Effect of Methylsulfonylmethane Pretreatment on Aceta-minophen Induced Hepatotoxicity in Rats.

OBJECTIVE(S): Methylsulfonylmethane (MSM) is a sulfur-containing compound found in a wide range of human foods including fruits, vegetables, grains and beverages. In this study the effect of MSM pretreatment on acetaminophen induced liver damage was investigated. MATERIALS AND METHODS: Male Sprague Dawley rats were pretreated with 100 mg/kg MSM for one week. On day seven rats were received acetaminophen (850 mg/kg, intraperitoneal). Twenty-four hours later, blood samples were taken to determine serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Tissue samples of liver were also taken for the determination of the levels of malondialdehyde (MDA); total glutathione (GSH), superoxide dismutase (SOD), and myeloperoxidase (MPO) activity together with histopathological observations. RESULTS: High dose of acetaminophen administration caused a significant decrease in the GSH level of the liver tissue, which was accompanied with a decrease in SOD activity and increases in tissue MDA level and MPO activity. Serum ALT, AST levels were also found elevated in the acetaminophen-treated group. Pretreatment with MSM for one week was significantly attenuated all of these biochemical indices. CONCLUSION: Our findings suggest that MSM pretreatment could alleviate hepatic injury induced by acetaminophen intoxication, may be through its sulfur donating and antioxidant effects.

Effect of single dose administration of methylsulfonylmethane on oxidative stress following acute exhaustive exercise.

Methylsulfonylmethane (MSM) is a sulfur-containing compound commonly found in diet and known to reduce oxidative stress. This trial was conducted to determine whether single dose supplementation with MSM attenuates post-exercise oxidative stress in healthy untrained young men. Sixteen untrained men volunteered for this study. Participants were randomized in a double-blind placebo-controlled fashion into 2 groups: Methylsulfonylmethane (MSM) (n = 8) and placebo (n = 8). The participants took supplementation or placebo before running on treadmill for 45 min at 75% VO2max. The MSM supplementation was prepared in water as 100 mg/ kg body weight. The placebo group received water. Serum Malondealdehyde (MDA), uric acid, bilirubin, protein carbonyl (PC) and plasma vitamin E levels were determined as the markers of oxidative stress. Plasma GSH (reduced Glutathione) and total antioxidant capacity (TAC) were measured as markers of plasma antioxidant system. MSM supplementation successfully lowered serum PC 2 and 24 h after exercise. Plasma TAC in MSM group was higher at 24 h after exercise. Serum level of uric acid and bilirubin were significantly low immediately after exercise in MSM supplemented group. There was no significant difference between groups in terms of plasma GSH level. These results complement earlier studies showing anti-oxidant effect of MSM and suggest that single dose oral supplementation with MSM lowers exercise induced oxidative stress in healthy untrained young men, but is not adequate to significantly affect plasma GSH level.

Protective effects of methylsulfonylmethane on hemodynamics and oxidative stress in monocrotaline-induced pulmonary hypertensive rats.

Methylsulfonylmethane (MSM) is naturally occurring organic sulfur that is known as a potent antioxidant/anti-inflammatory compound. The aim of this study was to investigate the effect of MSM on hemodynamics functions and oxidative stress in rats with monocrotaline- (MCT-) induced pulmonary arterial hypertension (PAH). Wistar rats were randomly assigned to 38-days treatment. MSM was administered to rats at 100, 200, and 400 mg/kg/day doses 10 days before a single dose of 60 mg/kg, IP, MCT. Hemodynamics of ventricles were determined by Powerlab AD instrument. Blood samples were obtained to evaluate changes in the antioxidative system including activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and the level of reduced glutathione (GSH) and malondialdehyde (MDA). Improvements in cardiopulmonary hemodynamics were observed in the MSM-treated pulmonary arterial hypertensive rats, with a significant reduction in right ventricular systolic pressure (RSVP) and an increase in the mean arterial pressure (MAP). The values of CAT, SOD, GSH-px activities, and GSH were significantly lower in MCT-induced PAH (P < 0.01), but they were recovered to control levels of MSM-treated groups. Our present results suggest that long-term administration of the MSM attenuates MCT-induced PAH in rats through modulation of oxidative stress and antioxidant defense.

MAML1 acts cooperatively with EGR1 to activate EGR1-regulated promoters: implications for nephrogenesis and the development of renal cancer.

Mastermind-like 1 (MAML1) is a transcriptional coregulator of activators in various signaling pathways, such as Notch, p53, myocyte enhancer factor 2C (MEF2C) and beta-catenin. In earlier studies, we demonstrated that MAML1 enhanced p300 acetyltransferase activity, which increased the acetylation of Notch by p300. In this study, we show that MAML1 strongly induced acetylation of the transcription factor early growth response-1 (EGR1) by p300, and increased EGR1 protein expression in embryonic kidney cells. EGR1 mRNA transcripts were also upregulated in the presence of MAML1. We show that MAML1 physically interacted with, and acted cooperatively with EGR1 to increase transcriptional activity of the EGR1 and p300 promoters, which both contain EGR1 binding sites. Bioinformatics assessment revealed a correlation between p300, EGR1 and MAML1 copy number and mRNA alterations in renal clear cell carcinoma and p300, EGR1 and MAML1 gene alterations were associated with increased overall survival. Our findings suggest MAML1 may be a component of the transcriptional networks which regulate EGR1 target genes during nephrogenesis and could also have implications for the development of renal cell carcinoma.

Cytotoxicity of methylsulfonylmethane on gastrointestinal (AGS, HepG2, and KEYSE-30) cancer cell lines.

PURPOSE: This study was conducted to assay cytotoxic effects of methylsulfonylmethane (MSM) on gastrointestinal cancer cell lines. METHODS: Human gastric carcinoma (AGS), human hepatocellular carcinoma (HepG2), and human esophageal squamous cell carcinoma (KYSE-30) cancer cell lines were treated by MSM and incubated for 24, 48, and 72 h. Cytotoxicity was examined through MTT, neutral red uptake, and protein measurement assays. Ethidium bromide/acridine orange (EB/AO) staining was used for apoptotic cell detection. A diamidino-2-phenylindole staining method was used to analysis cell cycle by flow cytometry. RESULTS: IC(50) of MSM on AGS, HepG2, and KYSE-30 cell lines were 28.04, 21.87 and 27.98 mg/ml after 72 h, respectively. The EB/AO staining showed an increase in apoptotic cells. Cell cycle analysis showed a significant increase in cell density at G2/M phase. CONCLUSION: MSM had cytotoxic effect on cancer cell lines but HepG2 cell line was more susceptible. This study suggests that MSM may induce cytotoxic effect on gastrointestinal cancer cell lines by apoptosis and cell cycle arrest.

Riluzole prevents morphine-induced apoptosis in rat cerebral cortex.

Neuronal apoptosis has been shown to be associated with the development of tolerance to morphine. In the present study, we investigated the effect of intracerebroventricular (icv) administration of an inhibitor of glutamate release, riluzole, on morphine-induced apoptosis in the rat cerebral cortex. Various groups of rats received either morphine (intraperitoneally, ip) and vehicle (icv) or morphine (ip) and different doses of riluzole (icv) once per day for 8 days. An in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method was used as an apoptosis assay. Levels of the anti-apoptotic factors Bcl-2 and HSP70 and the pro-apoptotic agent caspase-3 were evaluated by immunoblotting. The glutamate concentration in the cerebral cortex was measured by high performance liquid chromatography (HPLC). The results showed that icv administration of riluzole decreased the number of apoptotic cells in the cerebral cortex compared with the control group, which was treated with morphine (ip) and 1% Tween 80 in 0.9% normal saline (icv). The levels of the anti-apoptotic proteins Bcl-2 and HSP70 were higher in the riluzole groups than in the control. Furthermore, co-administration of riluzole with morphine significantly decreased caspase-3 protein levels and glutamate content of the cerebral cortex compared with the control. In conclusion, we found that icv administration of riluzole attenuates morphine-induced apoptosis in the cerebral cortex after the development of morphine tolerance.

Pharmacological preconditioning with L-carnitine: relevance to myocardial hemodynamic function and glycogen and lactate content.

Carnitine is a vital biologic substance facilitating fatty acids transport into mitochondria for ATP production. This study was to investigate the effects of pre-ischemic pharmacological preconditioning (PC) with L-carnitine (L-Car) on myocardial infarct size and cardiac functions in ischemic and reperfused isolated rat heart and meanwhile on left ventricular glycogen and lactate content. Isolated rat hearts were subjected to 30 min coronary artery occlusion followed by 120 min reperfusion. The hearts (n= 8-12) were perfused with L-Car (0.5-5 mM) only for 15 min before to 10 min after induction of ischemia. Preconditioning of the hearts with L-Car provided concentration-dependent cardioprotection as evidenced by improved postischemic ventricular functional recovery (developed pressure, left ventricular end diastolic pressure and coronary flow rate) and reduced myocardial infarct size (p<0.001). L-Car (2.5 mM) decreased both glycogen (p<0.001) and lactate (p>0.05) content in left ventricle during ischemia compared with the control. The results of this study demonstrate that L-Car pharmacologically precondition the hearts against ischemic and reperfusion injury in part by recovery of postischemic ventricular hemodynamic functions, depletion of glycogen and therefore reduction of lactate accumulation.

Evaluation the effects of dextromethorphan and midazolam on morphine induced tolerance and dependence in mice.

The main aim of this study was to evaluate the effects of dextromethorphan and midazolam and their combination on morphine tolerance and dependence in mice. In the present study, different groups of mice were rendered randomly and received morphine (50 mg kg(-1), s.c.), morphine (50 mg kg(-1), s.c.) + Dextromethorphan (25, 50 and 75 mg kg(-1), i.p.), morphine (50 mg kg(-1), s.c.) + midazolam (0.5, 1 and 2 mg kg(-1), i.p.), morphine (50 mg kg(-1), s.c.) + [Dextromethorphan (25 mg kg(-1), i.p. ) + midazolam (0.5 mg kg(-1), i.p.)] once a day for four days. Tolerance was assessed by administration of morphine (9 mg kg(-1), i.p.) on fifth day. Withdrawal symptoms (markers for dependence) was assessed by administration of naloxone (4 mg kg(-1), i.p.) 2 h after co-administration of morphine with either Dextromethorphan or midazolam or their combination. Results showed that pretreatment with Dextromethorphan or midazolam decreased the degree of tolerance and withdrawal symptoms significantly. Additionally co-administration ofDextromethorphan and midazolam couldn't decreased the tolerance and dependence significantly. From these results it may concluded that Dextromethorphan and midazolam alone or in combination could prevent the development of morphine induced tolerance and dependence. These effects can be related to the N-Methyl-D-Aspartate (NMDA) receptor antagonist behavior of Dextromethorphan and GABA-receptor agonist property of midazolam.

Comparative study of fig tree efficacy in the treatment of common warts (Verruca vulgaris) vs. cryotherapy.

BACKGROUND: A traditional method for the treatment of warts in some rural areas of Iran comprises the use of fig tree (ficus carica) latex as a local treatment; however, there is no scientific evaluation of its efficacy. METHODS: A prospective, open right/left comparative trial of fig tree latex therapy vs. local standard of cryotherapy was carried out. Twenty-five patients with common warts were recruited into the study from an outpatient clinic. The patients were instructed in self-application of fig tree latex to warts on one side of the body. The wart on the opposite side was treated using standard cryotherapy. A 6-month follow-up study was planned. RESULTS: In 11 (44%) of the 25 patients complete resolution of fig tree latex-treated warts was observed. The remaining 14 patients (56%) had a complete cure following cryotherapy. Two patients had complete remission on both sides. Two patients failed to respond to either cryotherapy or fig tree latex. It was found that fig tree latex therapy was marginally less effective than cryotherapy. Adverse effects were observed only in cryo-treated warts. At the 6-month follow-up study there was an 18% recurrence rate. CONCLUSION: Fig tree latex therapy of warts offers several beneficial effects including short-duration therapy, no reports of any side-effects, ease-of-use, patient compliance, and a low recurrence rate. The exact mechanism of the antiwart activity of fig tree latex is unclear but is likely to be the result of the proteolytic activity of the latex enzymes.