Gene transfer of somatostatin receptor type 2 by intratumoral injection inhibits established pancreatic carcinoma xenografts

AIM: To investigate the therapeutic effect of somatostatin receptor type 2 (SSTR2) gene transfection on pancreatic carcinoma xenograftsin vivo in experimental cancers.METHODS: Human pancreatic cancer cell line Panc-1 was inoculated subcutaneously into the back of nude mice. When tumor nodules were grown as large as about 5 mm×5 mm days after inoculation, the mice were randomly divided into 3 groups (6 mice in each group). Group Ⅰ served as untreated control group. Group Ⅱ received an intratumoral injection of a combination of human cytomegalovirus promoter-6C (pCMV-6C) and lipofectamine 2000. Group Ⅲ received an intratumoral injection of a combination of pCMV-6C-SSTR2 and lipofectamine 2000. The rate of tumor growth was compared among these three groups. The expression of SSTR2 in these tumors was detected by immunohistochemistry and Western-blot. Apoptosis index (AI) in these tumors was examined by using TUNEL in situ.RESULTS: Intratumoral injection of a combination of pCMV-6C-SSTR2 and lipofectamine 2000 resulted in the expression of SSTR2 protein. The tumor size and weight in group Ⅲ (0.318±0.098 cm3, and 0.523±0.090 g,respectively) were significantly lower than those in group Ⅰ (2.058±0.176 cm3, and 1.412±0.146 g, respectively) and group Ⅱ (2.025±0.163 cm3, and 1.365±0.116 g, respectively)(P＜0.05) The AI in group Ⅲ (1.47±0.13%) was significantly higher than that in group Ⅰ (0.56±0.09%) and group Ⅱ (0.57±0.11%) (P＜0.05). But there were no significant differences between groups Ⅰ and Ⅱ.CONCLUSION: Our data demonstrate that re-expression of SSTR2 gene has antitumor effects on experimental pancreatic cancer. Restoration of SSTR2 gene expression through gene transfer in vivo might be a potential gene therapy strategy for human pancreatic cancer.

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.

Role of renin-angiotensin system/angiotensin converting enzyme-2 mechanism and enhanced COVID-19 susceptibility in type 2 diabetes mellitus

Coronavirus disease 2019(COVID-19)is a disease that caused a global pandemic and is caused by infection of severe acute respiratory syndrome coronavirus 2 virus.It has affected over 768 million people worldwide,resulting in approx-imately 6900000 deaths.High-risk groups,identified by the Centers for Disease Control and Prevention,include individuals with conditions like type 2 diabetes mellitus(T2DM),obesity,chronic lung disease,serious heart conditions,and chronic kidney disease.Research indicates that those with T2DM face a hei-ghtened susceptibility to COVID-19 and increased mortality compared to non-diabetic individuals.Examining the renin-angiotensin system(RAS),a vital regulator of blood pressure and pulmonary stability,reveals the significance of the angiotensin-converting enzyme(ACE)and ACE2 enzymes.ACE converts angiotensin-I to the vasoconstrictor angiotensin-II,while ACE2 counters this by converting angiotensin-II to angiotensin 1-7,a vasodilator.Reduced ACE2 exp-ression,common in diabetes,intensifies RAS activity,contributing to conditions like inflammation and fibrosis.Although ACE inhibitors and angiotensin receptor blockers can be therapeutically beneficial by increasing ACE2 levels,concerns arise regarding the potential elevation of ACE2 receptors on cell membranes,potentially facilitating COVID-19 entry.This review explored the role of the RAS/ACE2 mechanism in amplifying severe acute respiratory syndrome cor-onavirus 2 infection and associated complications in T2DM.Potential treatment strategies,including recombinant human ACE2 therapy,broad-spectrum antiviral drugs,and epigenetic signature detection,are discussed as promising avenues in the battle against this pandemic.

Emerging roles of microRNAs as diagnostics and potential therapeutic interest in type 2 diabetes mellitus

BACKGROUND Type 2 diabetes mellitus(T2DM)is a metabolic disease of impaired glucose utilization.Uncontrolled high sugar levels lead to advanced glycation end products(AGEs),which affects several metabolic pathways by its receptor of advanced glycation end products(RAGE)and causes diabetic complication.MiRNAs are small RNA molecules which regulate genes linked to diabetes and affect AGEs pathogenesis,and target tissues,influencing health and disease processes.AIM To explore miRNA roles in T2DM's metabolic pathways for potential therapeutic and diagnostic advancements in diabetes complications.METHODS We systematically searched the electronic database PubMed using keywords.We included free,full-length research articles that evaluate the role of miRNAs in T2DM and its complications,focusing on genetic and molecular disease mechanisms.After assessing the full-length papers of the shortlisted articles,we included 12 research articles.RESULTS Several types of miRNAs are linked in metabolic pathways which are affected by AGE/RAGE axis in T2DM and its complications.miR-96-5p,miR-7-5p,miR-132,has_circ_0071106,miR-143,miR-21,miR-145-5p,and more are associated with various aspects of T2DM,including disease risk,diagnostic markers,complications,and gene regulation.CONCLUSION Targeting the AGE/RAGE axis,with a focus on miRNA regulation,holds promise for managing T2DM and its complications.MiRNAs have therapeutic potential as they can influence the metabolic pathways affected by AGEs and RAGE,potentially reducing inflammation,oxidative stress,and vascular complications.Additionally,miRNAs may serve as early diagnostic biomarkers for T2DM.Further research in this area may lead to innovative therapeutic strategies for diabetes and its associated complications.

Reconsidering the role of depression and common psychiatric disorders as partners in the type 2 diabetes epidemic

Common psychiatric disorders(CPDs)and depression contribute significantly to the global epidemic of type 2 diabetes(T2D).We postulated a possible pathophysiological mechanism that through Bridge-Symptoms present in depression and CPDs,promotes the establishment of emotional eating,activation of the reward system,onset of overweight and obesity and,ultimately the increased risk of developing T2D.The plausibility of the proposed pathophysiological mechanism is supported by the mechanism of action of drugs such as naltrexonebupropion currently approved for the treatment of both obesity/overweight with T2D and as separate active pharmaceutical ingredients in drug addiction,but also from initial evidence that is emerging regarding glucagon-like peptide 1 receptor agonists that appear to be effective in the treatment of drug addiction.We hope that our hypothesis may be useful in interpreting the higher prevalence of CPDs and depression in patients with T2D compared with the general population and may help refine the integrated psychiatric-diabetic therapy approach to improve the treatment and or remission of T2D.

MicroRNA-155 mediates endogenous angiotensin II type 1 receptor regulation:implications for innovative type 2 diabetes mellitus management

Type 2 diabetes mellitus(T2DM)is a lifelong condition and a threat to human health.Thorough understanding of its pathogenesis is acutely needed in order to devise innovative,preventative,and potentially curative pharmacological interventions.MicroRNAs(miRNA),are small,non-coding,one-stranded RNA molecules,that can target and silence around 60%of all human genes through translational repression.MiR-155 is an ancient,evolutionarily well-conserved miRNA,with distinct expression profiles and multifunctionality,and a target repertoire of over 241 genes involved in numerous physiological and pathological processes including hematopoietic lineage differentiation,immunity,inflammation,viral infections,cancer,cardiovascular conditions,and particularly diabetes mellitus.MiR-155 Levels are progressively reduced in aging,obesity,sarcopenia,and T2DM.Thus,the loss of coordinated repression of multiple miR-155 targets acting as negative regulators,such as C/EBPβ,HDAC4,and SOCS1 impacts insulin signaling,deteriorating glucose homeostasis,and causing insulin resistance(IR).Moreover,deranged regulation of the renin angiotensin aldosterone system(RAAS)through loss of Angiotensin II Type 1 receptor downregulation,and negated repression of ETS-1,results in unopposed detrimental Angiotensin II effects,further promoting IR.Finally,loss of BACH1 and SOCS1 repression abolishes cytoprotective,anti-oxidant,anti-apoptotic,and anti-inflam matory cellular pathways,and promotesβ-cell loss.In contrast to RAAS inhibitor treatments that further decrease already reduced miR-155 Levels,strategies to increase an ailing miR-155 production in T2DM,e.g.,the use of metformin,mineralocorticoid receptor blockers(spironolactone,eplerenone,finerenone),and verapamil,alone or in various combinations,represent current treatment options.In the future,direct tissue delivery of miRNA analogs is likely.

Effects of glucagon-like peptide-1 receptor agonists on glucose excursion and inflammation in overweight or obese type 2 diabetic patients

BACKGROUND Currently,the lack of comparative studies between weekly and daily formulations of glucagon-like peptide-1 receptor agonists(GLP-1RAs)for glucose excursion is worth investigation.AIM To investigate the effects of weekly and daily formulations of GLP-1RA on glucose excursion and inflammation in overweight and obese patients with type 2 diabetes.METHODS Seventy patients with type 2 diabetes mellitus who were treated at our hospital between January 2019 and January 2022 were enrolled in this retrospective analysis.All patients were treated with metformin.We evaluated changes in blood glucose levels and a series of important indicators in patients before and after treatment with either a weekly or daily preparation of GLP-1RA(group A;n=33 and group B;n=37).RESULTS The degree of decrease in the levels of fasting blood glucose,mean blood glucose,mean amplitude of glycemic excursions,total cholesterol,triglycerides,tumor necrosis factor-α,interleukin-6,and high-sensitivity C-reactive protein after treatment in group A was higher than that in group B(P<0.05),whereas the 2-h postprandial blood glucose levels decreased more so in group B than in group A(P<0.001).However,there were no statistically significant differences in the levels of glycated hemoglobin,standard deviation of blood glucose,coefficient of variation,absolute mean of daily differences,percentage of time with 3.9 mmol/L<glucose<10 mmol/L,and high-and low-density lipoproteins between the two groups(P>0.05).The incidence of adverse reactions was significantly lower in group A than in group B(P<0.05).CONCLUSION The effect of the weekly preparation of GLP-1RA in controlling blood glucose levels in the patients,suppressing inflammation,and reducing adverse reactions was significantly higher than that of the daily preparations,which is worthy of clinical promotion.

达格列净联合胰高血糖素样肽-1受体激动剂对2型糖尿病的疗效研究

目的探讨达格列净联合胰高血糖素样肽-1受体激动剂(GLP-1 RAs)对2型糖尿病患者血液流变学及胰岛素抵抗的影响。方法将2020年11月—2022年10月泉州市中医院收治的102例2型糖尿病患者随机分为2组,每组51例。对照组给予达格列净治疗,研究组采用达格列净联合GLP-1 RAs(利拉鲁肽)的治疗方案。比较2组临床疗效、血糖指标[空腹血糖(FBG)、餐后2 h血糖(2 hPG)、糖化血红蛋白(HbA1c)]、空腹胰岛素(FINS)及胰岛素抵抗[胰岛素抵抗指数(HOMA-IR)、胰岛素分泌指数(HOMA-β)]、血脂指标[总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)]、血液流变学指标[红细胞聚集指数(EAI)、红细胞压积(HCT)、红细胞变形指数(EDI)、血浆黏度(PV)]和不良反应。结果研究组总有效率为94.12%,高于对照组的80.39%,差异有统计学意义(P<0.05)。研究组和对照组治疗后FBG、2 hPG、HbAlc、BMI均低于治疗前,且研究组治疗后FBG、2 hPG、HbAlc水平低于对照组,差异有统计学意义(P<0.05)。治疗后,研究组FINS、HOMA-β水平高于对照组,HOMA-IR水平低于对照组,差异有统计学意义(P<0.05)。研究组和对照组治疗后HDL-C均高于治疗前,TC、TG、LDL-C水平均低于治疗前;研究组治疗后HDL-C水平高于对照组,TC、TG、LDL-C水平低于对照组,差异均有统计学意义(P<0.05)。治疗后,研究组和对照组EAI、HCT、EDI、PV水平均低于治疗前,且研究组EAI、HCT、EDI、PV水平低于对照组,差异均有统计学意义(P<0.05)。研究组不良反应总发生率为11.76%,与对照组的9.80%比较,差异无统计学意义(P>0.05)。结论达格列净联合GLP-1 RAs(利拉鲁肽)治疗2型糖尿病的疗效确切,可有效调节患者血糖及血脂水平,缓解胰岛素抵抗,改善血液流变学指标。

司美格鲁肽对2型糖尿病合并超重及肥胖患者的胰腺和肝脏脂肪含量以及胰岛β细胞功能的影响

目的探讨司美格鲁肽对2型糖尿病(T2DM)合并超重及肥胖患者的血糖控制、胰腺和肝脏脂肪含量以及胰岛β细胞功能的影响。方法采用单中心、前瞻性、临床病例对照试验的方法,选取2021年10月至2022年10月在金华市中心医院诊断为T2DM合并超重(BMI 25~<28 kg/m2)及肥胖(BMI≥28 kg/m2)的86例患者为研究对象,均接受稳定剂量的二甲双胍单药或联合口服用药至少3个月,糖化血红蛋白(HbA1C)为6.5%~8.0%。采用随机数字表法将患者分为对照组和观察组,各43例。对照组继续原方案口服降糖,观察组在原方案的基础上联合司美格鲁肽(起始剂量0.25 mg,4周后增加至0.5 mg并稳定,1次/周,皮下注射)。两组均干预24周。比较两组患者血糖(FPG、餐后2 h血糖和HbA1C)、血脂(TC、TG、LDL-C、HDL-C)、BMI、腰围、胰岛细胞功能[空腹胰岛素(FINS)、胰岛β细胞功能指数(HOMA-β)和胰岛素抵抗指数(HOMA-IR)]。通过非对称回波的最小二乘估算法迭代水脂分离序列测量胰头、胰体和胰尾的胰腺脂肪分数(PFF),计算平均PFF并进行组间比较;测量肝脏右上、右下和左叶的肝脏脂肪分数(HFF),计算平均HFF并进行组间比较。结果对照组39例和观察组40例随访至研究结束。治疗后观察组患者FPG、餐后2 h血糖、HbA1C、BMI、FINS、HOMA-IR、平均PFF和平均HFF均低于对照组,而HOMA-β高于对照组,差异均有统计学意义(均P<0.01)。结论司美格鲁肽应用方便,对T2DM合并超重及肥胖患者能够在常规降糖药的基础上进一步改善胰岛素和胰岛β细胞功能,降低血糖水平、胰腺和肝脏脂肪含量,同时可产生额外的减重获益。

Somatostatin receptor subtype 2-mediated scintigraphy and localization using ^(99m)Tc-HYNIC-Tyr^3-octreotide in human hepatocellular carcinoma-bearing nude mice

AIM: To investigate the uptake of 99mTc-HYNIC-Tyr3-octreotide (99mTc-HYNIC-TOC) in human hepatocellular carcinoma (HCC), which can provide the localizable diagnosis in hepatic carcinoma.METHODS: The expression of somatostatin receptor 2(SSTR2) messenger RNA (mRNA) in human HCC cell line HepG2 was examined by reverse transcriptase-polymerase chain reaction (RT-PCR). Uptake of 99mTc-HYNIC-TOC was evaluated in the human HCC implanted into BALB/c nude mice. ANMIS2000 nuclear medicine analysis system was used to calculate the ratio of 99mTC uptake between tumor tissue and vital organs.RESULTS: We demonstrated the expression of SSTR2mRNA in human HCC cell line HepG2 by RT-PCR. The size of the RT-PCR products was 364 bp detected by sequence analysis of the human SSTR2 mRNA. Scintigraphy proved that 99mTc-HYNIC-TOC was uptaken in the tumor tissue,liver and kidney of the tumor-bearing mice.CONCLUSION: Based on expression of the SSTR2 mRNA in human NCC, 99mTc-NYNIC-TOC can markedly bind with and be uptaken by human HCC tissues as compared with normal liver tissue. The significant retention of radionuclide in kidney and bladder is probably related to non-specific peptide uptake in the tubulus cells of kidney and possibly due to excretion by kidney. Our results show that localizable diagnosis and targeting radiotherapy with radionuclidelabeled somatostatin analog for HCC are of great value to be further studied.

血清Wnt5a、sIL-2R检测在老年2型糖尿病合并肺部感染患者中的应用及与肺部感染病情严重程度、预后的关系

目的 分析血清Wnt5a、可溶性白细胞介素-2受体(sIL-2R)水平对老年2型糖尿病(T2DM)合并肺部感染的诊断价值,及与肺部感染病情严重程度、预后的关系。方法 选取2021年1月—2022年12月河南科技大学第一附属医院收治的84例老年T2DM合并肺部感染患者作为观察组,选取同期住院的30例T2DM患者作为糖尿病组,选取同期该院体检的健康志愿者30例作为对照组。比较3组Wnt5a、sIL-2R水平,绘制受试者工作特征(ROC)曲线评估Wnt5a、sIL-2R水平对老年T2DM合并肺部感染的诊断价值,采用Pearson法分析观察组Wnt5a、sIL-2R水平与实验室指标的相关性;将观察组根据肺部感染严重程度分为轻度、中度、重度3个亚组,比较3个亚组Wnt5a、sIL-2R水平;根据观察组预后情况分为康复组及死亡组,比较2个亚组Wnt5a、sIL-2R水平。结果 观察组及糖尿病组Wnt5a、sIL-2R、FPG较对照组升高(P <0.05),FEV1较对照组降低(P <0.05),观察组sIL-2R较糖尿病组升高(P <0.05),FEV1较糖尿病组降低(P <0.05)。84例患者共检出病原菌98株,其中革兰阳性菌最多(50.00%),革兰阴性菌其次(47.96%),真菌最少(2.04%)。联合检测的曲线下面积(AUC)、敏感性最高,分别为0.935(95%CI:0.873,0.973)、85.71%(95%CI:0.760,0.921),sIL-2R的特异性最高,为93.33%(95%CI:0.765,0.988)。Pearson相关性分析显示,Wnt5a、sIL-2R水平与FEV1水平呈负相关(r=-0.228和-0.227,均P <0.05)。Wnt5a、sIL-2R水平与FPG水平呈正相关(r=0.450和0.647,均P <0.05)。重度组Wnt5a、sIL-2R水平较轻度组高(P <0.05),中度组sIL-2R水平较轻度组高(P <0.05),重度组sIL-2R水平较中度组高(P <0.05)。死亡组Wnt5a、sIL-2R水平高于康复组(P <0.05)。结论 老年T2DM合并肺部感染患者血清Wnt5a、sIL-2R水平升高,其与患者肺功能、血糖水平有相关性,能够辅助临床判断T2DM患者是否具有肺部感染以及感染严重程度、预后情况。

参苓白术散对2型糖尿病Zucker大鼠甜味觉受体的影响

目的探讨参苓白术散对于2型糖尿病Zucker大鼠甜味觉受体相关蛋白的影响。方法SPF级5周龄的瘦型对照Lean Zucker(LZ)雄性大鼠4只作为对照组,将自发型2型糖尿病肥胖Zucker(Zucker Diabetic Fatty,ZDF)大鼠雄性大鼠16只,随机分为模型组,低、中、高剂量参苓白术散治疗组。低、中、高剂量参苓白术散治疗组分别给予生药浓度为6、12、24 g·kg-1·d-1。对照组和模型组每日予同中药给药剂量超纯水灌胃,连续灌胃给药28 d。定期测量大鼠的体质量、摄食量、随机血糖,实验末期进行口服葡萄糖耐量试验(Oral glucose tolerance test,OGTT)。运用蛋白质印迹(Western blot,WB)技术检测舌组织、空肠组织及回肠组织样本检测葡萄糖转运蛋白-2(Glucose transporter 2,GLUT2)以及甜味觉受体1型成员2和3(Taste receptor 2 and 3,T1R2、T1R3)、α-gustducin的蛋白表达。结果2型糖尿病模型组Zucker大鼠的体质量增长、随机血糖值、食物摄入量水平明显高于瘦型对照组,葡萄糖耐量显著低于瘦型对照组。经治疗后,参苓白术散3个剂量组均能不同程度降低2型糖尿病Zucker大鼠的血糖、体质量增长及食物摄入量,并改善2型糖尿病Zucker大鼠葡萄糖耐量。干预4周后,参苓白术散3个剂量组均可以使2型糖尿病Zucker大鼠舌、回肠、空肠的GLUT2、T1R2、T1R3、α-gustducin蛋白表达水平不同程度恢复。结论参苓白术散剂量依赖性地降低2型糖尿病Zucker大鼠血糖,其作用可能与调控舌和肠道甜味感知和葡萄糖代谢有关。

5种GLP-1RAs治疗二甲双胍控制不佳的2型糖尿病的成本-效用分析

目的评估5种胰高血糖素样肽-1受体激动剂(GLP-1RAs)治疗二甲双胍控制血糖不佳的2型糖尿病(T2DM)的长期经济性。方法提取既往发表的荟萃分析及其纳入的随机对照研究(RCT)中患者的基线数据,使用英国前瞻性糖尿病研究结果模型2.1预测各组患者的生存情况、长期疗效和成本,采用成本-效用分析法比较5种GLP-1RAs(利拉鲁肽、利司那肽、艾塞那肽、度拉糖肽和司美格鲁肽)的经济性;采用敏感性分析和情境分析验证基础分析结果的稳定性。结果共纳入21项RCT,6796名患者。生存曲线表明,司美格鲁肽在降低因心血管疾病死亡风险上、度拉糖肽在降低全因死亡风险上较其他GLP-1RAs具有优势。成本-效用分析结果显示,5种方案的经济性从优到劣排序依次为利司那肽、司美格鲁肽、艾塞那肽、度拉糖肽和利拉鲁肽。单因素敏感性分析和概率敏感性分析表明基础分析结果稳健。情境分析结果显示,司美格鲁肽的价格至少降低54.64%,降至369.21元,其对比利司那肽才具有经济性。结论对于使用二甲双胍治疗后血糖控制不佳的我国T2DM患者,临床可考虑优先选择利司那肽和司美格鲁肽。

非奈利酮对2型糖尿病患者心肾保护作用的研究进展

盐皮质激素受体拮抗剂是心力衰竭患者的指南推荐治疗药物。然而,高钾血症和激素副作用的相关风险限制了其在2型糖尿病合并中晚期慢性肾脏病及心血管疾病高风险患者中的广泛使用。非奈利酮是一种新型非甾体类盐皮质激素受体拮抗剂,用于与2型糖尿病相关的心血管疾病和慢性肾脏病患者,达到心肾保护的作用。本文对非奈利酮在治疗2型糖尿病中心肾保护的作用机制、药理特性、安全性等进行综述,旨在为2型糖尿病合并心力衰竭及肾脏损伤患者的临床治疗提供帮助。

粉葛水提物对2型糖尿病db/db小鼠胰岛细胞炎症损伤的改善作用及其机制

为探讨粉葛水提物对2型糖尿病db/db小鼠胰岛细胞炎症损伤的作用及机制,将30只db/db小鼠随机分为模型组、粉葛水提物高、中、低剂量组和二甲双胍组,正常组则采用6只db/m小鼠。持续给药8周后,测量小鼠体质量变化、计算胰重比、检测血清空腹胰岛素(fasting serum lisulin,FINS)、血清空腹血糖(fasting blood glucose,FBG)、糖化血清蛋白(glycosylated serum protein,GSP),计算胰岛素抵抗指数(homeostasis model assess-ment for insulin resistance,HOMA-IR);苏木素-伊红(hematoxylin-eosin,HE)染色观察胰腺组织病理学变化;免疫组化(immunohistochemistry,IHC)法检测胰岛细胞中肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、核因子-κBp65(nuclear factor kappa-Bp65,NF-κBp65)和白细胞介素18(interleukin-18,IL-18)的蛋白表达;蛋白免疫印迹(Western blot,WB)法检测胰腺组织寡聚化结构域样受体蛋白3(NOD-like receptor protein 3,NLRP3)、凋亡相关斑点样蛋白(apoptosis-associated speck-like protein,ASC)、半胱氨酸天冬氨酸蛋白水解酶1(cystein-asparate protease 1,caspase-1)、白细胞介素1β(interle-ukin-1β,IL-1β)、IL-18的蛋白表达;免疫荧光(immunofluorescence,IF)法检测胰腺组织NLRP3的表达。结果表明:与正常组比较,模型组小鼠体质量、胰重比、血清GSP、FBG、FINS含量、HOMA-IR水平明显增加;胰岛细胞变形,出现炎性浸润,胰岛细胞和腺泡细胞边界不清晰,TNF-α、NF-κBp65和IL-18的蛋白表达量明显增加;胰腺组织中相关蛋白表达量明显升高。与模型组比较,二甲双胍和粉葛水提物组体质量、胰重比、血清GSP、FBG、FINS明显降低;胰岛细胞形态完整且边界清晰,炎性浸润明显降低,可见较多胰岛细胞,TNF-α、NF-κBp65和IL-18的蛋白表达量明显减少;胰腺组织中相关蛋白表达量明显降低。综上,粉葛水提物可以减轻db/db小鼠胰岛细胞的炎症损伤,降低胰岛素抵抗,改善2型糖尿病症状。其作用机制可能与抑制NLRP3炎性小体通路及其下游炎症因子IL-1β和IL-18的分泌有关。

基于Markov模型的胰高血糖素样肽1受体激动剂联合二甲双胍治疗2型糖尿病药物经济学评价

目的 对胰高血糖素样肽1受体激动剂(GLP-1RA)联合二甲双胍治疗2型糖尿病(T2DM)进行经济学评价。方法 从我国卫生体系角度出发,基于7项GLP-1RA联合二甲双胍治疗T2DM的随机对照试验(RCT),构建二甲双胍单药或联合GLP-1RA治疗T2DM的Markov模型,模拟治疗期间T2DM无并发症、T2DM伴并发症以及死亡3种状态的动态变化。模型以质量调整生命年(QALYs)为健康产出指标、以3倍我国2023年人均国内生产总值(GDP)为意愿支付(WTP)阈值。模型循环周期设定为1年,共计模拟20年,采用Markov模型进行队列模拟,以增量成本-效用比(ICUR)为评价指标,从而获得每种治疗策略的长期成本、效用及其经济性。通过对成本、效用及贴现的敏感性分析,检验研究结果的稳定性。结果 与二甲双胍单药治疗相比,5种GLP-1RA类药物(利拉鲁肽、度拉糖肽、艾塞那肽、聚乙二醇洛塞那肽、司美格鲁肽)联合二甲双胍治疗方案的ICUR均小于3倍我国2023年人均GDP,增加的成本可接受。敏感性分析中各参数在设定的范围内变化,或将模拟时间延长至30年或50年,对研究结论无显著影响;概率敏感性分析结果表明,WTP阈值为3倍我国2023年人均GDP值(268 074元)时,二甲双胍联合司美格鲁肽0.5 mg方案具有成本-效用优势的概率最高,约为99.7%。结论 对于T2DM患者,相比于二甲双胍单药治疗,利拉鲁肽、度拉糖肽、艾塞那肽、聚乙二醇洛塞那肽、司美格鲁肽以说明书推荐剂量联合二甲双胍治疗方案均属于优势方案,具有经济性。

急性冠脉综合征患者血清ACE2、suPAR水平与氧化应激损伤及不良预后的关系

目的 探讨急性冠脉综合征(Acute coronary syndrome, ACS)患者血清血管紧张素转化酶2(Angiotensin converting enzyme 2,ACE2)、可溶性尿激酶型纤溶酶原激活物受体(Soluble urokinase type plasminogen activator receptor, suPAR)与氧化应激损伤及不良预后的关系。方法 选择2019年9月-2022年9月大兴区人民医院收治的125例ACS患者作为ACS组,并选取与之性别、年龄相匹配的50例冠脉造影结果完全正常者作为对照组,比较两组血清ACE2、suPAR及氧化应激指标[丙二醛(Malondialdehyde, MDA)、过氧化脂质(Lipid peroxide, LPO)、超氧化物歧化酶(Superoxide dismutase, SOD)]水平,并分析血清ACE2、suPAR与氧化应激、不良预后的关系。结果 与对照组比较,ACS组ACE2、suPAR、MDA、LPO升高(P<0.05),SOD下降(P<0.05)。轻度病变、中度病变、重度病变患者ACE2、suPAR及冠脉狭窄Gensini评分显著上升(P<0.05)。ACS患者ACE2、suPAR与MDA、LPO、Gensini评分呈正相关(P<0.05),与SOD呈负相关(P<0.05)。与预后良好患者比较,预后不良患者年龄、发病至就诊时间、Gensini评分、ACE2、suPAR、MDA、LPO升高(P<0.05),LVEF、SOD降低(P<0.05)。年龄、发病至就诊时间、Gensini评分、ACE2、suPAR、MDA、LPO是ACS预后不良的危险因素(P<0.05),LVEF、SOD为其保护因素(P<0.05)。血清ACE2联合suPAR预测ACS预后不良的效能较高,其曲线下面积(Area under curve,AUC)为0.894。结论 ACS患者血清ACE2、suPAR高表达与氧化应激损伤、不良预后显著相关。

胰高血糖素样肽1受体激动剂治疗合并超重或肥胖的2型糖尿病的疗效和安全性的Meta分析

目的系统评价胰高血糖素样肽1受体激动剂(GLP-1RA)治疗合并超重或肥胖2型糖尿病(T2DM)患者的有效性与安全性。方法计算机检索PubMed、Embase、Cochrane Library、Ovid、ClinicalTrial.gov、SinoMed、CNKI、WanFang Data和VIP数据库,搜集有关GLP-1RA治疗T2DM合并超重或肥胖患者的随机对照试验(RCT),检索时限均从2005年1月1日至2023年11月1日。由2位研究者独立筛选文献、提取资料并评价纳入研究的偏倚风险后,采用R软件进行Meta分析,并采用GRADE系统进行证据质量评价。结果共纳入71个RCT,包括29476例患者。Meta分析结果显示,相比于其他降糖药,GLP-1RA在改善糖化血红蛋白[WMD=-0.55,95%CI(-0.65,-0.45),P<0.001]、减重[WMD=-2.61,95%CI(-3.25,-1.97),P<0.001]方面均具有优势;GLP-1RA对空腹血糖的改善效果呈时间依赖性[16周以内:WMD=0.25,95%CI(-0.17,0.66),P=0.250;16~52周:WMD=-0.06,95%CI(-0.32,0.20),P=0.650;>52~104周:WMD=-1.67,95%CI(-1.91,-1.43),P<0.001];安全性方面,GLP-1RA的总体不良反应发生率较高[RR=1.11,95%CI(1.07,1.15),P<0.001];但低血糖发生率低于胰岛素[RR=0.58,95%CI(0.48,0.71),P<0.001],而与口服降糖药的差异无统计学意义[RR=0.83,95%CI(0.58,1.19),P=0.310]。GRADE系统评价显示,仅低血糖发生率的证据等级为中等,其余结局指标的证据水平均为低级。结论当前证据显示,对于T2DM合并肥胖或超重患者,GLP-1RA尤其是司美格鲁肽相比于安慰剂、胰岛素或口服降糖药,能更有效兼顾降糖和减重,虽总体不良反应较多,但可减少低血糖发生。

HER2低表达乳腺癌的临床病理特征及预后分析

目的探讨人表皮生长因子受体2(HER2)低表达乳腺癌的临床病理特征、分子分型及生存预后。方法收集2016年1月至2021年9月1,684例原发性乳腺癌患者临床资料,其中浸润性导管癌患者1,023例,纳入805例HER2阴性乳腺癌患者,比较HER2低表达和无表达乳腺癌患者在临床病理特征、分子分型及生存预后方面的差异,采用Kaplan-Meier法绘制两组患者DFS和BCSS的生存曲线,Log-rank检验比较生存差异,单因素和多因素Cox比例风险回归模型分析预后影响因素。结果805例HER2阴性乳腺癌患者中,HER2无表达515例(64.0%),HER2低表达290例(36.0%)。HER2低表达乳腺癌占所有乳腺浸润性导管癌的28.3%,分子分型以Luminal B型为主。与HER2无表达组相比,HER2低表达组中N分期Ⅱ~Ⅲ期(P=0.004)、TNM分期Ⅲ期(P=0.002)、HR阳性患者(P=0.002)的占比更高。805例患者中,HR阳性629例(78.1%),HR阴性176例(21.9%)。629例HR阳性患者中,HER2无表达385例(61.2%),HER2低表达244例(28.8%),HER2低表达较无表达组的确诊年龄小(P=0.031),<45岁(P=0.003)、N分期Ⅱ~Ⅲ期(P=0.001)、TNM分期Ⅲ期(P=0.001)患者的占比更高。176例HR阴性患者中,HER2无表达130例(73.9%),HER2低表达46例(26.1%),与HER2无表达组相比,HER2低表达组患者确诊年龄大(P=0.047),≥45岁占比高(P=0.036),组织学分级(P<0.001)和Ki-67增殖指数(P=0.027)更低。结论HER2低表达乳腺癌占所有乳腺浸润性导管癌的28.3%,具有独特的临床病理特征和分子分型,HR状态可能是其生物学行为的主要驱动因素。HER2低表达和无表达乳腺癌患者的生存预后均无明显差异。

替西帕肽用于2型糖尿病治疗的研究进展

替西帕肽是一种新一代糖尿病药物,由礼来公司开发,并于2022年5月获得美国食品药物监督管理局(FDA)批准上市。替西帕肽基于多靶点激动剂与单一激动剂相比具有多重药理作用,是一种葡萄糖依赖性的促胰岛素多肽和胰高血糖素样肽-1受体双重激动剂。FDA批准替西帕肽皮下注射作为单一疗法或联合疗法,配合饮食和体育锻炼,以改善糖尿病患者的血糖水平。替西帕肽除了改善血糖控制外,该药物还能有效减轻体重、改善心脏代谢参数、改善血压、降低低密度脂蛋白、胆固醇和三酰甘油等。替西帕肽的有效性和安全性在一项超过1~5期临床试验项目中进行了评估,目前正在进行其他临床试验,以评估其在其他疾病中的应用。