基于p38 MAPK信号通路探讨生慧颗粒对AD模型大鼠EC与CA1区影响及作用机制

目的观察生慧颗粒对东莨菪碱致痴呆模型大鼠EC与CA1区影响,基于p38 MAPK信号通路探讨其作用机制。方法40只SD大鼠随机分为空白组、模型组、生慧颗粒组、多奈哌齐组4组,使用东莨菪碱进行造模处理。使用Morris水迷宫及旷场实验对大鼠认知及焦虑行为进行评价。使用HE染色观察EC与CA1区神经损伤。使用c-Fos免疫荧光染色观察EC与CA1区神经元活性。使用Western blot对p38MAPK通路相关蛋白进行检测。结果行为学实验发现生慧颗粒可以改善AD模型大鼠认知障碍及焦虑样行为。HE染色结果表明生慧颗粒对EC与CA1区具有保护作用。c-Fos免疫荧光染色结果表明生慧颗粒可提高EC与CA1区神经元活性。Western blot结果发现生慧颗粒可以下调海马Bax蛋白表达及p38、Tau磷酸化水平,提高Bcl-2蛋白表达。结论生慧颗粒对AD模型大鼠EC与CA1区均具有保护作用,可能通过p38MAPK信号通路起到治疗作用。

隔药灸对克罗恩病大鼠结肠p38MAPK、ERK1/2及c-fos调节作用的研究

目的观察隔药灸对克罗恩(Crohns Disease,CD)大鼠结肠p38MAPK、ERK1/2、c-fos的影响,探讨隔药灸治疗CD的作用机制。方法将清洁级雄性SD大鼠随机分为正常组、模型组、隔药灸组和假灸组4组。采用TNBS合50%乙醇溶液灌肠制备大鼠CD模型。模型制备成功后,隔药灸组取天枢穴(双)、气海穴进行隔药饼灸治疗;假灸组取穴、操作与隔药灸组相同,但不点燃艾炷。治疗结束后,采用HE染色,光镜下观察大鼠结肠组织形态学变化;采用实时荧光定量PCR技术检测结肠p38MAPK mRNA表达;应用ELISA技术检测结肠p38MAPK、c-fos蛋白含量,Western blot技术检测结肠ERK1/2蛋白表达。结果与正常组比较,模型组大鼠结肠组织损伤严重,可见全壁性炎症、裂隙状溃疡,部分大鼠结肠可见纤维化;与模型组、假灸组比较,隔药灸组大鼠结肠形态结构改善,肠道炎症减轻;假灸组大鼠结肠损伤程度、炎症反应与模型组类似。与正常组比较,模型组p38MAPK mRNA表达增加(P <0.01),p38MAPK、ERK1/2、c-fos蛋白含量均增加(均P <0.05);与模型组比较,隔药灸组p38MAPK mRNA表达降低(P <0.05),p38MAPK、ERK1/2、c-fos蛋白含量均降低(均P <0.05);假灸组均无显著变化(均P> 0.05)。结论隔药灸能下调克罗恩病大鼠结肠p38MAPK、ERK1/2、c-fos的表达,改善炎症、促进肠道组织修复。

连翘苷对牙周炎大鼠p38 MAPK/c-Fos信号通路及破骨细胞活化的影响

目的:探讨连翘苷对牙周炎大鼠p38丝裂原活化蛋白激酶(p38 MAPK)/c-Fos信号通路及破骨细胞活化的影响。方法:建立牙周炎大鼠模型,随机分为模型组、连翘苷低剂量组、连翘苷中剂量组、连翘苷高剂量组、维生素C组,每组12只,另取12只设为对照组,分组处理后,亚甲蓝染色检测大鼠牙槽骨吸收(釉牙骨质界到牙槽嵴顶距离)情况;HE染色检测各组大鼠牙周组织病理形态;TRAP染色检测各组大鼠牙周组织中破骨细胞数目;酶联免疫吸附试验(ELISA)检测大鼠血清肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)水平;蛋白免疫印迹实验检测大鼠牙周组织p38 MAPK/c-Fos通路相关蛋白表达情况。结果:与对照组相比,模型组大鼠牙周组织呈现上皮残缺、破裂,形态异常,牙周膜纤维排列紊乱,可见炎性细胞浸润等病理损伤,釉牙骨质界到牙槽嵴顶距离、破骨细胞数目、TNF-α、IL-6水平、牙周组织p38 MAPK/c-Fos通路相关蛋白c-Fos表达、p-p38 MAPK/p38 MAPK明显升高(P<0.05)。与模型组相比,连翘苷低、中、高剂量组及维生素C组大鼠牙周组织病理损伤减轻,釉牙骨质界到牙槽嵴顶距离、破骨细胞数目、TNF-α、IL-6水平、牙周组织c-Fos蛋白表达、p-p38 MAPK/p38 MAPK降低,且连翘苷各组呈剂量依赖性(P<0.05),连翘苷高剂量组与维生素C组相比,差异无统计学意义(P>0.05)。结论:连翘苷可下调p38 MAPK/c-Fos信号通路,抑制牙周炎症及破骨细胞活化,减轻牙周组织损伤,改善牙周炎大鼠症状。

Betulinic acid protects against ovarian impairment by decreasing F-2 toxin-induced oxidative stress and inflammation associated with the downregulation of p38 expression in mice

F-2 toxin is an estrogenic mycotoxin that causes reproductive disorders in animals.Betulinic acid(BA)is a natural pentacyclic lupane-structure triterpenoid that has diverse pharmacological activities.In this study,the antioxidative and anti-inflammatory effects of BA and its underlying mechanism are explored in F-2 toxin-triggered mouse ovarian damage.We found that BA alleviated the F-2 toxin-induced ovarian impairment by stimulating follicle growth,reducing inflammatory cell infiltration,repairing damaged mitochondria and endoplasmic reticulum.Simultaneously,BA not only reversed F-2 toxin-induced reduction of follicle stimulating hormone(FSH)and luteinizing hormone(LH)levels in the serum,but also restrained the protein expression of the estrogen receptors a(ERa)and ERβ.Moreover,BA restored the balance of F-2 toxin-induced ovarian redox system disorders.Subsequently,we found that 0.25 mg/kg BA played an anti-inflammatory role in the F-2 toxin-induced ovarian impairment by decreasing interleukin-1β(IL-1β).IL-6,and tumor necrosis factor-α(TNF-α)mRNA expression,as well as inhibiting p38 protein expression.These data demonstrated that BA exerts its protective effect on F-2 toxin-induced ovarian oxidative impairment and inflammation by inhibiting p38 expression,which implies a natural product-based medicine to ameliorate F-2 toxin-caused female reproductive toxicity and provides a detoxifying method for food contaminated by mycotoxin.

p38 MAPK is a Component of the Signal Transduction Pathway Triggering Cold Stress Response in the MED Cryptic Species of Bemisia tabaci

Cold stress responses help insects to survive under low temperatures that would be lethal otherwise.This phenomenon might contribute to the invasion of some Bemisia tabaci cryptic species from subtropical areas to temperate regions.However,the molecular mechanisms regulating cold stress responses in whitefly are yet unclear.Mitogen-activated protein kinases（MAPKs）which including p38,ERK,and JNK,are well known for their roles in regulating metabolic responses to cold stress in many insects.In this study,we explored the possible roles of the MAPKs in response to low temperature stresses in the Mediterranean cryptic species（the Q-biotype）of the B.tabaci species complex.First,we cloned the p38 and ERK genes from the whitefly cDNA library.Next,we analyzed the activation of MAPKs during cold stress in the Mediterranean cryptic species by immuno-blotting.After cold stress,the level of phospho-p38 increased but no significant change was observed in the phosphorylation of ERK and JNK,thus suggesting that the p38 might be responsible for the defense response to low temperature stress.Furthermore,we demonstrated that：i）3 min chilling at 0°C was sufficient for the activation of p38 MAPK pathway in this whitefly;and ii）the amount of phosphorylated p38 increased significantly in the first 20 min of chilling,reversed by 60 min,and then returned to the original level by 120 min.Taken together,our results suggest that the p38 pathway is important during response to low temperature stress in the Mediterranean cryptic species of the B.tabaci species complex.

To investigate the effects of butylphthalide on reducing neuronal apoptosis in rats with cerebral infarction by inhibiting the JNK/P38 MAPK signaling pathway

Objective:To investigate the effects of butylphthalide on reducing neuronal apoptosis in rats with cerebral infarction by inhibiting the JNK/P38 MAPK signaling pathway.Methods:Forty-eight SD male rats were divided into DZ group(control group),CI group(model group)and NBP group(butylphthalide group).Rats in CI group and NBP group were used to establish cerebral infarction models.NBP group used NBP.The solution(80 mg/(kg?d))was administered orally,and the remaining two groups were administered with the same volume of peanut oil.After 14 consecutive days of treatment,the Zea Longa score was used to evaluate the neurological function of DZ,CI and NBP rats.Scoring,TTC staining was used to observe the cerebral infarction volume of rats in DZ group,CI group and NBP group,HE staining was used to observe the pathological morphology of brain tissue in DZ group,CI group and NBP group.Neuronal apoptosis,Western blot was used to detect the expression of p-JNK and p-p38MAPK in brain tissues of DZ group,CI group and NBP group.Results:The neurological function of the rats in the CI group was higher than that in the DZ group,and the difference was statistically significant(P<0.05).The neurological function score of the rats in the NBP group was reduced compared with the CI group,and the difference was statistically significant(P<0.05).The cerebral infarction volume in the group was 35.56%higher than that in the DZ group,and the difference was statistically significant(P<0.05).The minor infarct volume in the NBP group was 21.59%,which was less than that in the CI group,and the difference was statistically significant(P<0.05).Nerve cells are neatly sorted,with a large number.The gap between blood vessels and interstitial tissue in the CI group is enlarged,the cells are severely contracted,and the neuron structure is incomplete.Compared with the CI group,the NBP group has reduced neuron contraction and increased number;The dead nerve cells were brown.The apoptosis rate of nerve cells in the CI group was 79.65%higher than that in the DZ group was 5.82%.The difference was statistically significant(P<0.05).The nerve cell apoptosis rate in the NBP group was 30.23%.Compared with CI group,the difference was statistically significant(P<0.05);Western blot results showed that p-JNK and p-p38MAPK protein expression in CI group was higher than that in DZ group,and the difference was statistically significant(P<0.05).The levels of p-JNK and p-p38MAPK proteins in the NBP group were lower than those in the CI group.There was statistically significant(P<0.05).Conclusion:Butylphthalide can improve neurological damage,reduce apoptotic nerve cells,and reduce infarct volume in rats with cerebral infarction,which is related to the inhibition of JNK/P38 MAPK pathway expression.

槐定碱对内毒素血症小鼠肺组织p38MAPK/AP-1表达的影响

目的观察槐定碱对内毒素血症小鼠p38MAPK信号分子、转录因子激活蛋白1(AP-1)及下游炎症因子TNF-α影响,探讨槐定碱抗内毒素的药理机制。方法 BALB/c小鼠尾静脉注射LPS(7mg.kg-1)制备内毒素血症小鼠模型,30min后腹腔注射槐定碱,剂量分别为12、6和3mg.kg-1,6h后取血和肺组织。免疫印迹法(Western-blot)检测肺组织总p38MAPK、磷酸化p38 MAPK蛋白表达,RT-PCR检测肺组织c-jun和c-fos mRNA表达,放免法检测血清中TNF-α含量。结果与内毒素血症模型组比较,三个剂量槐定碱干预组肺组织中磷酸化p38蛋白表达显著降低(P<0.01或P<0.05),c-jun和c-fos mRNA表达显著减少(P<0.01或P<0.05),血清中TNF-α含量明显下降(P<0.01或P<0.05)。结论槐定碱可抑制肺组织中p38MAPK的磷酸化,下调c-jun和c-fos mRNA的表达,抑制下游炎症因子TNF-α表达。

Promotion effect of FOXCUT as a microRNA sponge for miR-24-3p on progression in triple-negative breast cancer through the p38 MAPK signaling pathway

Background:Triple-negative breast cancer(TNBC)is a type of highly invasive breast cancer with a poor prognosis.According to new research,long noncoding RNAs(lncRNAs)play a significant role in the progression of cancer.Although the role of lncRNAs in breast cancer has been well reported,few studies have focused on TNBC.This study aimed to explore the biological function and clinical significance of forkhead box C1 promoter upstream transcript(FOXCUT)in triple-negative breast cancer.Methods:Based on a bioinformatic analysis of the cancer genome atlas(TCGA)database,we detected that the lncRNA FOXCUT was overexpressed in TNBC tissues,which was further validated in an external cohort of tissues from the General Surgery Department of the First Affiliated Hospital of Nanjing Medical University.The functions of FOXCUT in proliferation,migration,and invasion were detected in vitro or in vivo.Luciferase assays and RNA immunoprecipitation(RIP)were performed to reveal that FOXCUT acted as a competitive endogenous RNA(ceRNA)for the microRNA miR-24-3p and consequently inhibited the degradation of p38.Results:lncRNA FOXCUT was markedly highly expressed in breast cancer,which was associated with poor prognosis in some cases.Knockdown of FOXCUT significantly inhibited cancer growth and metastasis in vitro or in vivo.Mechanistically,FOXCUT competitively bounded to miR-24-3p to prevent the degradation of p38,which might act as an oncogene in breast cancer.Conclusion:Collectively,this research revealed a novel FOXCUT/miR-24-3p/p38 axis that affected breast cancer progression and suggested that the lncRNA FOXCUT could be a diagnostic marker and therapeutic target for breast cancer.

ANTI-OXIDATIVE MECHANISMS OF PRAVASTATIN PREVENTING AORTIC ATHEROSCLEROSIS IN apoE KNOCKOUT MICE:ROLE OF p38 MAPK PATHWAY

Objective To determine whether pravastatin exerts anti-oxidative effects on preventing aortic＂ atherosclerosis via modulating p38 MAPK pathway. Methods Male 8-week-old apoE^-/- mice fed a diet containing 1.25% cholesterol （wt/wt） were divided into pravastatin group administered with pravastatin （80 mg. kg ^-1· d^-1 ） and atherosclerosis group administered with PBS; and male 8-week-old C57BL/6J mice fed a normal diet were as control group （ n = 12 ）. In thoracoabdominal aortas of mice, levels of Malondialdehyde （ MDA ） and activities of superoxide dismutase （ SOD ） were measured and expression of phosphorylated p38 MAPK （ p-p38 MAPK） and phosphorylated signal transducer and activator of transcr（ption 1 （pSTAT1） were examined by Western blotting. Results After eight weeks, atherosclerosis in aortic root was significantly prevented by pravastatin. In aortic atherosclerosis lesion, the level of MDA was significantly reduced; adversely the activity, of SOD was increased. Expressions of p-p38 MAPK and pSTAT1 were significantly decreased in aortic atherosclerosis lesion. Conclusion Our results suggests that anti-oxidative mechanisms of pravastatin preventing aortic atherosclerosis may partially depend on modulating p38 MAPK signal pathway.

Mannitol inhibits the proliferation of neural stem cell by a p38 mitogen-activated protein kinase-dependent signaling pathway

Purpose:Mannitol is one of the first-line drugs for reducing cerebral edema through increasing the extracellular osmotic pressure.However,long-term administration of mannitol in the treatment of cerebral edema triggers damage to neurons and astrocytes.Given that neural stem cell(NSC)is a subpopulation of main regenerative cells in the central nervous system after injury,the effect of mannitol on NSC is still elusive.The present study aims to elucidate the role of mannitol in NSC proliferation.Methods:C57 mice were derived from the animal house of Zunyi Medical University.A total of 15 pregnant mice were employed for the purpose of isolating NSCs in this investigation.Initially,mouse primary NSCs were isolated from the embryonic cortex of mice and subsequently identified through immunofluorescence staining.In order to investigate the impact of mannitol on NSC proliferation,both cell counting kit-8 assays and neurospheres formation assays were conducted.Thein vitro effects of mannitol were examined at various doses and time points.In order to elucidate the role of Aquaporin 4(AQP4)in the suppressive effect of mannitol on NSC proliferation,various assays including reverse transcription polymerase chain reaction,western blotting,and immunocytochemistry were conducted on control and mannitol-treated groups.Additionally,the phosphorylated p38(p-p38)was examined to explore the potential mechanism underlying the inhibitory effect of mannitol on NSC proliferation.Finally,to further confirm the involvement of the p38 mitogen-activated protein kinase-dependent(MAPK)signaling pathway in the observed inhibition of NSC proliferation by mannitol,SB203580 was employed.All data were analyzed using SPSS 20.0 software(SPSS,Inc.,Chicago,IL).The statistical analysis among multiple comparisons was performed using one-way analysis of variance(ANOVA),followed by Turkey’’s post hoc test in case of the data following a normal distribution using a Shapiro-Wilk normality test.Comparisons between 2 groups were determined using Student’s t-test,if the data exhibited a normal distribution using a Shapiro-Wilk normality test.Meanwhile,data were shown as median and interquartile range and analyzed using the Mann-WhitneyU test,if the data failed the normality test.A p<0.05 was considered as significant difference.Results:Primary NSC were isolated from the mice,and the characteristics were identified using immunostaining analysis.Thereafter,the results indicated that mannitol held the capability of inhibiting NSC proliferation in a dose-dependent and time-dependent manner using cell counting kit-8,neurospheres formation,and immunostaining of Nestin and Ki67 assays.During the process of mannitol suppressing NSC proliferation,the expression of AQP4 mRNA and protein was downregulated,while the gene expression of p-p38 was elevated by reverse transcription polymerase chain reaction,immunostaining,and western blotting assays.Subsequently,the administration of SB203580,one of the p38 MAPK signaling pathway inhibitors,partially abrogated this inhibitory effect resulting from mannitol,supporting the fact that the p38 MAPK signaling pathway participated in curbing NSC proliferation induced by mannitol.Conclusions:Mannitol inhibits NSC proliferation through downregulating AQP4,while upregulating the expression of p-p38 MAPK.

The p38/MAPK pathway as a therapeutic target to prevent therapeutic escape of breast cancer stem cells

Cancer stem cells(CSCs)play an important role in metastasis development,tumor recurrence,and treatment resistance,and are essential for the eradication of cancer.Currently,therapies fail to eradicate CSCs due to their therapeutic stress-induced cellular escape,which leads to enhanced aggressive behaviors compared with CSCs that have never been treated.However,the underlying mechanisms regulating the therapeutic escape remain unknown.To this end,we established a model to isolate the therapeutic escaped CSCs(TSCSCs)from breast CSCs and performed the transcription profile to reveal the mechanism.Mechanistically,we demonstrated that the behavior of therapeutic escape was regulated through the p38/MAPK signaling pathway,resulting in TSCSCs exhibiting enhanced motility and metastasis.Notably,blocking the p38/MAPK signaling pathway effectively reduced motility and metastasis ability both in vitro and in vivo,which were further supported by downregulated motility-related genes and epithelial-mesenchymal transition(EMT)-related proteins vimentin and N-cadherin.The obtained findings reveal the p38/MAPK pathway as a potential therapeutic target for TSCSCs and would provide profound implications for cancer therapy.

Potential Mechanisms Involved in Ceramide-induced Apoptosis in Human Colon Cancer HT29 Cells

Objective To investigate the potential mechanisms of cell death after the treatment with ceramide. Methods MTT assay, DNA ladder, reporter assay, FACS and Western blot assay were employed to investigate the potential mechanisms of cell death after the treatment with C2-ceramide. Results A short-time treatment with C2-ceramide induced cell death, which was associated with p38 MAP kinase activation, but had no links with typical caspase activation or PARP degradation. Rather than caspase inhibitor, Inhibitor of p38 MAP kinase blocked cell death induced by a short-time treatment with ceramide （〈12 h）. However, inhibition of p38 MAP kinase could not block cell death induced by a prolonged treatment with ceramide （〉12 h）. Moreover, incubation of cells with ceramide for a long time （〉12 h） increased subG1, but reduced S phase accompanied by caspase-dependent and caspase-independent changes including NFr, B activation. Conclusion Ceramide-induced cell apoptosis involves both caspase-dependent and -independent signaling pathway. Caspase-independent cell death occurring in a relatively early stage, which is mediated via p38 MAP kinase, can progress into a stage involving both caspase-dependent and -independent mechanisms accompanied by cell signaling of MAPKs and NFκB.

Polysaccharides from Agrocybe cylindracea residue alleviate type 2-diabetes-induced liver and colon injuries by p38 MAPK signaling pathway

In this experiment,we investigated the possible mechanism of polysaccharides from Agrocybe cylindracea residue (PACR) on ameliorating the type-2-diabetes-induced liver and colon injuries.Animal experiments have proved that PACR could reduce the oxidative damage and inflammatory response.Meanwhile,the PACR could restore lipid levels,decrease the level of liver and colon lesions in injured mice,and finally play a role in protecting liver and colon.The results showed that PACR could be used as a supplement to decrease blood glucose and relieve T2DM and reduce oxidative stress and inflammatory response by inhibiting the activation of p38 MAPK signaling pathway.

The EGFR-P38 MAPK axis up-regulates PD-L1 through miR-675-5p and down-regulates HLA-ABC via hexokinase-2 in hepatocellular carcinoma cells

Background:Immunotherapy has been shown to be a promising strategy against human cancers.A better understanding of the immune regulation in hepatocellular carcinoma(HCC)could help the development of immunotherapy against HCC.The epidermal growth factor receptor(EGFR)signaling is frequently activated in HCC and plays important roles in tumorigenesis.However,its role in HCC immunity is still largely unknown.This study aimed to investigate the impact of EGFR signaling on programmed death-ligand 1(PD-L1)and human leukocyte antigen class-I(HLA-I)expression in HCC cells and its underlying mechanisms.Methods:The expression of phosphorylated EGFR(p-EGFR),PD-L1,and HLAI(HLA-ABC)in HCC specimens was detected by immunohistochemistry,and their correlations were analyzed.PD-L1 and HLA-ABC expression in EGFRactivated HCC cells were detected by quantitative real-time PCR,Western blotting,and flow cytometry,and T cell-mediated lysis was performed to test the immunosuppressive effects of PD-L1 and HLA-ABC alterations in HCC cells.Furthermore,the underlying mechanisms of EGFR activation-induced PD-L1 up-regulation and HLA-ABC down-regulation were explored by animal experiments,luciferase reporter assay,and gene gain-and loss-of-function studies.Results:p-EGFR was positively correlated with PD-L1 and negatively correlated with HLA-ABC expression in HCCs.EGFR activation by its ligand EGF up-regulated PD-L1 and down-regulated HLA-ABC in HCC cells,which was functionally important and could be abolished by the EGFR inhibitor,gefitinib,both in vitro and in vivo.Mechanistically,enhanced P38 mitogenactivated protein kinase(MAPK)activation down-regulated microRNA-675-5p(miR-675-5p)and up-regulated glycolysis-related enzyme hexokinase 2(HK2);miR-675-5p down-regulation enhanced the stability of PD-L1 mRNA probably via the 3’-untranslated region(3’-UTR)of PD-L1 and thereby caused PD-L1 accumulation,and HK2 up-regulation enhanced aerobic glycolysis and mediated a decrease in HLA-ABC.Conclusions:The EGFR-P38 MAPK axis could up-regulate PD-L1 through miR-675-5p and down-regulate HLA-ABC via HK2 in HCC cells.Our study reveals a novel signaling network that may cause immune suppression in HCC and suggests that EGFR signaling can be targeted for HCC immunotherapy.

The binding of actin to p38 MAPK and inhibiting its kinase activity in vitro

p38 MAP kinase mediates a signal pathway that is involved in many physiological and pathological processes such as inflammation, cellular stress, apoptosis, cell cycle and growth, ischemia/re-perfusion, and myocardium hypertrophy. To determine the molecular and regulative mechanism of p38 signal pathway, we used in vitro binding methods to screen the proteins that interact with p38. Here we report two proteins from mouse macrophage RAW264.7 strain treated with lipopolysaccharide (LPS) or ultraviolet radiation (UV), binding directly to p38. One of them is b-actin identified by peptide mass spectrum and ProFound program. Actin can inhibit the auto-phosphorylation of p38 and the phosphorylation of ATF by p38. It suggests that the binding of actin to p38 in vitro may represent a negative feedback to the kinase activity of p38, which leads to the regulation of p38 pathway and cellular function.

熊果酸抑制大鼠血管平滑肌细胞增殖的作用及其机制

目的:研究熊果酸(UA)对大鼠血管平滑肌细胞(VSMC)增殖的抑制作用,并探讨其对p38MAPK信号通路的影响。方法:高糖(葡萄糖,25mmol/L)诱导VSMC增殖为模型,MTT法检测UA对细胞增殖的影响,Cell-based ELISA测定UA对p38MAPK磷酸化水平变化,采用SABC免疫组化法测定UA对细胞c-fos蛋白表达水平的影响。结果:UA(20,40μmol/L)能抑制高糖诱导的VSMC增殖作用(P<0.05)。UA组p38MAPK的磷酸化水平明显低于葡萄糖模型组(P<0.05),且c-fos的蛋白表达水平较模型组也明显降低。结论:UA可以抑制大鼠VSMC增殖,此作用可能与其抑制p38MAPK信号传导通路激活,从而下调c-fos蛋白表达有关。

The functional analysis of transiently upregulated miR-101 suggests a “braking” regulatory mechanism during myogenesis

Skeletal muscle differentiation is a highly coordinated process that involves many cellular signaling pathways and microRNAs(miRNAs).A group of muscle-specific miRNAs has been reported to promote myogenesis by suppressing key signaling pathways for cell growth.However,the functional role and regulatory mechanism of most non-muscle-specific miRNAs with stage-specific changes during differentiation are largely unclear.Here,we describe the functional characterization of miR-101a/b,a pair of non-muscle-specific miRNAs that show the largest change among a group of transiently upregulated miRNAs during myogenesis in C2C12 cells.The overexpression of miR-101a/b inhibits myoblast differentiation by suppressing the p38/MAPK,Interferon Gamma,and Wnt pathways and enhancing the C/EBP pathway.Mef2a,a key protein in the p38/MAPK pathway,was identified as a direct target of miR-101a/b.Interestingly,we found that the long non-coding RNA(lncRNA)Malat1,which promotes muscle differentiation,interacts with miR-101a/b,and this interaction competes with Mef2a mRNA to relieve the inhibition of the p38/MAPK pathway during myogenesis.These results uncovered a“braking”role in differentiation of transiently upregulated miRNAs and provided new insights into the competing endogenous RNA(ceRNA)regulatory mechanism in myoblast differentiation and myogenesis.