Association of regulator of G protein signaling 4 gene polymorphism and methylation with schizophrenia / 中华行为医学与脑科学杂志

Objective:To explore the differences of regulator of G protein signaling 4 (RGS4) gene polymorphisms and methylation between schizophrenia and healthy controls, as well as the association between gene polymorphisms and methylation.Methods:A total of 129 schizophrenia patients and 131 healthy controls from Southen Fujian were enrolled in this study. The peripheral blood DNA of all the subjects was extracted.The three polymorphic loci of RGS4 (rs10759, rs12753561 and rs951436) were amplified, sequenced, and then genotyped. In addition, 32 subjects were randomly selected from the two groups respectively and the gene methylation level of RGS4 was detected by sequencing after bisulfite treatment. SPSS 20.0 software was used for data analysis. The χ2 test and independent sample t-test were used to analyze the difference of gene methylation of RGS4.Two-way ANOVA was used to analyze the association between RGS4 gene polymorphism and methylation. Results:There were three genotypes of AA, AC and CC for rs10759 locus in the subjects of patient group and control group. And the distribution difference of genotypes between the two groups was statistically significant ( χ2=6.431, P=0.040), but there was no significant difference in allele frequency( χ2=1.270, P=0.260). For rs12753561, there were three genotypes of GG, GT and TT, and their distribution of genotypes was significantly different ( χ2=6.217, P=0.045). There was no significant difference for the allele frequency for rs12753561( χ2=0.021, P=0.885). For rs951436, there were three genotypes of AA, AC and CC, and there were no significant difference in genotype distribution and allele frequency distribution between the two groups( χ2=0.008, 0.007, both P>0.05). Methylated CpG sites were found in 26 patients and 27 healthy controls, and these were no significant difference between the two groups( χ2=0.110, P=0.740). There was no significant difference ( t=-0.318, P=0.752) of individual methylation rate (number of methylation sites/10) between schizophrenia patient group (0.24±0.11) and healthy control group (0.26±0.18). There was also no significant difference of methylation rate between male and female in both groups(both P>0.05). Finally, there was no significant difference of individual methylation rate among rs10759, rs12753561 and rs951436 genotypes (all P>0.05). Conclusion:RGS4 rs10759 and rs12753561 genotypes may be involved in schizophrenia, while RGS4 gene methylation has no association with schizophrenia. In addition, RGS4 gene polymorphism has no association with the methylation in the current experimental setting.

Effect of the regulator of G-protein signaling 2 on the proliferation and invasion of oral squamous cell carcinoma cells and its molecular mechanism / 华西口腔医学杂志

OBJECTIVES@#This study aims to investigate the effect of the regulator of G-protein signaling 2 (RGS2) on the proliferation and invasion of oral squamous cell carcinoma (OSCC) cells and its potential molecular mechanism. Metho⁃ds The expression status and clinical significance of RGS2 in head and neck squamous cell carcinomas and matched adjacent normal tissues were evaluated using TCGA database. Three OSCC cell lines (i.e., SCC-9, Cal27, and Fadu) were overexpressed with RGS2, and the effect of RGS2 on cell proliferation and invasion was determined using the Transwell, clone formation, and cell counting kit (CCK)-8 assays. Moreover, the yeast two-hybrid scree-ning and co-immunoprecipitation (Co-IP) assays were conducted to detect the correlation of RGS2, four and a half LIM domains protein 1 (FHL1), and damage DNA-binding protein 1 (DDB1).@*RESULTS@#The expression level of RGS2 in OSCC was significantly lower than that in matched adjacent normal tissues (@*CONCLUSIONS@#RGS2 plays an important role in the inhibition of OSCC proliferation and invasion. The structure stability of RGS2 is competitively regulated by FHL1 and DDB1.

Role and molecular mechanism of RGS6 in regulation of cardiomyocyte hypertrophy / 中国药理学通报

Aim To explore the regulatory effect and mechanism of Regulators of G-protein Signaling 6 (RGS6) in Ang H-induced hypertrophy. Methods RGS6 expression was up-and down-regulated respectively by AdRGS6 and AdshRGSó lentivirus. Each group was treated with Ang II /PBS. Cell size and changes of hypertrophic markers(ANP and BNP) were evaluated. Then ROS levels and the total protein and phosphorylated protein of E R K 1 / 2, p38, JNK1/2 in each group were detected. When the altered signaling was clarified, a reversal experiment of hypertrophic cardiomyocytes was conducted to further verify the signaling pathway. The RGS6 up-regulated cardiomyocytes of hypertrophy treated with ROS inhibitor (DPI) were experimental group. Results (Î) After stimulated with Ang II for 48 h, the size of AdRGS6-infected cell increased compared with AdGFP infection group. In addition, the mRNA levels of ANP and BNP also i n - creased. After stimulated with Ang II , the ROS levels and p - J N K l / 2 proteins of AdRGS6-infected cells all increased compared with AdGFP infection group. (2) After stimulated with Ang II for 48 h, the size of A d - shRGS6-infected cell decreased compared with AdshRNA infection group and the mRNA levels of ANP and BNP also decreased. The ROS levels and p - J N K l / 2 proteins of AdshRGS6-infected cell all decreased compared with AdshRNA infection group. (3) In the reversal experiments, compared with AdRGS6 + Ang 1 1 / DMSO group, the size of AdRGS6 + Ang H / D P I cardiomyocytes significantly decreased, and the downstream signaling of p - J N K l / 2 was improved. Conclusions RGS6 may be a key factor to cardiac hypertrophy. RGS6 aggravates Ang II -induced cardiomyocyte hypertrophy via activating R 0 S - K N K 1 / 2 signaling pathway.

The inhibitory effect of endostar combined with radiotheraphy on gastric transplantation tumorinmice / 中华放射医学与防护杂志

Objective To observe the effect of endostatin(Endostar) combined with radiotheraphy on the growth,microvessel density (MVD),the expressions of regulators of G-protein signaling 5 (RGSS),vascular endothelial growth factor (VEGF) and hypoxia-induced factor-1 α (HIF-1 α) ingastric transplantation tumor,and to explore underlying mechanism.Methods Thirty-two tumor-bearing mice were randomly divided into four groups including control group,ES group,RT group and ES + RT group.Then the tumor-bearing mice survival and tumor volume alterations were observed.After treatments of drug and RT,the inhibition rate of tumor growth and tumor MVD were measured.Immunohistochemical staining method was used to detect the expressions of RGS5,VEGF and HIF-1α.Results Compared with the ES group and control group,the ES + RT and RT treatment had effective anti-tumor effect(t=7.4,5.6,P ＜ 0.05),where as the ES + RT was more obvious in anti-tumor with the lowest value of MVD in tumor.Compared with the control group,the expression of HIF-1α in ES group,RT group,and especially ES + RT group was significantly reduced (t =6.5,8.2,13.1,P ＜ 0.05).The expression levels of VEGF and RGS5 wereincreased in RT group but was reduced in ES group and ES + RT group,and the expressions of VEGF and RGS5 in ES group and ES + RT group had no significant difference (P ＞ 0.05).Rank correlation analysis showed the expression of HIF-1α and the expressions of VEGF and RGS5 were positively correlated (r =0.57,0.71,P ＜ 0.05).Conclusions A possible mechanism of Endostar combined with radiotherapy on tumor growth inhibition may due to the inhibition of HIF-1α and its downstream VEGF and RGS5,and then inhibit tumor angiogenesis that results in the recovery of tumor blood vessels and tumor oxygen supplement.

Roles of regulator of G-protein signaling 5 in tumors / 国际肿瘤学杂志

Regulator of G-protein signaling 5 (RGS5) belongs to RGS family,which can negatively regulate the conduction of this signaling pathway.RGS5 mainly expresses in vascular pericyte,and is closely related to the occurrence,development and maturation of the blood vessels.Loss of RGS5 results in pericyte maturation,tumor vascular normalization,and these changes can improve the curative effect combined with chemotherapy and immunotherapy,indicating that RGS5 may become a new target of anti-tumor treatment.In addition,RGS5 involves in tumor metastasis and apoptosis,which can improve antineoplastic effect by inducing tumor cells apoptosis.

Expression and Activity of Catalases Is Differentially Affected by GpaA (Ga) and FlbA (Regulator of G Protein Signaling) in Aspergillus fumigatus

Vegetative growth signaling of the opportunistic human pathogenic fungus Aspergillus fumigatus is mediated by GpaA (Galpha). FlbA is a regulator of G protein signaling, which attenuates GpaA-mediated growth signaling in this fungus. The flbA deletion (DeltaflbA) and the constitutively active GpaA (GpaA(Q204L)) mutants exhibit enhanced proliferation, precocious autolysis, and reduced asexual sporulation. In this study, we demonstrate that both mutants also show enhanced tolerance against H2O2 and their radial growth was approximately 1.6 fold higher than that of wild type (WT) in medium with 10 mM H2O2. We performed quantitative PCR (qRT-PCR) for examination of mRNA levels of three catalase encoding genes (catA, cat1, and cat2) in WT and the two mutants. According to the results, while levels of spore-specific catA mRNA were comparable among the three strains, cat1 and cat2 mRNA levels were significantly higher in the two mutants than in WT. In particular, the DeltaflbA mutant showed significantly enhanced and prolonged expression of cat1 and precocious expression of cat2. In accordance with this result, activity of the Cat1 protein in the DeltaflbA mutant was higher than that of gpaA(Q204L) and WT strains. For activity of the Cat2 protein, both mutants began to show enhanced activity at 48 and 72 hr of growth compared to WT. These results lead to the conclusion that GpaA activates expression and activity of cat1 and cat2, whereas FlbA plays an antagonistic role in control of catalases, leading to balanced responses to neutralizing the toxicity of reactive oxygen species.

Antagonism role of adenosine in right ventricular hypertrophy induced by hypoxia in rat / 中华实用儿科临床杂志

Objective To investigate the antagonism role of adenosine and its agonists in hypoxia-induced right ventricular hypertrophy in rat.Methods Fifty-six Sprague-Dawley rats were randomly divided into 7 groups,including normoxia control group,hypoxia control group,hypoxia plus adenosine group,hypoxia plus adenosine A1 receptor agonist(CPA) group,hypoxia plus adenosine A2 receptor agonist(NECA) group,hypoxia plus CPA and adenosine A1 receptor antagonist (DPCPX) group,hypoxia plus NECA and adenosine A2b receptor antagonist(MRS1754) group.There were 8 rats in each group.Rats in all groups except normoxia group were exposed to hypoxia for 21 days(oxygen volume concentration of 95-105 mL/L).On the 7th day,agents were continuously delivered with micro osmotic pump for 14 days.At the end of the experiment,both right ventricular to left ventricular plus septum weight[RV/(LV + S)] ratio and right ventricular to body weight (RV/BW) ratio were measured,and the expression of myosin heavy chain (β-MHC) mRNA and regulator of G protein signaling 4(RGS4) mRNA in the right ventricular myocardial tissues were detected by PCR method.Results 1.After chronic hypoxia for 21 days,the ratios of RV/(LV + S) and RV/ BW in the hypoxia control group were significantly higher than those in the normoxia control group respectively(all P ＜ 0.001) ; the ratios of RV/(LV + S) and RV/BW in the hypoxia plus adenosine group and hypoxia plus CPA group were significantly lower than those in the hypoxia control group (all P ＜ 0.05) ; the ratio of RV/(LV + S) in the hypoxia plus NECA group was significantly lower than that in the hypoxia control group(P ＜ 0.05).2.The expression level of β-MHC mRNA in the hypoxia control group was higher than that in the normoxia control group(P ＜ 0.001),and the expression level of RGS4 mRNA in the hypoxia group was lower than that in the normoxia group(P ＜ 0.001) ; the expression levels of β-MHC mRNA in the hypoxia plus adenosine group,hypoxia plus CPA group,or hypoxia plus NECA group were lower than those in the hypoxia control group (all P ＜ 0.001) ; the expression levels of RGS4 mRNA in hypoxia plus adenosine group,hypoxia plus CPA group,and hypoxia plus NECA group were higher than those in the hypoxia control group(all P ＜ 0.001).Conclusions Adenosine can attenuate hypoxia-induced right ventricular hypertrophy through RGS4 mediated pathway.

Gene Expression Analysis of Galpha13-/- Knockout Mouse Embryos Reveals Perturbations in Galpha13 Signaling Related to Angiogenesis and Hypoxia

Angiogenesis is regulated by a large number of molecules and complex signaling mechanisms. The G protein Galpha13 is a part of this signaling mechanism as an endothelial cell movement regulator. Gene expression analysis of Galpha13 knockout mouse embryos was carried out to identify the role of Galpha13 in angiogenesis signaling during embryonic development. Hypoxia-inducible response factors including those acting as regulators of angiogenesis were over expressed, while genes related to the cell cycle, DNA replication, protein modification and cell-cell dissociation were under expressed. Functional annotation and network analysis indicate that Galpha13 -/- embryonic mice were exposed to hypoxic conditions. The present analysis of the time course highlighted the significantly high levels of disorder in the development of the cardiovascular system. The data suggested that hypoxia-inducible factors including those associated with angiogenesis and abnormalities related to endothelial cell division contributed to the developmental failure of Galpha13 knockout mouse embryos.

Metformin down-regulates the expression of regulators of G protein signaling in OLETF rats / 中国糖尿病杂志

Objective To investigate the expression of regulators of G protein signaling(RGS), including RGS2, RGS3 and RGS4 in OLETF rats, as well as the effects of metformin on these expressions. Methods LETO rats were used as control group. Eight-week-old male OLETF rats were assigned to two guoups randomly:model and trial(metfomin dose during 8~(th) to 22~(nd) weeks:300mg kg~(-1)·d~(-1);during 23rd to 28th weeks:400 mg·kg~(-1) ·d~(-1))groups. Expressions of RGS mRNA in aorta and heart werequantified by real-time PCR. Results RGS2, RGS3 and RGS4 mRNA of the thoracic aorta and left ventricle were significantly higher in model group than in control group (P<0.01). Compared with model group, metformin significantly reduced their mRNA in trial group (P<0.01). Conclusions Upregulation of RGS2, RGS3 and RGS4 mRNA expression in the thoracic aorta and left ventricle of OLETF rats is in correlation with cardiovascular lesions; while downregulation of their expression is in correlation with the action of metformin.

RGS Proteins and Opioid Signaling / 대한통증학회지

The regulators of the G protein signaling (RGS) proteins are responsible for the rapid acceleration of the GTPase-activity intrinsic to the heterotrimeric G protein alpha subunits. As GTPase-activating proteins (GAP), the RGS proteins negatively regulate the G-protein signals. Recently, the RGS proteins are known to be one of the important regulators of opioid signal transduction and the development of tolerance. The aim of this study was to review the recent discovery and understanding of the role of RGS proteins in opioid signaling and the development of tolerance. This information will be useful for medical personnel, particularly those involved in anesthesia and pain medicine, by helping them improve the effective use of opioids and develop new drugs that can prevent opioid tolerance.