Effect of Methylsulfonylmethane on Paraquat-Induced Acute Lung and Liver Injury in Mice.
Department of Pharmacology, School of Medicine, Ardabil University of Medical Sciences, P.O. Box 5618953141, Ardabil, Iran, email@example.com.
Methylsulfonylmethane (MSM) is a natural organosulfur compound that exhibits antioxidative and anti-inflammatory effects. This study was carried out to investigate the effect of MSM on paraquat (PQ)-induced acute lung and liver injury in mice. A single dose of PQ (50 mg/kg, i.p.) induced acute lung and liver toxicity. Mice were treated with MSM (500 mg/kg/day, i.p.) for 5 days. At the end of the experiment, animals were euthanized, and lung and liver tissues were collected for histological and biochemical analysis. Tissue samples were used to determine malondialdehyde (MDA), myeloperoxidase (MPO), catalase (CAT), superoxide dismutase (SOD), glutathione (GSH), and tumor necrosis factor-α (TNF-α) levels. Blood samples were used to measure plasma alanine transaminase (ALT), γ-glutamyl transferase (GGT), and alkaline phosphatase (ALP). Histological examination indicated that MSM decreased lung and liver damage caused by PQ. Biochemical results showed that MSM treatment significantly reduced tissue levels of MDA, MPO, and TNF-α, while increased the levels of SOD, CAT, and GSH compared with PQ group. MSM treatment also significantly reduced plasma levels of ALT, GGT, and ALP.
These findings suggest that MSM as a natural product attenuates PQ-induced pulmonary and hepatic oxidative injury.
Hepatoprotective effect of methylsulfonylmethane against carbon tetrachloride-induced acute liver injury in rats.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Ein Helwan, Cairo, Egypt, firstname.lastname@example.org.
This study evaluated the effect of methylsulfonylmethane (MSM) on carbon tetrachloride (CCl4)-induced acute liver injury in rats. A single injection of CCl4 (2 ml/kg, i.p.) increased serum aminotransferases (ALT and AST) activities. In addition, CCl4 treatment led to elevation of hepatic malondialdehyde (MDA) content as well as decrease in superoxide dismutase (SOD) and catalase (CAT) activities. Furthermore, cytochrome P450 2E1 (CYP2E1) content was suppressed while proinflammatory cytokines tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels increased in liver tissue after CCl4 administration. We showed that acute CCl4-induced damage was accompanied by a rise in Bax/Bcl2 ratio indicating apoptosis. Pre-treatment with MSM (400 mg/kg) inhibited the increases of serum ALT and AST activities, decreased hepatic MDA, TNF-α, IL-6 and Bax/Bcl2 ratio compared to CCl4 treated group. On the other hand, MSM raised SOD and CAT activities as well as CYP2E1 level in liver tissues.
The present study shows that MSM possesses a hepatoprotective effect against CCl4-induced liver injury in rats. This protective effect might be through its antioxidant, anti-inflammatory and antiapoptotic properties.
MSM enhances GH signaling via the Jak2/STAT5b pathway in osteoblast-like cells and osteoblast differentiation through the activation of STAT5b in MSCs.
Joung YH, Lim EJ, Darvin P, Chung SC, Jang JW, Do Park K, Lee HK, Kim HS, Park T, Yang YM.
Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul, Republic of Korea.
Methylsulfonylmethane (MSM) is a naturally occurring sulfur compound with well-known anti-oxidant properties and anti-inflammatory activities. But, its effects on bone are unknown. Growth hormone (GH) is regulator of bone growth and bone metabolism. GH activates several signaling pathways such as the Janus kinase (Jak)/signal transducers and activators of transcription (STAT) pathway, thereby regulating expression of genes including insulin-like growth factor (IGF)-1. GH exerts effects both directly and via IGF-1, which signals by activating the IGF-1 receptor (IGF-1R). In this study, we investigated the effects of MSM on the GH signaling via the Jak/STAT pathway in osteoblasts and the differentiation of primary bone marrow mesenchymal stem cells (MSCs). MSM was not toxic to osteoblastic cells and MSCs. MSM increased the expression of GH-related proteins including IGF-1R, p-IGF-1R, STAT5b, p-STAT5b, and Jak2 in osteoblastic cells and MSCs. MSM increased IGF-1R and GHR mRNA expression in osteoblastic cells. The expression of MSM-induced IGF-1R and GHR was inhibited by AG490, a Jak2 kinase inhibitor. MSM induced binding of STAT5 to the IGF-1R and increased IGF-1 and IGF-1R promoter activities. Analysis of cell extracts by immunoprecipitation and Western blot showed that MSM enhanced GH-induced activation of Jak2/STAT5b. We found that MSM and GH, separately or in combination, activated GH signaling via the Jak2/STAT5b pathway in UMR-106 cells. Using siRNA analysis, we found that STAT5b plays an essential role in GH signaling activation in C3H10T1/2 cells. Osteogenic marker genes (ALP, ON, OCN, BSP, OSX, and Runx2) were activated by MSM, and siRNA-mediated STAT5b knockdown inhibited MSM-induced expression of osteogenic markers. Furthermore, MSM increased ALP activity and the mineralization of MSCs.
Taken together, these results indicated that MSM can promote osteogenic differentiation of MSCs through activation of STAT5b.
PMID: 23071812, PMCID: PMC3469535
Methylsulfonylmethane (MSM) has been reported to provide anti-inflammatory and antioxidant effects in both animal and man. Strenuous resistance exercise has the potential to induce both inflammation and oxidative stress. Using a pilot (proof of concept) study design, we determined the influence of MSM on markers of exercise recovery and performance in healthy men.
Eight, healthy men (27.1 ± 6.9 yrs old) who were considered to be moderately exercise-trained (exercising <150 minutes per week) were randomly assigned to ingest MSM at either 1.5 grams per day or 3.0 grams per day for 30 days (28 days before and 2 days following exercise). Before and after the 28 day intervention period, subjects performed 18 sets of knee extension exercise in an attempt to induce muscle damage (and to be used partly as a measure of exercise performance). Sets 1-15 were performed at a predetermined weight for 10 repetitions each, while sets 16-18 were performed to muscular failure. Muscle soreness (using a 5-point Likert scale), fatigue (using the fatigue-inertia subset of the Profile of Mood States), blood antioxidant status (glutathione and Trolox Equivalent Antioxidant Capacity [TEAC]), and blood homocysteine were measured before and after exercise, pre and post intervention. Exercise performance (total work performed during sets 16-18 of knee extension testing) was also measured pre and post intervention.
Muscle soreness increased following exercise and a trend was noted for a reduction in muscle soreness with 3.0 grams versus 1.5 grams of MSM (p = 0.080), with a 1.0 point difference between dosages. Fatigue was slightly reduced with MSM (p = 0.073 with 3.0 grams; p = 0.087 for both dosages combined). TEAC increased significantly following exercise with 3.0 grams of MSM (p = 0.035), while homocysteine decreased following exercise for both dosages combined (p = 0.007). No significant effects were noted for glutathione or total work performed during knee extension testing (p > 0.05).
MSM, especially when provided at 3.0 grams per day, may favorably influence selected markers of exercise recovery. More work is needed to extend these findings, in particular using a larger sample of subjects and the inclusion of additional markers of exercise recovery and performance.
PMID: 23013531, PMCID: PMC3507661
Methylsulfonylmethane suppresses breast cancer growth by down-regulating STAT3 and STAT5b pathways.
Lim EJ, Hong DY, Park JH, Joung YH, Darvin P, Kim SY, Na YM, Hwang TS, Ye SK, Moon ES, Cho BW, Do Park K, Lee HK, Park T, Yang YM.
Department of Pathology, School of Medicine, and Institute of Biomedical Science and Technology, Konkuk University Glocal Campus, Seoul, South Korea.
Breast cancer is the most aggressive form of all cancers, with high incidence and mortality rates. The purpose of the present study was to investigate the molecular mechanism by which methylsulfonylmethane (MSM) inhibits breast cancer growth in mice xenografts. MSM is an organic sulfur-containing natural compound without any toxicity. In this study, we demonstrated that MSM substantially decreased the viability of human breast cancer cells in a dose-dependent manner. MSM also suppressed the phosphorylation of STAT3, STAT5b, expression of IGF-1R, HIF-1α, VEGF, BrK, and p-IGF-1R and inhibited triple-negative receptor expression in receptor-positive cell lines. Moreover, MSM decreased the DNA-binding activities of STAT5b and STAT3, to the target gene promoters in MDA-MB 231 or co-transfected COS-7 cells. We confirmed that MSM significantly decreased the relative luciferase activities indicating crosstalk between STAT5b/IGF-1R, STAT5b/HSP90α, and STAT3/VEGF. To confirm these findings in vivo, xenografts were established in Balb/c athymic nude mice with MDA-MB 231 cells and MSM was administered for 30 days. Concurring to our in vitro analysis, these xenografts showed decreased expression of STAT3, STAT5b, IGF-1R and VEGF. Through in vitro and in vivo analysis, we confirmed that MSM can effectively regulate multiple targets including STAT3/VEGF and STAT5b/IGF-1R. These are the major molecules involved in tumor development, progression, and metastasis. Thus, we strongly recommend the use of MSM as a trial drug for treating all types of breast cancers including triple-negative cancers.
PMID: 22485142, PMCID: PMC3317666
Efficacy of methylsulfonylmethane supplementation on osteoarthritis of the knee: a randomized controlled study.
Debbi EM, Agar G, Fichman G, Ziv YB, Kardosh R, Halperin N, Elbaz A, Beer Y, Debi R.
Department of Orthopedics, Assaf Harofeh Medical Center, Zerifin, Israel. email@example.com
Patients with osteoarthritis (OA) take a variety of health supplements in an attempt to reduce pain and improve function. The aim of this study was to determine the efficacy of methylsulfonylmethane (MSM) in treating patients with knee OA.
This study was a prospective, randomized, double-blind, controlled clinical trial. Forty nine men and women 45-90 (mean 68 ± SD 7.3) years of age with knee OA according to the American College of Rheumatology clinical criteria for OA of the knee and with radiographic confirmed knee OA were enrolled in the study and randomly assigned into 2 groups: One received MSM in doses of 1.125 grams 3 times daily for 12 weeks and the other received a placebo in the same dosing frequency. The primary outcomes were the WOMAC Osteoarthritis Index for pain, stiffness and physical function, the Aggregated Locomotor Function (ALF) test that evaluates each patient’s physical function, the SF-36 quality of life health survey and the visual-analogue-scale (VAS) for pain. The secondary outcomes were Knee Society Clinical Rating System for Knee Score (KSKS) and Function Score (KSFS). Patients were assessed at baseline, 6 weeks and 12 weeks. All continuous variables were tested by the Kolmogorov-Smirnov test for Normal distribution. Changes within the groups and differences between the groups were calculated by repeated measures of analysis (ANOVA) with one nested variable.
There were significant differences between treatment groups over time in WOMAC physical function (14.6 mm [CI: 4.3, 25.0]; p = 0.04) and in WOMAC total score (15.0 mm [CI: 5.1, 24.9]; p = 0.03). Treatment groups did not differ significantly in WOMAC pain (12.4 mm [CI: 0.0, 24.8]); p = 0.08) or WOMAC stiffness (27.2 mm [CI: 8.2, 46.2]; p = 0.08). There was a non-significant difference in SF-36 total score between treatment groups (11.6 [CI: 1.0, 22.1]; p = 0.54). A significant difference was found between groups in VAS for pain (0.7 s [CI: -0.9, 2.4]; p = 0.05). Secondary outcomes showed non-significant differences between the two groups.
Patients with OA of the knee taking MSM for 12 weeks showed an improvement in pain and physical function. These improvements, however, are small and it is yet to be determined if they are of clinical significance.
PMID: 21708034, PMCID: PMC3141601
The anti-inflammatory effects of methylsulfonylmethane on lipopolysaccharide-induced inflammatory responses in murine macrophages.
Kim YH, Kim DH, Lim H, Baek DY, Shin HK, Kim JK.
Center for Efficacy Assessment and Development of Functional Foods and Drugs, Hallym University, Korea.
Methylsulfonylmethane (MSM), also known as dimethyl sulfone and methyl sulfone, is an organic sulfur-containing compound that occurs naturally in a variety of fruits, vegetables, grains, and animals, including humans. In the present study, we demonstrated the anti-inflammatory effects of MSM in lipopolysaccharide (LPS)-stimulated murine macrophages, RAW264.7 cells. MSM significantly inhibited the release of nitric oxide and prostaglandin E(2) by alleviating the expression of inducible nitric oxide synthase and cyclooxygenase-2 in LPS-stimulated RAW264.7 cells. Furthermore, the levels of interleukin-6 and tumor necrosis factor-alpha were decreased by MSM treatment in cell culture supernatants. Further study indicated that the translocation of the p65 subunit of nuclear factor (NF)-kappaB to the nucleus was inhibited by MSM treatment in LPS-stimulated RAW264.7 cells, in which it helped block degradation of inhibitor of NF-kappaB. In addition, in vivo studies demonstrated that topical administration of MSM at 500-1250 microg/ear resulted in similar inhibitory activities in 12-O-tetradecanoylphorbol 13-acetate-induced mouse ear edema. Collectively, theses results indicate that MSM inhibits LPS-induced release of pro-inflammatory mediators in murine macrophages through downregulation of NF-kappaB signaling.
Randomised, Double-Blind, Parallel, Placebo-Controlled Study of Oral Glucosamine, Methylsulfonylmethane and their Combination in Osteoarthritis.
Department of Clinical Pharmacology and Therapeutics, Nizam’s Institute of Medical Sciences, Hyderabad, India.
Glucosamine, classified as a slow-acting drug in osteoarthritis (SADOA), is an efficacious chondroprotective agent. Methylsulfonylmethane (MSM), the isoxidised form of dimethyl-sulfoxide (DSMO), is an effective natural analgesic and anti-inflammatory agent. The aim of this study was to compare the efficacy and safety of oral glucosamine (Glu), methylsulfonylmethane (MSM), their combination and placebo in osteoarthritis of the knee.
PATIENTS AND DESIGN:
A total of 118 patients of either sex with mild to moderate osteoarthritis were included in the study and randomised to receive either Glu 500mg, MSM 500mg, Glu and MSM or placebo capsules three times daily for 12 weeks. Patients were evaluated at 0 (before drug administration), 2, 4, 8 and 12 weeks post-treatment for efficacy and safety. The efficacy parameters studied were the pain index, the swelling index, visual analogue scale pain intensity, 15m walking time, the Lequesne index, and consumption of rescue medicine.
Glu, MSM and their combination significantly improved signs and symptoms of osteoarthritis compared with placebo. There was a statistically significant decrease in mean (+/- SD) pain index from 1.74 +/- 0.47 at baseline to 0.65 +/- 0.71 at week 12 with Glu (p < 0.001). MSM significantly decreased the mean pain index from 1.53 +/- 0.51 to 0.74 +/- 0.65, and combination treatment resulted in a more significant decrease in the mean pain index (1.7 +/- 0.47 to 0.36 +/- 0.33; p < 0.001). After 12 weeks, the mean swelling index significantly decreased with Glu and MSM, while the decrease in swelling index with combination therapy was greater (1.43 +/- 0.63 to 0.14 +/- 0.35; p < 0.05) after 12 weeks. The combination produced a statistically significant decrease in the Lequesne index. All treatments were well tolerated.
Glu, MSM and their combination produced an analgesic and anti-inflammatory effect in osteoarthritis. Combination therapy showed better efficacy in reducing pain and swelling and in improving the functional ability of joints than the individual agents. All the treatments were well tolerated. The onset of analgesic and anti-inflammatory activity was found to be more rapid with the combination than with Glu. It can be concluded that the combination of MSM with Glu provides better and more rapid improvement in patients with osteoarthritis.
Pharmacokinetics and distribution of [35S]methylsulfonylmethane following oral administration to rats.
Magnuson BA, Appleton J, Ames GB.
Burdock Group, 888 17th Street N.W., Suite 810, Washington, D.C. 20006, USA. firstname.lastname@example.org
Methylsulfonylmethane (MSM) is a sulfur-containing compound found in a wide range of human foods including fruits, vegetables, grains, and beverages. More recently, it has been marketed as a dietary supplement worldwide. The objective of this study was to evaluate the pharmacokinetic profile and distribution of radiolabeled MSM in rats. Male Sprague-Dawley rats were administered a single oral dose of [35S]MSM (500 mg/kg), and blood levels of radioactivity were determined at different time points for up to 48 h. Tissue levels of radioactivity at 48 and 120 h and urine and fecal radioactivity levels were measured at different time points for up to 120 h following [35S]MSM administration to rats. Oral [35S]MSM was rapidly and efficiently absorbed with a mean tmax of 2.1 h, Cmax of 622 microg equiv/mL, and AUC0-inf of 15124 h.microg equiv/mL. The t1/2 was 12.2 h. Soft tissue distribution of radioactivity indicated a fairly homogeneous distribution throughout the body with relatively lower concentrations in skin and bone. Approximately 85.8% of the dose was recovered in the urine after 120 h, whereas only 3% was found in the feces. No quantifiable levels of radioactivity were found in any tissues after 120 h, indicating complete elimination of [35S]MSM. The results of this study suggest that [35S]MSM is rapidly absorbed, well distributed, and completely excreted from the body.
Efficacy of methylsulfonylmethane (MSM) in osteoarthritis pain of the knee: a pilot clinical trial.
Kim LS, Axelrod LJ, Howard P, Buratovich N, Waters RF.
Southwest College Research Institute, Southwest College of Naturopathic Medicine and Health Sciences, Tempe, AZ 85282, USA. email@example.com
Osteoarthritis (OA) is the most common form of arthritis and the second most common cause of long-term disability among middle-aged and older adults in the United States. Methylsulfonylmethane (MSM) is a popular dietary supplement used as a single agent and in combination with other nutrients, and purported to be beneficial for arthritis. However, there is paucity of evidence to support the use of MSM.
A randomized, double-blind, placebo-controlled trial was conducted. Fifty men and women, 40-76 years of age with knee OA pain were enrolled in an outpatient medical center. Intervention was MSM 3g or placebo twice a day for 12 weeks (6g/day total). Outcomes included the Western Ontario and McMaster University Osteoarthritis Index visual analogue scale (WOMAC), patient and physician global assessments (disease status, response to therapy), and SF-36 (overall health-related quality of life).
Compared to placebo, MSM produced significant decreases in WOMAC pain and physical function impairment (P<0.05). No notable changes were found in WOMAC stiffness and aggregated total symptoms scores. MSM also produced improvement in performing activities of daily living when compared to placebo on the SF-36 evaluation (P<0.05).
MSM (3g twice a day) improved symptoms of pain and physical function during the short intervention without major adverse events. The benefits and safety of MSM in managing OA and long-term use cannot be confirmed from this pilot trial, but its potential clinical application is examined. Underlying mechanisms of action and need for further investigation of MSM are discussed.
Aspirin and methylsulfonylmethane (MSM): a search for common mechanisms, with implications for cancer prevention.
Departments of Microbiology and Immunology and of Biochemistry, University of Western Ontario, London, Ontario, N6A-5C1, Canada. firstname.lastname@example.org
Aspirin (acetylsalicylic acid), a prototypic nonsteroidal anti-inflammatory drug (NSAID), and MSM, a «nutritional supplement», are both used in the treatment of arthritis and described as cancer chemopreventive agents. Initial experimentation indicating that aspirin and MSM also induced the differentiation of murine erythroleukemia (MEL) cells led to a search for common mechanisms involving these two agents.
MATERIALS AND METHODS:
Since the major mechanism of action attributed to aspirin is the inhibition of cyclooxygenase (COX), prostaglandin (PG) production was examined under differentiation-inducing conditions in MEL cells.
Aspirin at low, nontoxic concentrations induced differentiation leading to terminal cell division. Aspirin had no effect on PGE2 production and minimal inhibitory effect on COX activity. Furthermore, salicylate, a major metabolite of aspirin and an ineffective COX inhibitor, induced differentiation at concentrations comparable to aspirin. Similar experiments with MSM indicated that MSM had no effect on PGE2 production or on COX activity under differentiation–inducing conditions and at concentrations reported in other studies.
These experiments indicated that aspirin and MSM induced differentiation by a COX-independent mechanism(s) and suggested that a common mechanism for the chemopreventive action invoked by both agents might be the activation of gene functions leading to differentiation and thereby dismantling the cellular capacity for proliferation.