Glucagon-like peptide 1 agonists are potentially useful drugs for treating metabolic dysfunction-associated steatotic liver disease

In this editorial,we comment on Yin et al’s recently published Letter to the editor.In particular,we focus on the potential use of glucagon-like peptide 1 receptor agonists(GLP-1RAs)alone,but even more so in combination therapy,as one of the most promising therapies in metabolic dysfunction-associated steatotic liver disease(MASLD),the new definition of an old condition,non-alcoholic fatty liver disease,which aims to better define the spectrum of steatotic pathology.It is well known that GLP-1RAs,having shown outstanding performance in fat loss,weight loss,and improvement of insulin resistance,could play a role in protecting the liver from progressive damage.Several clinical trials have shown that,among GLP-1RAs,semaglutide is a safe,well-studied therapeutic choice for MASLD patients;however,most studies demonstrate that,while semaglutide can reduce steatosis,including steatohepatitis histological signs(in terms of inflammatory cell infiltration and hepatocyte ballooning),it does not improve fibrosis.Combinations of therapies with different but complementary mechanisms of action are considered the best way to improve efficiency and slow disease progression due to the complex pathophysiology of the disease.In particular,GLP-1RAs associated with antifibrotic drug therapy,dual glucose-dependent insulinotropic polypeptide(GIP)/GLP-1RA or GLP-1 and glucagon RAs have promoted greater improvement in hepatic steatosis,liver biochemistry,and non-invasive fibrosis tests than monotherapy.Therefore,although to date there are no definitive indications from international drug agencies,there is the hope that soon the therapeutic lines in the most advanced phase of study will be able to provide a therapy for MASLD,one that will certainly include the use of GLP-1RAs as combination therapy.

Glucagon-like peptide 1 receptor activation:anti-inflammatory effects in the brain

The glucagon-like peptide 1 is a pleiotropic hormone that has potent insulinotropic effects and is key in treating metabolic diseases such as diabetes and obesity.Glucagon-like peptide 1 exerts its effects by activating a membrane receptor identified in many tissues,including diffe rent brain regions.Glucagon-like peptide 1 activates several signaling pathways related to neuroprotection,like the support of cell growth/survival,enhancement promotion of synapse formation,autophagy,and inhibition of the secretion of proinflammatory cytokines,microglial activation,and apoptosis during neural morphogenesis.The glial cells,including astrocytes and microglia,maintain metabolic homeostasis and defe nse against pathogens in the central nervous system.After brain insult,microglia are the first cells to respond,followed by reactive astrocytosis.These activated cells produce proinflammato ry mediators like cytokines or chemokines to react to the insult.Furthermore,under these circumstances,mic roglia can become chro nically inflammatory by losing their homeostatic molecular signature and,consequently,their functions during many diseases.Several processes promote the development of neurological disorders and influence their pathological evolution:like the formation of protein aggregates,the accumulation of abnormally modified cellular constituents,the formation and release by injured neurons or synapses of molecules that can dampen neural function,and,of critical impo rtance,the dysregulation of inflammato ry control mechanisms.The glucagonlike peptide 1 receptor agonist emerges as a critical tool in treating brain-related inflammatory pathologies,restoring brain cell homeostasis under inflammatory conditions,modulating mic roglia activity,and decreasing the inflammato ry response.This review summarizes recent advances linked to the anti-inflammato ry prope rties of glucagon-like peptide 1 receptor activation in the brain related to multiple sclerosis,Alzheimer’s disease,Parkinson’s disease,vascular dementia,or chronic migraine.

Glucagon-like peptide 1 receptor agonist:A potential game changer for cholangiocarcinoma

Glucagon-like peptide-1 receptor(GLP-1R)agonist,a subgroup of incretin-based anti-diabetic therapies,is an emerging medication with benefits in reducing blood glucose and weight and increasing cardiovascular protection.Contrarily,concerns have been raised about GLP-1R agonists increasing the risk of particular cancers.Recently,several epidemiological studies reported contradictory findings of incretin-based therapy on the risk modification for cholangiocarcinoma(CCA).The first cohort study demonstrated that incretin-based therapy was associated with an increased risk of CCA.Later studies,however,showed a null effect of incretinbased therapy on CCA risk for dipeptidyl peptidase-4 inhibitor nor GLP-1R agonist.Mechanistically,glucagon-like peptide 1 receptor is multifunctional,including promoting cell growth.High GLP-1R expressions were associated with progressive phenotypes of CCA cells in vitro.Unexpectedly,the GLP-1R agonist showed anti-tumor effects on CCA cells in vitro and in vivo with unclear mechanisms.Our recent report also showed that GLP-1R agonists suppressed the expression of GLP-1R in CCA cells in vitro and in vivo,leading to the inhibition of CCA tumor growth.This editorial reviews recent evidence,discusses the potential effects of GLP-1R agonists in CCA patients,and proposes underlying mechanisms that would benefit from further basic and clinical investigation.

A Retrospective Analysis of Glucagon-Like Peptide 1 Receptor Agonists in Treating Type 2 Diabetes Mellitus Complicated by Nonalcoholic Fatty Liver Disease

Background: The objective of this study was to compare and analyze the variations in clinical indices before and after treatment of type 2 mellitus (T2DM) combined with nonalcoholic fatty liver disease (NAFLD) that were treated with glucagon-like peptide 1 receptor agonists (GLP-1RAs). Methods: The electronic medical record system was utilized to search for a total of 16 patients with type 2 diabetes complicated by NAFLD who were hospitalized at the First Affiliated Hospital of Yangtze University from October 2022 to April 2023 and treated with GLP-1RA for the first time. The clinical indices were compared before and after 12 weeks of treatment with GLP-1RA. Results: The liver-spleen CT ratio (L/S), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) in all patients treated with GLP-1RA after 12 weeks were significantly different (P 0.05). The patients were categorized into two groups based on the types of GLP-1RAs. The changes in L/S, TC, TG, and LDL-C in the long-acting group after treatment were statistically significant (P Conclusions: GLP-1RAs can improve liver function, regulate lipid metabolism, and reduce the severity of fatty liver in patients with T2DM complicated by NAFLD, which demonstrates the importance of clinical applications.

Effects of Glucagon-Like Peptide 1 on PDX-1, PAX-6 and NKx2.2 Gene Expressions in Isolated Pancreatic Islets

Objective： To observe the effect of glucagon-like peptide 1 （GLP-1） on the gene expressions of transcription factors （PDX-1, PAX-6 and NKx2.2 ） in freshly isolated rat pancreatic islets and investigate the associated physiological and therapeutic implication of GLP-1. Methods： The isolated rat islets were incubated with 10 nmol/L GLP-1 for 1, 3 and 5 days, respectively. Total cellular RNA was extracted and the expressions of PDX-1, PAX-6 and NKx2.2 gene were detected by semiquantity RT-PCR. Results： Compared with the control group, the PDX-1, PAX-6 and NKx2.2 gene expressions were significantly increased after co-cultured with GLP-1 for 1 day （P 〈 0.05）. The effect was shown in a time-dependent manner. All three gene expressions reached the peak on the 5th day. Conclusion： GLP-1 can improve the function of pancreatic islet by regulating the gene expressions of transcription factors in β cells.

Is Glucagon-like peptide-1, an agent treating diabetes, a new hope for Alzheimer's disease?

Glucagon-like peptide- 1 （GLP- 1） has been endorsed as a promising and attractive agent in the treatment of type 2 diabetes mellitus （T2DM）. Both Alzheimer＇s disease （AD） and T2DM share some common pathophysiologic hallmarks, such as amyloid β （Aβ）, phosphoralation of tau protein, and glycogen synthase kinase-3. GLP-1 possesses neurotropic properties and can reduce amyloid protein levels in the brain. Based on extensive studies during the past decades, the understanding on AD leads us to believe that the primary targets in AD are the Aβ and tau protein. Combine these findings, GLP- 1 is probably a promising agent in the therapy of AD. This review was focused on the biochemistry and physiology of GLP- 1, communities between T2DM and AD, new progresses of GLP - 1 in treating T2MD and improving some pathologic hanmarks of AD.

Effects of glucagon-like peptide-1 receptor agonists on renal function

Glucagon-like peptide-1(GLP-1)receptor agonists result in greater improvements in glycemic control than placebo and promote weight loss with minimal hypoglycemia in patients with type 2 diabetes mellitus.A number of case reports show an association of GLP-1receptor agonists,mainly exenatide,with the development of acute kidney injury.The present review aims to present the available data regarding the effects of GLP-1 receptor agonists on renal function,their use in subjects with chronic renal failure and their possible association with acute kidney injury.Based on the current evidence,exenatide is eliminated by renal mechanisms and should not be given in patients with severe renal impairment or end stage renal disease.Liraglutide is not eliminated by renal or hepatic mechanisms,but it should be used with caution since there are only limited data in patients with renal or hepatic impairment.There is evidence from animal studies that GLP-1 receptor agonists exert protective role in diabetic nephropathy with mechanisms that seem to be independent of their glucose-lowering effect.Additionally,there is evidence that GLP-1 receptor agonists influence water and electrolyte balance.These effects may represent new ways to improve or even prevent diabetic nephropathy.

Glucagon-like peptide 1 in the pathophysiology and pharmacotherapy of clinical obesity

Though the pathophysiology of clinical obesity is un-doubtedly multifaceted, several lines of clinical evidence implicate an important functional role for glucagon-like peptide 1(GLP-1) signalling. Clinical studies assessing GLP-1 responses in normal weight and obese subjects suggest that weight gain may induce functional deficits in GLP-1 signalling that facilitates maintenance of the obesity phenotype. In addition, genetic studies implicate a possible role for altered GLP-1 signalling as a risk factor towards the development of obesity. As reductions in functional GLP-1 signalling seem to play a role in clinical obesity, the pharmacological replenishment seems a promising target for the medical management of obesity in clinical practice. GLP-1 analogue liraglutide at a high dose(3 mg/d) has shown promising results in achieving and maintaining greater weight loss in obese individuals compared to placebo control, and currently licensed antiobesity medications. Generally well tolerated, provided that longer-term data in clinical practice supports the currently available evidence of superior short- and longterm weight loss efficacy, GLP-1 analogues provide promise towards achieving the successful, sustainable medical management of obesity that remains as yet, an unmet clinical need.

Potential therapeutic targets for nonalcoholic fatty liver disease:Glucagon-like peptide 1

Nonalcoholic fatty liver disease(NAFLD)is the most rapidly growing contributor to liver mortality and morbidity.Hepatocellular injury in nonalcoholic steatohepatitis(NASH)is caused by an increase in metabolic substrates(glucose,fructose,and fatty acids),leading fatty acids to participate in pathways that cause cellular injury and a poor response to injury.The pathogenesis of this disease is largely associated with obesity,type 2 diabetes,and increasing age.To date,there are no Food and Drug Administration-approved treatments for NAFLD/NASH or its associated fibrosis.Since one of the pathogenic drivers of NASH is insulin resistance,therapies approved for the treatment of type 2 diabetes are being evaluated in patients with NASH.Currently,the glucagon-like peptide-1 receptor agonist(GLP-1RA)semaglutide is a safe,well-studied therapeutic for NAFLD/NASH patients.Existing research demonstrates that semaglutide can increase the resolution of NASH but not improve fibrosis.However,improving the fibrosis of NAFLD is the only way to improve the long-term prognosis of NAFLD.Given the complex pathophysiology of NASH,combining therapies with complementary mechanisms may be beneficial.Researchers have conducted trials of semaglutide in combination with antifibrotic drugs.However,the results have not fully met expectations,and it cannot be ruled out that the reason is the short trial time.We should continue to pay increasing attention to GLP-1RAs.

Glucagon-like peptide 1 receptor governs Wnt signaling to promote bone formation

Our previous investigation found that exendin-4 （Ex-4） , a peptide analogue of glucagon-like peptide 1 （GLP-1） , induced bone formation probably by osteoblast activation. Nevertheless, previous investigations did not observe any expression of GLP-1 receptors in osteoblasts, indicating that the direct cell target of GLP-1 and its ana- logues might not be osteoblasts but some other types of cells yet to be identified. To elucidate the underlying mecha- nisms, we performed further investigation in the present study and found that GLP-1 receptor was only identified in bone marrow mesenchymal stem cells （BMSCs）. Furthermore, activation of GLP-1 receptor by Ex-4 promoted the differentiation of B MSCs into osteoblast, which was associated with activation of PKA, nuclear translocation of [5- catenin, activation of PI3K/AKT and inhibition of GSK3β. Ex-4 also inhibited the adipocyte differentiation of BM- SCs, as evidenced by inhibition of PPARγ, lipoprotein lipase expression and lipid production. Blockade of GLP-1 receptor, PKA, PI3K or Wnt pathway, or respective knock-down of GLP-1 receptor and β-catenin in BMSCs inhib- ited the Ex-4 mediated effects. The results indicated that the GLP-1 receptor mediated osteoblastic differentiation and bone formation through stimulation of PKA/β-catenin signaling and inhibition of PKA/PI3IC/AKT/GSK3β？ signaling pathway in BMSCs. The findings reveal a new role of GLP-1 receptor for regulating osteoblastic differentia- tion of B MSCs and may provide a molecular basis for novel anabolic therapeutics against osteoporosis.

Postprandial glucagon-like peptide 1 secretion is associated with urinary albumin excretion in newly diagnosed type 2 diabetes patients

BACKGROUND Microalbuminuria is an early and informative marker of diabetic nephropathy.Our study found that microalbuminuria developed in patients with newly diagnosed type 2 diabetes mellitus(T2DM).AIM To investigate the association between glucagon-like peptide 1(GLP-1)and microalbuminuria in newly diagnosed T2DM patients.METHODS In total,760 patients were recruited for this cross-sectional study.The GLP-1 levels during a standard meal test and urinary albumin-creatinine ratio(UACR)were determined.RESULTS Patients with microalbuminuria exhibited lower GLP-1 levels at 30 min and 120 min during a standard meal test than patients with normal albuminuria(30 min GLP-1,16.7±13.3 pmol vs 19.9±15.6 pmol,P=0.007;120 min GLP-1,16.0±14.1 pmol vs 18.4±13.8 pmol,P=0.037).The corresponding area under the curve for active GLP-1(AUCGLP-1)was also lower in microalbuminuria patients(2257,1585 to 3506 vs 2896,1763 to 4726,pmol×min,P=0.003).Postprandial GLP-1 levels at 30 min and 120 min and AUCGLP-1 were negatively correlated with the UACR(r=0.159,r=0.132,r=0.206,respectively,P<0.001).The prevalence of microalbuminuria in patients with newly diagnosed T2DM was 21.7%,which decreased with increasing quartiles of AUCGLP-1 levels(27.4%,25.3%,18.9%and 15.8%).After logistic regression analysis adjusted for sex,age,hemoglobin A1c,body mass index,systolic blood pressure,estimated glomerular filtration rate,homeostasis model assessment of insulin resistance,AUC_(glucose)and AUC_(glucagon)patients in quartile 4 of the AUCGLP-1 presented a lower risk of microalbuminuria compared with the patients in quartile 1(odds ratio=0.547,95%confidence interval:0.325-0.920,P=0.01).A consistent association was also found between 30 min GLP-1 or 120 min GLP-1 and microalbuminuria.CONCLUSION Postprandial GLP-1 levels were independently associated with microalbuminuria in newly diagnosed Chinese T2DM patients.

Pharmacological inhibition of diacylglycerol acyltransferase-1 and insights into postprandial gut peptide secretion

AIM To examine the role that enzyme Acyl-CoA:diacylglycerol acyltransferase-1(DGAT1) plays in postprandial gut peptide secretion and signaling.METHODS The standard experimental paradigm utilized to evaluate the incretin response was a lipid challenge.Following a lipid challenge,plasma was collected via cardiac puncture at each time point from a cohort of 5-8 mice per group from baseline at time zero to 10 h.Incretin hormones [glucagon like peptide-1(GLP-1),peptide tyrosine-tyrosine(PYY) and glucose dependent insulinotropic polypeptide(GIP)] were then quantitated.The impact of pharmacological inhibition of DGAT1 on the incretin effect was evaluated in WT mice.Additionally,a comparison of loss of DGAT1 function either by genetic ablation or pharmacological inhibition.To further elucidate the pathways and mechanisms involved in the incretin response to DGAT1 inhibition,other interventions [inhibitors of dipeptidyl peptidase-IV(sitagliptin),pancreatic lipase(Orlistat),GPR119 knockout mice] were evaluated.RESULTS DGAT1 deficient mice and wildtype C57/BL6J mice werelipid challenged and levels of both active and total GLP-1 in the plasma were increased.This response was further augmented with DGAT1 inhibitor PF-04620110 treated wildtype mice.Furthermore,PF-04620110 was able to dose responsively increase GLP-1 and PYY,but blunt GIP at all doses of PF-04620110 during lipid challenge.Combination treatment of PF-04620110 and Sitagliptin in wildtype mice during a lipid challenge synergistically enhanced postprandial levels of active GLP-1.In contrast,in a combination study with Orlistat,the ability of PF-04620110 to elicit an enhanced incretin response was abrogated.To further explore this observation,GPR119 knockout mice were evaluated.In response to a lipid challenge,GPR119 knockout mice exhibited no increase in active or total GLP-1 and PYY.However,PF-04620110 was able to increase total GLP-1 and PYY in GPR119 knockout mice as compared to vehicle treated wildtype mice.CONCLUSION Collectively,these data provide some insight into the mechanism by which inhibition of DGAT1 enhances intestinal hormone release.

Antihypertensive Effect of Sodium-Glucose Cotransporter 2 Inhibitors and Glucagon-like Peptide 1 Receptor Agonists

An increasing body of evidence shows that new antidiabetic drugs—particularly sodium-glucose cotransporter 2(SGLT2)inhibitors and glucagon-like peptide 1(GLP-1)receptor agonists—have a beneficial effect on cardiovascular outcome.The majority of these studies have been performed in patients with heart failure and the results have shown first positive effect on blood pressure(BP)reduction.These effects are more pronounced with SGLT2 inhibitors than with GLP-1 receptor agonists.However,the reasons and mechanisms of action inducing BP reduction are still not sufficiently clear.Proposed mechanisms of SGLT2 inhibitors involve the natriuretic effect,modification of the renin-angiotensin-aldosterone system,and/or the reduction in the sympathetic nervous system.GLP-1 receptor agonists have several mechanisms that are related to glycemic,weight,and BP control.Current data show that SGLT2 inhibitors have a stronger antihypertensive effect than GLP-1 receptor agonists,which is mainly related to their renal effect.Briefly,SGLT2 inhibitors increase the response to diuretics and decrease the meal-related antinatriuretic pressure by lowering post-prandial hyperglycemia and hyperinsulinemia and prevent proximal sodium reabsorption.SGLT2 inhibitors can be used as second-line therapy in patients with diabetes mellitus or heart disease and concomitant hypertension.This article aims to summarize current knowledge regarding the antihypertensive effect of SGLT2 inhibitors and GLP-1 receptor agonists.

靶向PD-1的多肽阻断剂的设计及评价

以PD-1为靶标,设计了靶向结合PD-1的多肽P5-1;通过表面等离子共振(SPR)技术测得P5-1与PD-1的结合亲和力(KD)为0.21μmol/L,并通过分子水平竞争性实验验证P5-1可以阻断PD-1与PD-L1的结合;同时发现P5-1可恢复衰竭的Jurkat T细胞分泌IL-2的水平。本研究可为开发靶向PD-1的多肽阻断剂的肿瘤免疫治疗提供研究基础。

二代噬菌体展示淘选PD-1结合肽及其模拟位点分析

阻断PD-1/PD-L1相互作用可以激活肿瘤浸润性T细胞并恢复其抗肿瘤活性,对于恶性肿瘤具有较好的治疗作用。尽管靶向PD-1/PD-L1通路的抗体药物对癌症有一定的疗效,但现有抗体药物存在生产成本高、个体差异大、引发不恰当的免疫反应等问题,而且还伴随着不可避免的缺陷,如器官或肿瘤渗透性差、口服生物利用度差等,因此迫切需要寻求多肽抑制剂等来弥补当前PD-1/PD-L1相互作用抗体阻断剂的缺点。该文以重组人PD-1蛋白为靶标,首次采用二代噬菌体展示技术淘选Ph.D.-7和Ph.D.-12噬菌体展示文库,获得了400条潜在的PD-1结合肽同时基于BLOSUM62打分矩阵对PD-1结合肽数据集进行了聚类分析。最后,对PD-1结合肽数据集进行了氨基酸组成、基于位置的氨基酸偏好性分析以及模拟位点分析。该文获得的PD-1结合肽有望开发成阻断PD-1/PD-L1相互作用的候选多肽药物,研究结果对于PD-1结合肽的计算设计有一定的指导意义。

多肽IMB-P1的理性设计及活性评价

目的通过对多肽IMB-P1进行截短设计并进行体内和体外抗肿瘤活性评价,确定多肽IMB-P1的最小功能片段。方法分别从N端和C端对多肽IMB-P1进行截短,经固相合成法制备目标多肽。测定这些多肽对PD-1/PD-L1结合的抑制活性,在荷B16黑色素瘤小鼠模型中评价它们的体内抗肿瘤活性,并测定活性好的多肽在血浆中的稳定性及其二级结构特征。结果设计合成了6条IMB-P1截短多肽IMB-P1-1~6。经PD-1/PD-L1结合的抑制活性评价,发现IMB-P1-2、IMB-P1-3和IMB-P1-6抑制活性较好,其中多肽IMB-P1-6的抑制率最高,可达90%。在小鼠体内抗肿瘤活性研究发现IMB-P1-2的抑瘤作用与IMB-P1相当,其他多肽的抑瘤活性都有所下降。经过HPLC检测发现多肽IMB-P1-2在血浆中的稳定性优于IMB-P1-3和IMB-P1-6。多肽IMB-P1无论是在水中还是在SDS环境中均呈无规则卷曲状态,而多肽IMB-P1-2在水中形成了α-螺旋结构。结论鉴定出与多肽IMB-P1体内抗肿瘤活性相当的更短多肽IMB-P1-2及其二级结构特征,为将来进一步提高多肽活性的修饰策略提供了锁定其α-螺旋构象的方向。

TCP-1,a novel peptide to diagnose early colon cancer

A nine cyclic peptide(TCP-1)showed excellent specificity for colon cancer.TCP-1 binds with human tumor tissues at early stages and mice tumor with diameters of 1-4 mm,suggesting that TCP-1 may be used for early diagnosis of colon cancer.The mechanism of the targeted binding of TCP-1 to colon cancer was also studied using immunoprecipitation,LC-MS and bioinformatics.After screening and identifying of the possible binding target proteins of TCP-1,keratin,typeⅡcytoskeletal 5 was speculated to be the specific binding target protein of TCP-1 in human tumor tissue.Pharmacokinetics studies were conducted to investigate the target-mediated drug disposition of the new tumor-specific peptide by LC-MS/MS.The tissue distribution study showed that TCP-1 was found only in colon tumors(the target site)in tumor mice did not bind to any other tissues.Conjugating TCP-1 to tumor markedly increased its removal rate from blood circulation but mildly extended its staying time in vivo.In tumor mice,a lower AUC of TCP-1(reduced by almost 35%)and 2-fold higher clearance were found compared to that of normal mice.The proposed metabolic pathway of TCP-1 in the kidney was also determined using LC-MS^(n)-IT-TOF.The high specificity and low toxicity of the peptide may be caused by its extremely tight binding to the targets.Potential applications for future clinical use,including MRI and PET/CT were also explored,and this research may promote the development of colon cancer diagnostic technology research and provide new ideas and technical routes for tumor diagnostic technology.

重组人脑利钠肽联合比索洛尔治疗缺血性心肌病患者的临床疗效及对CITED2、miR-182、HIF-1水平的影响

【目的】探讨重组人脑利钠肽联合比索洛尔治疗缺血性心肌病(ICM)患者的临床疗效及对microRNA-182(miR-182)、蛋白反式作用因子(CITED2)、低氧诱导因子-1(HIF-1)水平的影响。【方法】前瞻性选取2018年10月至2020年10月山东省立第三医院收治的128例ICM患者,根据随机数字表法将其分为观察组和对照组,每组64例。常规治疗基础上,对照组给予比索洛尔,观察组在对照组的基础上给予重组人脑利钠肽治疗。比较两组临床疗效、不良反应发生情况,并比较治疗前后血清心肌细胞凋亡指标[可溶性凋亡相关因子(sFas)、可溶性凋亡相关因子配体(sFasL)],心肌缺血损伤标志物[肌钙蛋白T(cTnT)、肌红蛋白(Mb)、肌酸激酶同工酶(CK-MB)]及CITED2、miR-182、HIF-1水平。【结果】治疗1个月后,观察组总有效率高于对照组(P<0.05);观察组血清sFas、sFasL、cTnT、Mb、CK-MB水平均低于对照组,且观察组低于对照组,差异均有统计学意义(P<0.05);两组患者血清CITED2水平高于治疗前,miR-182、HIF-1水平低于治疗前,且两组间比较差异均有统计学意义(P<0.05)。观察组不良反应发生率高于对照组,但差异无统计学意义(P>0.05)。【结论】重组人脑利钠肽联合比索洛尔治疗ICM患者临床疗效好,可增强心肌抗缺氧、缺血能力,抑制心肌细胞凋亡,且安全性较好。

Phenotypic and Functional Analysis of LCMV gp33-41-Specific CD8 T Cells Elicited by Multiple Peptide Immunization in Mice Revealed the Up-regulation of PD-1 Expression on Antigen-Specific CD8 T Cells

The phenotype and function of antigen-specific CD8 T cells are closely associated with the efficacy of a therapeutic vaccination. Here we showed that multiple immunizations with LCMV gp33-41 peptide （KAV） in Freund＇s adjuvant could induce KAV-specific CD8 T cells with low expression of CD127 and CD62L molecules. The inhibitory receptor PD-1 was also expressed on a substantial part of KAV-specific CD8 T cells, and its expression level on KAV-specific CD8 T cells in spleen and lymph nodes was much higher when compared to those in peripheral blood. Furthermore, KAV-specific CD8 T cells could specifically kill KAV-pulsed target cells in vivo but the efficiency was low. These data suggest that prime-boost vaccination schedule with peptide in Freund＇s adjuvant can elicit antigen-specific CD8 T cells of effector-like phenotype with partial functional exhaustion, which may only provide short-term protection against the pathogen. Cellular ＆ Molecular Immunology.

利拉鲁肽对2型糖尿病合并骨量异常患者CA19—9、CA724、CEA及SF的影响

【目的】探讨利拉鲁肽治对2型糖尿病合并骨量异常患者的糖类抗原19—9（CA199）、糖类抗原724（CA724）、癌胚抗原（CEA）及血清铁蛋白（SF）水平的影响。【方法】选择2015年12月至2017年3月本院内分泌科收治的诊断为2型糖尿病合并骨量异常的患者182例作为研究对象，随机分为观察组和对照组各91例。两组患者均给予饮食调节、运动调节干预，给予甘精胰岛素进行强化治疗。对照组患者根据血糖水平采用二甲双胍进行治疗；观察组患者采用利拉鲁肽进行治疗，并根据其血糖水平逐步减少甘精胰岛素剂量至停用胰岛素；两组患者均治疗至少3个月。对比两组患者治疗前后的空腹血糖（FPG）、2小时餐后血糖（2hPG）、糖化血红蛋白（HbA1c）及空腹胰岛素水平（FINS）水平，同时对比两组患者治疗前后的肿瘤标志物及SF水平变化情况。【结果】治疗前，两组患者FPG、2hPG、HbA1c、FINS水平比较，差异均无统计学意义（P〉0．05）；治疗后，两组患者的FPG、2hPG、HbA1c、FINS水平均显著降低，且观察组2hPG和FINs水平显著低于对照组，差异均具有统计学意义（P〈0．05）。治疗前，两组CA19-9、CA724、CEA及SF水平比较，差异无统计学意义（P〉0．05）；治疗后，两组各指标均显著降低，且观察组CA19-9、CA724、CEA及SF水平均显著低于对照组，差异具有统计学意义（P〈O．05）。【结论】利拉鲁肽能够有效降低2型糖尿病合并骨量异常患者的血糖水平、改善胰岛素敏感性，同时能显著降低患者的CA199、CA724、CEA及SF水平，并有可能减少患者糖尿病并发症和恶性肿瘤的发生风险。