G protein-coupled estrogen receptor in colon function, immune regulation and carcinogenesis

Estrogens play important roles in the development and progression of multiple tumor types.Accumulating evidence points to the significance of estrogen action not only in tumors of hormonally regulated tissues such as the breast,endometrium and ovary,but also in the development of colorectal cancer(CRC).The effects of estrogens in physiological and pathophysiological conditions are mediated by the nuclear estrogen receptorsαandβ,as well as the membranebound G protein-coupled estrogen receptor(GPER).The roles of GPER in CRC development and progression,however,remain poorly understood.Studies on the functions of GPER in the colon have shown that this estrogen receptor regulates colonic motility as well as immune responses in CRC-associated diseases,such as Crohn’s disease and ulcerative colitis.GPER is also involved in cell cycle regulation,endoplasmic reticulum stress,proliferation,apoptosis,vascularization,cell migration,and the regulation of fatty acid and estrogen metabolism in CRC cells.Thus,multiple lines of evidence suggest that GPER may play an important role in colorectal carcinogenesis.In this review,we present the current state of knowledge regarding the contribution of GPER to colon function and CRC.

G-protein-coupled estrogen receptor as a new therapeutic target for treating coronary artery disease

Coronary heart disease(CHD) continues to be the greatest mortality risk factor in the developed world. Estrogens are recognized to have great therapeutic potential to treat CHD and other cardiovascular diseases; however,a significant array of potentially debilitating side effects continues to limit their use. Moreover,recent clinical trials have indicated that long-term postmenopausal estrogen therapy may actually be detrimental to cardiovascular health. An exciting new development is the finding that the more recently discovered G-protein-coupled estrogen receptor(GPER) is expressed in coronary arteries-both in coronary endothelium and in smooth muscle within the vascular wall. Accumulating evidence indicates that GPER activation dilates coronary arteries and can also inhibit the prolif-eration and migration of coronary smooth muscle cells. Thus,selective GPER activation has the potential to increase coronary blood flow and possibly limit the debilitating consequences of coronary atherosclerotic disease. This review will highlight what is currently known regarding the impact of GPER activation on coronary arteries and the potential signaling mechanisms stimulated by GPER agonists in these vessels. A thorough understanding of GPER function in coronary arteries may promote the development of new therapies that would help alleviate CHD,while limiting the potentially dangerous side effects of estrogen therapy.

血清可溶性神经调节蛋白-1、G蛋白偶联雌激素受体-1在急性胰腺炎患者病情及预后评估中临床价值研究

目的探讨血清可溶性神经调节蛋白-1(sNRG-1)、G蛋白偶联雌激素受体-1(GPER-1)在急性胰腺炎(AP)患者病情及预后评估中的临床价值。方法选取自2019年6月至2022年6月邯郸市第一医院收治的106例AP患者为研究对象,根据AP病情严重程度分为轻症组(n=49)、中重症组(n=36)及重症组(n=21);根据预后生存情况分为存活组(n=83)与死亡组(n=23)。采用酶联免疫吸附法检测血清sNRG-1、GPER-1水平。采用受试者工作特性(ROC)曲线评估血清sNRG-1、GPER-1及两者联合检测对AP患者预后的评估价值。采用多因素Logistic回归分析探讨AP患者预后影响因素。结果中重症组、重症组患者血清sNRG-1水平低于轻症组,且重症组低于中重症组;中重症组、重症组患者血清GPER-1水平高于轻症组,且重症组高于中重症组,差异均有统计学意义(P<0.05)。存活组与死亡组病情严重程度、入院急性生理与慢性健康评分(APACHEⅡ)、白细胞计数、C反应蛋白、血肌酐、乳酸脱氢酶、血淀粉酶、血脂肪酶、sNRG-1、GPER-1比较,差异有统计学意义(P<0.05)。APACHEⅡ评分≥12分、sNRG-1≤17.74 pg/ml、GPER-1≥4.82 pg/ml是影响AP患者预后的独立危险因素(P<0.05)。血清sNRG-1、GPER-1预测AP患者预后的ROC曲线下面积分别为0.846、0.753。两者联合预测AP患者预后的ROC曲线下面积为0.917,特异度为86.75%,灵敏度为86.96%。结论血清sNRG-1低表达、GPER-1高表达与AP患者的病情严重程度及预后有关,有望作为评估AP患者预后的生物学指标。

G蛋白偶联雌激素受体1在骨代谢中作用的研究进展

G蛋白偶联雌激素受体1(G protein-coupled estrogen receptor 1,GPER1)是一种雌激素的膜受体,其通过快速的细胞多效应作用引发下游反应,对成骨细胞的增殖分化产生影响。因此,GPER1在雌激素介导的骨代谢中有着重要作用。本文对GPER1在骨代谢中的作用作了简要总结,包括GPER1在青春期参与骨生长的过程,在机体不同雌激素水平下的骨代谢中体现出的不同功能,以及其与其他受体共同作用参与了骨代谢。

G蛋白偶联雌激素受体1、表皮生长因子受体和趋化因子受体1在甲状腺乳头状癌中的表达及意义

目的探讨G蛋白偶联雌激素受体1(G protein-coupled estrogen receptor1,GPER1)、表皮生长因子受体(epidermal growth factor receptor,EGFR)和趋化因子受体1(chemokine receptor1,CXCR1)在甲状腺乳头状癌(papillary thyroid carcinoma,PTC)组织中的表达及意义。方法甲状腺乳头状癌68例、结节性甲状腺肿42例,采用免疫组织化学S-P法检测GPER1、EGFR和CXCR1的表达,分析其与患者临床病理特征的关系,以及三者间表达的相关性。结果在PTC组织中,GPER1、EGFR和CXCR1的表达阳性率分别为76.5%、66.2%、64.7%,明显高于结节性甲状腺肿组的21.4%、16.7%和11.9%(P<0.01);GPER1、EGFR和CXCR1在PTC中的表达与颈部淋巴结转移相关(P<0.05),而与其他临床病理特征(年龄、性别、肿瘤大小及TNM分期)无相关性(P>0.05);在PTC及PTC淋巴转移癌组织中,GPER1与EGFR的表达呈显著正相关(r=0.262,P=0.031;r=0.542,P=0.002)、GPER1与CXCR1的表达也呈显著正相关(r=0.276,P=0.025;r=0.483,P=0.006)。结论 GPER1、EGFR和CXCR1的两两共表达与PTC的发生、发展密切相关,三者间可能存在一种相互作用。

GPER1在EGFR突变的肺腺癌中的表达

目的:探讨肺腺癌中表皮生长因子受体(epidermal growth factor receptor,EGFR)与G蛋白偶联雌激素受体1(G-protein cou⁃pled estrogen receptor 1,GPER1)/GPR30之间的关系。方法:采用免疫组织化学方法检测83例术后肺腺癌组织样本中GPER1的表达,同时收集患者的临床病理资料,采用二代基因测序方法检测相应组织中EGFR基因突变状态,并分析GPER1与EGFR之间的相关性,Western blot检测EGFR野生型肺腺癌细胞A549,EGFR突变型肺腺癌细胞PC-9以及使用吉非替尼处理的PC-9细胞的GPER1表达水平。结果:GPER1的阳性表达与患者性别、年龄、肿瘤大小、吸烟、分化程度无显著性差异(均P>0.05);EGFR突变与肿瘤TNM分期无显著性差异(P=0.542);GPER1阳性表达与EGFR突变呈正相关(P=0.003);GPER1在Ⅲ、Ⅳ期肺腺癌中较Ⅰ、Ⅱ期高表达(P=0.008);在PC-9细胞中使用吉非替尼抑制EGFR活性引起GPER1表达下调。结论:GPER1在EGFR基因突变型的肺腺癌中的表达高于EGFR野生型肺腺癌,GPER1的表达可能受EGFR活性调控。

G-1通过抑制细胞凋亡减轻大鼠心肌缺血/再灌注损伤

目的 研究雌激素受体GPR30激动剂G-1对大鼠心肌缺血/再灌注损伤的保护作用.方法 32只雌性大鼠随机分为假手术组（Sham组）、卵巢切除组（OVX组）、缺血/再灌注组（I/R组）和G-1组,每组8只.除Sham组外,其他各组大鼠均切除双侧卵巢,G-1组卵巢切除后予G-1皮下注射2周,剂量为120 μg·kg-1·d-1.2周后取各组实验动物心脏,Langendorff灌流,记录左心室收缩压（LVSP）、左心室舒张末压（LVEDP）、左心室压变化最大速率（±dp/dtmax）;I/R组和G-1组进行离体心脏缺血/再灌注;检测各组心肌梗死面积,TUNEL检测心肌细胞凋亡.结果 与Sham组和OVX组相比,I/R组左心室发展压（LVDP）和±dp/dtmax降低,LVEDP升高,心肌梗死面积增加,凋亡心肌细胞数量增多;G-1组心功能改善,心肌梗死面积减小,心肌细胞凋亡数量减少.结论 G-1通过抑制细胞凋亡减轻大鼠心肌缺血/再灌注损伤.

沉默GPER1表达逆转乳腺癌细胞三苯氧胺耐药的实验研究

目的探讨沉默G蛋白偶联雌激素受体1(GPER1)对乳腺癌MCF-7细胞三苯氧胺(TAM)的逆转作用及可能的作用机制。方法体外培养乳腺癌TAM耐药细胞株MCF-7 TAMR及其亲本非耐药细胞株MCF-7,采用MTT法检测MCF-7 TAMR细胞对TAM的耐药性。shCtrl、shGPER1-1、shGPER1-2和shGPER1-3分别转染MCF-7 TAMR细胞为shCtrl组、shGPER1-1组、shGPER1-2组和shGPER1-3组,另设空白对照组(CTL组),实时荧光定量PCR(QPCR)鉴定转染效果。采用MTT法和Ca 2+荧光检测法检测shGPER1-1组细胞增殖活性和Ca 2+变化。Western blotting检测各组自噬相关蛋白微管相关蛋白1轻链3(LC3-Ⅱ)和Beclin 1表达;采用免疫荧光技术观察细胞自噬泡的形成情况。结果MCF-7和MCF-7 TAMR对TAM的半数抑制浓度(IC 50)分别为1.15 nmol/L和19.47 nmol/L。MCF-7 TAMR的耐药指数(RI)为16.93。MCF-7细胞和MCF-7 TAMR细胞中GPER1的表达水平分别为1.00±0.08和1.27±0.12,差异有统计学意义(P<0.05)。shGPER1-1、shGPER1-2、shGPER1-3组中GPER1的表达水平分别为0.45±0.09、0.66±0.08、0.91±0.07,均较CTL组和shCtrl组明显降低,差异有统计学意义(P<0.05)。shGPER1-1组经TAM作用1~2 min内细胞内Ca 2+浓度迅速升高,而CTL组和shCtrl组变化不明显。0.01、0.1、1、10、100 nmol/L TAM对shGPER1-1组细胞的增殖抑制率分别为(5.44±1.79)%、(17.64±2.34)%、(40.56±3.79)%、(69.51±3.70)%、(76.62±4.15)%,高于CTL组和shCtrl组细胞(P<0.05)。IC 50为2.41 nmol/L。shGPER1-1组对TAM的敏感性较CTL组增加7.08倍。shGPER1-1组Beclin1、LC3-Ⅱ蛋白表达量分别为0.45±0.10、0.33±0.07,低于CTL组和shCtrl组(P<0.05);shGPER1组LC3-Ⅱ荧光斑点的数量明显少于CTL组和shCtrl组。结论沉默GPER1表达可逆转MCF-7 TAMR细胞对TAM的耐药性,其可能的作用机制可能与抑制细胞保护性自噬有关。

GPER agonist G1 suppresses neuronal apoptosis mediated by endoplasmic reticulum stress after cerebral ischemia/reperfusion injury

Studies have confirmed a strong association between activation of the endoplasmic reticulum stress pathway and cerebral ischemia/reperfusion(I/R) injury.In this study,three key proteins in the endoplasmic reticulum stress pathway(glucose-regulated protein 78,caspase-12,and C/EBP homologous protein) were selected to examine the potential mechanism of endoplasmic reticulum stress in the neuroprotective effect of G protein-coupled estrogen receptor.Female Sprague-Dawley rats received ovariectomy(OVX),and then cerebral I/R rat models(OVX+ I/R) were established by middle cerebral artery occlusion.Immediately after I/R,rat models were injected with 100 μg/kg E2(OVX + I/R +E2),or 100 μg/kg G protein-coupled estrogen receptor agonist G1(OVX + I/R + G1) in the lateral ventricle.Longa scoring was used to detect neurobehavioral changes in each group.Infarct volumes were measured by 2,3,5-triphenyltetrazolium chloride staining.Morphological changes in neurons were observed by Nissl staining.Terminal dexynucleotidyl transferase-mediated nick end-labeling staining revealed that compared with the OVX + I/R group,neurological function was remarkably improved,infarct volume was reduced,number of normal Nissl bodies was dramatically increased,and number of apoptotic neurons in the hippocampus was decreased after E2 and G1 intervention.To detect the expression and distribution of endoplasmic reticulum stress-related proteins in the endoplasmic reticulum,caspase-12 distribution and expression were detected by immunofluorescence,and mRNA and protein levels of glucose-regulated protein 78,caspase-12,and C/EBP homologous protein were determined by polymerase chain reaction and western blot assay.The results showed that compared with the OVX+ I/R group,E2 and G1 treatment obviously decreased mRNA and protein expression levels of glucose-regulated protein 78,C/EBP homologous protein,and caspase-12.However,the G protein-coupled estrogen receptor antagonist G15(OVX + I/R + E2 + G15) could eliminate the effect of E2 on cerebral I/R injury.These results confirm that E2 and G protein-coupled estrogen receptor can inhibit the expression of endoplasmic reticulum stress-related proteins and neuronal apoptosis in the hippocampus,thereby improving dysfunction caused by cerebral I/R injury.Every experimental protocol was approved by the Institutional Ethics Review Board at the First Affiliated Hospital of Shihezi University School of Medicine,China(approval No.SHZ A2017-171) on February 27,2017.

氯化锂匹罗卡品诱导癫痫大鼠海马神经元GPER1表达的变化

目的:观察G蛋白偶联雌激素受体1(GPER1)在癫痫大鼠海马神经元中表达的变化。方法:成年雄性SD大鼠分成对照组(control)和癫痫组(epilepsy),利用腹腔注射氯化锂-匹罗卡品方法制备癫痫模型,分别在1、2、3、7、14 d和28 d,利用Morris水迷宫检测大鼠学习记忆能力,利用尼氏染色观察大鼠海马神经元形态变化;利用免疫组化和Western Blot技术观察GPER1在海马的表达。结果:水迷宫结果显示,与Control组相比,造模14 d的大鼠逃逸潜伏时间明显延长(P <0. 05),穿越目标象限区域的次数较Control组显著降低(P <0. 05)。尼氏染色结果显示:与Control组相比,造模1 d和2 d的大鼠CA1及CA3区锥体细胞层细胞及DG区颗粒细胞层细胞体积缩小,细胞间距增加,尼氏染色减弱;造模3和7 d的大鼠细胞体积明显缩小,细胞间隙明显增大,尼氏染色加深,CA1及CA3细胞数量明显减少;造模14 d和28 d的大鼠神经元体积逐渐向正常恢复,但仍较Control组小。免疫组化结果显示:GPER1免疫阳性细胞以海马锥体细胞和齿状回颗粒细胞为主,主要分布在细胞膜。与Control组相比,造模2 d和3 d的大鼠海马CA1及CA3区GPER1表达增加(P <0. 05),7 d后增加最明显(P <0. 01),14、28 d后表达下降;在DG区,造模3 d及7 d的大鼠GPER1表达增加(P <0. 05),14 d后表达下降(P <0. 05),28 d大鼠无显著差异。Western Blot结果显示:与Control组比较,造模2 d和3 d的大鼠GPER1相对表达量开始增高,7 d后明显增高(P <0. 05),14 d及28 d的大鼠表达降低。结论:GPER1在海马神经元的表达随着神经元损伤的加重而增高,随着神经元损伤的恢复逐渐降低,提示其表达变化与神经元的损伤与修复有关。

G protein-coupled receptor 35 attenuates nonalcoholic steatohepatitis by reprogramming cholesterol homeostasis in hepatocytes

Nonalcoholic fatty liver disease(NAFLD)is the most common chronic liver disease worldwide.Fat accumulation“sensitizes”the liver to insult and leads to nonalcoholic steatohepatitis(NASH).G protein-coupled receptor 35(GPR35)is involved in metabolic stresses,but its role in NAFLD is unknown.We report that hepatocyte GPR35 mitigates NASH by regulating hepatic cholesterol homeostasis.Specifically,we found that GPR35 overexpression in hepatocytes protected against high-fat/cholesterol/fructose(HFCF)diet-induced steatohepatitis,whereas loss of GPR35 had the opposite effect.Administration of the GPR35 agonist kynurenic acid(Kyna)suppressed HFCF diet-induced steatohepatitis in mice.Kyna/GPR35 induced expression of StAR-related lipid transfer protein 4(STARD4)through the ERK1/2 signaling pathway,ultimately resulting in hepatic cholesterol esterification and bile acid synthesis(BAS).The overexpression of STARD4 increased the expression of the BAS rate-limiting enzymes cytochrome P450 family 7 subfamily A member 1(CYP7A1)and CYP8B1,promoting the conversion of cholesterol to bile acid.The protective effect induced by GPR35 overexpression in hepatocytes disappeared in hepatocyte STARD4-knockdown mice.STARD4 overexpression in hepatocytes reversed the aggravation of HFCF diet-induced steatohepatitis caused by the loss of GPR35 expression in hepatocytes in mice.Our findings indicate that the GPR35–STARD4 axis is a promising therapeutic target for NAFLD.

GPR30在子宫平滑肌瘤细胞增殖中的作用研究

目的探讨跨膜G蛋白偶联受体30(G protein-coupled receptor30,GPR30)在子宫平滑肌瘤细胞中的表达及其对肌瘤中平滑肌细胞的增殖作用。方法培养子宫平滑肌瘤原代细胞,应用免疫组织化学、免疫荧光及蛋白质印迹法检测GPR30的表达。应用蛋白印迹检测GPR30干扰后,其下游信号通路的变化。应用MTT检测在雌激素刺激下,正常子宫平滑肌细胞及平滑肌瘤细胞的生长活性。结果子宫平滑肌瘤细胞中有GPR30蛋白的高表达,其主要位于细胞质中,在细胞核上无明显表达。在未处理组平滑肌细胞中,雌激素刺激雌激素信号通路中的ERK1/2表达增强。在GPR30干扰后的平滑肌细胞中,雌激素刺激后ERK1/2表达无显著改变。MTT结果表明在雌激素作用下,未处理组细胞存活和生长率显著增加;干扰组细胞的存活和生长率显著下降。结论 GPR30在子宫肌瘤平滑肌细胞的细胞质中高表达,可能参与子宫平滑肌细胞的增殖。

GPER:雌激素相关疾病治疗的新靶点

G蛋白耦联雌激素受体(GPER)是一种G蛋白偶联受体家族的新型雌激素受体,可与雌二醇等雌激素结合,但其信号途径及作用机制与经典核雌激素受体(ERα和ERβ)不同,是一种既能够介导非基因型快速反应也可通过第二信使系统发挥间接转录调控作用的膜性受体。由于GPER可能与雌激素相关疾病的发生、发展密切相关,很可能成为治疗相关疾病的新靶点,近年来备受关注。本文就GPER的发现、结构、亚细胞定位、配体、信号转导途径及与相关疾病之间的关系等方面进行阐述。

GRK2 mediated degradation of SAV1 initiates hyperplasia of fibroblast-like synoviocytes in rheumatoid arthritis

Hyperplasia and migration of fibroblast-like synoviocytes(FLSs)are the key drivers in the pathogenesis of rheumatoid arthritis(RA)and joint destruction.Abundant Yes-associated protein(YAP),which is a powerful transcription co-activator for proliferative genes,was observed in the nucleus of inflammatory FLSs with unknown upstream mechanisms.Using Gene Expression Omnibus database analysis,it was found that Salvador homolog-1(SAV1),the pivotal negative regulator of the Hippo-YAP pathway,was slightly downregulated in RA synovium.However,SAV1 protein expression is extremely reduced.Subsequently,it was revealed that SAV1 is phosphorylated,ubiquitinated,and degraded by interacting with an important serine-threonine kinase,G protein-coupled receptor(GPCR)kinase 2(GRK2),which was predominately upregulated by GPCR activation induced by ligands such as prostaglandin E2(PGE2)in RA.This process further contributes to the decreased phosphorylation,nuclear translocation,and transcriptional potency of YAP,and leads to aberrant FLSs proliferation.Genetic depletion of GRK2 or inhibition of GRK2 by paroxetine rescued SAV1 expression and restored YAP phosphorylation and finally inhibited RA FLSs proliferation and migration.Similarly,paroxetine treatment effectively reduced the abnormal proliferation of FLSs in a rat model of collagen-induced arthritis which was accompanied by a significant improvement in clinical manifestations.Collectively,these results elucidate the significance of GRK2 regulation of Hippo-YAP signaling in FLSs proliferation and migration and the potential application of GRK2 inhibition in the treatment of FLSs-driven joint destruction in RA.

Molecular mechanism of endocrine-disruptive effects induced by Bisphenol A:The role of transmembrane G-protein estrogen receptor 1 and integrin αvβ3

Bisphenol A(BPA) is one of the highest volume industrial products worldwide and has been widely used to make various products as the intermediates of polycarbonate plastics and epoxy resins.Inevitably, general population has been widely exposed to BPA due to extensive use of BPAcontaining products. BPA has similar chemical structure with the natural estrogen and has been shown to induce a variety of estrogen-like endocrine effects on organism in vivo or in vitro. High doses of BPA tend to act as antagonist of estrogen receptors(ERs) by directly regulating the genomic transcription. However, BPA at environmentally relevant low-dose always disrupt the biological function via a non-genomic manner mediated by membrane receptors, rather than ERs. Although some studies had investigated the non-genomic effects of low-dose BPA, the exact molecular mechanism still remains unclear. Recently, we found that membrane G protein-coupled estrogen receptor 1 and integrin αvβ3 and its relative signal pathways participate in the induction of male germ cell proliferation and thyroid transcription disruption by the low-dose BPA. A profound understanding for the mechanism of action of the environmentally relevant BPA exposure not only contributes to objectively evaluate and predict the potential influence to human health, but also provides theoretical basis and methodological support for assessing health effects trigged by other estrogen-like environmental endocrine disruptors. Based mainly on our recent findings, this review outlines the research progress of molecular mechanism on endocrine disrupting effects of environmental low-dose BPA, existing problems and some consideration for future studies.

Role of bile acids in liver diseases mediated by the gut microbiome

The intensive crosstalk between the liver and the intestine performs many essential functions.This crosstalk is important for natural immune surveillance,adaptive immune response regulation and nutrient metabolism and elimination of toxic bacterial metabolites.The interaction between the gut microbiome and bile acids is bidirectional.The gut microbiome regulates the synthesis of bile acids and their biological signaling activity and circulation via enzymes.Similarly,bile acids also shape the composition of the gut microbiome by modulating the host’s natural antibacterial defense and the intestinal immune system.The interaction between bile acids and the gut microbiome has been implicated in the pathophysiology of many intestinal and extra intestinal diseases,especially liver diseases.As essential mediators of the gut-liver crosstalk,bile acids regulate specific host metabolic pathways and modulate the inflammatory responses through farnesoid X-activated receptor and G protein-coupled bile acid receptor 1.Several clinical trials have demonstrated the signaling effects of bile acids in the context of liver diseases.We hypothesize the existence of a gut microbiome-bile acids-liver triangle and explore the potential therapeutic strategies for liver diseases targeting the triangle.

Novel and emerging diabetes mellitus drug therapies for the type 2 diabetes patient

Type 2 diabetes mellitus is a metabolic disorder of deranged fat, protein and carbohydrate metabolism resulting in hyperglycemia as a result of insulin resistance and inadequate insulin secretion. Although a wide variety of diabetes therapies is available, yet limited efficacy, adverse effects, cost, contraindications, renal dosage adjustments, inflexible dosing schedules and weight gain significantly limit their use. In addition, many patients in the United States fail to meet the therapeutic HbA1c goal of < 7% set by the American Diabetes Association. As such new and emerging diabetes therapies with different mechanisms of action hope to address some of these drawbacks to improve the patient with type 2 diabetes. This article reviews new and emerging classes, including the sodium-glucosecotransporter-2 inhibitors, 11β-Hydroxysteroid dehydrogenase type 1 inhibitors, glycogen phosphorylase inhibitors; protein tyrosine phosphatase 1B inhibitors, G Protein-Coupled receptor agonists and glucokinase activators. These emerging diabetes agents hold the promise of providing benefit of glucose lowering, weight reduction, low hypoglycemia risk, improve insulin sensitivity, pancreatic β cell preservation, and oral formulation availability. However, further studies are needed to evaluate their safety profile, cardiovascular effects, and efficacy durability in order to determine their role in type 2 diabetes management.

Arrestin-mediated signaling: Is there a controversy?

The activation of the mitogen-activated protein(MAP) kinases extracellular signal-regulated kinase(ERK)1/2 was traditionally used as a readout of signaling of G protein-coupled receptors(GPCRs) via arrestins, as opposed to conventional GPCR signaling via G proteins. Several recent studies using HEK293 cells where all G proteins were genetically ablated or inactivated, or both non-visual arrestins were knocked out, demonstrated that ERK1/2 phosphorylation requires G protein activity, but does not necessarily require the presence of non-visual arrestins. This appears to contradict the prevailing paradigm. Here we discuss these results along with the recent data on gene edited cells and arrestinmediated signaling. We suggest that there is no real controversy. G proteins might be involved in the activation of the upstream-most MAP3Ks, although in vivo most MAP3K activation is independent of heterotrimeric G proteins, being initiated by receptor tyrosine kinases and/or integrins. As far as MAP kinases are concerned, the best-established role of arrestins is scaffolding of the three-tiered cascades(MAP3K-MAP2 K-MAPK). Thus, it seems likely that arrestins, GPCRbound and free, facilitate the propagation of signals in these cascades, whereas signal initiation via MAP3K activation may be independent of arrestins. Different MAP3Ks are activated by various inputs, some of which are mediated by G proteins, particularly in cell culture, where we artificially prevent signaling by receptor tyrosine kinases and integrins, thereby favoring GPCR-induced signaling. Thus, there is no reason to change the paradigm: Arrestins and G proteins play distinct non-overlapping roles in cell signaling.

Microbial transformations of bile acids and their receptors in the regulation of metabolic dysfunction-associated steatotic liver disease

Bile acids(BAs)play important roles in the digestion of dietary fats and molecular signal transduction,and modulation of the BA composition usually affects the progression of metabolic diseases.While the liver produces primary BAs,the gut microbiota modifies these products into various forms that greatly increase their diversity and biological functions.Mechanistically,BAs can regulate their own metabolism and transport as well as other key aspects of metabolic processes via dedicated BA receptors.Disruption of BA transport and homeostasis leads to the progression of liver diseases,including metabolic dysfunction-associated steatotic liver disease(MASLD)and hepatocellular carcinoma(HCC).Here,we summarize the microbial transformations of BAs and their downstream signaling in the development of metabolic diseases and present new insights into novel therapeutic strategies targeting BA pathways that may contribute to these diseases.

G蛋白偶联雌激素受体1对颞叶癫痫大鼠发作易感性的影响

目的探讨G蛋白偶联雌激素受体1(GPER1)特异性激动剂G1、拮抗剂G15对癫痫大鼠发作易感性的影响。方法将60只大鼠按随机数字表法分为对照组、G1处理组、G15处理组,每组20只。后2组大鼠分别腹腔注射GPER1特异激动剂G1(10μg)、拮抗剂G15(40μg),连续注射12 d。3组大鼠均制备氯化锂-匹罗卡品癫痫模型。观察大鼠腹腔注射匹罗卡品后1 h内的行为学表现,每隔5分钟采用Racine分级评估癫痫发作严重程度,比较3组大鼠癫痫发作(Racine分级Ⅳ级)的潜伏期和不同时间点癫痫发作级别。使用脑电监测系统监测大鼠脑电图,记录匹罗卡品注射前10 min到注射后2 h的脑电数据,采用傅立叶变换(FFT)进行脑电的时频分析。比较3组大鼠脑电能量值的分布和癫痫持续状态20 min内θ、α波能量值的变化。结果(1)与对照组、G1处理组比较,G15处理组大鼠的癫痫发作潜伏期明显缩短,差异均有统计学意义(P<0.05)。注射匹罗卡品后15 min、20 min,G1处理组大鼠癫痫发作分级较对照组低,差异均有统计学意义(P<0.05)。注射匹罗卡品后15~35 min,G15处理组大鼠癫痫发作分级较对照组高,差异均有统计学意义(P<0.05)。(2)与对照组比较,G1处理组大鼠癫痫发作时脑电波幅较小,而G15处理组大鼠癫痫发作时间较早,且脑电波幅大、频率高。与对照组比较,G1处理组大鼠的脑电能量值变化不明显,而G15处理组大鼠在2 h内呈现出更高的脑电能量值。与对照组和G1处理组比较,G15处理组大鼠在癫痫持续状态20 min内θ、α波能量值明显增强,差异均有统计学意义(P<0.05)。结论GPER1的活性水平与癫痫发作易感性有关,特异性抑制GPER1活性可增强癫痫易感性,增大癫痫过程中特定频率波段的能量值。