RIPK3-MLKL-Mediated Neutrophil Death Requires Concurrent Activation of Fibroblast Activation Protein-α.

Cytokine-primed neutrophils can undergo a nonapoptotic type of cell death using components of the necroptotic pathway, including receptor-interacting protein kinase-3 (RIPK3), mixed lineage kinase-like (MLKL) and NADPH oxidase. In this report, we provide evidence for a potential role of serine proteases in CD44-mediated necroptotic death of GM-CSF-primed human neutrophils. Specifically, we observed that several inhibitors known to block the enzymatic function of fibroblast activation protein-α (FAP-α) were able to block CD44-mediated reactive oxygen species production and cell death, but not FAS receptor-mediated apoptosis. To understand how FAP-α is involved in this nonapoptotic death pathway, we performed immunoblotting experiments in the presence and absence of inhibitors of RIPK3, MLKL, p38 MAPK, PI3K, and FAP-α. The results of these experiments suggested that FAP-α is active in parallel with RIPK3, MLKL, and p38 MAPK activation but proximal to PI3K and NADPH oxidase activation. Interestingly, neutrophils isolated from the joints of patients suffering from rheumatoid arthritis underwent a GM-CSF-independent necroptosis following CD44 ligation; this effect was also blocked by both FAP-α and MLKL inhibitors. Taken together, our evidence shows that the RIPK3-MLKL pathway activates NADPH oxidase but requires, in addition to p38 MAPK and PI3K, a serine protease activity, whereby FAP-α is the most likely candidate. Thus, FAP-α could be a potential drug target in neutrophilic inflammatory responses to avoid exaggerated nonapoptotic neutrophil death, leading to tissue damage.

Thalidomide reduces glycerol-induced acute kidney injury by inhibition of NF-κB, NLRP3 inflammasome, COX-2 and inflammatory cytokines.

Acute kidney injury (AKI) is an important clinical complication of rhabdomyolysis. The inflammatory processes are involved in the pathogenesis of AKI induced by rhabdomyolysis. Thalidomide is an anti-inflammatory agent that has been used in the treatment of inflammatory disorders. The aim of this study was to investigate the therapeutic effect of thalidomide and its underlying mechanisms on a mouse model of rhabdomyolysis-induced AKI. Mice were injected with a single dose of glycerol (50%, 10 ml/kg, im) to induce AKI, and treated with thalidomide (40 and 80 mg/kg/day, orally) for 2 days. Renal tissue and blood samples were collected for histological and biochemical analysis. In thalidomide treated mice, blood urea nitrogen (BUN) (59.3 ± 19.6 vs. 223 ± 33 mg/dl), plasma creatinine (0.58 ± 0.3 vs. 1.28 ± 0.3 mg/dl), relative kidney weight (0.93 ± 0.13% vs. 1.22 ± 0.1%) and histopathological damage (1.5 ± 0.8 vs. 3.3 ± 1.1 score) were significantly lower as compared to the glycerol group. The results also showed that the levels of malondialdehyde (MDA) (0.13 ± 0.02 vs. 0.2 ± 0.01 µM/mg), myeloperoxidase (MPO) (0.1 ± 0.05 vs. 0.25 ± 0.02 U/mg) and the expression of nuclear factor kappa B (NF-κB) (1.7-fold), NLRP3 inflammasome (1.4-fold) and cyclooxygenase (COX)-2 (3-fold) in renal tissue were significantly lower in thalidomide treated group than those in the glycerol group. Thalidomide treatment resulted in lower renal pro-inflammatory cytokines tumor necrosis factor (TNF)-α (6.7 ± 0.8 vs. 12.3 ± 1.2 ng/ml), interleukin (IL)-1ß (3.2 ± 0.5 vs. 5.1 ± 0.3 pg/mg), IL-6 (24.7 ± 2.4 vs. 33 ± 3 pg/mg) and transforming growth factor (TGF)-ß1 (0.6 ± 0.17 vs. 1.56 ± 0.24 ng/ml) than those in the glycerol treated mice. In addition the levels of monocyte chemoattractant protein (MCP)-1 (9.5 ± 1 vs. 12.8 ± 1.1 pg/mg) and intercellular adhesion molecule (ICAM)-1 (22.8 ± 7.8 vs. 53.3 ± 5.5 pg/mg) were significantly lower in renal tissue of mice treated with thalidomide as compared to the glycerol treated mice. In conclusion these data revealed that thalidomide may be a potential therapeutic approach against rhabdomyolysis-induced AKI through inhibition of inflammatory responses.

Carvedilol prevents pancreatic ß-cell damage and the development of type 1 diabetes in mice by the inhibition of proinflammatory cytokines, NF-κB, COX-2, iNOS and oxidative stress.

Inflammation is one of the main mechanisms of pancreatic ß-cell damage and the development of type 1 diabetes (T1D). Carvedilol, a beta-adrenergic receptor blocker, has been demonstrated to have anti-inflammatory and antioxidant effects. The aim of this study was to investigate the protective effect of carvedilol against pancreatic ß-cell damage and the development of T1D in an experimental model. T1D was induced in mice by multiple low-dose streptozotocin (STZ) injections. Diabetic mice were treated with carvedilol (15 and 20 mg/kg/day, orally) for 14 days. Results showed that blood glucose levels, diabetes incidence, body weight loss and insulitis in the pancreatic tissue were significantly reduced in mice treated with carvedilol. Treatment of mice with carvedilol significantly increased the levels of antioxidants glutathione (GSH), superoxide dismutase (SOD), and catalase and decreased the levels of malondialdehyde (MDA), nitric oxide (NO) and myeloperoxidase (MPO) in the pancreatic tissue as compared with those in the STZ-induced diabetic mice. Carvedilol decreased the expression of nuclear factor kappa B (NF-κB), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) as important modulators of inflammation and ß-cell damage in the pancreatic tissue. In addition, carvedilol significantly reduced the levels of proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6 IL-12, IL-17, interferon (IFN)-γ and chemokine MCP-1, while increased the anti-inflammatory cytokine IL-10 in the pancreatic tissue. In conclusion, these findings suggest that carvedilol is able to prevent pancreatic ß-cell damage and the development of T1D in mice by the inhibition of inflammatory and oxidative mediators.

Carvedilol attenuates paraquat-induced lung injury by inhibition of proinflammatory cytokines, chemokine MCP-1, NF-κB activation and oxidative stress mediators.

Paraquat is a highly toxic herbicide that selectively accumulates in the lungs and causes pulmonary damage through the oxidative and inflammatory processes. Carvedilol is a nonselective beta and alpha-adrenergic blocking agent that has been shown to possess powerful antioxidant and anti-inflammatory properties. In the present study, we evaluated the protective effects and the underlying mechanisms of carvedilol on paraquat-induced lung injury in a mouse model. Mice were injected with a single dose of paraquat (20mg/kg, ip), and treated with carvedilol (10 and 20mg/kg/day, orally) for eight days. At the end of the experiment, lung tissue and blood samples were collected for histological and biochemical analysis. The results showed that carvedilol treatment improved the histopathological changes in the lung tissue of mice exposed to paraquat. Carvedilol significantly decreased the levels of malondialdehyde (MDA), carbonyl protein, myeloperoxidase (MPO), and nitric oxide (NO), while increased the levels of glutathione (GSH), superoxide dismutase (SOD), catalase and glutathione reductase compared with paraquat group. Carvedilol treatment also significantly reduced the levels of proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, transforming growth factor (TGF)-ß1 and monocyte chemoattractant protein (MCP)-1 in the lung tissue. Treatment of mice with carvedilol decreased paraquat-induced expression of nuclear factor kappa B (NF-κB). In addition the plasma levels of matrix metalloproteinase (MMP)-9 and the lung hydroxyproline content significantly reduced by carvedilol treatment. Taken together, these results indicate that carvedilol is able to decrease the severity of paraquat-induced lung injury through inhibition of inflammation and oxidative stress.

Therapeutic Effect of Levetiracetam Against Thioacetamide-Induced Hepatic Encephalopathy Through Inhibition of Oxidative Stress and Downregulation of NF-κB, NLRP3, iNOS/NO, Pro-Inflammatory Cytokines and Apoptosis.

Hepatic encephalopathy (HE) is a serious brain disorder which associated with neurological and psychiatric manifestations. Oxidative stress and neuroinflammation and apoptosis play main roles in the development of brain damage in HE. Levetiracetam is an antiseizure drug with established antioxidant and anti-inflammatory activities. In the present study we investigated the therapeutic effects of levetiracetam against brain injury in HE and its underlying mechanisms of action. Male C57BL/6 mice were subjected to the induction of HE by the injection of thioacetamide (200 mg/kg) for 2 days. Mice were treated with levetiracetam at two doses (50 or 100 mg/kg/day) for 3 days in the treatment groups. Animals were subjected to a behavioral test and the brain tissues were dissected for histopathological, biochemical, gene expression and immunofluorescence analysis. The results showed that levetiracetam alleviated body weight loss and improved locomotor activity of mice with HE. Levetiracetam treatment decreased the histopathological changes, lipid peroxidation and protein carbonylation while restored the antioxidants (GSH, SOD and CAT) in the brain. Levetiracetam decreased the expression and activity of NF-κB, NOD-like receptor pyrin domain-containing protein 3 (NLRP3) and pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6, and IFN-γ) in the brain tissue. Administration of levetiracetam inhibited iNOS/NO pathway and myeloperoxidase (MPO) activity in the brain. Moreover, caspase-3 was decreased and the ratio of Bcl2/Bax was increased in the brain of mice treated with levetiracetam. These findings suggest that levetiracetam may be a promising therapeutic agent for brain injury in HE through inhibiting the oxidative, inflammatory and apoptotic pathways.

Carvedilol attenuates inflammatory reactions of lipopolysaccharide-stimulated BV2 cells and modulates M1/M2 polarization of microglia via regulating NLRP3, Notch, and PPAR-γ signaling pathways.

Microglial cells coordinate immune responses in the central nervous system. Carvedilol (CVL) is a non-selective ß-blocker with anti-inflammatory and anti-oxidant effects. This study aims to investigate the anti-inflammatory effects and the underlying mechanisms of CVL on lipopolysaccharide (LPS)-induced inflammation in microglial BV2 cells. BV2 cells were stimulated with LPS, and the protective effects of CVL were investigated via measurement of cell viability, reactive oxygen species (ROS), and interleukin (IL)-1ß liberation. The protein levels of some inflammatory cascade, Notch, and peroxisome proliferator-activated receptor (PPAR)-γ pathways and relative markers of M1/M2 microglial phenotypes were assessed. Neuroblastoma SH-SY5Y cells were cultured with a BV2-conditioned medium (CM), and the capacity of CVL to protect cell viability was evaluated. CVL displayed a protective effect against LPS stress through reducing ROS and down-regulating of nuclear factor kappa B (NF-κB) p65, NLR family pyrin domain containing-3 (NLRP3), and IL-1ß proteins. LPS treatment significantly increased the levels of the M1 microglial marker inducible nitric oxide synthase (iNOS) and M1-associated cleaved-NOTCH1 and hairy and enhancer of split-1 (HES1) proteins. Conversely, LPS treatment reduced the levels of the M2 marker arginase-1 (Arg-1) and PPAR-γ proteins. CVL pre-treatment reduced the protein levels of iNOS, cleaved-NOTCH1, and HES1, while increased Arg-1 and PPAR-γ. CM of CVL-primed BV2 cells significantly improved SH-SY5Y cell viability as compared with the LPS-induced cells. CVL suppressed ROS production and alleviated the expression of inflammatory markers in LPS-stimulated BV2 cells. Our results demonstrated that targeting Notch and PPAR-γ pathways as well as directing BV2 cell polarization toward the M2 phenotype may provide a therapeutic strategy to suppress neuroinflammation by CVL.

Levetiracetam attenuates experimental ulcerative colitis through promoting Nrf2/HO-1 antioxidant and inhibiting NF-κB, proinflammatory cytokines and iNOS/NO pathways.

Ulcerative colitis (UC) is a serious inflammatory disease of the colon. The pathogenic mechanisms of UC involve the activation of inflammatory and oxidative stress responses in the colon. Levetiracetam is an antiepileptic drug with anti-inflammatory and antioxidant effects. The aim of this study was to investigate the potential protective effect of levetiracetam against UC in a mouse model. UC was induced in mice by intrarectal administration of acetic acid and then mice were treated with levetiracetam (50 or 100 mg/kg/day, i.p.) for three days. The colonic tissue samples were dissected for biochemical, RT-PCR and immunofluorescence analysis. Results showed that levetiracetam treatment significantly decreased colonic mucosal injury as evidenced by the macroscopic and histopathological analysis. Levetiracetam induced Nrf2/HO-1 and antioxidants while reduced lipid peroxidation and myeloperoxidase activity in colon tissue. Levetiracetam treatment decreased NF-κB activity and the expression of proinflammatory mediators TNF-α, IL-6, IL-1ß, IFN-γ, MCP-1 and ICAM-1. The colonic levels of anti-inflammatory cytokines IL-10 and TGF-ß1 were increased by levetiracetam treatment. Furthermore, levetiracetam significantly diminished iNOS expression and NO production in colon tissue. These findings suggest that levetiracetam ameliorates the severity of UC in mice through the regulation of inflammatory and oxidative responses.

Carvedilol attenuates brain damage in mice with hepatic encephalopathy.

Brain injury is the most common and serious consequence of hepatic encephalopathy (HE), and its pathophysiology is poorly understood. Excessive inflammatory, oxidative and apoptotic responses are the major mechanisms involved in the progression of brain injury induced by HE. Carvedilol is an adrenergic receptor antagonist with pronouncedantioxidant and anti-inflammatory activity. The present study aimed to investigatethe effects and underlying mechanisms of carvedilol on HE-induced brain damage in mice. Experimental model of HE was induced by the injection of thioacetamide (200 mg/kg) for two consecutive days and then mice were treated with carvedilol (10 or 20 mg/kg/day, orally) for 3 days in treatment groups. After the behavioral test, animals were sacrificed and the brain tissues were collected for biochemical, real time PCR and immunohistochemical analysis. The results showed that carvedilol improved locomotor impairment and reduced mortality rate in mice with HE. Carvedilol treatment decreased the brain levels of oxidative stress markers and induced Nrf2/HO-1 pathway. Carvedilol inhibited the activity of nuclear factor kappa B (NF-κB) and the expression of pro-inflammatory cytokines TNF-α, IL1ß and IL-6 in the brain tissues. Treatment of mice with carvedilol caused a significant reduction in the brain levels of iNOS/NO, myeloperoxidase (MPO), cyclooxygenase (COX)-2 and chemokine MCP-1 as proinflammatory mediators in HE. Moreover, the ratio of Bcl2/Bax was increased and apoptotic cell death was decreased in the brain of mice treated with carvedilol. In conclusion, carvedilol exerted protective effect against HE-induced brain injury through increasing antioxidant defense mechanisms and inhibitionof inflammatory and apoptotic pathways.

Carvedilol attenuates acrylamide-induced brain damage through inhibition of oxidative, inflammatory, and apoptotic mediators.

Objectives: Acrylamide is a potent neurotoxic compound and has harmful effects on brain cells. Acrylamide promotes oxidative, inflammatory, and apoptotic mediators in the CNS leading to neurological disorders. The goal of the current study was to examine the potential protective effect of carvedilol and its underlying mechanisms in a mouse model of acrylamide-induced brain injury. Materials and Methods: Mice were treated with acrylamide (50 mg/kg/day, IP) and carvedilol (5 and 10 mg/kg/day, oral) for 11 continuous days. At the end of the experiment, mice were subjected to gait assessment. They were sacrificed and brain tissues were collected for histological and biochemical analysis. Results: The results showed that treatment of mice with carvedilol decreased acrylamide-induced bodyweight loss, abnormal gait, and histopathological damage in the brain tissue. Carvedilol treatment significantly reduced the levels of malondialdehyde (MDA) and carbonyl protein and increased the levels of glutathione (GSH), catalase, superoxide dismutase (SOD), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1). Carvedilol treatment also decreased myeloperoxidase (MPO) activity, expression of nuclear factor kappa B (NF-κB), inducible nitric oxide synthase (iNOS), overproduction of nitric oxide (NO) and proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 in the brain of mice exposed to acrylamide. Furthermore, administration of carvedilol significantly decreased the levels of bax, cytochrome-c, and caspase-3 as markers of apoptosis in acrylamide-treated mice. Conclusion: These findings indicate that carvedilol is able to attenuate acrylamide-induced damage to the CNS by inhibition of oxidative stress, inflammation, and apoptosis.

Methylsulfonylmethane protects against ethanol-induced brain injury in mice through the inhibition of oxidative stress, proinflammatory mediators and apoptotic cell death.

Excessive ethanol consumption causes brain injury through oxidative stress, inflammation and apoptotic cell death. Methylsulfonylmethane (MSM) is a natural compound that has therapeutic effects on oxidative and inflammatory disorders. The aim of this study was to investigate the protective effect and underlying mechanisms of MSM on ethanol-induced brain injury in an experimental model. Male C57BL/6 mice were exposed to binge ethanol (5 g/kg/day, orally) and treated with MSM (200 and 400 mg/kg/day) concomitantly for 12 days. At the end of the experiment brain tissues were removed for histological and biochemical analysis. The results showed that MSM reduced ethanol-mediated oxidative stress by decreasing the levels of malondialdehyde (MDA) and carbonyl protein. The Nrf2/HO-1 pathway and the levels of cytoprotective antioxidants superoxide dismutase (SOD), catalase and glutathione (GSH) were increased by MSM in the brain tissue. MSM treatment reduced the ethanol-induced inflammatory factors including myeloperoxidase (MPO), iNOS/NO, cyclooxygenase (COX)-2, nuclear factor kappa B (NF-κB), NLRP3 inflammasome and proinflammatory cytokines including TNF-α, IL-1ß, IL-6 and MCP-1. MSM also decreased the levels of pro-apoptotic caspase-3 and TUNEL positive cells while increased the level of anti-apoptotic Bcl-2 in the brain tissue. Our findings demonstrated that MSM protects against ethanol-induced brain injury by improving anti-oxidant defense mechanism and reducing ethanol-mediated inflammation and apoptosis. Therefore, MSM may be a potential protective approach for brain damage caused by high levels of alcohol.

Taxonomical Investigation, Chemical Composition, Traditional Use in Medicine, and Pharmacological Activities of Boswellia sacra Flueck.

Aromatic oleo-gum-resin secreted from B. sacra, reputed as frankincense, is widely used in traditional medicine to treat Alzheimer's disease, gastric disorders, hepatic disorders, etc. Frankincense is also used in the cosmetic, perfume, and beverage and food industries. Frankincense is a rich resource for bioactive compounds, especially boswellic acids and derivatives. Although several reports have described frankincense's constituents and pharmacological activities, there is no comprehensive study that covers the valuable information on this species. Therefore, the current review will focus on the phytochemistry, traditional uses, and pharmacological activities of B. sacra.

Acrylamide exposure aggravates the development of ulcerative colitis in mice through activation of NF-κB, inflammatory cytokines, iNOS, and oxidative stress.

OBJECTIVES: Acrylamide is a toxic compound that forms during food processing at high temperatures. Acrylamide has been shown to induce toxicity in various organs in the body. This study aimed to investigate the effect of acrylamide exposure on the susceptibility of the colon to ulcerative colitis in a mouse model. MATERIALS AND METHODS: Mice were pretreated with acrylamide (oral, 20 and 30 mg/kg/day) for 21 consecutive days, and colitis was induced by intrarectal administration of acetic acid. RESULTS: The results revealed that acrylamide-pretreatment significantly increased disease activity index (DAI), macroscopic damage, histological changes of the colonic mucosa and oxidative stress markers carbonyl protein, malondialdehyde (MDA), and nitric oxide (NO), whereas it decreased the levels of anti-oxidants glutathione (GSH), superoxide dismutase (SOD) and catalase. Moreover, induction of colitis in acrylamide-pretreated mice caused a higher increase in colonic levels of myeloperoxidase (MPO), matrix metalloproteinase (MMP)-9, monocyte chemoattractant protein (MCP)-1, cytochrome-c, caspase-3, proinflammatory cytokine tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1ß, and interferon (IFN)-γ, whereas it reduced the level of IL-10. The mRNA expression of nuclear factor kappa B (NF-κB) and inducible nitric oxide synthase (iNOS) were further increased in colon tissue of mice exposed to acrylamide. CONCLUSION: These findings suggest that acrylamide can accelerate the development of acetic acid-induced colitis. In conclusion, chronic acrylamide exposure may aggravate the severity of ulcerative colitis and increase colonic mucosal damage through oxidative stress and inflammatory responses.

The Neuroprotective Effect of Mesna on Cisplatin-Induced Neurotoxicity: Behavioral, Electrophysiological, and Molecular Studies.

Peripheral neuropathy and cognitive impairments following cisplatin administration may interfere with the clinical usage of the drug. Mesna is a chemoprotective agent with anti-inflammatory and anti-oxidant effects. Our study aimed to investigate the protective effects of mesna against cisplatin-induced neurotoxicity. Neurotoxicity was induced by the administration of 2.5 mg/kg cisplatin twice a week for four consecutive weeks in male Wistar rats. The neuroprotective effect of mesna (150 mg/kg/day) was evaluated through behavioral, electrophysiological, and molecular studies. Cisplatin treatment caused passive avoidance memory impairment, increased anxiety-like behaviors, altered thermal sensitivity, and decreased muscle strength in a grip strength test. Our electrophysiological studies indicated that administration of cisplatin induced peripheral sensory neuropathy and decreased the amplitudes of the compound action potential of sensory nerves. Cisplatin administration increased MDA and 4-HNE levels and decreased anti-oxidant (SOD and GPx) enzymes. Proinflammatory cytokines (IL-1ß and TNF-α) and metalloproteinase-2 and 9 (MMP-2/9) were increased by cisplatin treatment. Morphological alterations were observed in the dorsal root ganglion (DRG) of cisplatin-treated rats. Cognitive impairments, anxiety, muscle strength, and thermal sensitivity changes induced by cisplatin were improved with mesna treatment. The reduced conduction velocity in sensory nerves was recovered in the cisplatin + mesna group. Mesna partially alleviated redox imbalance, reduced the proinflammatory cytokines, and MMP-2/9 levels. Mesna administration also relieved the morphological changes in DRG of cisplatin-treated rats. In conclusion, our results revealed that mesna can alleviate cisplatin-induced central and peripheral nervous system toxicity. These results support the concept that chemotherapy-induced neuropathy can be partially inhibited via mesna.

Febuxostat attenuates ulcerative colitis by the inhibition of NF-κB, proinflammatory cytokines, and oxidative stress in mice.

Ulcerative colitis is a chronic inflammatory disorder characterized by oxidative stress and upregulation of proinflammatory mediators in colonic tissue. Febuxostat, a xanthine oxidase inhibitor has been shown to exert anti-inflammatory and antioxidant effects. The aim of this study was to investigate the protective effect of febuxostat against ulcerative colitis, and to elucidate the potential mechanisms involved. Experimental colitis was induced in mice by intrarectal administration of 5% acetic acid. Mice were treated with febuxostat (10 and 20 mg/kg/day, orally) for three days. Results showed that body weight loss, colon shortening, macroscopic damage and histopathological changes of colonic mucosa were reduced in mice treated with febuxostat. Treatment of mice with febuxostat significantly increased the levels of glutathione (GSH) and superoxide dismutase (SOD), and decreased the levels of malondialdehyde (MDA), carbonyl protein, xanthine oxidase, nitric oxide (NO) and myeloperoxidase (MPO) activity of colon tissue compared with those in the acetic acid-induced colitis group. The expression of nuclear factor kappa B (NF-κB) as a key regulator of inflammation in the colonic tissue was decreased by febuxostat. Furthermore treatment with febuxostat significantly reduced the levels of proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6 and interferon (IFN)-γ, while increased the levels of IL-10 compared with the colitis group. These results suggest that febuxostat is able to decrease the severity of acetic acid-induced colitis by inhibition of oxidative stress and inflammatory responses through NF-κB pathway.

Methylsulfonylmethane is effective against gastric mucosal injury.

Methylsulfonylmethane (MSM) is a natural organosulfur compound has been widely used as a dietary supplement. MSM has protective effects against various disorders through its anti-inflammatory and antioxidant properties however the effect of MSM on gastric mucosal injury remains unclear. The aim of the present study is to determine whether MSM has beneficial effects on ethanol/HCl-induced gastric ulcer in mice. Macroscopic and histopathological evaluation of gastric mucosa revealed that ethanol/HCl administration produced apparent mucosal injuries, while pretreatment with MSM (200 and 400mg/kg, orally) could effectively protect gastric mucosa against the injuries caused by acidified ethanol. MSM significantly increased the levels of glutathione (GSH), catalase (CAT) and prostaglandin E2 (PGE2), and decreased the levels of malondialdehyde (MDA), myeloperoxidase (MPO), carbonyl protein, and nitric oxide (NO) in gastric tissues compared with those in the ethanol group. MSM suppressed gastric inflammation by reducing the levels of proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, monocyte chemoattractant protein (MCP)-1 and matrix metalloproteinase (MMP)-9. Moreover, pretreatment of mice with MSM decreased the expression of nuclear factor kappa B (NF-κB) as a key regulator of inflammation in gastric mucosa. Taken together, these data suggest that MSM is able to decrease the severity of ethanol/HCl-induced gastric mucosal injury through inhibition of oxidative stress and inflammation.

Gastroprotective effect of 2-mercaptoethane sulfonate against acute gastric mucosal damage induced by ethanol.

Gastric mucosal damage induced by ethanol is a serious medical problem. Recent evidences suggest that reactive oxygen species and inflammatory mediators play a key role in the destruction of gastric mucosa. The present study was aimed to evaluate the potential beneficial effect of MESNA (2-mercaptoethane sulfonate) against ethanol-induced gastric mucosal damage in mice. The animals were orally pretreated with vehicle or MESNA and then treated with acidified ethanol to induce gastric mucosal damage. One hour after ethanol ingestion mice were euthanized and stomach samples were collected for biochemical analysis. Macroscopic and histopathological evaluation of gastric mucosa showed that pretreatment with MESNA attenuated gastric lesions induced by ethanol. Administration of MESNA significantly increased glutathione content and superoxide dismutase and catalase activity in the gastric tissues. In addition, MESNA markedly reduced ethanol-induced lipid peroxidation, myeloperoxidase activity, tumor necrosis factor-alpha, interleukin (IL)-1ß, IL-6, and monocyte chemotactic protein-1 levels. These findings suggest that the thiol-containing compound MESNA is able to decrease alcohol-induced oxidative stress and inflammation in the gastric tissue. It seems that MESNA may have a protective effect against ethanol-induced gastric mucosal damage.

The effect of thalidomide on ethanol-induced gastric mucosal damage in mice: involvement of inflammatory cytokines and nitric oxide.

Excessive ethanol ingestion causes gastric mucosal damage through the inflammatory and oxidative processes. The present study was aimed to evaluate the protective effect of thalidomide on ethanol-induced gastric mucosal damage in mice. The animals were pretreated with vehicle or thalidomide (30 or 60 mg/kg, orally), and one hour later, the gastric mucosal injury was induced by oral administration of acidified ethanol. The animals were euthanized one hour after ethanol ingestion, and gastric tissues were collected to biochemical analyzes. The gastric mucosal lesions were assessed by macroscopic and histopathological examinations. The results showed that treatment of mice with thalidomide prior to the administration of ethanol dose-dependently reduced the gastric ulcer index. Thalidomide pretreatment significantly reduced the levels of pro-inflammatory cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6], malondialdehyde (MDA) and myeloperoxidase (MPO) activity. In addition, thalidomide significantly inhibited ethanol-induced nitric oxide (NO) overproduction in gastric tissue. Histological observations showed that ethanol-induced gastric mucosal damage was attenuated by thalidomide pretreatment. It seems that thalidomide as an anti-inflammatory agent may have a protective effect against alcohol-induced mucosal damage by inhibition of neutrophil infiltration and reducing the production of nitric oxide and inflammatory cytokines in gastric tissue.

Thalidomide ameliorates cisplatin-induced nephrotoxicity by inhibiting renal inflammation in an experimental model.

Cisplatin is a platinum-based chemotherapy drug. However, its chemotherapeutic use is restricted by serious side effects, especially nephrotoxicity. Inflammatory mechanisms have a significant role in the pathogenesis of cisplatin-induced nephrotoxicity. Thalidomide is an immunomodulatory and anti-inflammatory agent and is used for the treatment of various inflammatory diseases. The purpose of this study was to investigate the potential nephroprotective effect of thalidomide in a mouse model of cisplatin-induced nephrotoxicity. Nephrotoxicity was induced in mice by a single injection of cisplatin (15 mg/kg, i.p.) and treated with thalidomide (50 and 100 mg/kg/day, orally) for 4 days, beginning 24 h prior to the cisplatin injection. Renal toxicity induced by cisplatin was demonstrated by increasing plasma levels of creatinine and blood urea nitrogen (BUN). Cisplatin increased the renal production of the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and transforming growth factor (TGF)-ß1. In addition, kidney levels of malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) were increased by cisplatin. Biochemical results showed that thalidomide reduced cisplatin-induced increase in plasma creatinine and BUN. Thalidomide treatment also significantly reduced tissue levels of the proinflammatory cytokines, MDA, MPO, and NO and increased anti-inflammatory cytokine IL-10. Furthermore, histological examination indicated that thalidomide ameliorated renal damage caused by cisplatin. These data suggest that thalidomide attenuates cisplatin-induced nephrotoxicity possibly by inhibition of inflammatory reactions. Taken together, our findings indicate that thalidomide might be a valuable candidate for the prevention of nephrotoxicity in patients receiving cisplatin.

Anti-inflammatory effect of thalidomide in paraquat-induced pulmonary injury in mice.

Thalidomide has been used in inflammatory and autoimmune disorders due to its anti-inflammatory activity. Paraquat (PQ) poisoning causes severe lung injury. PQ-induced pulmonary inflammation and fibrosis are due to its ability to induce oxidative stress, inflammatory and fibrotic reactions. This study was designed to evaluate the anti-inflammatory and anti-fibrotic effect of thalidomide on PQ-induced lung damage in a mouse model. Mice were injected with a single dose of PQ (20mg/kg, i.p.), and treated with thalidomide (25 and 50mg/kg/day, i.p.) for six days. Lung tissues were dissected six days after PQ injection. The results showed that thalidomide ameliorated the biochemical and histological lung alterations induced by PQ. Thalidomide decreased production of inflammatory and fibrogenic cytokine tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and transforming growth factor (TGF)-ß1. In addition thalidomide reduced myeloperoxidase (MPO), nitric oxide (NO), and hydroxyproline content in lung tissue. Taken together, the results of this study suggest that thalidomide might be a valuable therapeutic drug in preventing the progression of PQ-induced pulmonary injury.

Effect of methylsulfonylmethane on paraquat-induced acute lung and liver injury in mice.

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.