电针预处理对切口痛大鼠中脑导水管周围灰质5-HT_(7)受体表达的影响

目的:建立足趾部切口痛大鼠模型,探讨重复电针预处理对切口痛大鼠镇痛效果及其对中脑导水管周围灰质(periaqueductal gray,PAG)5-HT_(7)受体(5-HT_(7)R)表达的影响。方法:40只成年雄性SD大鼠按随机数字表法均等分为对照组(Control,Con组)、切口痛模型组(Incision pain,IP组)、正常+电针预处理组(Control+Electroacupuncture,Con+EA组)、模型+电针预处理组(Incision Pain+Electroacupuncture,IP+EA组)。IP组和IP+EA组大鼠右足趾部行疼痛造模,且造模前,Con+EA组和IP+EA组大鼠行右侧“足三里”穴和“环跳”穴电针刺激(2/10 Hz疏密波,刺激强度数值为1档,每日1次30 min),连续5天。于第1次电针预处理前2 h(T1)、术前2 h(T2)、术后4 h(T3)、术后24 h(T4)测定大鼠机械刺激缩足反射阈值(mechanical withdrawal threshold,MWT)和热缩足潜伏期(thermal withdrawal latency,TWL);酶联免疫吸附法检测脑脊液中5-HT浓度;免疫组化和免疫荧光方法分别检测大鼠PAG中c-Fos和5-HT_(7)R蛋白表达情况。结果:与Con组比较,IP组大鼠T3、T4时间点MWT和TWL均明显降低,脑脊液中5-HT浓度增加,PAG中c-Fos蛋白和5-HT_(7)R表达明显上调(P<0.05);Con+EA组和IP+EA组脑脊液中5-HT含量和PAG中5-HT_(7)R表达均上升(P<0.05)。与IP组相比,IP+EA组大鼠T3、T4时间点的MWT和TWL显著升高,PAG中c-Fos蛋白表达减少,5-HT_(7)R蛋白表达增加(P<0.05)。结论:电针预处理可能通过上调PAG中5-HT_(7)R蛋白表达发挥镇痛作用。

5-HT_(2A)受体拮抗剂治疗神经精神疾病幻觉症状研究进展

帕金森病、阿尔茨海默病和精神分裂症等神经精神疾病在发展过程中会出现幻觉、妄想等精神病症状,这些症状发病率高、治愈难,严重影响患者生活质量。尽管经典抗精神病药物氯丙嗪、舒必利和奋乃静等通过拮抗多巴胺2型(D_(2))受体可治疗相关症状,但也会引发不可控的锥体外系反应和高泌乳素症等不良反应。近年来研究发现,奥氮平、氯氮平、利培酮和匹莫范色林等非经典抗精神病药物通过拮抗5-羟色胺2A(5-HT_(2A))受体或同时拮抗5-HT_(2A)受体(强)和D_(2)受体(弱)治疗神经精神疾病的幻觉症状。非临床研究结果表明,在多种因素诱导的幻觉模型上,非经典抗精神病药物均表现出良好的治疗作用;临床研究进一步证实,该类药物显著改善精神病症状(以幻觉和妄想为主),尤其是匹莫范色林,其对氯氮平、利培酮不敏感或耐受的患者仍能表现出良好的治疗效果。同时,非经典抗精神病药物不良反应的发生率和严重程度较低,总体耐受性较好。本文综述了5-HT_(2A)受体拮抗剂改善神经精神疾病伴随的幻觉症状的研究进展,为设计开发新型神经精神疾病治疗药物提供参考。

5-HT_(2A)受体反向激动剂LPM6690061改善普拉克索致PD小鼠躁狂

为探讨5-HT_(2A)受体反向激动剂LPM6690061对普拉克索引起的帕金森病(PD)躁狂小鼠的症状改善作用及作用机制,采用1-甲基-4-苯基-1,2,3,6,-四氢吡啶(MPTP)建立小鼠PD模型,同时腹腔注射PPX建立小鼠PD躁狂模型,后灌胃给予2.0,6.0,18.0 mg/kg LPM6690061进行治疗。转棒、爬杆实验检测PD小鼠的运动障碍;悬尾、强迫游泳实验检测PD躁狂小鼠的情绪障碍;旷场实验检测PD躁狂小鼠的过度活动;Y迷宫实验检测PD躁狂小鼠的空间记忆;苏木精-伊红染色法检测海马体齿状回(DG)区细胞的损伤;蛋白免疫印迹法检测小鼠海马体糖原合酶激酶3β(GSK-3β)、磷酸化GSK-3β(P-GSK-3β)、丝氨酸/苏氨酸激酶(Akt)、磷酸化Akt(P-Akt)、细胞外调节蛋白激酶(Erk)、磷酸化Erk(P-Erk)、环磷腺苷效应元件结合蛋白(CREB)、磷酸化CREB(P-CREB)的表达。结果表明,5-HT_(2A)受体反向激动剂LPM6690061可改善普拉克索引起的PD小鼠的躁狂症状,抑制Akt/GSK-3β信号通路,降低海马体P-GSK-3β、P-Akt蛋白的表达;增强Erk/CREB通路,增加海马体P-Erk和P-CREB蛋白的表达,减少神经元凋亡,改善PD躁狂小鼠的空间记忆能力,减轻海马体DG区的颗粒细胞损伤。

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.

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.

高血压合并焦虑病人血清微RNA-451a、胰岛素样生长因子-1受体表达水平与焦虑程度的关系

目的探讨高血压合并焦虑病人血清微RNA-451a(miR-451a)、胰岛素样生长因子-1受体(IGF1R)表达水平与焦虑程度的关系。方法选取2020年2月至2022年1月在汉中市中心医院进行治疗的高血压病人160例,根据临床诊断和汉密尔顿焦虑量表(HAMA)评估将病人分为高血压组60例、高血压合并轻度焦虑情绪组48例、高血压合并中度焦虑情绪组32例和高血压合并重度焦虑情绪组20例,收集整理所有病例的临床基础资料。采用实时荧光定量PCR法检测血清miR-451a表达水平、ELISA法检测血清IGF1R表达水平;比较分析高血压病人和高血压合并焦虑情绪病人的临床病理特征;采用Pearson法分析HAMA评分与血清miR-451a、IGF1R表达水平的相关性;采用logistic回归分析高血压合并焦虑的影响因素。结果高血压组、轻度焦虑、中度焦虑和重度焦虑组病人血清miR-451a水平依次降低(0.88±0.30,0.59±0.14,0.48±0.11,0.38±0.09),IGF1R水平依次升高[(2.14±0.60)μg/L,(2.66±0.62)μg/L,(3.08±0.66)μg/L,(3.51±0.74)μg/L];血清miR-451a水平与HAMA评分呈负相关(r=−0.50,P<0.05),血清IGF1R水平与HAMA评分呈正相关(r=0.43,P<0.05);高血压合并焦虑组收缩压[(142.26±18.51)mmHg,(135.29±17.84)mmHg]、舒张压[(84.25±11.30)mmHg,(78.23±10.25)mmHg]、C-反应蛋白[(4.47±0.96)mg/L,(4.16±0.91)mg/L]、IL-6水平[(36.95±6.31)μg/L,(27.48±5.49)μg/L]显著高于高血压组,IL-10水平[(12.34±3.26)ng/L,(16.24±3.91)ng/L]显著低于高血压组(P<0.05);多因素logistic回归分析结果显示,收缩压[OR 95%CI=1.33(1.06,1.67)]、舒张压[OR 95%CI=1.20(1.00,1.45)]、IL-6[OR 95%CI=1.89(1.22,2.93)]、IL-10[OR 95%CI=0.38(0.17,2.93)]、miR-451a[OR 95%CI=0.01(0.00,0.47)]、IGF1R[OR 95%CI=7.62(1.21,48.03)]水平为高血压合并焦虑的影响因素(P<0.05)。结论高血压合并焦虑病人血清中miR-451a低表达,IGF1R高表达,且与病人焦虑程度密切相关。

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.

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.

Identification of transient receptor potential channel genes and functional characterization of TRPA1 in Spodoptera frugiperda

Spodoptera frugiperda is a highly destructive pest that has become a global problem due to its robust reproductive and migratory capabilities.Transient receptor potential(TRP)channels,which constitute a vast ion channel family,play pivotal roles in sensing the external environment and maintaining internal homeostasis in insects.TRP channels have been widely investigated for their critical roles in regulating various insect behaviors in recent years.In this study,we identified 15 TRP gene loci encoding 26 transcripts in the genome of S.frugiperda and analyzed their expression profiles at different developmental stages.The results revealed that S.frugiperda possesses four TRPC genes,six TRPA genes,one TRPM gene,two TRPV genes,one TRPN gene,and one TRPML gene,while a canonical TRPP is absent.Moreover,the SfruTRPA1 was functionally characterized using the Xenopus oocyte expression system.The results showed that SfruTRPA1 is activated by temperature increases from 20 to 45℃,and there is no significant desensitization after repeated stimuli within the same temperature range.Additionally,SfruTRPA1 is activated by certain natural chemicals,including allyl isothiocyanate(AITC)and cinnamaldehyde(CA).These findings provide valuable insights to the TRP genes in S.frugiperda.

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.

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.

Activation of G-protein-coupled receptor 39 reduces neuropathic pain in a rat model

Activated G-protein-coupled receptor 39(GPR39)has been shown to attenuate inflammation by interacting with sirtuin 1(SIRT1)and peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α).However,whether GPR39 attenuates neuropathic pain remains unclear.In this study,we established a Sprague-Dawley rat model of spared nerve injury-induced neuropathic pain and found that GPR39 expression was significantly decreased in neurons and microglia in the spinal dorsal horn compared with sham-operated rats.Intrathecal injection of TC-G 1008,a specific agonist of GPR39,significantly alleviated mechanical allodynia in the rats with spared nerve injury,improved spinal cord mitochondrial biogenesis,and alleviated neuroinflammation.These changes were abolished by GPR39 small interfering RNA(siRNA),Ex-527(SIRT1 inhibitor),and PGC-1αsiRNA.Taken together,these findings show that GPR39 activation ameliorates mechanical allodynia by activating the SIRT1/PGC-1αpathway in rats with spared nerve injury.

Receptor tyrosine kinase-like orphan receptor 1:A novel antitumor target in gastrointestinal cancers

Receptor tyrosine kinase-like orphan receptor 1(ROR1)is a member of the type I receptor tyrosine kinase family.ROR1 is pivotal in embryonic development and cancer,and serves as a biomarker and therapeutic target.It has soluble and membrane-bound subtypes,with the latter highly expressed in tumors.ROR1 is conserved throughout evolution and may play a role in the development of gastrointestinal cancer through multiple signaling pathways and molecular mechanisms.Studies suggest that overexpression of ROR1 may increase tumor invasiveness and metastasis.Additionally,ROR1 may regulate the cell cycle,stem cell characteristics,and interact with other signaling pathways to affect cancer progression.This review explores the structure,expression and role of ROR1 in the development of gastrointestinal cancers.It discusses current antitumor strategies,outlining challenges and prospects for treatment.

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.

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.

New perspectives in prognostication of hepatocellular carcinoma:The role and clinical implications of transient receptor potential family genes

The study titled“Transient receptor potential-related risk model predicts prognosis of hepatocellular carcinoma patients”is a significant contribution to hepatocellular carcinoma(HCC)research,highlighting the role of transient receptor potential(TRP)family genes in the disease’s progression and prognosis.Utilizing data from The Cancer Genome Atlas database,it establishes a new risk assessment model,emphasizing the interaction of TRP genes with tumor proliferation pathways,key metabolic reactions like retinol metabolism,and the tumor immune microenvironment.Notably,the overexpression of the TRPC1 gene in HCC correlates with poorer patient survival outcomes,suggesting its potential as a prognostic biomarker and a target for personalized therapy,particularly in strategies combining immunotherapy and anti-TRP agents.

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.

Diabetes and high-glucose could upregulate the expression of receptor for activated C kinase 1 in retina

BACKGROUND Diabetic retinopathy(DR)is a major ocular complication of diabetes mellitus,leading to visual impairment.Retinal pigment epithelium(RPE)injury is a key component of the outer blood retinal barrier,and its damage is an important indicator of DR.Receptor for activated C kinase 1(RACK1)activates protein kinase C-ε(PKC-ε)to promote the generation of reactive oxygen species(ROS)in RPE cells,leading to apoptosis.Therefore,we hypothesize that the activation of RACK1 under hypoxic/high-glucose conditions may promote RPE cell apoptosis by modulating PKC-ε/ROS,thereby disrupting the barrier effect of the outer blood retinal barrier and contributing to the progression of DR.AIM To investigate the role and associated underlying mechanisms of RACK1 in the development of early DR.METHODS In this study,Sprague-Dawley rats and adult RPE cell line-19(ARPE-19)cells were used as in vivo and in vitro models,respectively,to explore the role of RACK1 in mediating PKC-εin early DR.Furthermore,the impact of RACK1 on apoptosis and barrier function of RPE cells was also investigated in the former model.RESULTS Streptozotocin-induced diabetic rats showed increased apoptosis and upregulated expression of RACK1 and PKC-εproteins in RPE cells following a prolonged modeling.Similarly,ARPE-19 cells exposed to high glucose and hypoxia displayed elevated mRNA and protein levels of RACK1 and PKC-ε,accompanied by an increases in ROS production,apoptosis rate,and monolayer permeability.However,silencing RACK1 significantly downregulated the expression of PKC-εand ROS,reduced cell apoptosis and permeability,and protected barrier function.CONCLUSION RACK1 plays a significant role in the development of early DR and might serve as a potential therapeutic target for DR by regulating RPE apoptosis and barrier function.

Human epidermal growth factor receptor 2 expression level and combined positive score can evaluate efficacy of advanced gastric cancer

BACKGROUND Although treatment options for gastric cancer(GC)continue to advance,the overall prognosis for patients with GC remains poor.At present,the predictors of treatment efficacy remain controversial except for high microsatellite instability.AIM To develop methods to identify groups of patients with GC who would benefit the most from receiving the combination of a programmed cell death protein 1(PD-1)inhibitor and chemotherapy.METHODS We acquired data from 63 patients with human epidermal growth factor receptor 2(HER2)-negative GC with a histological diagnosis of GC at the Cancer Hospital,Chinese Academy of Medical Sciences between November 2020 and October 2022.All of the patients screened received a PD-1 inhibitor combined with chemotherapy as the first-line treatment.RESULTS As of July 1,2023,the objective response rate was 61.9%,and the disease control rate was 96.8%.The median progression-free survival(mPFS)for all patients was 6.3 months.The median overall survival was not achieved.Survival analysis showed that patients with a combined positive score(CPS)≥1 exhibited an extended trend in progression-free survival(PFS)when compared to patients with a CPS of 0 after receiving a PD-1 inhibitor combined with oxaliplatin and tegafur as the first-line treatment.PFS exhibited a trend for prolongation as the expression level of HER2 increased.Based on PFS,we divided patients into two groups:A treatment group with excellent efficacy and a treatment group with poor efficacy.The mPFS of the excellent efficacy group was 8 months,with a mPFS of 9.1 months after excluding a cohort of patients who received interrupted therapy due to surgery.The mPFS was 4.5 months in patients in the group with poor efficacy who did not receive surgery.Using good/poor efficacy as the endpoint of our study,univariate analysis revealed that both CPS score(P=0.004)and HER2 expression level(P=0.015)were both factors that exerted significant influence on the efficacy of treatment the combination of a PD-1 inhibitor and chemotherapy in patients with advanced GC(AGC).Finally,multivariate analysis confirmed that CPS score was a significant influencing factor.CONCLUSION CPS score and HER2 expression both impacted the efficacy of immunotherapy combined with chemotherapy in AGC patients who were non-positive for HER2.

支气管哮喘患者血清miR-181a、S1PR1 mRNA表达水平与急性发作期发生的相关性

目的探究支气管哮喘患者血清微小RNA-181a(miR-181a)、1-磷酸鞘氨醇受体1(S1PR1)信使RNA(mRNA)表达水平与急性发作期发生的关系。方法选择2021年1月至2023年5月石家庄市急救中心收治的支气管哮喘急性发作期患者132例作为急性期组,支气管哮喘缓解期患者89例作为缓解期组,体检健康者90例作为对照组。将急性期组患者分为轻度组(50例)、中度组(45例)、重度组(37例)。收集受试者临床资料并检查肺功能[第1秒用力呼气容积和用力肺活量比值(FEV_(1)/FVC)、呼气峰流速占预计值百分比(PEF%pred)];采用实时荧光定量PCR法检测血清miR-181a、S1PR1 mRNA表达;采用Pearson法分析支气管哮喘急性发作期患者血清miR-181a、S1PR1 mRNA及二者与肺功能指标的相关性,采用多因素Logistic回归分析影响支气管哮喘患者急性发作期发生的因素,采用受试者工作特征(ROC)曲线评估血清miR-181a、S1PR1 mRNA预测支气管哮喘患者急性发作期发生的价值。结果对照组、缓解期组、急性期组FEV_(1)/FVC、PEF%pred、血清miR-181a相对表达水平依次降低,S1PR1 mRNA相对表达水平依次升高(P<0.05);轻度组、中度组、重度组血清miR-181a相对表达水平依次降低,S1PR1 mRNA相对表达水平依次升高(P<0.05);支气管哮喘急性发作期患者血清miR-181a与S1PR1 mRNA呈负相关(P<0.05),血清miR-181a与FEV_(1)/FVC、PEF%pred呈正相关(P<0.05),血清S1PR1 mRNA与FEV_(1)/FVC、PEF%pred呈负相关(P<0.05);低水平FEV_(1)/FVC、低水平PEF%pred、低相对表达水平miR-181a、高相对表达水平S1PR1 mRNA均是影响支气管哮喘患者急性发作期发生的独立危险因素(P<0.05);血清miR-181a、S1PR1 mRNA二者联合预测支气管哮喘患者急性发作期发生的曲线下面积(AUC)为0.890,分别高于miR-181a、S1PR1 mRNA单独预测的AUC(P<0.05)。结论支气管哮喘患者血清miR-181a呈低表达,S1PR1 mRNA呈高表达,二者与急性发作期的发生和严重程度及肺功能相关,对急性发作期的发生有较高预测效能。