P2Y1 receptor in Alzheimer’s disease

Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer’s disease treatments in the last decades.However,existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic,necessitating the exploration of alternative therapeutic strategies.Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer’s disease patients,with dysregulated astrocytic purinergic receptors,particularly the P2Y1 receptor,all of which constitute the pathophysiology of Alzheimer’s disease.These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer’s disease.This review delves into recent insights into the association between P2Y1 receptor and Alzheimer’s disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer’s disease by mitigating neuroinflammation,thus offering promising avenues for developing drugs for Alzheimer’s disease and potentially contributing to the development of more effective treatments.

Clinicopathological Features and Long-Term Prognostic Role of Human Epidermal Growth Factor Receptor-2 Low Expression in Chinese Patients with Early Breast Cancer:A Single-Institution Study

Objective This study aimed to comprehensively analyze and compare the clinicopathological features and prognosis of Chinese patients with human epidermal growth factor receptor 2(HER2)-low early breast cancer(BC)and HER2-IHC0 BC.Methods Patients diagnosed with HER2-negative BC(N=999)at our institution between January2011 and December 2015 formed our study population.Clinicopathological characteristics,association between estrogen receptor(ER)expression and HER2-low,and evolution of HER2 immunohistochemical(IHC)score were assessed.Kaplan-Meier method and log-rank test were used to compare the long-term survival outcomes(5-year follow-up)between the HER2-IHC0 and HER2-low groups.Results HER2-low BC group tended to demonstrate high expression of ER and more progesterone receptor(PgR)positivity than HER2-IHC0 BC group(P<0.001).The rate of HER2-low status increased with increasing ER expression levels(Mantel-Haenszelχ^(2)test,P<0.001,Pearson’s R=0.159,P<0.001).Survival analysis revealed a significantly longer overall survival(OS)in HER2-low BC group than in HER2-IHC0 group(P=0.007)in the whole cohort and the hormone receptor(HR)-negative group.There were no significant differences between the two groups in terms of disease-free survival(DFS).The discordance rate of HER2 IHC scores between primary and metastatic sites was 36.84%.Conclusion HER2-low BC may not be regarded as a unique BC group in this population-based study due to similar clinicopathological features and prognostic roles.

Serotonin receptor 2B induces visceral hyperalgesia in rat model and patients with diarrhea-predominant irritable bowel syndrome

BACKGROUND Serotonin receptor 2B(5-HT2B receptor)plays a critical role in many chronic pain conditions.The possible involvement of the 5-HT2B receptor in the altered gut sensation of irritable bowel syndrome with diarrhea(IBS-D)was investigated in the present study.AIM To investigate the possible involvement of 5-HT2B receptor in the altered gut sensation in rat model and patients with IBS-D.METHODS Rectosigmoid biopsies were collected from 18 patients with IBS-D and 10 patients with irritable bowel syndrome with constipation who fulfilled the Rome IV criteria and 15 healthy controls.The expression level of the 5-HT2B receptor in colon tissue was measured using an enzyme-linked immunosorbent assay and correlated with abdominal pain scores.The IBS-D rat model was induced by intracolonic instillation of acetic acid and wrap restraint.Alterations in visceral sensitivity and 5-HT2B receptor and transient receptor potential vanilloid type 1(TRPV1)expression were examined following 5-HT2B receptor antagonist adminis-tration.Changes in visceral sensitivity after administration of the TRPV1 antago-INTRODUCTION Irritable bowel syndrome(IBS)is a chronic functional bowel disorder characterized by recurrent abdominal pain with altered bowel habits that affects approximately 15%of the population worldwide[1].IBS significantly impacts the quality of life of patients.Although the pathogenesis of IBS is not completely understood,the role of abnormal visceral sensitivity in IBS has recently emerged[2,3].5-Hydroxytryptamine(5-HT)is known to play a key role in the physiological states of the gastrointestinal tract.Plasma 5-HT levels in IBS with diarrhea(IBS-D)patients were greater than those in healthy controls[4],suggesting a possible role of 5-HT in the pathogenesis of IBS-D.The serotonin receptor 2(5-HT2 receptor)family comprises three subtypes:5-HT2A,5-HT2B,and 5-HT2c.All 5-HT2 receptors exhibit 46%-50%overall sequence identity,and all of these receptors preferentially bind to Gq/11 to increase inositol phosphates and intracellular calcium mobilization[5].5-HT2B receptors are widely expressed throughout the gut,and experimental evidence suggests that the primary function of 5-HT2B receptors is to mediate contractile responses to 5-HT through its action on smooth muscle[6].The 5-HT2B receptor is localized to both neurons of the myenteric nerve plexus and smooth muscle in the human colon.The 5-HT2B receptor mediates 5-HT-evoked contraction of longitudinal smooth muscle[6].These findings suggest that the 5-HT2B receptor could play an important role in modulating colonic motility,which could affect sensory signaling in the gut.Other laboratories have shown that the 5-HT2B receptor participates in the development of mechanical and formalin-induced hyperalgesia[7,8].A 5-HT2B receptor antagonist reduced 2,4,6-trinitrobenzene sulfonic acid(TNBS)and stress-induced visceral hyperalgesia in rats[9,10].However,the role of the 5-HT2B receptor in IBS-D patients and in acetic acid-and wrap restraint-induced IBS-D rat models was not investigated.

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.

Leukocyte immunoglobulin-like receptor B2:A promising biomarker for colorectal cancer

According to the latest global cancer statistics,colorectal cancer(CRC)has emerged as the third most prevalent malignant tumor across the globe.In recent decades,the medical field has implemented several levels of CRC screening tests,encompassing fecal tests,endoscopic examinations,radiological examinations and blood tests.Previous studies have shown that leukocyte immunoglobulin-like receptor B2(LILRB2)is involved in inhibiting immune cell function,immune evasion,and promoting tumor progression in acute myeloid leukemia and nonsmall cell lung cancer.However,its interaction with CRC has not been reported yet.Recently,a study published in the World Journal of Gastroenterology revealed that LILRB2 and its ligand,angiopoietin-like protein 2,are markedly overexpressed in CRC.This overexpression is closely linked to tumor progression and is indicative of a poor prognosis.The study highlights the potential of utilizing the concentration of LILRB2 in serum as a promising biomarker for tumors.However,there is still room for discussion regarding the data processing and analysis in this research.

PRaG 3.0 therapy for human epidermal growth factor receptor 2-positive metastatic pancreatic ductal adenocarcinoma:A case report

BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly fatal disease with limited effective treatment especially after first-line chemotherapy.The human epidermal growth factor receptor 2(HER-2)immunohistochemistry(IHC)positive is associated with more aggressive clinical behavior and shorter overall survival in PDAC.CASE SUMMARY We present a case of multiple metastatic PDAC with IHC mismatch repair proficient but HER-2 IHC weakly positive at diagnosis that didn’t have tumor regression after first-line nab-paclitaxel plus gemcitabine and PD-1 inhibitor treatment.A novel combination therapy PRaG 3.0 of RC48(HER2-antibody-drug conjugate),radio-therapy,PD-1 inhibitor,granulocyte-macrophage colony-stimulating factor and interleukin-2 was then applied as second-line therapy and the patient had confirmed good partial response with progress-free-survival of 6.5 months and overall survival of 14.2 month.She had not developed any grade 2 or above treatment-related adverse events at any point.Percentage of peripheral CD8^(+) Temra and CD4^(+) Temra were increased during first two activation cycles of PRaG 3.0 treatment containing radiotherapy but deceased to the baseline during the maintenance cycles containing no radiotherapy.CONCLUSION PRaG 3.0 might be a novel strategy for HER2-positive metastatic PDAC patients who failed from previous first-line approach and even PD-1 immunotherapy but needs more data in prospective trials.

Adenosine A_(2A)receptor blockade attenuates excitotoxicity in rat striatal medium spiny neurons during an ischemic-like insult

During brain ischemia,excitotoxicity and peri-infarct depolarization injuries occur and cause cerebral tissue damage.Indeed,anoxic depolarization,consisting of massive neuronal depolarization due to the loss of membrane ion gradients,occurs in vivo or in vitro during an energy failure.The neuromodulator adenosine is released in huge amounts during cerebral ischemia and exerts its effects by activating specific metabotropic receptors,namely:A_(1),A_(2A),A_(2B),and A_(3).The A_(2A)receptor subtype is highly expressed in striatal medium spiny neurons,which are particularly susceptible to ischemic damage.Evidence indicates that the A2Areceptors are upregulated in the rat striatum after stroke and the selective antagonist SCH58261 protects from exaggerated glutamate release within the first 4 hours from the insult and alleviates neurological impairment and histological injury in the following 24 hours.We recently added new knowledge to the mechanisms by which the adenosine A2Areceptor subtype participates in ischemia-induced neuronal death by performing patch-clamp recordings from medium spiny neurons in rat striatal brain slices exposed to oxygen and glucose deprivation.We demonstrated that the selective block of A2Areceptors by SCH58261 significantly reduced ionic imbalance and delayed the anoxic depolarization in medium spiny neurons during oxygen and glucose deprivation and that the mechanism involves voltage-gated K+channel modulation and a presynaptic inhibition of glutamate release by the A2Areceptor antagonist.The present review summarizes the latest findings in the literature about the possibility of developing selective ligands of A2Areceptors as advantageous therapeutic tools that may contribute to counteracting neurodegeneration after brain ischemia.

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.

高良姜素调节CCL2/CCR2信号轴对自身免疫性甲状腺炎大鼠炎症反应的影响

目的:探讨高良姜素调节趋化因子配体2(CCL2)/趋化因子受体2(CCR2)通路对自身免疫性甲状腺炎(AIT)大鼠炎症反应的影响。方法:84只大鼠随机分为对照组、模型组、高良姜素低剂量组、高良姜素中剂量组、高良姜素高剂量组、硒酵母片组、高良姜素高剂量+大鼠CCL2重组蛋白(rCCL2)组,每组12只。除对照组外,其他组大鼠均构建AIT模型,造模成功后给药,1次/d,持续8周。ELISA检测大鼠血清中甲状腺球蛋白抗体(TGAb)、甲状腺过氧化物酶抗体(TPOAb)、游离甲状腺素(FT4)、游离三碘甲状腺原氨酸(FT3)水平及甲状腺组织TNF-α、IL-6、IL-1β水平;HE染色检测大鼠甲状腺组织病理变化并对甲状腺组织进行炎症评分;qRT-PCR检测大鼠甲状腺组织CCL2、CCR2 mRNA表达;Western blot检测大鼠甲状腺组织CCL2、CCR2蛋白表达。结果:与对照组比较,模型组大鼠甲状腺组织病理损伤严重,炎症评分、TGAb、TPOAb、FT4、FT3、TNF-α、IL-6、IL-1β水平、CCL2、CCR2 mRNA及蛋白表达升高(P<0.05);与模型组比较,高良姜素低剂量组、高良姜素中剂量组、高良姜素高剂量组、硒酵母片组大鼠甲状腺组织病理损伤减轻,炎症评分、TGAb、TPOAb、FT4、FT3、TNF-α、IL-6、IL-1β水平、CCL2、CCR2 mRNA及蛋白表达降低(P<0.05);与高良姜素高剂量组比较,高良姜素高剂量+rCCL2组大鼠甲状腺组织病理损伤加剧,炎症评分、TGAb、TPOAb、FT4、FT3、TNF-α、IL-6、IL-1β水平、CCL2、CCR2 mRNA及蛋白表达升高(P<0.05)。结论:高良姜素可能通过抑制CCL2/CCR2信号通路抑制AIT大鼠炎症反应。

电针对脑出血后偏瘫痉挛大鼠脊髓颈膨大处GluR2表达的影响

目的研究电针经穴对脑出血后偏瘫痉挛大鼠脊髓颈膨大处谷氨酸受体2(GluR2)表达的影响,探讨电针缓解脑出血后偏瘫痉挛症状的机制。方法将45只健康SD大鼠随机分为假手术组9只、模型组18只、电针组18只。模型组和电针组大鼠采用立体定向在右侧内囊注入自体尾血方法建立脑出血模型,假手术组大鼠不注射自体尾血。造模后电针组采用电针刺激大鼠曲池与足三里穴,假手术组与模型组不给予任何干预。术后第3天、第7天对大鼠分别进行行为学检测[神经功能状态(采用Zea-longa评分评定)、肌张力(采用改良的Ashworth分级评分测定)、旷场实验],并采用Western blot法和免疫组化法检测脊髓颈膨大处GluR2表达情况。结果术后第3天、第7天与假手术组比较,模型组大鼠的Zea-longa评分和左前肢、左后肢的改良Ashworth评分均明显增高(P均<0.05),运动总路程明显缩短(P均<0.05),平均速度明显减慢(P均<0.05),静止时间明显延长(P均<0.05),脊髓颈膨大处GluR2蛋白相对表达量和阳性表达平均光密度值均明显降低(P均<0.05)。与模型组比较,电针组大鼠的Zea-longa评分和左前肢、左后肢的改良Ashworth评分均明显降低(P均<0.05),运动总路程明显延长(P均<0.05),平均速度明显加快(P均<0.05),静止时间明显缩短(P均<0.05),脊髓颈膨大处GluR2蛋白相对表达量和阳性表达平均光密度值均明显增高(P均<0.05)。结论电针刺激曲池和足三里穴可以显著改善脑出血大鼠痉挛性瘫痪症状,缓解肌张力增高,上调脊髓颈膨大处GluR2表达可能是电针治疗缓解脑出血后肢体痉挛的机制之一。

伊尼妥单抗治疗人表皮生长因子受体2阳性转移性乳腺癌伴胃肠功能紊乱1例

乳腺癌是女性常见的肿瘤,如今乳腺癌实体肿瘤通过相应的治疗可取得较好的疗效,但人表皮生长因子受体2(HER2)阳性乳腺癌侵袭性较强、恶性程度高,需引起患者及医务人员的重视。本文回顾性分析1例激素受体阴性、HER2阳性伴胃肠功能紊乱的乳腺癌患者诊治经过。患者初诊为局部晚期炎症乳腺癌伴腋窝淋巴结转移,给予新辅助化疗及手术治疗。术后3年后病情进展,予以伊尼妥单抗联合白蛋白紫杉醇,后续伊尼妥单抗单独靶向治疗,病情持续缓解。提示对于HER2阳性晚期乳腺癌,伊尼妥单抗是个很好的单抗类药物选择。

外周血sIL-2R、CD4^(+)/CD8^(+)、TNF-α对初治活动性肺结核老年患者化疗疗效的评估价值

目的探讨外周血可溶性白细胞介素2受体(sIL-2R)、CD4^(+)淋巴细胞百分比/CD8^(+)淋巴细胞百分比比值(下称CD4^(+)/CD8^(+))、肿瘤坏死因子-α(TNF-α)对初治活动性肺结核老年患者化疗疗效的评估价值。方法将2019年12月至2022年12月该院收治的102例初治活动性肺结核老年患者纳入研究作为观察组,另选取102例年龄≥60岁且同期于该院体检的健康者作为对照组。比较两组外周血sIL-2R、TNF-α、CD4^(+)/CD8^(+)水平并分析sIL-2R、TNF-α、CD4^(+)/CD8^(+)间的相关性。观察组均采用2HRZE/4HR抗结核治疗方案,比较观察组治疗前、治疗1个月、治疗6个月时不同疗效患者外周血sIL-2R、TNF-α、CD4^(+)/CD8^(+);分析sIL-2R、CD4^(+)/CD8^(+)、TNF-α水平与疗效的相关性;采用受试者工作特征(ROC)曲线分析各指标用于老年患者化疗疗效评估的效能。结果观察组sIL-2R、TNF-α水平高于对照组,而CD4^(+)/CD8^(+)低于对照组,差异均有统计学意义(P<0.05)。观察组sIL-2R、TNF-α与CD4^(+)/CD8^(+)呈负相关(P<0.05),sIL-2R与TNF-α呈正相关(P<0.05)。治疗1个月、治疗6个月时显效患者sIL-2R、TNF-α水平低于有效患者,而后者又低于无效患者,显效患者CD4^(+)/CD8^(+)高于有效患者,而后者又高于无效患者,差异均有统计学意义(P<0.05)。sIL-2R、TNF-α水平与疗效呈负相关(P<0.05),CD4^(+)/CD8^(+)与疗效呈正相关(P<0.05)。ROC曲线分析显示,治疗1个月、6个月时sIL-2R、CD4^(+)/CD8^(+)、TNF-α联合用于评估疗效的曲线下面积(AUC)明显大于各时间点单项指标用于评估的AUC(P<0.05),而且治疗6个月时各指标联合评估的AUC大于治疗1个月(P<0.05)。结论初治活动性肺结核老年患者sIL-2R、CD4^(+)/CD8^(+)、TNF-α水平与患者疗效密切相关,将以上指标联合用于评估患者化疗疗效具有一定参考价值。

肺腺癌组织中前列腺素内过氧化物合酶2表达水平与表皮生长因子受体基因突变的相关性分析

目的 分析肺腺癌组织中前列腺素内过氧化物合酶2(PTGS2)表达水平与表皮生长因子受体(EGFR)基因突变的相关性。方法 选取57例肺腺癌患者为研究对象,收集肺腺癌组织及其相应癌旁组织。采用实时荧光定量PCR(RT-PCR)法检测癌组织及癌旁组织中PTGS2 mRNA表达水平;采用免疫组织化学法分析PTGS2蛋白表达;采用RT-PCR法检测癌组织及癌旁组织EGFR基因突变情况。分析肺腺癌患者临床病理参数与PTGS2 mRNA水平、EGFR基因突变情况的关系。采用Spearman秩相关分析探讨肺腺癌患者EGFR基因突变情况与PTGS2 mRNA水平的相关性。结果 57例肺腺癌患者中,5例癌旁组织EGFR基因突变型患者,其对应癌组织也均发生突变,且为同一突变类型。26例(45.61%)癌组织EGFR基因突变型患者,未发现双重突变,其中19外显子突变17例(29.82%),均为缺失突变;21外显子突变9例(15.79%),均为L858R点突变。癌组织中PTGS2mRNA表达水平、PTGS2蛋白阳性率及EGFR基因突变型比例高于癌旁组织,EGFR基因野生型比例低于癌旁组织(P<0.01)。肺腺癌患者性别、TNM分期、吸烟与PTGS2 mRNA表达水平、EGFR基因突变情况有关(P<0.05或0.01)。EGFR基因突变型PTGS2 mRNA表达水平高于EGFR基因野生型(P<0.01)。肺腺癌患者EGFR基因突变与PTGS2 mRNA表达水平呈正相关(r=0.512,P<0.01)。结论 肺腺癌患者癌组织中PTGS2mRNA表达水平及PTGS2蛋白阳性率升高,且与EGFR基因突变关系密切,二者可能共同影响疾病进程。

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。

基质血管片段通过ANG-1/Tie-2信号通路促进移植脂肪血管再生和存活

目的:探讨基质血管片段(SVF)促进脂肪移植后的新血管形成的机制。方法:设计裸鼠的脂肪移植模型,设置对照组、SVFs组及酪氨酸激酶抑制剂(TKI)组3组脂肪组织移植动物模型组,采用大体称重、HE染色、Masson染色、Western blot法和免疫荧光染色等方法检测各实验组体质量、病理学表现、胶原沉积情况及各组ANG-1、p-Tie-2、CD31、BAX及BCL-2的蛋白表达情况并做统计学分析,研究SVFs对脂肪成活的影响。结果:SVFs组的移植物体质量明显高于对照组(P<0.001)。在给予TKI后,SVFs对移植物脂肪体质量的改善被逆转,TKI组移植物体质量明显小于SVFs组(P<0.001);SVFs组脂肪细胞周围胶原沉积明显减少,TKI组脂肪组织变得碎片化和不完整。SVFs组较对照组ANG-1和p-Tie-2的表达水平上调,CD31蛋白表达显著增加(P<0.05);TKI给药后,TKI组较SVFs组p-Tie-2和CD31蛋白表达水平下降(P<0.05)。SVFs组较对照组BAX表达降低,BCL-2表达升高(P<0.05);TKI给药后,TKI组较SVFs组BAX表达升高,BCL-2表达降低(P<0.05)。结论:SVFs可以通过ANG-1/Tie-2信号通路促进血管生成,抑制细胞凋亡,从而提高移植脂肪的存活。

基于NOD2介导的AMPK/mTOR信号通路探讨宫颈癌细胞恶性行为的机制

目的 基于核苷酸结合寡聚化结构域受体2(NOD2)介导的AMP活化蛋白激酶(AMPK)/雷帕霉素靶蛋白(mTOR)信号通路探讨宫颈癌(CC)细胞恶性行为的机制。方法 生物信息学分析确定NOD2在CC组织中的表达。将靶向NOD2(shNOD2)、shRNAs阴性对照(shNC)以及NOD2过表达(NOD2)质粒和载体(Vec)转染CC细胞。通过CCK-8测定、集落形成和Transwell细胞侵袭测定来确定NOD2对CC细胞生长的影响。通过高通量RNA测序(RNA-Seq)进行转录组分析。Western blot试验检测细胞系中NOD2、AMPK/mTOR信号通路和自噬蛋白的表达。24只雌性BALB/c裸鼠随机分为4组,每组6只:载体组(Vec组)、NOD2过表达组(NOD2组)、shNC组和shNOD2组。构建小鼠远处转移模型,监测肺转移的荧光强度,计数肺转移结节的数量。结果 在线数据库分析显示,NOD2在CC组织中表达明显高于正常组织,并且不同分期的CC中NOD2的mRNA表达差异有统计学意义(P<0.05)。此外,NOD2的高表达与较差的总生存期和无病生存期相关(P<0.05)。NOD2过表达对CC细胞增殖、集落形成、迁移和侵袭具有促进作用,而NOD2敲低则相反。与体外结果一致,在转移的小鼠尾静脉注射模型中,NOD2组CC细胞的肺定殖、肺转移灶较Vec组增加(P<0.05),而shNOD2组CC细胞的肺定殖、肺转移灶较shNC组减少(P<0.05)。RNA-Seq结果显示NOD2表达与AMPK信号激活、mTOR信号抑制、自噬调节途径激活和自噬体形成显著相关。与shNC组相比,shNOD2组磷酸化AMPK、LC3蛋白表达水平减少(P<0.05),磷酸化mTOR、p62蛋白表达水平增加(P<0.05);与Vec组相比,NOD2组LC3、AMPK蛋白表达水平增加(P<0.05),磷酸化mTOR、p62蛋白表达水平减少(P<0.05)。与shNC组相比,shNOD2组GFP-mRFP-LC3的点积累减少(P<0.05);与Vec组相比,GFP-mRFP-LC3的点积累增加(P<0.05)。结论 NOD2可能通过AMPK/mTOR信号促进CC增殖、迁移和侵袭,其作用机制部分涉及自噬激活。

miR-10b介导NKG2D调节脑胶质瘤细胞免疫效应的实验研究

目的:观察微小核糖核酸-10b(miR-10b)对脑胶质瘤细胞免疫效应的调节作用并探讨其作用机制。方法:取人脑胶质瘤细胞U251进行培养和传代,获得处于对数生长期的细胞。按照1.0×105个/ml浓度制备细胞悬液,并设置对照组、过表达组、低表达组、空白组,每组6个复孔。对照组、过表达组、低表达组分别采用脂质体转染法转染阴性对照、miR-10b模拟物、miR-10b抑制剂,空白组予以等量无菌生理盐水。分离和培养1例健康志愿者外周血自然杀伤(NK)细胞。MTT法检测不同效靶比时NK细胞的杀伤活性;流式细胞仪检测各组NK细胞表面NK细胞激活受体(NKG2D)表达,并检测各组人脑胶质瘤细胞U251表面主要组织相容性复合物Ⅰ链相关基因A(MICA)、UL16结合蛋白2(ULBP2)、UL16结合蛋白3(ULBP3)表达。结果:对照组、过表达组、低表达组转染效率分别为(93.55±2.05)%、(95.67±3.14)%、(94.18±3.26)%;与对照组和空白组相比,过表达组miR-10b表达升高,低表达组miR-10b表达降低,差异均有统计学意义(P<0.05),且对照组和空白组miR-10b表达差异无统计学意义(P>0.05);与对照组和空白组相比,过表达组NK细胞不同效靶比杀伤活性均降低、NKG2D表达降低,低表达组NK细胞不同效靶比杀伤活性均增高、NKG2D表达增高,差异均有统计学意义(P<0.05),各组NK细胞杀伤活性均随效靶比增加而增高,差异均有统计学意义(P<0.05),且对照组与空白组相比,相同效靶比NK细胞杀伤活性、NKG2D表达差异均无统计学意义(P>0.05);与对照组和空白组相比,过表达组人脑胶质瘤细胞U251表面MICA、ULBP2、ULBP3表达均降低,低表达组人脑胶质瘤细胞U251表面MICA、ULBP2、ULBP3表达均增高,差异均有统计学意义(P<0.05),且对照组与空白组人脑胶质瘤细胞U251表面MICA、ULBP2、ULBP3表达差异均无统计学意义(P>0.05)。结论:抑制miR-10b表达能够增加NK细胞表面NKG2D和人脑胶质瘤细胞U251表面MICA、ULBP2、ULBP3表达,增强NK细胞对人脑胶质瘤细胞U251的杀伤活性。

TET2重塑CXCR4 DNA甲基化对急性心肌梗死小鼠心肌组织自噬、炎症反应及凋亡的影响

目的:探究急性心肌梗死(AMI)过程中内皮细胞tet甲基胞嘧啶双加氧酶2(TET2)对趋化因子受体4(CXCR4)DNA甲基化的影响以及对AMI小鼠心肌组织自噬、炎症反应及组织细胞凋亡的影响机制,为临床探究AMI发展的分子机制提供理论依据。方法:8周龄雄性C57/BL6小鼠50只,制备AMI模型,尾部注射TET2、CXCR4过表达质粒;蛋白免疫印迹(Western Blot)法检测心肌组织TET2、CXCR4、微管相关蛋白3(LC3)、P62、B细胞淋巴瘤/白血病-2基因(Bcl-2)关联X蛋白(Bax)、半胱氨酸蛋白酶3(Caspase-3)、Bcl-2表达;甲基化检测CXCR4 DNA甲基化水平;酶联免疫吸附法(ELISA)检测心肌组织内炎性因子白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)水平;原位末端转移酶标记技术(TUNEL)检测各组心肌组织细胞凋亡指数。结果:与假手术组比较,模型组心肌组织内TET2、CXCR4均表达上调,TET2、CXCR4均在心肌组织内过表达,TET2过表达促进CXCR4表达,差异有统计学意义(P<0.05);与模型组比较,TET2 mimic组CXCR4启动子区域DNA甲基化程度降低,CXCR4蛋白表达升高,差异有统计学意义(P<0.05);与假手术组比较,模型组小鼠心肌组织自噬蛋白LC3、抑制细胞凋亡蛋白Bcl-2表达下调,炎性因子IL-6、TNF-α、IL-1β水平、自噬蛋白P62、促细胞凋亡蛋白Bax、cleaved Caspase-3表达上调,差异有统计学意义(P<0.05);TET2、CXCR4过表达进一步下调LC3、Bcl-2蛋白表达,上调炎性因子IL-6、TNF-α、IL-1β水平,P62、Bax、cleaved Caspase-3蛋白表达;TET2、CXCR4二者联合体现出最低LC3、Bcl-2蛋白表达,最高炎性因子IL-6、TNF-α、IL-1β水平以及P62、Bax、cleaved Caspase-3蛋白表达,差异有统计学意义(P<0.05)。结论:AMI发展中,TET2通过降低CXCR4 DNA甲基化,促进CXCR4基因表达,进而抑制AMI小鼠心肌组织自噬,上调炎症反应及细胞凋亡程度,促进疾病发展。

炎性因子IL-8、PCT、IL-2R与严重细菌性颅内感染GCS评分的关系及预测预后的价值

目的分析严重细菌性颅内感染患者炎性因子白介素-8(IL-8)、降钙素原(PCT)、白介素-2受体(IL-2R)与格拉斯哥昏迷量表(GCS)评分的关系,并探讨其预测预后的价值。方法前瞻性选取2020年1月至2023年1月平顶山市第一人民医院收治的80例严重颅内感染患者作为研究对象,根据GCS评分分为轻中度组(9~14分)32例和重度组(≤8分)48例。比较两组患者的GCS评分和血清IL-8、PCT、IL-2R水平,采用Pearson相关系数分析血清IL-8、PCT、IL-2R水平与GCS评分的相关性,并以格拉斯哥预后量表(GOS)评估预后情况,比较预后良好、预后不良患者的临床资料和血清IL-8、PCT、IL-2R水平,通过Lasso回归筛选预后不良的预测因素,采用受试者工作特征(ROC)曲线分析血清IL-8、PCT、IL-2R预测预后不良的价值,并比较含与不含血清IL-8、PCT、IL-2R预测方案对预后不良的预测能力。结果重度组患者入院时血清IL-8、PCT、IL-2R水平分别为(35.12±4.26)pg/mL、(11.83±2.26)pg/mL、(912.35±105.83)U/m L,明显高于轻中度组的(26.74±3.81)pg/m L、(8.49±2.03)pg/m L、(749.21±92.56)U/m L,差异均有统计学意义(P<0.05);Pearson相关系数分析结果显示,严重细菌性颅内感染患者入院时的血清IL-8、PCT、IL-2R水平与GCS评分呈负相关(P<0.05);预后不良患者的年龄、机械通气占比、糖尿病占比、感染至入院时间、入院时血清IL-8、PCT、IL-2R水平分别为(65.13±7.26)岁、67.57%、27.03%、(38.05±4.17)h、(40.12±4.81)pg/m L、(12.67±2.59)pg/m L、(951.46±121.49)U/mL,明显高于预后良好患者的(56.39±6.41)岁、41.86%、9.30%、(26.92±3.46)h、(24.59±3.95)pg/mL、(8.61±2.24)pg/mL、(757.28±97.28)U/mL,入院时GCS评分为(6.72±0.39)分,明显低于预后良好患者的(10.81±0.82)分,差异均有统计学意义(P<0.05);经Lasso回归分析结果显示,年龄、感染至入院时间、GCS评分、血清IL-8、PCT、IL-2R水平均为预后不良的预测因素(P<0.05);经ROC分析结果显示,血清IL-8、PCT、IL-2R预测预后不良的曲线下面积(AUC)分别为0.729、0.717、0.719;含炎性因子预测方案的AUC为0.933,不含炎性因子预测方案的AUC为0.811;经DeLong检验结果显示,与不含炎性因子预测方案比较,含炎性因子预测方案的AUC明显增大(P<0.05),净重新分类指数(NRI)、综合判别改善指数(IDI)均>0(P<0.05)。结论严重细菌性颅内感染患者血清IL-8、PCT、IL-2R水平与GCS评分存在明显负相关,且与预后转归密切相关,可为临床预测预后提供参考。

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/m^(2))及肥胖(BMI≥28 kg/m^(2))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。