Efficacy and safety of chiglitazar,a novel peroxisome proliferatoractivated receptor pan-agonist,in patients with type 2 diabetes:a randomized,double-blind,placebo-controlled,phase 3 trial(CMAP)

Chiglitazar(Carfloglitazar)is a novel non-thiazolidinedione(TZD)structured peroxisome proliferatoractivated receptor(PPAR)pan-agonist that has shown promising effects on glycemic control and lipid regulation in patients with type 2 diabetes in previous clinical studies.This randomized phase 3 trial aimed to compare the efficacy and safety of chiglitazar with placebo in patients with type 2 diabetes with insufficient glycemic control by strict diet and exercise alone.Eligible patients were randomly assigned to receive chiglitazar 32 mg(n=167),chiglitazar 48 mg(n=166),or placebo(n=202)once daily.The primary endpoint was the change in glycosylated hemoglobin A_(1c)(HbA_(1c))at week 24 with superiority of chiglitazar over placebo.The results showed that both chiglitazar 32 and 48 mg resulted in significant and clinically meaningful reductions in HbA_(1c),and placebo-adjusted estimated treatment differences at week 24 for chiglitazar 32 and 48 mg were-0.87%(95%confidential interval(CI):-1.10 to-0.65;P<0.0001)and-1.05%(95%CI:-1.29 to-0.81;P<0.0001),respectively.Secondary efficacy parameters including glycemic control,insulin sensitivity and triglyceride reduction were also significantly improved in the chiglitazar groups.The overall frequency of adverse events and study discontinuation attributable to adverse events were similar among the groups.Low incidences of mild edema and body weight gain were reported in the chiglitazar dose groups.The results from this phase 3 trial demonstrated that the PPAR pan-agonist chiglitazar possesses an overall good efficacy and safety profile in patients with type 2 diabetes inadequately controlled with lifestyle interventions,thereby providing adequate supporting evidence for using this PPAR pan-agonist as a treatment option for type 2 diabetes.

CMHX008,a PPAR γ partial agonist,enhances insulin sensitivity with minor influences on bone loss

Traditional thiazolidinediones(TZDs),such as rosiglitazone,are peroxisome proliferator-activated receptor g(PPARg)potent agonists that can be used to treat type 2 diabetes but carry unwanted effects,including increased risk for fracture.The present work aimed to compare the insulin-sensitizing efficacies and bone-loss side effects of CMHX008,a novel TZDs-like PPARg partial agonist,with those of rosiglitazone.A TR-FRET PPARg competitive binding assay was used to compare the binding affinity between CMHX008 and rosiglitazone.Mice were administered vehicle,CMHX008 or rosiglitazone for 16 weeks.Mesenchymal stem cells(MSCs)were used to examine differences in differentiation into osteoblasts after compounds treatment.TR-FRET showed lower affinity to PPARg by CMHX008 compared with rosiglitazone.Mice treated with CMHX008 showed insulin sensitization similar to that of mice treated with rosiglitazone,which was related to the significant inhibition of PPARg Ser273 phosphorylation and improved insulin sensitivity by facilitating the phosphorylation of insulin receptor and Akt in adipose tissues.Micro-CT and histomorphometric analyses demonstrated that the degree of trabecular bone loss after treatment with CMHX008 was weaker than that observed with rosiglitazone,as evidenced by consistent changes in BV/TV,Tb.N,Tb.Th,Tb.Sp,and the mineral apposition rate.MSCs treated with CMHX008 showed higher ALP activity and mRNA levels of bone formation markers than did cells treated with rosiglitazone in the osteoblast differentiation test.Thus,CMHX008 showed insulin-sensitizing effects similar to those of rosiglitazone with a lower risk of bone loss,suggesting that PPARg sparing eliminates the skeletal side effects of TZDs while maintaining their insulin-sensitizing properties.

Hippocampal overexpression of TREM2 ameliorates high fat diet induced cognitive impairment and modulates phenotypic polarization of the microglia

Type 2 diabetes mellitus(T2DM)and Alzheimer's disease(AD)share several common pathophysiological features.Rare variants of triggering receptor expressed on myeloid cells 2(TREM2)increase the risk of developing AD,suggesting the involvement of TREM2 and innate immunity in AD development.It is still unknown whether TREM2 is related to cognitive impairment in T2DM.Here,we investigated the effects of the hippocampal overexpression of TREM2 on cognitive in long-term high-fat diet(HFD)-fed mice.Male C57BL/6J mice were maintained on HFD for 50 weeks.TREM2 was overexpressed in the hippocampus 36 weeks after HFD feeding using adeno-associated virus vector(AAV)-mediated gene delivery.The results showed that the HFD feeding induced rapid and persistent weight gain,glucose intolerance and significant impairments in learning and memory.Compared with AAV-con,AAV-TREM2 significantly ameliorated cognitive impairment without altering body weight and glucose homeostasis in HFD mice.The overexpression of TREM2 upregulated the synaptic proteins spinophilin,PSD95 and synaptophysin,suggesting the improvement in synaptic transmission.Dendritic complexity and spine density in the CA1 region were rescued after TREM2 overexpression.Furthermore,TREM2 markedly increased the number of iba-1/Arg-1-positive microglia in the hippocampus,suppressed neuroinflammation and microglial activation.In sum,hippocampal TREM2 plays an important role in improving HFD-induced cognitive dysfunction and promoting microglial polarization towards the M2 anti-inflammatory phenotype.Our study also suggests that TREM2 might be a novel target for the intervention of obesity/diabetes-associated cognitive decline.

精索静脉取血辅助诊断一例肾素瘤的应用体会并文献复习

探讨肾静脉及精索静脉取血在辅助诊断肾素瘤中的应用。回顾性分析1例肾素瘤患者临床资料及诊治经过,查阅肾静脉及精索静脉取血诊断肾素瘤的相关文献。患者为青年男性,因头痛伴高血压入院。入院后多次查血浆肾素>500 mIU/L,上腹部增强计算机断层扫描(CT)示左肾下极占位病变。静脉取血示左精索静脉肾素浓度明显高于肾静脉、肾静脉分支及外周静脉,考虑左肾素瘤可能,手术切除左肾占位,组织病检提示肾素瘤,患者术后肾素和血压恢复正常。文献报道肾静脉分段取血定位肾素瘤的阳性率仅8.3%~64%,推测可能与肾素瘤位于肾皮质,肿瘤血液由肾包膜静脉而非肾静脉收集有关。事实上,肾包膜静脉与精索静脉外侧支有交汇,但目前国内外尚未见精索静脉取血辅助定位肾素瘤的报道。鉴于肾素瘤分泌的肾素可能通过肾包膜静脉回流至精索静脉,肾静脉分段取血定位肾素瘤时应注意同时采集精索静脉血检测肾素。

Human herpesvirus 6B infection in mesial temporal lobe epilepsy:a meta-analysis

Background Whether human herpesvirus 6B(HHV-6B)can affect mesial temporal lobe epilepsy(MTLE)remains controversial.The present meta-analysis was aimed to evaluate whether HHV-6B is significantly associated with MTLE.Methods Six studies were included in this meta-analysis,comprising 183 MTLE patients and 75 controls.In these studies,HHV-6B infection in astrocytes and brain samples of MTLE patients and controls was investigated by polymerase chain reaction and immunofluorescence.Results The frequency of HHV-6B infection detection is significantly higher in the MTLE group than in the control group(OR=9.42,95%CI:3.66–24.25),(P<0.00001).Although febrile convulsion is strongly associated with MTLE,the formation of febrile convulsion leading to MTLE is not associated with HHV-6B infection(OR=2.68,95%CI:0.93–7.73),(P=0.07).Moreover,the HHV-6B-specific antigen is co-localized to cells positive for GFAP that morphologically resemble astrocytes.HHV-6B mainly infects astrocytes,oligodendrocytes and microglia,and could damage the vascular endothelial cells of the central nervous system.Conclusions There is an association between HHV-6B infection and MTLE.Future large-scale,multi-center,controlled,prospective studies are required to confirm these findings.In addition,the exact mechanism underlying the effects of HHV-6B infection on MTLE needs to be further investigated.