MSM (METHYL SULPHONYL METHANE)
MSM modulates the immune response through the crosstalk between oxidative stress and inﬂammation - MSM down regulates NF-κB pathway and other pro-inﬂammatory signaling pathways responsible for the upregulation of genes encoding cytokines, chemokines, and adhesion molecules.
Methylsulfonylmethane: Applications and Safety of a Novel Dietary Supplement Published: 16 March 2017
Center for Nutraceutical and Dietary Supplement Research, School of Health Studies, The University of Memphis, Memphis, TN 38152, USA.
"In 1981 Dr. Herschler was granted a United States utility patent for the use of MSM to smooth and soften skin, to strengthen nails, or as a blood diluent. In addition to the applications laid out in the ﬁrst Herschler patent, subsequent Herschler patents claimed MSM to relieve stress, relieve pain, treat parasitic infections, increase energy, boost metabolism, enhance circulation, and improve wound healing [9–16], though there is little supporting scientiﬁc evidence .
On the other hand, the scientiﬁc literature does suggest that MSM may have clinical applications for arthritis [18–20] and other inﬂammatory disorders such as interstitial cystitis , allergic rhinitis [22,23], and acute exercise-induced inﬂammation ."
Mechanisms of Actions
Due to its enhanced ability to penetrate membranes and permeate throughout the body, the full mechanistic function of MSM may involve a collection of cell types and is therefore difﬁcult to elucidate. Results from in vitro and in vivo studies suggest that MSM operates at the crosstalk of inﬂammation and oxidative stress at the transcriptional and subcellular level.
In vitro studies indicate that MSM inhibits transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [85,86] by impeding the translocation into the nucleus while also preventing the degradation of the NF-κB inhibitor . MSM has been shown to alter post-translational modiﬁcations including blocking the phosphorylation of the p65 subunit at Serine-536 , though it is unclear whether this is a direct or indirect effect. Modiﬁcations to subunits such as these contribute heavily to the regulation of the transcriptional activity of NF-κB, and thus more details are required to further understand this anti-inﬂammatory mechanism. Traditionally, the NF-κB pathway is thought of as a pro-inﬂammatory signaling pathway responsible for the upregulation of genes encoding cytokines, chemokines, and adhesion molecules . The inhibitory effect of MSM on NF-κB results in the down regulation of mRNA for interleukin(IL)-1, IL-6, and tumor necrosis factor-α (TNF-α) in vitro [90,91]. As expected, translational expression of these cytokines is also reduced; furthermore, IL-1 and TNF-α are inhibited in a dose-dependent manner. MSM may indirectly have an inhibitory role on mast cell mediation of inﬂammation. With the reduction in cytokines and vasodilating agents, ﬂux and recruitment of immune cells to sites of local inﬂammation are inhibited.
The antioxidant effect of MSM was ﬁrst noticed when the neutrophil stimulated production of ROS was suppressed in vitro but unaffected in a cell free system ; for that reason, it was proposed that the antioxidant mechanism acts on the mitochondria rather than at the chemical level. MSM inﬂuences the activation of at least four types of transcription factors: NF-κB, signal transducers and activators of transcription (STAT), p53, and nuclear factor (erythroid-derived 2)-like 2 (Nrf2). By mediating these transcription factors, MSM can regulate the balance of ROS and antioxidant enzymes. It is important to note that each of these is also, in part, activated by ROS. As mentioned previously, MSM can inhibit NF-κB transcriptional activity and thus reduce the expression of enzymes and cytokines involved in ROS production. Downregulation of COX-2 and iNOS reduces the amount of superoxide radical (O2−) and nitric oxide (NO), respectively . Additionally, MSM suppresses the expression of cytokines such as TNF-α [86,90,91],which may reduce any stimulated mitochondrial generated ROS . Decrements in cytokine expression may also be involved in reduced paracrine signaling and activation of other transcription factors and pathways.
Stress can trigger an acute response by the innate immune system and an ensuing adaptive immune response if the stressor is pathogenic. Sulfur containing compounds including MSM play a critical role in supporting the immune response [112–114]. Through an integrated mechanism including those mentioned above, MSM modulates the immune response through the crosstalk between oxidative stress and inﬂammation. Chronic exposure to stressors can have detrimental effects to the immune system as it becomes desensitized or over-stressed and unable to elicit a typical immune response. The broad effects of IL-6 have been implicated in the maintenance of chronic inﬂammation . MSM has been shown to reduce IL-6 in vitro, which may mitigate these chronic deleterious effects [86,87,90]. Pre-treatment with MSM, prior to exhaustive exercise, prevented the over-stress of immune cells as lipopolysaccharide (LPS)-treated blood was still able to mount a response through the secretion of cytokines ex vivo, an effect not observed in the placebo group.
MSM has long been thought of as a sulfur donor for sulfur containing compounds such as methionine, cysteine, homocysteine, taurine, and many others. Guinea pigs fed radiolabeled MSM incorporated labeled sulfur into serum proteins containing methionine and cysteine . This study suggested that microbial metabolism may be responsible for the utilization of MSM to form methionine and subsequent synthesis to cysteine. More recent in vivo studies with radiolabeled MSM suggest that this compound is metabolized rapidly in a homogenous distribution of tissues [63,64]. These studies reportedly collected most labeled sulfur as metabolites of MSM in urine but did not determine the metabolites. Further study regarding the activity of MSM as a sulfur donor is ongoing. In humans, no MSM dose-dependent trends are observed between individuals for plasma sulfate and homocysteine changes . With microorganisms largely responsible for sulfur utilization throughout the sulfur cycle, MSM as a sulfur donor may be dependent on the existing microbiome with mammalian hosts. MSM is reportedly a non-alkylating agent and does not methylate DNA.
MSM does not appear to cause chromosome aberration in vitro or micronucleation in vivo according to two ﬁnal study reports.
As a therapeutic agent, MSM utilizes its unique penetrability properties to alter physiological effects at the cellular and tissue levels. Furthermore, MSM has the ability to act as a carrier or co-transporter for other therapeutic agents, even furthering its potential applications.
Arthritis and Inﬂammation
Arthritis is an inﬂammatory condition of the joints that currently affects approximately 58 million adults, with an estimated increase to 78.4 million by 2040 . This inﬂammation is characterized by pain, stiffness, and a reduced range of motion with regards to the arthritic joint(s). MSM is currently a CAM treatment alone and in combination for arthritis and other inﬂammatory conditions. MSM,as a micronutrient with enhanced penetrability properties, is commonly integrated with other anti-arthritic agents including glucosamine, chondroitin sulfate, and boswellic acid. As mentioned previously, a number of in vitro studies suggest that MSM exerts an antiinﬂammatory effect through the reduction in cytokine expression [86,87,90,91]. Similar results have been observed with MSM in experimentally induced-arthritic animal models, as evidenced by cytokine reductions in mice  and rabbits [86,87,90,91,132].
Additionally, MSM in a combinatorial supplement with glucosamine and chondroitin sulfate effectively reduced C-reactive protein (CRP) in rats with experimentally-induced acute and chronic rheumatoid arthritis .
To date, most arthritic human studies have been non-invasive and assess joint condition through the use of subject questionnaires such as the Western Ontario and McMaster Universities Arthritis Index (WOMAC), 36-Item Short Form Survey (SF36), Visual Analogue Scale (VAS) pain, and the Lequesne Index. In his overview of MSM, Dr. Stanley Jacob references eleven case studies of patients suffering from osteoarthritis who experienced improved symptoms following supplementation with MSM . Clinical trials suggest MSM is effective in reducing pain, as indicated by the VAS pain scale [18,134], WOMAC pain subscale [18,19,135,136], SF36 pain subscale [18,136], and Lequesne Index . Concurrent improvements were also noted in stiffness [18,135,136] and swelling . Furthermore,in the study conducted by Usha and Naidu, MSM in combination with glucosamine potentiated the improvements in pain, pain intensity, and swelling. Other human studies utilizing combination therapies report similar results. For instance, arthritis associated pain and stiffness was signiﬁcantly improved through the use of Glucosamine, Chondroitin sulfate, and MSM (GCM) [137,138]. Only marginal improvements in pain and stiffness were observed when a GCM combination was supplemented on top of modiﬁcations to diet and exercise in sedentary obese women diagnosed with osteoarthritis (OA) .
MSM was also shown to be effective in reducing arthritis pain when used in combination with boswellic acid  and type II collagen . In addition to arthritis, MSM improves inﬂammation in a number of other conditions. For example, MSM attenuated cytokine expression in vivo for induced colitis , lung injury , and liver injury [143,144].
Hasegawa and colleagues  reported that MSM was useful in protecting against UV-induced inﬂammation when applied topically and acute allergic inﬂammation after pre-treatment with a 2.5% aqueous drinking solution. MSM is effective at reducing other inﬂammatory pathologies in humans as well. In a physician’s review of clinical case studies, MSM was an effective treatment for four out of six patients suffering from interstitial cystitis . Additionally, MSM is also suggested to alleviate the symptoms of seasonal allergic rhinitis [22,23]. Though the reduction in systemic exercise-induced inﬂammation by MSM has been observed , human studies have not explored the inﬂammatory effects directly at the cartilage or synovium, as seen in the reduced synovitis inﬂammation in mice given MSM .
Cartilage degradation has long been thought of as the driving force of osteoarthritis . Articular cartilage is characterized by a dense extracellular matrix (ECM) with little to no blood supply driving nutrient extraction from the adjacent synovial ﬂuid . Pro-inﬂammatory cytokines, particularly IL-1β and TNF-α, are implicated in the destructive process of cartilage ECM . With minimal blood supply and possible hypoxic microenvironments, in vitro studies suggest that MSM protects cartilage through its suppressive effects on IL-1β and TNF-α [86,90,91] and its possibly normalizing hypoxia-driven alterations to cellular metabolism . Disruption of this destructive autocrine or paracrine signaling by MSM has also been observed in surgically-induced OA rabbits by the reduction in cartilage and synovial tissue , TNF-α, and the protected articular cartilage surface during OA progression. Histopathology of a rheumatoid arthritis (RA) rat model supplemented with a GCM combination demonstrated decreased synovium proliferation and the development of an irregular edge at the articular joint . Furthermore, MSM supplementation in OA mice signiﬁcantly decreased cartilage surface degeneration .
In fact the protective effects of MSM can be seen as far back as 1991,when Murav’ev and colleagues described the decreased knee joint degeneration of arthritic mice . Interestingly, endogenous serum MSM becomes elevated in sheep post-meniscal destabilization caused osteoarthritis ; however, the magnitude of this physiological response was not large enough to protect against cartilage erosion.
Improve Range of Motion and Physical Function
With the aforementioned improvements in inﬂammation and cartilage preservation, not surprisingly beneﬁcial changes in overall physical function have also been noted through the use of subjective measurements [18,19,135,136]. In studies with osteoarthritic populations given MSM daily, signiﬁcant improvements in physical function were observed, as assessed through the WOMAC [18,19,135,136], SF36 [19,135,136], and Aggregated Locomotor Function (ALF) . Objective kinetic knee measurements following eccentric exercise-induced muscle damage were not conclusive but suggest that MSM may aid in maximal isometric knee extensor recovery . MSM has been usedinanumberofcombinationtherapieswithpositiveresults.
* Supplementation with glucosamine, chondroitin sulfate, MSM, guava leaf extract, and Vitamin D improved physical function in patients with knee osteoarthritis based on the Japanese Knee OA Measure . A GCM supplement was successful in increasing functional ability and joint mobility .
MSM in combination with boswellic acid was also shown to improve knee joint function as assessed through the Lequesne Index . MSM with arginine L-α-ketoglutarate, hydrolyzed Type I collagen, and bromelain taken for three months daily post-rotator cuff repair improved repair integrity without affecting objective functional outcomes . Other studies exploring the uses of MSM in combination therapies failed to show signiﬁcant improvements. In one such study in geriatric horses, a GCM combination supplement given orally for three months failed to show signiﬁcant changes in gait characteristics .
In humans, MSM and boswellic acid reduced the need for anti-inﬂammatory drugs but was not more effective than the placebo as a treatment for gonarthrosis . However, when a GCM combination supplement was administered in addition to dietary and exercise interventions, no signiﬁcant improvements were noted when compared to the non-supplemented group . Subjects with lower back pain undergoing conventional physical therapy with supplementation of a glucosamine complex containing MSM reported an improvement in their quality of life . A 2011 systematic review of GCM supplements as a treatment for spinal degenerative joint disease and degenerative disc disease failed to come to a conclusion on efﬁcacy due to the scarcity of quality literature .
To Reduce Muscle Soreness Associated with Exercise
Prolonged strenuous exercise can result in muscle soreness caused by microtrauma to muscles and surrounding connective tissue leading to a local inﬂammatory response. MSM is alluded to be an effective agent against muscle soreness because of its anti-inﬂammatory effects as well as its possible sulfur contribution to connective tissue. Endurance exercise-induced muscle damage was reduced with MSM supplementation, as measured by creatine kinase . Pre-treatment with MSM reduced muscle soreness following strenuous resistance exercises [152,160,161] and endurance exercise .
Reduce Oxidative Stress
In vitro studies suggest that MSM does not chemically neutralize ROS in stimulated neutrophils but instead suppresses mitochondrial generation of superoxide, hydrogen peroxide, and hypochlorous acid . Additionally, MSM is able to restore the reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio to normal levels, decrease NO production, and reduce neuronal ROS production following HIV-1 Tat exposure . Animal studies using MSM as the primary treatment for experimentally induced injuries show reductions in malondialdehyde (MDA) [142–144,163–165], GSSG , myeloperoxidase (MPO) [142,143,163], NO , and carbon monoxide (CO)  and/or increases in GSH [142,143,163–166], CAT [142–144,165], SOD [143,144,163,165], and GPx . Treatment modalities for these animal studies were either an acute one time dose or pre-treatment prior to inducing injury [144,163,165].
** In humans, MSM pre-treatment prior to endurance exercise results in acute attenuation of induced protein oxidation [167,168], bilirubin [159,168], lipid peroxidation , creatine kinase , oxidized glutathione , and uric acid  and also an increase in total antioxidant capacity [159,168]. Following endurance exercise, reduced glutathione was elevated with 10 days of pre-treatment  but was insigniﬁcantly affected by a single oral dose just prior to exercise . Pre-treatment with MSM in subjects undergoing resistance exercise exhibits more variability. Supplementation for 28 days with 3.0g / day prior to exhaustive resistance exercise showed an increase in Trolox equivalent antioxidant capacity (TEAC) and a decrease in homocysteine ; whereas, supplementation for 14 days at the same dosage reported no signiﬁcant changes in TEAC or homocysteine . The longer period of supplementation may have allowed bioavailable MSM stores to reach a level where it could upregulate Nrf2 enough to produce a more signiﬁcant rise in antioxidant enzymes. Combination therapies including MSM have become more popular recently, particularly with ethylenediaminetetraacetic acid (EDTA) due to the permeability enhancement provided by MSM .
For instance, topical EDTA-MSM is effective at reducing oxidative damage in the form of protein-lipid aldehyde adducts [170–172]. EDTA-MSM reduced lens opaciﬁcation in diabetic cataract  but was ineffective in reversing experimentally induced intraocular pressure in rats . In humans, EDTA-MSM lotion signiﬁcantly improved pitting edema symptoms after two weeks of application, with circulating total antioxidant capacity and MDA reductions noted . Humans studies show promise for MSM as an antioxidant with similar results noted, including reductions in MDA [19,167,168], protein carbonyls (PC) [167,168], and uric acid  and increases in GSH  and TEAC [159,161,168]. Contrary to previous literature, Kantor et al. reported that MSM users experienced reduced lymphocyte DNA repair capacity at 60 min. . This conﬂicting result may be explained by the samples being collected at different points in the day, since the circadian clock can modulate this measure .
Improve Seasonal Allergies
In an evaluation of MSM on seasonal allergies, 2.6 g/day PO MSM for 30 days improved upper and total respiratory symptoms as well as lower respiratory symptoms by week 3 . All these improvements were maintained throughout the 30 days of supplementation. A drawback of this study was the lack of reporting on pollen counts and a symptoms questionnaire . This was later corrected when Barrager and Schauss published the additional requested data . Barrager et al. used a subsection of this sample population to measure histamine release but found no signiﬁcant changes in plasma IgE or histamine levels .
Improve Skin Quality and Texture
Since the initial patent awarded to Herschler in 1981, MSM has been suggested to have therapeutic uses for the improvement of skin quality and texture by acting as a sulfur donor to keratin. According to one ﬁnal study report, MSM is non-irritating to the skin of rabbits via an occlusive patch. Another ﬁnal study report indicated that MSM may be slightly irritating to skin of guinea pigs. Using a lotion containing EDTA and MSM, mild improvement in burn sites on rats were noticed following three days of topical application every 8 h . Skin appearance and condition after MSM treatment signiﬁcantly improved as assessed by expert grading, instrumental analysis, and participant self-assessment . Human combination studies with four peeling sessions using pyruvic acid and MSM once every two weeks improved the degree of pigmentation of melisma, skin elasticity, and the degree of wrinkling . A combination treatment of silymarin and MSM proved useful in managing rosacea symptoms . A case study of a 44 year old man with severe X-linked type ichthyosis showed improvement of symptoms after four weeks of topical moisturizer containing amino acids, vitamins, antioxidants, and MSM .
MSM and Cancer
An emerging area of MSM research deals with the anti-cancer effect of the organosulfurcompound.
In vitro studies using MSM alone or in combination have evaluated the metabolic and phenotypic effects of a number of cancer cell lines including breast [100,101,122,123,126,181], esophagus , stomach , liver [119,120], colon , bladder , and skin cancers [123,125] with promising results.
* MSM independently has been shown to be cytotoxic to cancer cells by inhibiting cell viability through the induction of cell cycle arrest [119,122,123], necrosis , or apoptosis [100,101,119–121]. The inhibition of cell growth and proliferation may be attributed to the metabolic alterations induced by MSM at the transcriptional and/or post-translational stages. For instance, MSM has been shown to inhibit expression and DNA binding of transcription factors such as STAT3 [100,101] and STAT5b [100,101,181]; meanwhile, the p53 transcription factor is maintained by MSM  and does not induce apoptosis .
Though MSM inhibition of DNA binding by STAT3 may be an indirect effect of the phosphorylation of Jak2 . Nonetheless, by inhibiting the binding of STAT3 and STAT5b to promoters, the reduced expression of oncogenic proteins such as vascular endothelial growth factor (VEGF) [99–101,123], heat shock protein (HSP)90α , and insulin-like growth factor-1 receptor (IGF-1R) [99–101] has been observed.
** The reduced expression of IGF-1R and VEGF may help prevent the development of tumors by reducing the insulin-like growth factor-1 (IGF-1)-mediated cell survival and proliferation pathways and preventing tumor-induced angiogenesis [182,183]. These metabolic alterations contribute to profound alterations at the cellular level as well. In vitro studies with cancer cell lines suggest that MSM has the ability to stimulate phenotypic changes more closely resembling non-cancerous cells. Treatment with MSM results in the induction of contact inhibition and cell senescence [122,123,125,126], anchorage-dependent growth [122,125], reduced migration of metastatic lines [101,122,125,126], and normalized wound healing [122,125]. This could in part be attributed to the robust changes to cellular ﬁlaments, including the disassembly and indirect reassembly of microtubules  and reorganization of actin localization .
While preventing angiogenesis may prompt a state of hypoxia, MSM has also been shown to reduce levels of HIF-1α under hypoxic conditions [100,123] and prevent or improve various metastatic biomarkers in response to hypoxia . In vitro MSM studies have also been supported by additional xenograft and in vivo studies conﬁrming the results. When cancer cells are xenotransplanted into animal models treated with MSM, tumor growth suppression has been observed [99–101],though two of these studies included a combination treatment of MSM and AG490  or Tamoxifen .
** Tumor tissue from mice treated exclusively with MSM exhibited reduced expression of IGF-1, STAT3, STAT5b, and VEGF without signiﬁcant suppression of IGF-1R . Tissues isolated from xenografted mice treated with combination treatments both displayed downregulation of STAT5b and IGF-1R signaling [99,101]. Previous studies also suggest that pre-treatment with MSM for approximately one week prior to inducing cancer in rats results in a signiﬁcant reduction in the mean time to tumor onset [184,185].
** Human trials with MSM as a cancer treatment have not been conducted to date; however, one study suggests that MSM use may be associated with a decreased risk of lung and colorectal cancer . In vitro and in vivo results warrant further investigation of MSM as a treatment for cancer.
MSM appears to be well-tolerated and safe.
A number of toxicity studies have been conducted in an array of animals including rats [184,185,187–189], mice , and dogs [191,192]. In a preliminary toxicity study report, a single mortality was reported in a female rat given an oral aqueous dose of 15.4g/kg after two days; however, a post-mortem necropsy examination showed no gross pathological alterations. Other technical reports indicate that mild skin and eye irritation have been observed when MSM is applied topically. Nonetheless, under the Food and Drug Administration (FDA) GRAS notiﬁcation, MSM is considered safe at dosages under 4845.6 mg/day.
MSM is a naturally occurring organo sulfur compound with broad biological effects. Human absorption and biosynthesis of this compound likely depends heavily on the co-metabolism between microbiota and host. Whether naturally produced or manufactured, MSM exhibits no biochemical differences in its ability to intermediate oxidative stress and inﬂammation. This micronutrient is well tolerated for arthritis and a number of other conditions related to inﬂammation, physical function, and performance. Emerging research suggests that MSM may one day aid in the treatment of various types of cancer [49,99–101,119–123,125,126,181,184–186,194] or metabolic syndromes .
Nutr Cancer. 2019 Sep 2:1-14. doi: 10.1080/01635581.2019.1655073. [Epub ahead of print]
Co-Treatment with Sulforaphane and Nano-Metformin Molecules Accelerates Apoptosis in HER2+ Breast Cancer Cells by Inhibiting Key Molecules.
Breast cancer cell lines MCF-10, MCF-7 and BT-474 expressing various levels of HER2 were examined for their response to treatment with sulforaphane (SLFN), metformin (MTFN), Nano-MTFN or combinations. Direct correlation was found between SLFN effect on cell death and HER2 levels. Bioinformatic studies suggested the possibility of additive co-effects on cell fate by SLFN-MTFN co-treatment. This co-treatment specially with SLFN + Nano-MTFN significantly affected the survival of the cells and killed more BT-474 cells than the other two. Cell sensitivity to SLFN-MTFN combination correlated with HER2 expression levels. RT-PCR showed that parallel with cell death, expression of BCL-2, SRC, WNT1, β-catenin and CD44 are diminished, whereas BAX levels are elevated significantly. Cell co-staining indicated that apoptosis percent correlates with cell death following different treatments. We also found that cell death induced by SLFN-MTFN co-treatment is in direct correlation with HER2 levels and increased cell death correlates directly with BAX levels but inversely with levels of cancer stem cell (CSC) signaling genes and CD44.
* In conclusion, our data indicate that SLFN and MTFN can reduce cancer cell viability via both collaborative and differential effects and suggest that MTFN increases SLFN effectiveness by targeting common molecules/pathways downstream of HER2 and key for CSC signaling.
Poult Sci. 2017 Jul 1;96(7):2168-2175. doi: 10.3382/ps/pew480.
Effects of dietary methyl sulfonyl methane (MSM) supplementation on growth performance, nutrient digestibility, meat quality, excreta microbiota, excreta gas emission, and blood profiles in broilers.
A 29-d trial was conducted to evaluate the effects of dietary methyl sulfonyl methane (MSM) supplementation on growth performance, meat quality, nutrient digestibility, excreta microbiota, excreta gas emission, and blood profiles in broilers. A total of 816 1-day-old male Ross 308 broilers (44 ± 0.44 g) were assigned to 4 dietary treatments, composed of 12 replicates with 17 birds per replicate. The 4 treatments were: 1) CON, basal diet; 2) S1, CON + 0.05% MSM; 3) S2, CON + 0.10% MSM; 4) S3, CON + 0.20% MSM. In the current study, body weight (BW) on d 14 and 29 showed significant improvement as dietary MSM increased from 0.05% to 0.20% (P < 0.05). During d 1 to 14 and overall, higher (P < 0.05) body weight gain (BWG) and lower feed conversion ratio (FCR) were observed in broilers fed MSM diets. Between d 15 and 29, higher (P < 0.05) BWG was observed in broilers fed MSM diets. Redness (a*) was increased linearly (P < 0.05) in broilers fed MSM diets. On d 3, 5, and 7, drip loss was decreased linearly (P < 0.05) in broilers fed MSM diets. Lactobacillus and E. coli were effected linearly (P < 0.05) in broilers fed MSM diets. Alanine aminotransferase (ALT), white blood cells (WBC) and lymphocytes were improved linearly (P < 0.05) in broilers fed MSM diets. In conclusion, dietary supplementation MSM has positive effects on growth performance, meat quality, excreta microbiota, and blood profiles in broilers.
J Neurosurg. 2017 Jan 6:1-12. doi: 10.3171/2016.8.JNS161197. [Epub ahead of print]
Sulforaphane suppresses the growth of glioblastoma cells, glioblastoma stem cell-like spheroids, and tumor xenografts through multiple cell signaling pathways.
OBJECTIVE Defects in the apoptotic machinery and augmented survival signals contribute to drug resistance in glioblastoma (GBM). Moreover, another complexity related to GBM treatment is the concept that GBM development and recurrence may arise from the expression of GBM stem cells (GSCs). Therefore, the use of a multifaceted approach or multitargeted agents that affect specific tumor cell characteristics will likely be necessary to successfully eradicate GBM. The objective of this study was to investigate the usefulness of sulforaphane (SFN)-a constituent of cruciferous vegetables with a multitargeted effect-as a therapeutic agent for GBM.
METHODS The inhibitory effects of SFN on established cell lines, early primary cultures, CD133-positive GSCs, GSC-derived spheroids, and GBM xenografts were evaluated using various methods, including GSC isolation and the sphere-forming assay, analysis of reactive oxygen species (ROS) and apoptosis, cell growth inhibition assay, comet assays for assessing SFN-triggered DNA damage, confocal microscopy, Western blot analysis, and the determination of in vivo efficacy as assessed in human GBM xenograft models.
RESULTS SFN triggered the significant inhibition of cell survival and induced apoptotic cell death, which was associated with caspase 3 and caspase 7 activation. Moreover, SFN triggered the formation of mitochondrial ROS, and SFN-triggered cell death was ROS dependent. Comet assays revealed that SFN increased single- and double-strand DNA breaks in GBM. Compared with the vehicle control cells, a significantly higher amount of γ-H2AX foci correlated with an increase in DNA double-strand breaks in the SFN-treated samples. Furthermore, SFN robustly inhibited the growth of GBM cell-induced cell death in established cell cultures and early-passage primary cultures and, most importantly, was effective in eliminating GSCs, which play a major role in drug resistance and disease recurrence. In vivo studies revealed that SFN administration at 100 mg/kg for 5-day cycles repeated for 3 weeks significantly decreased the growth of ectopic xenografts that were established from the early passage of primary cultures of GBM10.
CONCLUSIONS These results suggest that SFN is a potent anti-GBM agent that targets several apoptosis and cell survival pathways and further preclinical and clinical studies may prove that SFN alone or in combination with other therapies may be potentially useful for GBM therapy.
Sulforaphane Attenuates Matrix Metalloproteinase-9 Expression Following Spinal Cord Injury in Mice
Annals of Clinical & Laboratory Science, vol. 40, no. 4, 2010
Abstract. Inflammation plays an important role in the pathogenesis of secondary damage after spinal cord injury (SCI).
The present study explored the effect of sulforaphane (SFN), a potent anti-inflammatory extract of cruciferous vegetables, on the expression of two inflammatory mediators, metalloproteinase (MMP)-9 and TNF-α, in a murine model of SCI. Murine spinal cord injury was induced by the application of vascular clips (force of 10 g) to the dura after a three-level T8-T10 laminectomy. The wet/dry weight ratio was used to reflect the percentage of water content of impaired spinal cord tissue at 48 hr after SCI. The mRNA levels of MMP-9 were determined using the reverse-transcriptase polymerase chain reaction (RT-PCR), and protein levels of TNF-α and MMP-9 were detected by enzyme-linked immunosorbent assays (ELISA) at 24 hr after SCI. Gelatin zymography was used to determine MMP-9 activity of spinal cord tissue at 24 hr after SCI. Mice treated with SFN at 1 hr after SCI had lower expression and activity of MMP-9 compared to mice with SCI. The decrease of MMP-9 in mice treated with SFN was associated with decreased levels of spinal cord water content and TNF-α. In summary, suforaphane decreases MMP-9 and TNF-α expression and vascular permeability changes following spinal cord injury in mice. Keywords: spinal cord injury, sulforaphane, matrix metalloproteinase-9, TNF-α