (HbA1c ≤ 8) had significantly higher level of KTR. HOMA-B was significantly correlated with serum tryptophan and inversely correlated with HbA1c. CONCLUSION: Serum KTR is increased in T2DM patients with poor glycemic control. Potential clinical implications and possible pathogenic roles of IDO in T2DM development should be further elucidated.

The Protective Effects of Coenzyme Q10 and Lisinopril Against Doxorubicin-Induced Cardiotoxicity in Rats: A Stereological and Electrocardiogram Study.

Doxorubicin (DOX) is used as an anticancer drug despite its several side effects, especially its irreversible impacts on cardiotoxicity. Coenzyme Q10 (Q10) as a powerful antioxidant and lisinopril (LIS) as an angiotensin-converting enzyme inhibitor seem to provide protection against DOX-induced cardiotoxicity. Therefore, this study aimed to assess the cardioprotective effects of Q10 and LIS against DOX-induced cardiotoxicity in rats. Adult male Sprague-Dawley rats were randomly assigned into the control, LIS, Q10, DOX, DOX + LIS, and DOX + Q10 groups. On day 21, ECG was recorded and the right ventricle was dissected for evaluation of catalase activity and malondialdehyde (MDA) concentration. Additionally, the left ventricle and the sinoatrial (SA) node were dissected to assess the stereological parameters. The results of ECG indicated bradycardia and increase in QRS duration and QT interval in the DOX group compared to the control group. Meanwhile, the total volumes of the left ventricle, myocytes, and microvessels and the number of cardiomyocyte nuclei decreased, whereas the total volume of the connective tissue and the mean volume of cardiomyocytes increased in the DOX group. On the other hand, the SA node and the connective tissue were enlarged, while the volume of the SA node nuclei was reduced in the DOX group. Besides, catalase activity was lower and MDA concentration was higher in the DOX-treated group. Q10 could recover most stereological parameters, catalase activity, and MDA concentration. LIS also prevented some stereological parameters and ECG changes and improved catalase activity and MDA concentration in the DOX group. The findings suggested that Q10 and LIS exerted cardioprotective effects against DOX-induced cardiac toxicity.

Synthesis, in vitro biological evaluation and in silico molecular docking studies of novel ß-lactam-anthraquinone hybrids.

Schiff bases from 2-aminoanthraquinone have been prepared by reaction with aldehydes and used to prepare novel ß-lactam-anthraquinone hybrids via [2+2] ketene-imine cycloaddition (Staudinger reaction) reaction. In vitro antibacterial studies of all synthesized compound were carried out against three gram-positive strains Staphylococcus aureus (Methicillin-resistant strain), Enterococcus faecium (Vancomycin-resistant strain) and Bacillus subtilis, and two gram-negative strains Escherichia coli and Pseudomonas aeruginosa. These compounds were further evaluated for their in vitro antifungal activity against Candida albicans, Aspergillus niger and Trichophyton mentagrophytes. Hybrid compounds showed moderate to excellent antibacterial and antifungal activities. Surprisingly, among the tested compounds, some of them revealed equal antibacterial and antifungal properties and even better than standards. In addition, results demonstrated that the new hybrids are very promising antibacterial agents against resistant strains. Also molecular docking studies were carried out by Autodoc software. Penicillin-binding protein 2a (PDB ID: 1VQQ) from methicillin-resistant Staphylococcus aureus strain used as a target which good binding interactions were observed.

Erythrocyte glucose-6-phosphate dehydrogenase activity and risk of gestational diabetes.

PURPOSE: Glucose-6-phosphate dehydrogenase (G6PD) is the regulating enzyme in the pentose phosphate pathway. A link between the activity of G6PD and diabetes mellitus has previously been reported. The association of G6PD activity with the pathogenesis of gestational diabetes mellitus (GDM) has not yet been investigated. The aim of the present study was to investigate the association of erythrocyte G6PD activity with major characteristics of GDM. METHODS: This case-control study was conducted at Hafez Hospital, Shiraz University of Medical Sciences, Shiraz, Iran from March to November 2017. Eighty-four age-matched pregnant women including GDM (n = 33), impaired glucose tolerance (IGT; n = 7), and normal glucose tolerance (NGT; n = 44) subjects were enrolled in this study. The levels of erythrocyte G6PD activity, fasting plasma glucose (FPG), insulin, malondialdehyde (MDA), and ferric reducing power (FRAP) of serum were measured. The level of homeostasis model for the assessment of insulin resistance (HOMA-IR) was calculated. The data were analyzed using SPSS software. P < 0.05 was considered statistically significant. RESULTS: The values of FPG, insulin, HOMA-IR, G6PD activity, and FRAP were significantly higher in GDM patients compared to NGT subjects. G6PD activity was correlated with FPG ((r = 0.224; P = 0.041). Binary logistic regression analysis revealed independent association of body mass index >25.88 [OR = 3.23, 95% CI 1.071-9.75, P = 0.037], HOMA- IR >2.33 [OR = 7.15, 95% CI 2.26-22.56, P < 0.001], and G6PD activity>21.17 U/g Hb [OR = 4.63, 95% CI 1.49-14.38, P = 0.008] with an increased risk of GDM. No significant change was observed among serum MDA levels in the three groups. CONCLUSION: The findings demonstrate that increased G6PD activity is positively associated with the risk of GDM.

Sodium valproate ameliorates aluminum-induced oxidative stress and apoptosis of PC12 cells.

OBJECTIVES: According to recent studies, valproate shows some protection against oxidative stress (OS) induced by neurotoxins. Current investigation tried to determine the possible ameliorating effects of sodium valproate (SV) against aluminum (Al)-induced cell death, apoptosis, mitochondrial membrane potential (MMP), and OS in PC12 cells. MATERIALS AND METHODS: In this in vitro study, PC12 cells were treated with different concentrations of aluminum maltolate (Almal) with and without SV (50-400 µM). Cell viability was assessed by MTT assay. To measure quantitatively the effects of SV on Al-induced apoptosis and reactive oxygen species (ROS), flowcytometry using 7AAD/annexin-V and 2', 7'-dichlorofluorescein diacetate staining were employed, respectively. MMP was monitored using the retention of rhodamine 123. Catalase (CAT) activity was assayed by the rate of decomposition of hydrogen peroxide. RESULTS: Exposure of PC12 cells for 48 hr to Almal (125-2000 µM) significantly reduced cell viability (IC50=1090 µM), increased ROS generation and apoptosis, and reduced MMP and CAT activity. SV reduced the Almal-induced cell death and apoptosis. Furthermore, the effects of Almal on ROS generation, catalase activity, and MMP reduction were significantly diminished by SV. CONCLUSION: Data from this study suggest that SV can inhibit Al-induced cell death and apoptosis of PC12 cells via ameliorating OS.

Serum ischemia modified albumin is a possible new marker of oxidative stress in phenylketonuria.

The role of oxidative stress in the pathogenesis of phenylketonuria (PKU)-associated disorders has been implicated. Ischemia modified albumin (IMA) is a modified form of serum albumin, which is produced under the conditions of oxidative stress. The aim of this study was to measure the serum level of IMA in the PKU patients and to investigate its ability in predicting the status of oxidative stress in these patients. Fifty treated-PKU patients and fifty age- and sex-matched healthy subjects were included in the study. The blood samples were obtained and the serum level of phenylalanine (Phe) was measured using reverse phase HPLC method. The levels of IMA, malondialdehyde (MDA), gamma-glutamyl transferase (GGT) activity, and uric acid (UA) were determined using colorimetric methods. The levels of serum Phe, IMA, and MDA were significantly higher (p < 0.001) and the level of UA (p < 0.05) was lower in the PKU patients compared to control group. Serum IMA level was positively correlated with MDA (r = 0.585, p < 0.001) and UA (r = 0.6, p < 0.001). An inverse relationship was observed between the serum level of IMA and Phe (r = - 0.410, p < 0. 01). Results of the present study suggest that serum IMA level could be used as a novel marker for the evaluation of oxidative stress in the PKU patients.

Evaluation of Antioxidant Potentials and α-Amylase Inhibition of Different Fractions of Labiatae Plants Extracts: As a Model of Antidiabetic Compounds Properties.

In an attempt to identify herbal drugs which may become useful in the prevention of diabetes, antioxidant potentials and α-amylase inhibition by the ethanol extracts of two plants belonging to Lamiaceae family, Otostegia persica and Zataria multiflora, and their different fractions were studied. Also, inhibition of α-amylase by Salvia mirzayanii and its fractions was evaluated. All of the samples exhibited antioxidant activities, among which ethyl acetate fraction of Zataria multiflora (17.21 ± 0.17 mg GAE/g) was found to contain the highest amounts of phenols and the ethyl acetate fraction of Zataria multiflora (218 ± 2.76 mg QUE/g) had the most values of flavonoids. Ethyl acetate fraction of Zataria multiflora (IC50 = 3.05 ± 0.51 µg/ml) was shown to have the most reducing power and the ethyl acetate fraction of Zataria multiflora (IC50 = 32.17 ± 1.82 µg/ml) exhibited the highest DPPH radical scavenging. The ethyl acetate fraction of Otostegia persica (99.39 ± 0.94%) showed the highest α-amylase inhibitory activity which was similar to acarbose used as a standard. Mode of α-amylase inhibition of the most samples was uncompetitive except for ZMC, OPP, OPC, and SMP which presented competitive inhibition. The present findings showed that studied samples may have some compounds with antioxidant and antidiabetic effects.

Functional Promoter Polymorphisms of MMP-2 C-735T and MMP-9 C-1562T and Their Synergism with MMP-7 A-181G in Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system. Matrix metalloproteinases (MMPs) play an important role in breakdown of blood-brain barrier, transmigration, and invasion of immune cells and formation of MS lesions. The aim of present study was to investigate the influence of MMP-2 C-735T and MMP-9 C-1562T variants and their synergism with MMP-7 A-181G on susceptibility to MS. In a case-control study 125 MS patients and 235 healthy individuals from Western Iran were investigated. The various genotypes of MMP-2, MMP-9, and MMP-7 were detected using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). In females the presence of MMP-2 C allele was associated with an increased risk of MS (OR = 1.69, p = 0.041). No significant difference was detected between the frequency of MMP-9 T allele in MS patients (8.2%) and controls (12.8%, p = 0.068). The concomitant presence of both MMP-2 C and MMP-7 G alleles was associated with 1.82-fold increased risk of MS (p = 0.002). Also, a synergism was detected between MMP-9 C and MMP-7 G alleles that elevated the risk of MS by 1.5-times (p = 0.035). The presence of haplotype MMP-9 T, MMP-7 G, and MMP-2 C (TGC) compared to haplotype CAG increased the risk of MS by 3.13-fold (p = 0.16). The present study suggests that gene-gene interactions and variants of more genes instead of single gene might play a role in susceptibility to MS. We indicated that synergism between variants of MMP-2, MMP-7, and MMP-9 genes might increase the risk of MS.

The status of antioxidants, malondialdehyde and some trace elements in serum of patients with breast cancer.

BACKGROUND: There are studies that indicated dyshomeostasis of oxidant/antioxidant and trace elements in breast cancer patients, but the data regarding the status of these parameters in various stages of breast cancer are limited. The aim of this study was to highlight the status of these biochemical factors in various stages of breast cancer. METHODS: Fifty-eight breast cancers patients participated in this study and underwent staging work up for the assessment of disease stage. Serum total antioxidant capacity and lipid peroxidation were determined spectrophotometically. Glutathione peroxidase (GPX), catalase (CAT) and superoxide dismutase (SOD) levels were analyzed by ELISA method. The serum level of Cu, Mn and Zn was measured by atomic absorption spectrophotometer. Student t-test and one-way analysis of variance (ANOVA) were used to compare group means. RESULTS: All the patients included in the study classified as mild (stages I+II) and advanced stages (stages III+IV). Patients in advanced stage had lower serum antioxidant capacity and higher lipid peroxidation levels, but the differences were not statistically differet (P=0.690 and 0.666, respectively). Patients in advanced stage had higher, but not statistically different serum levels of CAT, GPX and SOD levels (p>0.05). Patients in both groups had to some extent similar serum Cu, Mn and Zn levels. CONCLUSION: There was no evidence of remarkable discrepancy in the status of analyzed factors in various stages of breast cancer. It seems that the severity of oxidative stress in different stages of breast cancer is similar to some extent.

AT1R A1166C variants in patients with type 2 diabetes mellitus and diabetic nephropathy.

BACKGROUND: There are inconsistent reports related to the role of angiotensin II type 1 receptor (AT1R) on the risk of type 2 diabetes mellitus (T2DM) and its renal complications. OBJECTIVES: To identify the association between AT1R A1166C variants with the risk of T2DM and also with diabetic nephropathy (DN). PATIENTS AND METHODS: In a case-control study, the AT1R A1166C polymorphism was detected in 135 T2DM patients with and without DN and in 98 healthy subjects from Western Iran. The genotypes of AT1R A1166C polymorphism were detected using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: The frequencies of AT1R A1166C genotypes and alleles were not significantly difference between patients with and without DN and controls. The frequencies of rare allele of 1166 C were 10%, 16.5%, 15.9% and 15.3% in micro-, macro- and normo-albuminuric patients and in healthy individuals, respectively ( P > 0.05). The systolic blood pressure and serum creatinine level in DN patients were significantly higher in carriers of AT1R CC compared to carriers of AT1R AA genotype. In the presence of uncontrolled hyperglycemia (HbA1c > 7.5%), there was a trend toward increased risk of macro-albuminuria in carriers of AC+CC genotype (OR=3.66, [95% CI: 0.81-16.58], P = 0.092). CONCLUSIONS: Our study indicated the absence of an association between AT1R A1166C polymorphism with the risk of T2DM and DN. It seems in carriers of AT1R C allele systolic blood pressure and serum creatinine level to be higher compared to the A allele carriers.

Altered expression of alpha 2 beta 1 integrin in kidney fibroblasts: a potential mechanism for CsA-induced nephrotoxicity.

BACKGROUND: Nephrotoxicity is considered a significant cause of patient morbidity following chronic Cyclosporine A (CsA) treatment.  The exact mechanism of CsA-induced nephrotoxicity remains to be fully clarified.  Tubulointerstitial fibrosis is widely regarded as a major pathway of CsA toxicity; therefore, the role of integrins as regulators of collagen in the extra-cellular matrix can be deemed pivotal. The objective of the present study was to observe the expression levels of alpha2beta1 integrin following CsA treatment +/- antioxidants. METHODS: Adhesion assay, immunofluorescent and flow cytometric analyses were performed on kidney fibroblasts obtained from rats after administration of CsA (25 mg/kg/day) +/- Vitamin E (vit. E) and Quercetin (Q) for 4 weeks.  Total RNA was collected from the aforementioned fibroblasts for semi-quantitative reverse transcriptase-polymerase chain reaction analysis of α2 and ß1 integrins. RESULTS: We found that α2 and ß1 integrins were both markedly reduced following treatment with CsA, i.e., 25% and 13%, respectively, but were normal following subsequent consumption of the antioxidants vit. E and Q.  Attachment and spreading of the CsA-treated fibroblasts declined from 82% to 50%; however, this effect was partially reversed to 70% following antioxidant treatment. Similar results were observed in the spreading assay in which the level of spreading decreased from 73% to 21% and was subsequently restored to 46%. CONCLUSION: We conclude that cell adhesion, mediated by binding of integrin to collagen, which is a prerequisite of normal cell viability and collagen regulation, may be a novel pathway further explaining the nephrotoxic effects of CsA.

eNOS 4a/b polymorphism and its interaction with eNOS G894T variants in type 2 diabetes mellitus: modifying the risk of diabetic nephropathy.

To investigate the possible association between eNOS 4a/b polymorphism and the risk of developing type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) 173 T2DM patients with and without DN and 101 healthy subjects with ethnic background of Kurds were examined for the frequency of eNOS variants using PCR-RFLP method. The frequency of eNOS 4a/b genotypes between T2DM and controls was not significantly difference. Studying eNOS 4a/b variants alone indicated that the presence of eNOS 4a allele was not associated with the risk of developing DN. However, considering both polymorphisms of eNOS 4a/b and G894T indicated that the risk of macroalbuminuria significantly increased in the presence of either eNOS 4a or 894T allele by 2.45 times (p=0.014) and 3.7-fold (p=0.016), respectively. However, the concomitant presence of both alleles was not associated with the risk of macroalbuminuria. In microalbuminuric patients, in the presence of each allele, the risk of microalbuminuria increased 2.2 times (p=0.028) and 2.72-fold (p=0.057) for eNOS 4a and 894T alleles, respectively. However, the combined presence of both eNOS 894T and 4a alleles was not associated with the risk of microalbuminuria. The present study indicates the absence of association between eNOS 4a/b variants and the risk of developing T2DM and DN. Also, we demonstrated that eNOS 4a or 894T allele alone increased the risk of developing DN but this effect was modified by the concomitant presence of both alleles.

Role of music in morphine rewarding effects in mice using conditioned place preference method.

OBJECTIVES: This research aims at studying the neuroendocrine effects of music on creating morphine dependence in mice using conditioned place preference (CPP). METHODS: The mice treated with 10 mg/kg morphine subcutaneously, fast music and slow music. Morphine was used to create dependence. In order to recognize the morphine rewarding effects, CPP technique was used. In the conditioning stage that lasted for 8 days, different groups of mice, after receiving the treatment were randomly placed in compartment for 30 minutes. The post-conditioning stage included the fourth day, the ninth day, the 12th day and the 16th day. RESULTS: Comparing place preference between morphine group and the control group, a significant increase (p<0.05) was observed in the place preference of morphine group, while a significant decrease (p<0.05) was demonstrated in the place preferences of morphine + taxi girl music group compared with morphine group alone. In addition morphine + alone in the rain music group demonstrated a significantly increased conditioned place preference (p<0.05) compared with the morphine group. CONCLUSIONS: Alone in the rain music acts as a positive pleasant emotion increasing the dopaminergic activity in the Nucleus Accumbens (NAc) and Ventral Tegmental Area (VTA) and through associated learning mechanisms of reward-related behavior increases morphine addiction. However, taxi girl music may act as unpleasant experiences producing negative emotions and reducing morphine addiction.

Association of CD1A +622 T/C, +737 G/C and CD1E +6129 A/G genes polymorphisms with multiple sclerosis.

Antibodies and specific T cells to glycolipids have been found in MS patients. CD1 molecules are involved in presentation of lipid antigens to T-cells. Therefore, functional polymorphisms in two CD1 genes (+622 T/C and +737 G/C in CD1A along with +6129 A/G in CD1E) might be associated with susceptibility to MS. First, 351 MS patients and 342 controls were enrolled in this study. Allele-specific oligonucleotide polymerase chain reaction and PCR-RFLP methods were used for genotyping. The frequency of CD1A genotypes was not different between cases and controls. However, investigating females, the frequency of CD1A*01 allele was significantly higher in patients with PP-MS compared to controls (p = 0.028) as well as to RR-MS and SP-MS (p = 0.042 and 0.021, respectively). The distribution of CD1E +6129 A allele (CD1E*01) and CD1E*01/01 genotype is more frequent in normal controls in comparison with MS patients (p = 0.001 and p = 0.0003, respectively). In addition, after categorization of study groups according to disease types, differences between alleles and genotypes of CD1E gene polymorphism remained significant for RR-MS patients compared to those of normal controls (p = 0.0001 and p = 0.0003, respectively). CD1E and CD1A genes may be involved in networks which determine susceptibility to RR-MS and PP-MS, respectively.

Pre- and post-treatment of streptozocin administered rats with melatonin: effects on some hepatic enzymes of carbohydrate metabolism.

BACKGROUND: Melatonin, found in high concentrations in the pineal gland, organs within the digestive system and in some plants and fungi, acts as an antioxidant which decreases reactive oxygen species in streptozocin-induced diabetic rats, raises insulin secretion by the pancreatic beta-cells and increases the number of insulin receptors on hepatocyte membranes. METHODS: The protective and therapeutic effects of melatonin feeding in streptozocin-induced diabetic rats were studied. Streptozocin administered rats were gavaged with melatonin, pre- and post-treatment, at a level of 5 mg/kg body weight daily for a period of 15 days. Levels of plasma glucose, cholesterol, triacylglycerol, oral glucose tolerance test, and some hepatic enzymes of carbohydrate metabolism including insulin inducible glucokinase, hexokinase and glucose 6-P dehydrogenase were measured using standard methods and compared with the values in normoglycemic and diabetic control groups. RESULTS: Both pre- and post-treatment of the streptozocin administered rats with melatonin normalized plasma glucose, cholesterol, and triacylglycerol, improved oral glucose tolerance test and increased hepatic glucokinase, hexokinase and glucose 6-P dehydrogenase specific activities to the levels seen in normal rats. CONCLUSION: Melatonin pre-treatment prevents the injurious effects of streptozocin in rats. In streptozocin induced diabetic animals, post-treatment with this antioxidant normalizes both blood and liver constituents which were ameliorated by streptozocin.

Protective effects of a combination of quercetin and vitamin E against cyclosporine A-induced oxidative stress and hepatotoxicity in rats.

AIM: Cyclosporine A (CsA) is the most widely used immunosuppressive drug in transplant surgery. It is able to generate reactive oxygen species (ROS) and cause lipid peroxidation (thiobarbituric acid-reacting substances [TBARS]), which will directly result in CsA hepatotoxicity. METHODS: In this study, the potential of quercetin (Q) and vitamin E (E), in attenuating CsA-induced liver dysfunction in rats was investigated. Male Sprague-Dawley rats were divided into six groups and treated with either olive oil, ethanol + olive oil, CsA, CsA + E, CsA + Q, or CsA + E + Q for both 4 and 8 weeks. Hepatotoxicity was assessed by morphological alterations in tissue architecture and by reduced serum total protein and increased serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. RESULTS: The results indicated that CsA treatment increases TBARS and decreases activities of catalase (CAT) and glutathione peroxidase (GPx) in the rat liver. The co-administration of E and Q with CsA treatment improved both liver morphology changes and function. A combination of these antioxidants significantly reduced TBARS and increased CAT and GPx activities in the hepatic tissue. CONCLUSION: Our data demonstrates that E + Q plays a protective role against the imbalance elicited by CsA between the production of free radicals and antioxidant defence systems, and suggests that a combination of these two antioxidants may find clinical application where cellular damage is a consequence of ROS.

Comparison of the effects of vitamin E and/or quercetin in attenuating chronic cyclosporine A-induced nephrotoxicity in male rats.

1. The aim of the present study was to investigate the effects of vitamin E and/or quercetin (Q) on renal function, oxygen radical concentrations in the kidney and some anti-oxidant enzyme activities in rats treated with cyclosporine A (CsA). 2. Groups of rats (270 +/- 15 g), on standard rat chow and water, received all their treatments by gavage for either 4 or 8 weeks. Control groups received either olive oil (0.5 mL) or 25% ethanol (0.5 mL) + olive oil (0.5 mL) per day as vehicle. All experimental groups received 25 mg CsA/kg per day in 0.5 mL olive oil. The vitamin E group received 100 mg vitamin E/kg per day in olive oil in addition to CsA treatment. The quercetin group received 15 mg of Q/kg per day in 0.5 mL of 25% ethanol in addition to CsA treatment. The vitamin E + quercetin group received the two anti-oxidants at the concentrations given in addition to CsA treatment. 3. Quercetin, at a concentration less than one-quarter of vitamin E, was more efficient in lowering blood urea nitrogen, serum creatinine and kidney malondialdehyde in CsA-treated rats. However, neither of the two anti-oxidants was able to normalize these analytes to control values after either 4 or 8 weeks treatment. 4. Quercetin (50 micromol/kg per day) elevated all renal anti-oxidant enzyme activities to values observed in the negative controls. However, vitamin E (232 micromol/kg per day) only normalized glutathione peroxidase activity at the end of either 4 or 8 weeks treatment. Combination treatment with the two anti-oxidants abolished all the ill-effects of CsA. 5. Combination treatment with the two anti-oxidants of renal transplant patients receiving CsA may be beneficial in ameliorating the chronic nephrotoxic effects of the important immunosuppressive drug CsA.

IL-8 (-251 A/T) and CXCR2 (+1208 C/T) gene polymorphisms and risk of multiple sclerosis in Iranian patients.

IL-8 plays important roles in CNS development, modulation of neuronal survival and excitability. Among IL-8 receptors, only CXCR2 is known to be present in the brain. The ability of individuals in producing IL-8 is partially determined by IL-8 -251 A/T polymorphism. Therefore, the aim of the present study was to investigate the association between IL-8 -251 A/T and CXCR2 +1208 C/T gene polymorphisms and susceptibility to multiple sclerosis (MS). Two hundred and twenty-three MS patients and 319 healthy and ethnic matched controls were included in this study. IL-8 promoter (-251 A/T) and CXCR2 (+1208 C/T) gene polymorphisms were genotyped via allele specific PCR (AS-PCR) method. A significant difference was found in IL-8 -251 A/T polymorphism between MS patients and controls (p = 0.04). This deference was a result of a higher incidence of the low producer allele of IL-8 (T allele) in MS patients compared to controls. However, there was no significant association between different clinical findings (EDSS score, progression index, disease onset age, and the type of disease) and IL-8 -251 A/T polymorphism. Furthermore, no significant association existed between CXCR2 +1208 C/T polymorphism and MS susceptibility or different clinical parameters in patients. In summary, carriers of IL-8 -251 T allele may have increased susceptibility to MS because of their differences in neuron survival or increased chances of viral persistence compared to carriers of A allele.

Prohibitin attenuates insulin-stimulated glucose and fatty acid oxidation in adipose tissue by inhibition of pyruvate carboxylase.

Prohibitin (PHB-1) is a highly conserved protein involved in mitochondrial biogenesis and function. It is secreted in lipid droplets from adipocytes and is present in the circulation. In adipose tissue it functions as a membrane receptor and can target binding partners to the mitochondria. Here we report that PHB-1 has a hitherto undescribed role as an inhibitor of pyruvate carboxylase (PC). As a consequence, it can modulate insulin-stimulated glucose and fatty acid oxidation. It had no effect on insulin-stimulated 2-deoxglucose uptake by isolated adipocytes but inhibited insulin-stimulated oxidation of [14C]glucose with a half-maximal concentration of approximately 4 nM. It also inhibited oleic acid oxidation in glucose-depleted adipocytes via depletion of oxaloacetate. In vitro experiments using broken-cell assays confirmed that PHB-1 inhibited PC. MALDI-TOF analysis of proteins identified by cross-linking of PHB-1 to adipocyte membranes indicated that PHB-1 is closely associated with PC and EH domain 2 (EHD2). On the basis of these data, we propose that PHB-1 is recycled between the extracellular space and the mitochondria by a mechanism involving lipid rafts and EHD2 and can modulate mitochondrial fuel metabolism by inhibition of PC.