GLP-1 receptor agonists and myocardial metabolism in atrial fibrillation

Atrial fibrillation(AF)is the most common cardiac arrhythmia.Many medical conditions,including hypertension,diabetes,obesity,sleep apnea,and heart failure(HF),increase the risk for AF.Cardiomyocytes have unique metabolic characteristics to maintain adenosine triphosphate production.Significant changes occur in myocardial metabolism in AF.Glucagon-like peptide-1 receptor agonists(GLP-1RAs)have been used to control blood glucose fluctuations and weight in the treatment of type 2 diabetes mellitus(T2DM)and obesity.GLP-1RAs have also been shown to reduce oxidative stress,inflammation,autonomic nervous system modulation,and mitochondrial function.This article reviews the changes in metabolic characteristics in cardiomyocytes in AF.Although the clinical trial outcomes are unsatisfactory,the findings demonstrate that GLP-1 RAs can improve myocardial metabolism in the presence of various risk factors,lowering the incidence of AF.

Non-alcoholic fatty liver disease in type 2 diabetes:Emerging evidence of benefit of peroxisome proliferator-activated receptors agonists and incretin-based therapies

Nonalcoholic fatty liver disease(NAFLD)is a global epidemic,affecting more than half of the people living with type 2 diabetes(T2D).The relationship between NAFLD and T2D is bidirectional and the presence of one perpetuates the other,which significantly increases the hepatic as well as extrahepatic complications.Until recently,there was no approved pharmacological treatment for NAFLD/nonalcoholic steatohepatitits(NASH).However,there is evidence that drugs used for diabetes may have beneficial effects on NAFLD.Insulin sensitizers acting through peroxisome proliferator-activated receptor(PPAR)modulation act on multiple levels of NAFLD pathogenesis.Pioglitazone(PPARγ agonist)and saroglitazar(PPARα/γagonist)are particularly beneficial and recommended by several authoritative bodies for treating NAFLD in T2D,although data on biopsyproven NASH are lacking with the latter.Initial data on elafibanor(PPARα/δ agonist)and Lanifibranor(pan PPAR agonist)are promising.On the other hand,incretin therapies based on glucagon-like peptide-1(GLP-1)receptor agonists(GLP-1RA)and dual-and triple-hormone receptor co-agonists reported impressive weight loss and may have anti-inflammatory and antifibrotic properties.GLP-1 RAs have shown beneficial effects on NAFLD/NASH and more studies on potential direct effects on liver function by dual-and triple-agonists are required.Furthermore,the long-term safety of these therapies in NAFLD needs to be established.Collaborative efforts among healthcare providers such as primary care doctors,hepatologists,and endocrinologists are warranted for selecting patients for the best possible management of NAFLD in T2D.

Is it necessary to stop glucagon-like peptide-1 receptor agonists prior to endoscopic procedure? A retrospective study

BACKGROUND Glucagon-like peptide-1 receptor agonists(GLP-1 RA)are effective in diabetes and obesity,reducing hyperglycemia by increasing insulin release and delaying gastric emptying.However,they can cause gastroparesis,raising concerns about aspiration during procedures.Recent guidelines advise discontinuing GLP-1 RA before surgery to reduce the risk of pulmonary aspiration.AIM To evaluate the effect of GLP-1 RAs on gastric residual contents during endosco-pic procedures.METHODS A retrospective chart review at BronxCare Health System,New York,from January 2019 to October 2023,assessed gastric residue and aspiration in GLP-1 RA patients undergoing endoscopic procedures.Two groups were compared based on dietary status before the procedure.Data included demographics,symptoms of gastroparesis,opiate use,hemoglobin A1c,GLP-1 agonist indication,endo-scopic details,and aspiration occurrence.IBM SPSS was used for analysis,cal-culating means,standard deviations,and applying Pearson’s chi-square and t-tests for associations,with P<0.05 as being significant.RESULTS During the study,306 patients were included,with 41.2%on a clear liquid/low residue diet and 58.8%on a regular diet before endoscopy.Most patients(63.1%)were male,with a mean age of 60±12 years.The majority(85.6%)were on GLP-1 RAs for diabetes,and 10.1%reported digestive symptoms before endoscopy.Among those on a clear liquid diet,1.5%had residual food at endoscopy compared to 10%on a regular diet,which was statistically significant(P=0.03).Out of 31 patients with digestive symptoms,13%had residual food,all from the regular diet group(P=0.130).No complications were reported during or after the procedures.CONCLUSION The study reflects a significant rise in GLP-1 RA use for diabetes and obesity.A 24-hour liquid diet seems safe for endoscopic procedures without aspiration.Patients with upper gastrointestinal symptoms might have a higher residual food risk,though not statistically significant.Further research is needed to assess risks based on diabetes duration,gastroparesis,and GLP-1 RA dosing,aiming to minimize interruptions in therapy during procedures.

Practical guide:Glucagon-like peptide-1 and dual glucosedependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonists in diabetes mellitus

Practical guide:Glucagon-like peptide-1 and dual glucosedependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonists in diabetes mellitus common second-line choice after metformin for treating T2DM.Various considerations can make selecting and switching between different GLP-1 RAs challenging.Our study aims to provide a comprehensive guide for the usage of GLP-1 RAs and dual GIP and GLP-1 RAs for the management of T2DM.

The Association between GLP-1 Receptor-Based Agonists and the Incidence of Asthma in Patients with Type 2 Diabetes and/or Obesity:A Meta-Analysis

Objective Recent studies have indicated potential anti-inflammatory effects of glucagon-like peptide-1 receptor agonists(GLP-1RAs)on asthma,which is often comorbid with type 2 diabetes mellitus(T2DM)and obesity.Therefore,we conducted a meta-analysis to assess the association between the administration of glucagon-like peptide-1(GLP-1)receptor-based agonists and the incidence of asthma in patients with T2DM and/or obesity.Methods PubMed,Web of Science,Embase,the Cochrane Central Register of Controlled Trials,and Clinicaltrial.gov were systematically searched from inception to July 2023.Randomized controlled trials(RCTs)of GLP-1 receptor-based agonists(GLP-1RA,GLP-1 based dual and triple receptor agonist)with reports of asthma events were included.Outcomes were computed as risk ratios(RR)using a fixedeffects model.Results Overall,39 RCTs with a total of 85,755 participants were included.Compared to non-GLP-1 receptor-based agonist users,a trend of reduced risk of asthma was observed in patients with T2DM or obesity using GLP-1 receptor-based agonist treatments,although the difference was not statistically significant[RR=0.91,95%confidence interval(CI):0.68 to 1.24].Further Subgroup analyses indicated that the use of light-molecular-weight GLP-1RAs might be associated with a reduced the risk of asthma when compared with non-users(RR=0.65,95%CI:0.43 to 0.99,P=0.043).We also performed sensitivity analyses for participant characteristics,study design,drug structure,duration of action,and drug subtypes.However,no significant associations were observed.Conclusion Compared with non-users,a modest reduction in the incidence of asthma was observed in patients with T2DM or obesity using GLP-1 receptor-based agonist treatments.Further investigations are warranted to assess the association between GLP-1 receptor-based agonists and the risk of asthma.

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.

Peroxisome proliferator-activated receptor agonists:A new hope towards the management of alcoholic liver disease

In this editorial,we examine a paper by Koizumi et al,on the role of peroxisome proliferator-activated receptor(PPAR)agonists in alcoholic liver disease(ALD).The study determined whether elafibranor protected the intestinal barrier and reduced liver fibrosis in a mouse model of ALD.The study also underlines the role of PPARs in intestinal barrier function and lipid homeostasis,which are both affected by ALD.Effective therapies are necessary for ALD because it is a critical health issue that affects people worldwide.This editorial analyzes the possibility of PPAR agonists as treatments for ALD.As key factors of inflammation and metabolism,PPARs offer multiple methods for managing the complex etiology of ALD.We assess the abilities of PPARα,PPARγ,and PPARβ/δagonists to prevent steatosis,inflammation,and fibrosis due to liver diseases.Recent research carried out in preclinical and clinical settings has shown that PPAR agonists can reduce the severity of liver disease.This editorial discusses the data analyzed and the obstacles,advantages,and mechanisms of action of PPAR agonists for ALD.Further research is needed to understand the efficacy,safety,and mechanisms of PPAR agonists for treating ALD.

Impact of glucagon-like peptide receptor agonists on endoscopy and its preoperative management: Guidelines, challenges, and future directions

Glucagon-like peptide receptor agonists(GLP-1RA)are used to treat type 2 diabetes mellitus and,more recently,have garnered attention for their effect-iveness in promoting weight loss.They have been associated with several gastrointestinal adverse effects,including nausea and vomiting.These side effects are presumed to be due to increased residual gastric contents.Given the potential risk of aspiration and based on limited data,the American Society of Anesthesi-ologists updated the guidelines concerning the preoperative management of patients on GLP-1RA in 2023.They included the duration of mandated cessation of GLP-1RA before sedation and usage of“full stomach”precautions if these medications were not appropriately held before the procedure.This has led to additional challenges,such as extended waiting time,higher costs,and increased risk for patients.In this editorial,we review the current societal guidelines,clinical practice,and future directions regarding the usage of GLP-1RA in patients undergoing an endoscopic procedure.

Role of incretins and glucagon receptor agonists in metabolic dysfunction-associated steatotic liver disease:Opportunities and challenges

Metabolic dysfunction-associated steatotic liver disease(MASLD)has become the most common chronic liver disease worldwide,paralleling the rising pandemic of obesity and type 2 diabetes.Due to the growing global health burden and com-plex pathogenesis of MASLD,a multifaceted and innovative therapeutic approach is needed.Incretin receptor agonists,which were initially developed for diabetes management,have emerged as promising candidates for MASLD treatment.This review describes the pathophysiological mechanisms and action sites of three major classes of incretin/glucagon receptor agonists:glucagon-like peptide-1 receptor agonists,glucose-dependent insulinotropic polypeptide receptor agonists,and glucagon receptor agonists.Incretins and glucagon directly or indirectly impact various organs,including the liver,brain,pancreas,gastro-intestinal tract,and adipose tissue.Thus,these agents significantly improve glycemic control and weight management and mitigate MASLD pathogenesis.Importantly,this study provides a summary of clinical trials analyzing the effect-iveness and safety of incretin receptor agonists in MASLD management and provides an in-depth analysis highlighting their beneficial effects on improving liver function,hepatic steatosis,and intrahepatic inflammation.There are emerging challenges associated with the use of these medications in the real world,particularly adverse events,drug-drug interactions,and barriers to access,which are discussed in detail.Additionally,this review highlights the evolving role of incretin receptor agonists in MASLD management and suggests future research directions.

Glucagon-like peptide-1 receptor agonists:Exploring the mechanisms from glycemic control to treatment of multisystemic diseases

This editorial takes a deeper look at the insights provided by Soresi and Giannitrapani,which examined the therapeutic potential of glucagon-like peptide-1 receptor agonists(GLP-1RAs)for metabolic dysfunction-associated fatty liver disease.We provide supplementary insights to their research,highlighting the broader systemic implications of GLP-1RAs,synthesizing the current understanding of their mechanisms and the trajectory of research in this field.GLP-1RAs are revolutionizing the treatment of type 2 diabetes mellitus and beyond.Beyond glycemic control,GLP-1RAs demonstrate cardiovascular and renal protective effects,offering potential in managing diabetic kidney disease alongside renin–angiotensin–aldosterone system inhibitors.Their role in bone metabolism hints at benefits for diabetic osteoporosis,while the neuroprotective properties of GLP-1RAs show promise in Alzheimer's disease treatment by modulating neuronal insulin signaling.Additionally,they improve hormonal and metabolic profiles in polycystic ovary syndrome.This editorial highlights the multifaceted mechanisms of GLP-1RAs,emphasizing the need for ongoing research to fully realize their therapeutic potential across a range of multisystemic diseases.

Glucagon-like peptide-1 receptor agonists as a possible intervention to delay the onset of type 1 diabetes:A new horizon

Type 1 diabetes(T1D)is a chronic autoimmune condition that destroys insulinproducing beta cells in the pancreas,leading to insulin deficiency and hyperglycemia.The management of T1D primarily focuses on exogenous insulin replacement to control blood glucose levels.However,this approach does not address the underlying autoimmune process or prevent the progressive loss of beta cells.Recent research has explored the potential of glucagon-like peptide-1 receptor agonists(GLP-1RAs)as a novel intervention to modify the disease course and delay the onset of T1D.GLP-1RAs are medications initially developed for treating type 2 diabetes.They exert their effects by enhancing glucose-dependent insulin secretion,suppressing glucagon secretion,and slowing gastric emptying.Emerging evidence suggests that GLP-1RAs may also benefit the treatment of newly diagnosed patients with T1D.This article aims to highlight the potential of GLP-1RAs as an intervention to delay the onset of T1D,possibly through their potential immunomodulatory and anti-inflammatory effects and preservation of beta-cells.This article aims to explore the potential of shifting the paradigm of T1D management from reactive insulin replacement to proactive disease modification,which should open new avenues for preventing and treating T1D,improving the quality of life and long-term outcomes for individuals at risk of T1D.

Determination of Ten Kinds of Alpha-2 Agonists Residues in Animal Derived Food by UHPLC-Triple Quadrupole/Composite Linear Ion Trap Mass Spectrometry

[Objectives]The paper was to establish an ultra high performance liquid chromatography-quadrupole/linear ion trap complex mass spectrometry for the determination of 10 kinds ofα2-receptor agonists in animal derived food.[Methods]The samples were extracted with sodium carbonate buffer solution and ethyl acetate,and analyzed by mass spectrometry after solid phase extraction and high performance liquid chromatography separation.[Results]Ten kinds ofα2-receptor agonists showed a good linear relationship in the range of 1-100μg/mL,with the average recovery of over 69%and the relative standard deviation less than 8.32%.The detection limit of 10 kinds of α_(2)-receptor agonists was up to 1μg/kg.[Conclusions]The method has good selectivity and strong anti-interference ability,and can meet the requirements of 10 kinds ofα2-receptor agonists residues in animal derived food.

三七总皂苷通过激活PPARα/Nrf2减轻内皮细胞屏障和功能损伤

目的研究三七总皂苷(PNS)对氧糖剥夺/复氧(OGD/R)诱导的内皮细胞屏障和功能损伤的保护作用,并探讨其作用机制。方法使用OGD/R诱导bEnd.3细胞以建立缺血再灌注损伤模型,同时设立对照组(Control)、模型组(OGD/R)、PNS高剂量组(OGD/R+PNS 400μg/mL)、PPARα抑制剂组(OGD/R+PNS 400μg/mL+PPARαinhibitor)和Nrf2抑制剂组(OGD/R+PNS 400μg/mL+Nrf2 inhibitor)。采用CCK-8检测bEnd.3细胞活性损伤,LDH试剂盒检测乳酸脱氢酶(LDH)表达,蛋白印迹法检测ZO-1、claudin-5、occludin表达;采用细胞划痕和细胞侵袭实验检测bEnd.3细胞侵袭和迁移的水平;借助小管形成实验检测bEnd.3细胞小管形成能力。结果PNS通过激活过氧化物酶体增殖物激活受体α/核因子E2相关因子2(PPARα/Nrf2)信号减轻OGD/R诱导的bEnd.3细胞活性损伤和内皮屏障损伤,抑制细胞迁移和侵袭能力,改善血管生成损伤。结论PNS通过激活PPARα/Nrf2信号减轻OGD/R诱导的内皮细胞屏障和功能损伤。

罗格列酮调控PPARγ/NLRP3介导的细胞焦亡减轻大鼠对比剂诱导的急性肾损伤

目的探讨罗格列酮(RSG)减轻大鼠对比剂诱导的急性肾损伤(CI-AKI)的作用机制。方法雄性SD大鼠随机分为对照组(Control组)、CI-AKI模型组(Model组)、RSG治疗组[RSG组,40 mg/(kg·d)]和过氧化物酶体增殖物激活受体γ(PPARγ)抑制剂组(T0070907组,0.15 mg/mL),每组各6只。建立CI-AKI大鼠模型,给药3 d后收集各组大鼠的血清和肾脏组织。检测肾功能指标血清肌酐(Scr)和血尿素氮(BUN)水平;ELISA检测白细胞介素-1β(IL-1β)、IL-18、活性氧(ROS)和一氧化氮(NO)含量;苏木精-伊红(H-E)染色观察肾组织病理学变化;免疫组织化学(IHC)染色检测PPARγ、NLRP3蛋白表达;TUNEL染色检测肾组织细胞焦亡指数;Western-blot检测肾组织NLRP3、凋亡相关斑点样蛋白(ASC)、含半胱氨酸的天冬氨酸蛋白水解酶-1(Caspase-1)、消皮素D(GSDMD)、IL-1β和IL-18蛋白表达。结果与Control组比较,Model组大鼠的Scr、BUN、IL-1β、IL-18、ROS和NO含量均增加(P<0.05或P<0.01);肾组织出现明显的病理损伤,细胞焦亡指数、NLRP3、ASC、Caspase-1、GSDMD、IL-1β和IL-18蛋白表达升高(P<0.01),PPARγ蛋白表达降低(P<0.01),差别均有统计学意义。与Model组比较,RSG组大鼠血清的Scr、BUN、IL-1β、IL-18、ROS和NO含量均降低,差别有统计学意义(P<0.05或P<0.01);肾组织病理损伤减轻,细胞焦亡指数、NLRP3、ASC、Caspase-1、GSDMD、IL-1β和IL-18蛋白表达降低,PPARγ蛋白表达升高,差别均有统计学意义(P<0.01)。与RSG组比较,T0070907可逆转RSG对CI-AKI大鼠上述指标的影响。结论RSG能够改善大鼠CI-AKI,促进PPARγ表达,抑制NLRP3炎症小体活化介导的细胞焦亡。

基于PPARγ/LXRα/ABCA1信号通路探讨芪黄疽愈方对ApoE^(-/-)小鼠动脉粥样硬化形成的影响及其作用机制

目的 基于过氧化物酶体增殖物激活受体(PPAR)γ/肝X受体(LXR)α/三磷酸腺甘结合盒转运体(ABC)A1信号通路探讨芪黄疽愈方影响对ApoE^(-/-)小鼠动脉粥样硬化(AS)形成及其作用机制。方法 选取25只C57BL/6小鼠作为空白组给予普通饲料喂饲配合生理盐水灌胃,68只ApoE^(-/-)小鼠随机分为模型组(24只)、中药组(22只)、对照组(22只)给予高脂饲料喂饲配合对应药物灌胃,12 w后通过主动脉苏木素-伊红(HE)染色证实造模成功,通过小鼠状态了解小鼠一般状况;主动脉HE染色、油红O染色观察动脉硬化及脂质沉积情况;肝脏HE染色、油红O染色观察肝脏病理变化、红染脂滴情况,并通过Western印迹、聚合酶链反应(PCR)检测PPARγ、LXRα、ABCA1蛋白表达情况。结果 空白组皮毛水润光泽,精神状态良好,活跃,饮食饮水正常;模型组精神萎靡,皮毛晦暗,倦怠懒动,饮食差,饮水正常;与模型组相比,中药组及对照组给药后各症状均有不同程度改善。各组主动脉HE、油红O染色显示,空白组主动脉切片未见AS斑块,主动脉大体标本未见明显红染脂质;与空白组相比,模型组主动脉切片可见斑块,大体标本可见明显红染脂质;与模型组相比,中药组及对照组动脉切片中AS斑块面积较小,大体标本中红染脂质面积较小。小鼠肝脏HE、油红O染色显示,空白组肝细胞结构正常,细胞核位于细胞中央,细胞沿中央静脉为中心向四周放射排列,未见脂肪变性;油红O未见红染脂质;与空白组比较,模型组肝细胞排列紊乱,胞内可见形态不同、大小不等、数量不一的脂滴空泡,油红O切片可见大量红染脂质。与模型组比较,对照组、中药组肝脏病变程度减轻,肝细胞结构大部分清晰可见,脂滴数量减少,油红O红染脂质明显减少。Western印迹检测肝脏PPARγ、LXRα、ABCA1蛋白的表达;与空白组相比,模型组PPARγ、LXRα、ABCA1蛋白表达均明显降低(P<0.05);与模型组相比,中药组均显著升高(P<0.05)。PCR检测肝脏PPARγ、LXRα、ABCA1 mRNA的表达,与空白组相比,模型组PPARγ、LXRα、ABCA1 mRNA表达均明显降低(P<0.05);与模型组相比,中药组显著升高(P<0.05)。结论 芪黄疽愈方能够影响小鼠动脉硬化,升高肝脏PPARγ、LXRα、ABCA1蛋白表达,调节肝脏脂质代谢,促进胆固醇逆转运,延缓AS进展。

白藜芦醇通过AMPK/PPARα/PGC1α影响酒精依赖致肝损伤机制研究

目的 观察白藜芦醇(Resveratrol, RES)对酒精依赖大鼠肝组织损伤以及AMP依赖的蛋白激酶(adenosine 5-monophosphate-activated protein, AMPK)/过氧化物酶体增殖物激活受体α(peroxisome proliferator-activated receptorα,PPARα)/过氧化物酶体增殖物激活受体γ辅激活子1α(peroxisome proliferator activated receptor gamma coactivator 1 alpha, PGC1α)信号通路的影响,讨论RES治疗酒精依赖致肝损伤的修复机制,为临床应用RES提供科学依据。方法 将SPF级雄性大鼠采用随机数字表法设立空白对照组、酒精依赖模型组,采用双瓶自由饮建立20%的酒精依赖模型;酒精依赖模型组制备成功后随机分为酒精依赖模型组、RES高、中、低剂量治疗组,继续给与双瓶自由饮,RES按照100、50、25 mg/(kg·d)剂量灌胃14 d。建模期间检测大鼠体重、饮酒量和饮水量,RES治疗后蛋白免疫印迹法检测大鼠肝组织AMPK、磷酸化AMP依赖的蛋白激酶(phosphorylation-adenosine 5’-monophosphate-activated protein kinas, p-AMPK)、PPARα和PGC1α蛋白表达。结果 蛋白免疫印迹法结果显示:与空白对照组比较,酒精依赖模型组p-AMPK(t=6.61,P<0.05)、PPARα(t=3.08,P<0.05)和PGC1α(t=7.09,P<0.05)表达水平显著下调;与酒精依赖模型组比较,RES高剂量治疗组p-AMPK(F=8.60,P<0.05)、PPARα(F=4.38,P<0.05)和PGC1α(F=11.33,P<0.05)显著上调。结论 结果显示RES可能通过调控AMPK/PPARα/PGC1α信号发挥保护作用。

干扰PPARγ基因对绵羊滋养层细胞增殖、凋亡、迁移和脂质积累的影响

旨在通过干扰PPARγ基因的表达,探究PPARγ对绵羊滋养层细胞增殖活性、细胞凋亡、细胞迁移率以及脂质累积的影响,为深入研究PPARγ在绵羊滋养层细胞中的分子机制提供基础依据。本研究设计并合成干扰PPARγ基因的siRNA干扰片段,通过Western Blot和RT-qPCR筛选干扰效率最高的siRNA,并转染至分离培养的绵羊滋养层细胞中。通过BODIPY染色检测干扰PPARγ基因后滋养层细胞中脂滴的聚积,比色法检测细胞中甘油三酯的含量,并利用RT-qPCR检测脂代谢相关基因的转录水平。采用CCK-8法、划痕试验和流式细胞法,分别探究干扰PPARγ基因对滋养层细胞增殖活性、细胞迁移率及细胞凋亡的影响。筛选得到了干扰效率最高的siPPARγ-1片段用于转染滋养层细胞,在干扰滋养层细胞PPARγ基因表达后,细胞中脂滴聚积能力下降,甘油三酯含量降低(P<0.01),脂代谢相关基因CD36、FABP4和PLIN2的转录水平也受到抑制(P<0.01)。同时,滋养层细胞的增殖活力也显著降低(P<0.05),细胞迁移率减少(P<0.01),而细胞凋亡率显著上升(P<0.01)。本研究表明PPARγ基因在调控滋养层细胞功能方面起重要作用,可对其具体分子机制进行深入研究,以期用于繁殖育种实践中。

卡格列净联合洛塞那肽对2型糖尿病胰岛素抵抗患者胰岛功能、YKL-40、PPARγ的影响

目的研究卡格列净联合洛塞那肽对2型糖尿病胰岛素抵抗患者疗效,及对胰岛功能、血清YKL-40、过氧化物酶体增殖物激活受体γ(PPARγ)的影响。方法选择2型糖尿病患者98例,随机均分为对照组(洛塞那肽治疗)和联合组(卡格列净联合洛塞那肽治疗),比较两组临床疗效、胰岛功能、血清YKL-40、PPARγ水平、血糖指标及不良反应发生率。结果联合组治疗总有效率高于对照组(P<0.05)。两组不良反应总发生率比较差异无显著性(P>0.05)。与治疗前比较,两组治疗后胰岛素曲线下面积、胰岛β细胞功能指数、PPARγ升高,胰岛素抵抗指数、YKL-40、空腹血糖、2 h餐后血糖、糖化血红蛋白、体质指数降低;且联合组变化更为显著(P<0.05)。结论卡格列净联合洛塞那肽治疗可有效提高2型糖尿病胰岛素抵抗患者胰岛功能,并显著改善YKL-40、PPARγ水平。

鲤PPARγ基因序列特征及其与脂肪沉积的相关性

为探讨过氧化物酶体增殖物激活受体γ(peroxisome proliferator activated receptor,PPARγ)对鲤(Cyprinus carpio)脂肪沉积的调控机制,采用RACE和实时荧光定量PCR技术克隆体质量(215.20±8.21)g鲤的PPARγ基因,分析其组织表达特征。结果显示,PPARγ基因c DNA全长为3 077 bp,包括233 bp的5′非编码区、1 311bp的3′非编码区和编码510个氨基酸的开放阅读框。鲤PPARγ包括4个功能结构域,即A/B区,DNA结合区(DNA binding domain,DBD区),铰链区和配体结合区(ligand binding domain,LBD区)。鲤PPARγ与鲫(Carassius auratus)、斑马鱼(Danio rerio)的氨基酸序列相似性最高,分别为98.63%和87.28%。PPARγ基因在各组织均有表达,肝脏中相对表达量最高,脑次之,脾和心脏中最少。腹腔脂肪中PPARγ基因表达量多脂鲤显著高于少脂鲤(P<0.05),背部肌肉中PPARγ基因表达量多脂鲤极显著高于少脂鲤(P<0.01)。推测PPARγ具有促进脂肪沉积的作用,PPARγ基因可以作为鲤脂肪沉积候选基因用于分子选择。本研究为进一步解析鲤PPARγ基因调控脂肪沉积分子机制研究奠定了理论基础。

益智仁激活PPARα介导的自噬作用改善糖尿病肾病

目的:利用体内和体外模型研究益智仁对糖尿病肾病(diabetic kidney disease,DKD)的潜在保护作用,并探讨其作用机制。方法:体内实验将6只db/m小鼠作为正常组,30只db/db小鼠分为模型组、益智仁低剂量组、益智仁中剂量组、益智仁高剂量组、卡格列净组,每组6只。正常组和模型组给予生理盐水,治疗组小鼠分别给予相应药物。治疗8周后,收集血清、尿液和肾脏组织样本。测定随机血糖、24 h尿微量白蛋白、肌酐、尿素氮、甘油三酯和总胆固醇含量。通过HE染色观察肾组织的病理变化。采用60 mmol/L葡萄糖干预HK-2细胞72 h构建DKD体外模型,同时给予不同浓度益智仁含药血清(2%、5%、10%)干预24 h后,通过CCK8法测定细胞活力以及透射电镜观察HK-2细胞中自噬溶酶体的数量。采用RT-qPCR和Western blot检测小鼠及细胞中PPARα、LC3BⅡ、Beclin1、P62 mRNA及蛋白的表达水平。结果:体内实验表明,与正常组相比,模型组的血糖、24 h尿微量白蛋白、肌酐、尿素氮、甘油三酯和总胆固醇含量升高(P<0.0001);与模型组相比,经益智仁治疗后上述生化指标含量降低(P<0.05,P<0.01,P<0.001,P<0.0001)。HE染色显示,模型组肾小球肿胀加重,基底膜增厚,肾小管肿胀且管腔变窄。药物干预后,肾脏病理变化均有不同程度的减轻。且中、高剂量益智仁的疗效均优于低剂量。体外实验表明,益智仁含药血清可提高高糖胁迫下HK-2细胞活力,且10%的剂量效果最佳(P<0.01)。透射电镜发现,与正常组相比,高糖组HK-2细胞中自噬溶酶体数量降低,脂滴增加;经益智仁干预后,自噬溶酶体数量增加,脂滴减少。体内和体外研究中RT-qPCR和Western blot结果一致,表明益智仁能够提高PPARαmRNA和蛋白(P<0.05,P<0.01,P<0.001)水平,促进Beclin1、LC3BⅡ和降低P62蛋白表达水平(P<0.05,P<0.01,P<0.001)。结论:益智仁可能通过激活PPARα介导的自噬作用改善DKD。