Anti-inflammatory Effects Of Atorvastatin Research Articles

The additional effect of 5% atorvastatin shampoo in the treatment of adult patients with mild to moderate seborrheic dermatitis of the scalp: A prospective, randomised, double-blind trial

Background Seborrheic dermatitis (SD) is a long-lasting inflammatory skin condition that predominantly impacts regions abundant in sebaceous glands, including the scalp. Objectives To assess the efficacy and anti-inflammatory effect of atorvastatin as an additive treatment among SD patients. Materials and Methods In a prospective, randomised, double-blind trial, 46 patients over 18 years old with mild to moderate scalp SD were randomly assigned to receive either 2% ketoconazole shampoo or 2% ketoconazole shampoo plus 5% atorvastatin. The severity of dermatitis was assessed based on the symptom scale of seborrheic dermatitis (SSSD), and the variables of erythema, scaling, and itching, at baseline and 4 weeks after the intervention. Results Based on our analyses, both treatment methods significantly reduced the SSSD scores. However, the average SSSD score in patients using ketoconazole shampoo plus atorvastatin decreased by an average of five points after 1 month. This reduction was comparable to the average decline of 3.5 points observed in the group using ketoconazole shampoo alone. Specifically, the severity of dermatitis, as assessed by the SSSD score, significantly decreased by 1.92 points more, in individuals using the atorvastatin-containing shampoo compared to the comparison group (P = 0.02). Limitation This research was conducted at a single centre which limits the validity of the findings. Conclusion The results of this study suggest that shampoo containing atorvastatin provides a statistically significant effect compared to ketoconazole shampoo alone, indicating its potential as an alternative treatment for SD. The treatment notably alleviates symptoms associated with scaling and itching which are the common manifestations of the condition.

Anti-Inflammatory Effect of Atorvastatin and Rosuvastatin on Monosodium Urate-Induced Inflammation through IL-37/Smad3-Complex Activation in an In Vitro Study Using THP-1 Macrophages.

Objective: The pleiotropic effect of hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) is responsible for potent defense against inflammatory response. This study evaluated the inhibitory effects of HMG-CoA reductase inhibitors on the monosodium urate (MSU)-induced inflammatory response through the regulation of interleukin-37 (IL-37) expression. Methods: Serum was collected from patients with gout (n = 40) and from healthy controls (n = 30). The mRNA and protein expression of the target molecules IL-1β, IL-37, caspase-1, and Smad3 were measured in THP-1 macrophages stimulated with MSU, atorvastatin, or rosuvastatin using a real-time quantitative polymerase chain reaction and Western blot assay. Transfection with IL-1β or Smad3 siRNA in THP-1 macrophages was used to verify the pharmaceutical effect of statins in uric-acid-induced inflammation. Results: Serum IL-37 levels in gout patients were significantly higher than in controls (p < 0.001) and was associated with the serum uric acid level (r = 0.382, p = 0.008). THP-1 cells stimulated with MSU markedly induced IL-37 mRNA expression and the transition of IL-37 from the cytoplasm to the nucleus. Recombinant IL-37 treatment dose-dependently inhibited activation of caspase-1 and IL-1β in MSU-induced inflammation. Atorvastatin and rosuvastatin attenuated caspase-1 activation and mature IL-1β expression but augmented translocation of IL-37 from the cytoplasm to the nucleus. Atorvastatin and rosuvastatin induced phosphorylation of Smad3 in THP-1 cells treated with MSU crystals. Statins potently attenuated translocation of IL-37 from the cytoplasm to the nucleus in THP-1 macrophages transfected with Smad3 siRNA compared to cells with negative control siRNA. Conclusions: This study revealed that statins inhibit the MSU-induced inflammatory response through phosphorylated Smad3-mediated IL-37 expression in THP-1 macrophages.

Anti-Inflammatory Effect of Atorvastatin on Primary Human Endothelial Cells Incubated under Genotoxic Load.

The level of cytokine expression was measured in human coronary artery (HCAEC) and internal thoracic artery (HITAEC) endothelial cells exposed to 500 ng/ml alkylating mutagen mitomycin C (MMC) and 5 μM atorvastatin. It was found that treatment of MMC-exposed HCAEC with atorvastatin decreased secretion of macrophage migration inhibitory factor (MIF), IL-8, and IL8 gene expression, but increased the expression of SERPINE1 gene encoding the PAI-1 protein. In atorvastatin-treated HITAEC, the concentration of MIF protein and the expression of the IL8 and SERPINE1 genes were reduced. We can conclude that atorvastatin prevents proinflammatory activation of endothelial cells cultured under conditions of genotoxic load. However, the molecular mechanisms of this effect require further research.

Anti-Inflammatory Effect of Atorvastatin on Colitis Induced in Male Mice

Abstract Background: Statins are approved for cholesterol reduction and may also be beneficial in the management of inflammatory diseases. Another essential pleiotropic effect of β-hydroxy β-methylglutaryl-CoA (HMG-CoA) reductase inhibitors is their anti-inflammatory properties. Statins lower C-reactive protein (CRP) levels while also inhibiting inflammatory mediators like tumor necrosis factor-alpha and interleukins including interleukin-6 (IL-6). Objective: The purpose of this study was to determine the relationship between the severity index and other inflammatory markers in animals with colitis and to investigate the possible effects of atorvastatin on disease activity index and the inflammatory markers in experimentally induced colitis. Materials and Methods: Mice were given acetic acid to induce colitis. For 7 days, mice were divided into four groups (control group, induction group, standard group treated with prednisolone, and atorvastatin-treated group) and monitored daily for weight loss, feces consistency, and rectum bleeding for measuring the disease activity index. At last, we killed the animals and took blood samples for IL-6. Results: Acetic acid caused significant colonic inflammatory response and shrinking, as well as a reduction in body weight. The use of atorvastatin to treat acetic acid-induced colitis resulted in weight-loss recovery and decrease in expression concentration of IL-6 in the treated group compared with the colitis group when using in high dose. Conclusion: These findings indicate that atorvastatin preserves intestinal integrity in colitis, most likely by modifying the Th cell-mediated immune response independently of innate immunity.

ZeXieYin formula alleviates atherosclerosis by inhibiting the MAPK/NF-κB signaling pathway in APOE−/− mice to attenuate vascular inflammation and increase plaque stability

Ethnopharmacological relevanceZexieyin formula (ZXYF), a traditional Chinese herbal formula recorded in the Huangdi Neijing to have efficacy in relieving spleen dampness and heat accumulation syndrome, which is also the key pathogenesis of atherosclerosis (AS). The efficacy has demonstrated by our previous studies. However, the intrinsic mechanism of ZXYF for treating vascular inflammation and the effect of inflammatory response on plaque are not known. Currently, plaque stabilization is crucial for the prognosis of AS. Aim of the studyOur study mainly focused on the therapeutic effects of ZXYF on high-fat diet (HFD)-induced vascular inflammation and vulnerable plaques (VP) in mice and explored its underlying mechanism. Methods and materialsMale apolipoprotein E knockout (APOE−/−) mice were fed HFD for 8 weeks to establish a VP model. During this period, the mice were also administered ZXYF, while atorvastatin (ATO) was used as a positive control. Aortic plaque area and morphology were detected by oil red staining and HE staining. Aortic plaque collagen content was detected by Masson staining. M1/M2 type macrophages were detected using immunofluorescence (IF). The study analyzed the levels of inflammation-related cytokines (IL-1β, IL-10, IL-6), MAPK/NF-κB pathway proteins, and NLRP3 inflammasomes (NLRP3, Caspase-1) using Western blot. Additionally, the levels of matrix metalloproteinase (MMP)-2 and MMP-9 and α-smooth muscle actin (α-SMA) in the aorta were analyzed using immunohistochemistry (IHC). The plaque instability index was calculated for each group using the vulnerable plaque formula. ResultsIn this study, APOE−/− mice were fed high-fat diet for 8 weeks. The results of oil-red and HE staining indicated a significant increase in the aortic plaque area of the mice, which exhibited a typical VP phenotype. ZXYF and ATO significantly improved AS plaques and prevented plaque rupture. HFD exacerbated vascular inflammation, stimulated macrophage conversion to M1-type through the MAPK/NF-κB signaling pathway, and released pro-inflammatory factors such as interleukin (IL)-1β, IL-1α, and IL-6. These factors activated NLRP3 inflammasome, leading to cellular death. However, ZXYF could reverse this trend and promote the conversion of macrophages to the anti-inflammatory M2 type. The anti-inflammatory effect of ATO was not significant. Moreover, HFD promoted the release of MMP-2 and MMP-9 from macrophages, which degraded plaque collagen, and induced a decrease in plaque SMC content, resulting in a thinning of the plaque fibrous cap. In contrast, ZXYF inhibited the decomposition of plaque collagen and increased the content of plaque smooth muscle cells (SMC) by reducing macrophage secretion of MMPs, thereby stabilizing plaques. Although ATO could reverse the decrease in plaque collagen and SMC content, its effect on MMPs was not significant. Finally, we calculated the vulnerability index to assess the overall risk of the plaque vulnerability phenotype. In line with these findings, ZXYF and ATO were able to effectively reverse the increase in the vulnerability index caused by HFD and lower the risk of adverse cardiovascular events. ConclusionOur results suggested that ZXYF could reduce inflammation and increase plaque stability by inhibiting the MAPK/NF-κB signaling pathway, which provided a theoretical basis for clinical application and subsequent research.

Оценка противовоспалительного эффекта аторвастатина на примере культур первичных эндотелиальных клеток человека, культивируемых в условиях генотоксической нагрузки

Оценка противовоспалительного эффекта аторвастатина на примере культур первичных эндотелиальных клеток человека, культивируемых в условиях генотоксической нагрузки

Atorvastatin ameliorated myocardial fibrosis in db/db mice by inhibiting oxidative stress and modulating macrophage polarization.

People with diabetes mellitus (DM) suffer from multiple chronic complications due to sustained hyperglycemia, especially diabetic cardiomyopathy (DCM). Oxidative stress and inflammatory cells play crucial roles in the occurrence and progression of myocardial remodeling. Macrophages polarize to two distinct phenotypes: M1 and M2, and such plasticity in phenotypes provide macrophages various biological functions. To investigate the effect of atorvastatin on cardiac function of DCM in db/db mice and its underlying mechanisms. DCM mouse models were established and randomly divided into DM, atorvastatin, and metformin groups. C57BL/6 mice were used as the control. Cardiac function was evaluated by echocardiography. Hematoxylin and eosin and Masson staining was used to examine the morphology and collagen fibers in myocardial tissues. The expression of transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α), interleukin-1 β (IL-1β),M1 macrophages (iNOS+), and M2 macrophages (CD206+) were demonstrated by immunohistochemistry and immunofluorescence staining. The levels of TGF-β1, IL-1β, and TNF-α were detected by ELISA and real-time quantitative polymerase chain reaction. Malondialdehyde (MDA) concentrations and superoxide dismutase (SOD) ac-tivities were also measured. Treatment with atorvastatin alleviated cardiac dysfunction and decreased db/db mice. The broken myocardial fibers and deposition of collagen in the myocardial interstitium were relieved especially by atorvastatin treatment. Atorvastatin also reduced the levels of serum lactate dehydrogenase, creatine kinase isoenzyme, and troponin; lowered the levels of TGF-β1, TNF-α and IL-1β in serum and myocardium; decreased the concentration of MDA and increased SOD activity in myocardium of db/db mice; inhibited M1 macrophages; and promoted M2 macrophages. Administration of atorvastatin attenuates myocardial fibrosis in db/db mice, which may be associated with the antioxidative stress and anti-inflammatory effects of atorvastatin on diabetic myocardium through modulating macrophage polarization.

The anti-inflammatory effects of atorvastatin upon the outcome of traumatic brain injury patients: A randomized-controlled double-blind clinical trial

ABSTRACT Background Traumatic brain injury (TBI) is a quite common health problem. A lot of delayed complications are related to inflammatory responses that occurred within the brain itself. Atorvastatin is related to lipid lowering drugs carrying some anti-inflammatory properties and upon this fact this study hypothesis was built. Methods Twenty adult patients with TBI, Glasgow coma scale (GCS) 9–11. Patients were equally and randomly allocated into two groups (group C as control group and group S received atorvastatin 40 mg once daily for 48 h). After 48 h, participants have undergone magnetic resonance imaging brain spectroscopy examination (MRS). The spectral peaks of N-Acetyl aspartate (NAA), Choline, and Creatinine (Cr) were assessed in brain tissue. The primary outcome was presented as ratios of NAA/Cr), Cho/Cr, and NAA/Cho. Other outcomes included GCS and ICU stay. Results There were insignificant variations between groups were found in the MRS results for metabolite alterations (NAA, Cr, and Cho). Contrasted with the control group, the statin group’s Cho/Cr ratio was significantly lower (P = 0.005), and NAA/Cho was significantly greater in the statin group than control group (P = 0.022). Statin group showed higher GCS the 1st day (P = 0.01), and lesser ICU stay (P = 0.04) Conclusion Atorvastatin can be used safely in mild-to-moderate TBI patients with a favourable outcome in the form of decreased Cho/Cr ratio and increased NAA/Cho ratio, higher GCS, and decreased ICU length of stay.

The effect of atorvastatin on inflammatory markers in sulfur mustard gas induced bronchitis: a randomized double-blinded, placebo-control clinical trial

BackgroundThis study was performed to evaluate the anti-inflammatory effect of atorvastatin in patients with chronic bronchitis, exposed to sulfur mustard gas.MethodsIn this randomized double-blinded clinical trial we recruited patients with chronic bronchitis after exposure to sulfur mustard gas. Ninety men 45–75 years old diagnosed with chronic bronchitis after exposure to mustard gas during the Iran-Iraq war, were randomly assigned to receive either atorvastatin (40 mg) or placebo once a day for 3 months. The interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), procalcitonin, highly sensitive CRP and COPD assessment test (CAT) score was compared at baseline and after 12 weeks.ResultsAfter consuming atorvastatin for 12 weeks, IL-6 level (mean difference [95%CI]; 0.2 [− 0.05, 0.5]), TNF-α (mean difference [95%CI]; − 0.07 [− 0.2, 0.07]), high sensitive CRP (mean difference [95%CI] − 0.1 [− 1.2, 0.9]), and procalcitonin (mean difference [95%CI]; 0.003 [− 0.02, 0.03]) did not change significantly. However, in the placebo group, only IL-6 (mean difference [95%CI]; 0.6 [0.2, 1.05]) decreased significantly after 12 weeks, but levels of high sensitive CRP (mean difference [95%CI]; − 0.3 [− 1.4, 0.8]) TNF-α (mean difference [95%CI]; − 0.2 [− 0.34, − 0.06]) and procalcitonin (mean difference [95%CI]; 0.02 [− 0.001, 0.04]) did not change significantly. After 12 weeks, the mean differences in TNF- α, IL-6 level, high sensitive CRP, procalcitonin, and CAT score did not significantly differ between the two groups.ConclusionsThe administration of 40 mg atorvastatin for 3 months did not significantly change the inflammatory markers or the quality of life of patients exposed to mustard gas with chronic bronchitis.Trial registration: IRCT, IRCT138904144312N1. Registered 16 August 2014, https://en.irct.ir/trial/4577.

Atorvastatin alleviates microglia-mediated neuroinflammation via modulating the microbial composition and the intestinal barrier function in ischemic stroke mice

Our previous work has shown that atorvastatin exerts anti-inflammatory properties in ischemic stroke, and recent studies have revealed that intestinal microbiota plays a vital role in the pathogenesis of stroke. However, it is not clear whether the anti-inflammatory effects of atorvastatin against ischemic stroke is related to gut function and microbiota. We report herein that atorvastatin significantly ameliorated the defects in sensorimotor behaviors and reduced microglia-mediated neuroinflammation by inhibiting proinflammatory polarization of microglia in the peri-infarct cortex of the mice with permanent middle cerebral artery occlusion (pMCAO). Moreover, atorvastatin reversed microbial composition (characterized by increased abundance of Firmicutes and Lactobacillus and decreased Bacteroidetes abundance), increased fecal butyrate level, promoted intestinal barrier function (elevated protein levels of claudin-1, occludin and mucoprotein 2), as well as regulated intestinal immune function (decreased MCP-1, TNF-α and increased IL-10). Atorvastatin also significantly reduced the level of circulating endotoxin (lipopolysaccharide-binding protein), which is a biomarker of leaky gut. Transplantation of fecal microbiota collected from atorvastatin treated mice potently attenuated neuroinflammation in pMCAO mice, and the anti-inflammatory effects of fecal microbiota transplantation were similar to those of oral atorvastatin administration. These results suggested that the atorvastatin-mediated restoration of gut microbiota, improvement of intestinal barrier function and regulation of intestinal immunity were involved in the anti-inflammatory function in stroke mice.

Effect of atorvastatin on inflammatory markers in hemodialysis patients

BackgroundCardiovascular disease is the commonest cause of death in patients with end-stage renal disease (ESRD) under maintenance hemodialysis. Dyslipidemia, oxidative stress, and low-grade inflammation with increased circulating cytokines are factors that increase the cardiovascular risk in patients with chronic kidney disease, in addition to traditional risk factors, such as obesity, hypertension, and diabetes. We aimed to investigate the possible anti-inflammatory effects of atorvastatin in prevalent hemodialysis patients. Fifty-three stable adult hemodialysis patients were assigned into two groups (a drug group and a control group). Patients in the drug group received 20 mg of atorvastatin daily for 6 months. Serum levels of highly sensitive C-reactive protein (hs-CRP) and interleukin-6 (IL-6) were measured in both groups at baseline and at the end of the study period.ResultsAtorvastatin therapy caused a statistically significant decrease in levels of hs-CRP but no change in levels of IL-6 after 6 months of therapy.ConclusionsIn addition to its favorable effect on lipid profile parameters, atorvastatin therapy can be considered as an effective and safe modality to overcome the problem of chronic inflammation encountered in end-stage renal disease patients.

Influence of the Nursing Effect on the Antiinflammatory Effect of Atorvastatin in Acute Cerebral Infarction

To observe the antiinflammatory effect and nursing effect of atorvastatin on acute cerebral infarction, 180 patients with acute cerebral infarction who were treated in the Chengdu Fifth People’s Hospital were selected as research subjects. They were divided into the control group (90) which received the routine treatment and the research group which was given atorvastatin treatment (90 cases). In addition, the patients in the research group were provided with a comprehensive nursing intervention program, while the control group was given routine nursing mode. The therapeutic effects and nursing effects of the two groups were compared. By comparing the serum lipid-related indices of the two groups, it was found that the patients in the research group had a significant advantage over the control group. Through observing and comparing the levels of markers of immune inflammation, the improvement in the serum tumor necrosis factor level, IL-6 and intercellular adhesion molecule 1 concentrations in the research group was more significant, P<0.05. In addition, the comprehensive life quality evaluation score and FMA exercise ability score of the research group showed significant advantages, P<0.05. For patients with acute cerebral infarction, atorvastatin treatment can produce good antiinflammatory effect and the treatment effect can be significantly improved after adopting scientific nursing measures.

Correction: Heme oxygenase-1—Dependent anti-inflammatory effects of atorvastatin in zymosan-injected subcutaneous air pouch in mice

[This corrects the article DOI: 10.1371/journal.pone.0216405.].

Effect of atorvastatin on behavioral alterations and neuroinflammation during epileptogenesis

Temporal lobe epilepsy (TLE) is the most frequent and medically refractory type of epilepsy in humans. In addition to seizures, patients with TLE suffer from behavioral alterations and cognitive deficits. Poststatus epilepticus model of TLE induced by pilocarpine in rodents has enhanced the understanding of the processes leading to epilepsy and thus, of potential targets for antiepileptogenic therapies. Clinical and experimental evidence suggests that inflammatory processes in the brain may critically contribute to epileptogenesis. Statins are inhibitors of cholesterol synthesis, and present pleiotropic effects that include antiinflammatory properties. We aimed the present study to test the hypothesis that atorvastatin prevents behavioral alterations and proinflammatory state in the early period after pilocarpine-induced status epilepticus. Male and female C57BL/6 mice were subjected to status epilepticus induced by pilocarpine and treated with atorvastatin (10 or 100mg/kg) for 14days. Atorvastatin slightly improved the performance of mice in the open-field and object recognition tests. In addition, atorvastatin dose-dependently decreased basal and status epilepticus-induced levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interferon-γ (INF-γ) and increased interleukin-10 (IL-10) levels in the hippocampus and cerebral cortex. The antiinflammatory effects of atorvastatin were qualitatively identical in both sexes. Altogether, these findings extend the range of beneficial actions of atorvastatin and indicate that its antiinflammatory effects may be useful after an epileptogenic insult.

Erratum to: Anti-inflammatory Effects of Atorvastatin in Human Glioblastoma Spheroids Cultured in a Three-dimensional Model: Possible Relevance to Glioblastoma Treatment.

Glioblastoma multiform (GBM) is a primary malignant brain tumor with a few therapeutic targets available for it. The interaction between the immune system and glioma is an important factor that could lead to novel therapeutic approaches to fight glioma. In this study, we investigated in vitro anti-inflammatory and apoptotic activity of atorvastatin in different concentrations 1, 5, and 10 μM on glioma spheroid cells cultured in a three-dimensional model in fibrin gel that indicate the complex in vivo microenvironment better than a simple two-dimensional cell culture. A mechanistic insight into the role of IL-17RA, TRAF3IP2, and apoptotic genes in progression of glioma could provide an important way for therapy of malignant tumors with manipulation of this inflammatory axis. To reach for these aims, after 24 and 48 h exposure with different concentrations of atorvastatin, caspase-8, caspase-3, Bcl-2, TRAF3IP2, and IL-17RA gene expression were assayed. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and cell cycle assay were used for evaluating the cell apoptosis and proliferation. The results showed that atorvastatin has anti-inflammatory and apoptotic effects against glioma spheroids. Atorvastatin induced the expression of caspase-3 and caspase-8 and downregulated the expression of Bcl-2, TRAF3IP2, and IL-17RA especially at 10 μM concentration. These effects are dose dependent. The most likely mechanisms are the inhibition of inflammation by IL-17RA interaction with TRAF3IP2 and NF-κB signaling pathway. Finally, these results suggest that atorvastatin could be used as an anti-cancer agent for glioblastoma treatment.

Atorvastatin reduces cardiac and adipose tissue inflammation in rats with metabolic syndrome

BackgroundStatins are strong inhibitors of cholesterol biosynthesis and help to prevent cardiovascular disease. They also exert additional pleiotropic effects that include an anti-inflammatory action and are independent of cholesterol, but the molecular mechanisms underlying these additional effects have remained unclear. We have now examined the effects of atorvastatin on cardiac and adipose tissue inflammation in DahlS.Z-Leprfa/Leprfa (DS/obese) rats, which we previously established as a model of metabolic syndrome (MetS). Methods and resultsDS/obese rats were treated with atorvastatin (6 or 20mgkg−1day−1) from 9 to 13weeks of age. Atorvastatin ameliorated cardiac fibrosis, diastolic dysfunction, oxidative stress, and inflammation as well as adipose tissue inflammation in these animals at both doses. The high dose of atorvastatin reduced adipocyte hypertrophy to a greater extent than did the low dose. Atorvastatin inhibited the up-regulation of peroxisome proliferator–activated receptor γ gene expression in adipose tissue as well as decreased the serum adiponectin concentration in DS/obese rats. It also activated AMP-activated protein kinase (AMPK) as well as inactivated nuclear factor–κB (NF-κB) in the heart of these animals. The down-regulation of AMPK and NF-κB activities in adipose tissue of DS/obese rats was attenuated and further enhanced, respectively, by atorvastatin treatment. ConclusionsThe present results suggest that the anti-inflammatory effects of atorvastatin on the heart and adipose tissue are attributable at least partly to increased AMPK activity and decreased NF-κB activity in this rat model of MetS.

Anti-inflammatory Effects of Atorvastatin in Human Glioblastoma Spheroids Cultured in a Three-dimensional Model: Possible Relevance to Glioblastoma Treatment.

Glioblastoma multiform (GBM) is a primary malignant brain tumor with a few therapeutic targets available for it. The interaction between the immune system and glioma is an important factor that could lead to novel therapeutic approaches to fight glioma. In this study, we investigated in vitro anti-inflammatory and apoptotic activity of atorvastatin in different concentrations 1, 5, and 10μM on glioma spheroid cells cultured in a three-dimensional model in fibrin gel that indicate the complex in vivo microenvironment better than a simple two-dimensional cell culture. A mechanistic insight into the role of IL-17RA, TRAF3IP2, and apoptotic genes in progression of glioma could provide an important way for therapy of malignant tumors with manipulation of this inflammatory axis. To reach for these aims, after 24 and 48h exposure with different concentrations of atorvastatin, caspase-8, caspase-3, Bcl-2, TRAF3IP2, and IL-17RA gene expression were assayed. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and cell cycle assay were used for evaluating the cell apoptosis and proliferation. The results showed that atorvastatin has anti-inflammatory and apoptotic effects against glioma spheroids. Atorvastatin induced the expression of caspase-3 and caspase-8 and downregulated the expression of Bcl-2, TRAF3IP2, and IL-17RA especially at 10μM concentration. These effects are dose dependent. The most likely mechanisms are the inhibition of inflammation by IL-17RA interaction with TRAF3IP2 and NF-κB signaling pathway. Finally, these results suggest that atorvastatin could be used as an anti-cancer agent for glioblastoma treatment.

Involvement of peroxisome proliferator activated receptor-γ in the anti-inflammatory effects of atorvastatin in oxygen-glucose deprivation/reperfusion-stimulated RAW264.7 murine macrophages

Ischemia-reperfusion (I/R) injury is important in the pathogenesis and/or progression of various diseases, including stroke, cardiovascular disease and acute renal injury. Increasing evidence indicates that atorvastatin exerts protective effects in I/R injury-associated diseases; however, the underlying mechanisms remain to be fully elucidated. In the present study, oxygen-glucose deprivation (OGD)/reperfusion-stimulated. RAW264.7 murine macrophages served as a model of I/R injury. The knockdown of peroxisome proliferator activated receptor-γ (PPARγ) expression in these cells increased OGD/reperfusion-induced expression of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), and enhanced OGD/reperfusion-induced downregulation of the expression of cluster of differentiation (CD) 206, at the mRNA and protein levels. Conversely, overexpression of PPARγ significantly attenuated OGD/reperfusion-induced alterations in the expression of iNOS, TNF-α, IFN-γ and CD206 at the mRNA and protein levels. Notably, atorvastatin inhibited OGD/reperfusion-induced iNOS expression and reversed OGD/reperfusion-induced downregulation of the expression of CD206 and PPARγ at the mRNA and protein levels. The results of the present study indicate that atorvastatin exhibits significant anti-inflammatory effects in OGD/reperfusion-stimulated RAW264.7 cells, possibly via PPARγ regulation. The findings of the present study may reveal a novel mechanism underlying the protective effects of atorvastatin in I/R injury-associated diseases.

Atorvastatin attenuates TNBS-induced rat colitis: the involvement of the TLR4/NF-kB signaling pathway.

The aim of the present study is to explore whether atorvastatin improves intestinal inflammation through the inhibition of the TLR4/NFkB signaling pathway in TNBS-induced rat colitis. Acute colitis was induced by intra-rectal administration of 100mg/kg TNBS dissolved in 0.25ml of 50% ethanol. Twenty four hours after colitis induction, saline, atorvastatin (20 and 40mg/kg) and sulfasalazine (100mg/kg) were given to the animals by oral route. This was repeated daily for 1week. Body weight changes, macroscopic and microscopic lesions were assessed. MPO and TNF-α activities were detected by immunohistochemistry (IHC) and the expression level of TLR4, MyD88 and NF-κB p65 proteins were measured by western blotting analysis. Atorvastatin and sulfasalazine reduced the body weight loss, macroscopic and microscopic lesions. Additionally, both drugs decreased the expression of MPO and TNF-α positive cells in the colon tissue. Furthermore, they inhibited the TNBS-induced expression of TLR4, MyD88 and NF-κB p65 proteins. It is suggested that the anti-inflammatory effect of atorvastatin on TNBS-induced rat colitis may involve the inhibition of the TLR4/NFkB signaling pathway.

Statins attenuate hyperalgesia and inflammation in experimentally induced acute and neuropathic pain in rats

Background Available medications for the treatment of neuropathic pain, such as steroidal anti-inflammatory drugs and NSAIDs, were shown to be of limited therapeutic benefit. Objectives This study aimed to evaluate the analgesic and anti-inflammatory effects of atorvastatin and pravastatin in acute and neuropathic pain in rats. Materials and methods Acute and neuropathic pains were induced in rat models by means of subplantar carrageenan injection and partial sciatic nerve ligation (PSNL), respectively. The anti-inflammatory effect of statins was assessed by the reduction in plantar edema (at 0, 1, 2, and 3 h) and prolongation of paw withdrawal reaction time in response to thermal stimulation (at 0, 0.5, 1, 2, 3, and 4 h) after carrageenan injection. Atorvastatin (2, 4, or 8 mg/kg) and pravastatin (4, 8, or 12 mg/kg) were administered intraperitoneally 30 min before carrageenan injection. The effect of statins on neuropathic pain was assessed by prolongation of paw withdrawal reaction time in response to thermal stimulation evaluated at 0, 3, 6, 9, 12, 15, and 18 days after PSNL. Atorvastatin (2, 4, or 8 mg/kg) and pravastatin (4, 8, or 12 mg/kg) were administered orally for 18 consecutive days after PSNL. In addition, the effect of atorvastatin and pravastatin on total cholesterol and tumor necrosis factor-α levels was also assessed. Results Both atorvastatin and pravastatin ameliorated carrageenan-induced rat paw edema and prolonged withdrawal time in response to thermal-induced pain. Both statins were also effective in ameliorating neuropathic pain induced by PSNL. These effects were independent of statin-induced hypolipidemic action but were concomitant with reduction of serum tumor necrosis factor-α levels. Conclusion Atorvastatin and pravastatin demonstrated effective therapeutic potentials to reduce acute and chronic pain together with the associated inflammation and hyperalgesia independent of their hypolipidemic effect.