C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 pathway as a therapeutic target and regulatory mechanism for spinal cord injury

Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis exhibits significant differences before and after injury.Recent studies have revealed that the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis is closely associated with secondary inflammatory responses and the recruitment of immune cells following spinal cord injury,suggesting that this axis is a novel target and regulatory control point for treatment.This review comprehensively examines the therapeutic strategies targeting the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis,along with the regenerative and repair mechanisms linking the axis to spinal cord injury.Additionally,we summarize the upstream and downstream inflammatory signaling pathways associated with spinal cord injury and the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review primarily elaborates on therapeutic strategies that target the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the latest progress of research on antagonistic drugs,along with the approaches used to exploit new therapeutic targets within the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the development of targeted drugs.Nevertheless,there are presently no clinical studies relating to spinal cord injury that are focusing on the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review aims to provide new ideas and therapeutic strategies for the future treatment of spinal cord injury.

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.

Role of triggering receptor expressed on myeloid cells 1/2 in secondary injury after cerebral hemorrhage

Intracerebral hemorrhage(ICH)is a common severe emergency in neurosurgery,causing tremendous economic pressure on families and society and devastating effects on patients both physically and psychologically,especially among patients with poor functional outcomes.ICH is often accompanied by decreased consciousness and limb dysfunction.This seriously affects patients’ability to live independently.Although rapid advances in neurosurgery have greatly improved patient survival,there remains insufficient evidence that surgical treatment significantly improves long-term outcomes.With in-depth pathophysiological studies after ICH,increasing evidence has shown that secondary injury after ICH is related to long-term prognosis and that the key to secondary injury is various immune-mediated neuroinflammatory reactions after ICH.In basic and clinical studies of various systemic inflammatory diseases,triggering receptor expressed on myeloid cells 1/2(TREM-1/2),and the TREM receptor family is closely related to the inflammatory response.Various inflammatory diseases can be upregulated and downregulated through receptor intervention.How the TREM receptor functions after ICH,the types of results from intervention,and whether the outcomes can improve secondary brain injury and the long-term prognosis of patients are unknown.An analysis of relevant research results from basic and clinical trials revealed that the inhibition of TREM-1 and the activation of TREM-2 can alleviate the neuroinflammatory immune response,significantly improve the long-term prognosis of neurological function in patients with cerebral hemorrhage,and thus improve the ability of patients to live independently.

Interleukin-1 receptor associated kinase 2 is a functional downstream regulator of complement factor D that controls mitochondrial fitness in diabetic cardiomyopathy

Diabetic cardiomyopathy is a disorder of the cardiac muscle that affects patients with diabetes.The exact mechanisms underlying diabetic cardiomyopathy are mostly unknown,but several factors have been implicated in the pathogenesis of the disease and its progression towards heart failure,including endothelial dysfunction,autonomic neuropathy,metabolic alterations,oxidative stress,and alterations in ion homeostasis,especially calcium transients[1].In Military Medical Research,Jiang et al.[2]sought to determine the functional role of complement factor D(Adipsin)in the pathophysiology of diabetic cardiomyopathy.

lncRNA-BBOX1-2通过调控成纤维细胞生长因子受体1促进胃癌的发生和发展

目的探讨长链非编码RNA(long non-coding RNA,lncRNA)BBOX1-2通过调控成纤维细胞生长因子受体1(fibroblast growth factor receptor 1,FGFR1)对胃癌的发生发展机制的影响。方法回顾性选取2017年4月至2019年1月于上海交通大学医学院附属瑞金医院卢湾分院接受胃癌根治术30例病人肿瘤组织及癌旁相应正常组织作为研究对象,采用实时定量PCT(real-time PCR,RT-PCR)检测lncRNA-BBOX1-2和FGFR1表达;si-linc-BBOX1-2转染SGC-7901细胞后,通过蛋白质印迹法/细胞存活率分析(MTT)、细胞迁移和侵袭(Transwell)实验、细胞划痕、平板克隆一系列生物学功能实验,检测肿瘤细胞生物学功能及FGFR1表达的变化。结果胃癌组织中的lncRNA-BBOX1-2(3.68±0.58比1.15±0.11)和FGFR1(4.26±0.71比1.19±0.18)表达显著高于癌旁正常组织(P<0.05);si-linc-BBOX1-2转染SGC-7901细胞后,FGFR1表达下调,细胞活力、迁移、侵袭和生存能力明显下降。结论LincRNA-BBOX1-2可通过调控FGFR1的表达介导胃癌细胞的增殖、凋亡、迁移和侵袭,可能为胃癌的治疗提供了新的靶点和潜在的生物学标志物。

Changes in soluble interleukin-2 receptor level in serum and Na^+ -K^+ -exchanging ATPase activity in semen of infertile men caused by antisperm antibody

Aim: To explore the possible mechanisms of male infertility caused by antisperm antibody (AsAb). Methods: Thesoluble interleukin-2 receptor (sIL-2R) level in serum was analyzed by ELISA and Na^+ -K^+ -exchanging ATPase activi-ty in semen by phosphorus (Pi) assay. Results: The slL-2R level in serum was significantly higher and the Na^+ -K^+ -exchanging ATPase activity in semen significantly lower in AsAb positive infertile men when compared with thecontrols. Conclusion: The AsAb titer varies with the slL-2R level in serum. A decrease in Na^+ -K^+ -exchangingATPase activity in semen may play a role in male infertility caused by AsAb.

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.

Serum soluble interleukin-2 receptor levels in patients with chronic hepatitis B virus infection and its relation with antiHBc

AIM： To investigate the relationship between serum soluble interleukin-2 receptor （sIL-2R） level and anti-HBc in patients with chronic hepatitis B virus （HBV） infection. METHODS： Sera from 100 patients with chronic HBV infection and 30 healthy controls were included in this study. The patients were divided into group A [HBsAg （＋）, HBeAg （＋） and anti-HBc （＋）, n = 50] and group B [HBsAg （＋）, HBeAg （＋） and anti-HBc （-）, n = 50]. sIL-2R levels were determined using ELISA. HBV DNA and alanine aminotransferase （ALT） were also detected. RESULTS： Serum sIL-2R levels were significantly higher in patients with chronic HBV infection than in healthy controls. Moreover, serum sIL-2R levels were significantly higher in patients with HBsAg （＋）, HBeAg （＋） and antiHBc （＋） （976.56±213.51×10^3 U/L） than in patients with HBsAg （＋）, HBeAg （＋） and anti-HBc （-） （393.41±189.54 ×10^3 U/L, P〈 0.01）. A significant relationship was found between serum sIL-2R and ALT levels （P〈 0.01） in patients with chronic HBV infection, but there was no correlation between sIL-2R and HBV DNA levels. The anti-HBc status was significantly related to the age of patients （P〈 0.01）. CONCLUSION： The high sIL-2R level is related to positive anti-HBc in chronic hepatitis B patients. Positive anti-HBc may be related to T-lymphocyte activation and negative anti-HBc may imply immune tolerance in these patients.

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.

Fluence of Glucosidorum Tripterygii Totorum on joint and serum soluble interleukin-2 receptor in patients with ankylosing spondylitis

Objective The current study was designed to find out the effect of Glucosidorum Tripterygii Totorum (GTT) on the serum level of soluble interleukin-2 receptor (sIL-2R) in patient with ankylosing spondylitis (AS). Method 29 patients with active AS were selected to take GTT (1mg per kg) three times a day for one year. After that, its curative effect was evaluated. The serum level of sIL-2R of these patients was measured by sandwich ELISA method and was compared with that of normal subjects. Result The serum level of sIL-2R in active AS patients was obviously higher than that of the non-active AS patients. (P<0.01). The total effective rate of GTT on AS was 89.6%, while clinical relief rate 27.6%, obvious effective rate 44.8%, effective rate 17.2% and non-effective rate 10.4%. The patients’ serum level of sIL-2R after therapy was significantly lower than that before therapy except patients with no effect. (P<0.05). Conclusion GTT has positive curative effect on active AS patients and could cause obvious decrease of the serum level of sIL-2R. The serum level of sIL-2R can be used as an important index of activity of AS and as a guide of therapy.

Study of the Effect of Leeching on Plasma Endothelin and Soluble Interleukin-2 Receptor in Patients with Systemic Lupus Erythematosus

Objective: to explore the mechanism of leeching in treating systemic lupus erythematosus (SLE). Methods: Forty-four patients with SLE were randomly divided into conventional corticosteroid treated group (control group, n =20) and conventional treatment group with leeching intervention added (leeching group, n =24). Before and after treatment the concentration of plasma endothelin (ET) and soluble interleukin-2 receptor (sIL-2R) were determined. Results: Before treatment the level of plasma ET and sIL-2R in the SLE patients were all higher than those in the normal healthy group, ( P <0.01). But after treatment the level of these in both groups were significantly improved than those of before treatment ( P <0.05), and comparison between these two treated groups showed that the difference between them was significant ( P <0.05). Conclusion: Leeching added to conventional treatment of SLE could be more effective in improving the level of plasma ET and sIL-2R, and ameliorating the impairment of renal tissues.

Interleukin-22 receptor 1 is expressed in multinucleated giant cells:A study on intestinal tuberculosis and Crohn’s disease

BACKGROUND It is challenging to distinguish intestinal tuberculosis from Crohn’s disease due to dynamic changes in epidemiology and similar clinical characteristics. Recent studies have shown that polymorphisms in genes involved in the interleukin (IL)- 23/IL-17 axis may affect intestinal mucosal immunity by affecting the differentiation of Th17 cells. AIM To investigate the specific single-nucleotide polymorphisms (SNPs) in genes involved in the IL-23/IL-17 axis and possible pathways that affect susceptibility to intestinal tuberculosis and Crohn's disease. METHODS We analysed 133 patients with intestinal tuberculosis, 128 with Crohn’s disease, and 500 normal controls. DNA was extracted from paraffin-embedded specimens or whole blood. Four SNPs in the IL23/Th17 axis (IL22 rs2227473, IL1β rs1143627, TGFβ rs4803455, and IL17 rs8193036) were genotyped with TaqMan assays. The transcriptional activity levels of different genotypes of rs2227473 were detected by dual luciferase reporter gene assay. The expression of IL-22R1 in different intestinal diseases was detected by immunohistochemistry. RESULTS The A allele frequency of rs2227473 (P = 0.030, odds ratio = 0.60, 95% confidence interval: 0.37-0.95) showed an abnormal distribution between intestinal tuberculosis and healthy controls. The presence of the A allele was associated with a higher IL-22 transcriptional activity (P < 0.05). In addition, IL-22R1 was expressed in intestinal lymphoid tissues, especially under conditions of intestinal tuberculosis, and highly expressed in macrophage-derived Langhans giant cells. The results of immunohistochemistry showed that the expression of IL-22R1 in patients with Crohn's disease and intestinal tuberculosis was significantly higher than that in patients with intestinal polyps and colon cancer (P < 0.01). CONCLUSION High IL-22 expression seems to be a protective factor for intestinal tuberculosis. IL-22R1 is expressed in Langhans giant cells, suggesting that the IL-22/IL-22R1 system links adaptive and innate immunity.

Effects of Aprotinin on Serum Interleukin-2 and Soluble Interleukin-2 Receptor during Cardiopulmonary Bypass

Interleukin-2 and its receptor are of importance in regulating immunity responses. The changes of interleukin-2 (IL-2) and soluble interleukin-2 receptor (IL-2R) during heart valve (s) replacement operation and effects of aprotinin on them were observed. Twenty patients undergoing heart valve (s) replacement were randomly divided into two groups: control group (n=10) and apro- tinin group (n=10). In aprotinin group, 1 000 000 KIU aprotinin was given by vein injection and then 2 000 000 KIU was given as a bolus in prime. Blood samples were collected before CPB, right after CPB and on the 1st, 3rd and 7th postoperative day (POD) for serum IL-2 and sIL-2R determination. Results showed that after CPB, IL-2 was reduced and slL-2R increased. Meanwhile, serum IL-2R was lower in aprotinin group than that of control. It is concluded that the immunity depression after CPB is associated with low level of IL-2 and high level of sIL-2R and aprotinin can ameliorate the situation.

Elevated pancreatic enzymes, IgM, soluble interleukin-2 receptor in anti-GADab(+) type 1 diabetes

Type 1 diabetes can be classified into immune-mediated diabetes (type 1A) and idiopathic diabetes, which lacks immunological evidence for beta cell autoimmunity (type 1B). Type 1A diabetes is characterized by the presence of the anti-glutamic acid decarboxylase antibody (anti-GADab). Fulminant type 1 diabetes is classified as type 1B diabetes, and characterized by the absence of anti-GADab, flu-like symptoms, and elevated serum exocrine pancreatic enzymes. We report a type 1 diabetic patient who showed flu-like symptoms, elevated serum exocrine pancreatic enzymes, and an extremely high-titer of anti-GADab, manifesting the characteristics of both type 1A and fulminant type 1 diabetes.

Evaluating the role of interleukin-2 and interleukin-12 in pediatric patients with concurrent Mycoplasma pneumoniae and Epstein-Barr virus infections

BACKGROUND Mycoplasma pneumoniae(MP)frequently causes respiratory infections in children,whereas Epstein-Barr virus(EBV)typically presents subclinical manifestations in immunocompetent pediatric populations.The incidence of MP and EBV coinfections is often overlooked clinically,with the contributory role of EBV in pulmonary infections alongside MP remaining unclear.AIM To evaluate the serum concentrations of interleukin-2(IL-2)and interleukin-12(IL-12)in pediatric patients with MP pneumonia co-infected with EBV and assess their prognostic implications.METHODS We retrospectively analyzed clinical data from patients diagnosed with MP and EBV co-infection,isolated MP infection,and a control group of healthy children,spanning from January 1,2018 to December 31,2021.Serum IL-2 and IL-12 levels were quantified using enzyme-linked immunosorbent assay.Logistic regression was employed to identify factors influencing poor prognosis,while receiver operating characteristic(ROC)curves evaluated the prognostic utility of serum IL-2 and IL-12 levels in co-infected patients.RESULTS The co-infection group exhibited elevated serum IL-2 and C-reactive protein(CRP)levels compared to both the MP-only and control groups,with a reverse trend observed for IL-12(P<0.05).In the poor prognosis cohort,elevated CRP and IL-2 levels,alongside prolonged fever duration,contrasted with reduced IL-12 levels(P<0.05).Logistic regression identified elevated IL-2 as an independent risk factor and high IL-12 as a protective factor for adverse outcomes(P<0.05).ROC analysis indicated that the area under the curves for IL-2,IL-12,and their combination in predicting poor prognosis were 0.815,0.895,and 0.915,respectively.CONCLUSION Elevated serum IL-2 and diminished IL-12 levels in pediatric patients with MP and EBV co-infection correlate with poorer prognosis,with combined IL-2 and IL-12 levels offering enhanced predictive accuracy.

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.

Exploring the role of interleukin-6 receptor blockade in epilepsy and associated neuropsychiatric conditions through a mendelian randomization study

BACKGROUND The interplay between inflammation,immune dysregulation,and the onset of neurological disorders,including epilepsy,has become increasingly recognized.Interleukin(IL)-6,a pro-inflammatory cytokine,is suspected to not only mediate traditional inflammatory pathways but also contribute to neuroinflammatory responses that could underpin neuropsychiatric symptoms and broader psychiatric disorders in epilepsy patients.The role of IL-6 receptor(IL6R)blockade presents an intriguing target for therapeutic intervention due to its potential to attenuate these processes.neuropsychiatric conditions due to neuroinflammation.METHODS Mendelian randomization(MR)analysis employing single nucleotide poly-morphisms(SNPs)in the vicinity of the IL6R gene(total individuals=408225)was used to evaluate the putative causal relationship between IL6R blockade and epilepsy(total cases/controls=12891/312803),focal epilepsy(cases/controls=7526/399290),and generalized epilepsy(cases/controls=1413/399287).SNP weights were determined by their effect on C-reactive protein(CRP)levels and integrated using inverse variance-weighted meta-analysis as surrogates for IL6R effects.To address potential outlier and pleiotropic influences,sensitivity analyses were conducted employing a variety of MR methods under different modeling assumptions.RESULTS The genetic simulation targeting IL6R blockade revealed a modest but significant reduction in overall epilepsy risk[inverse variance weighting:Odds ratio(OR):0.827;95%confidence interval(CI):0.685-1.000;P=0.05].Subtype analysis showed variability,with no significant effect observed in generalized,focal,or specific childhood and juvenile epilepsy forms.Beyond the primary inflammatory marker CRP,the findings also suggested potential non-inflammatory pathways mediated by IL-6 signaling contributing to the neurobiological landscape of epilepsy,hinting at possible links to neuroinflammation,psychiatric symptoms,and associated mental disorders.CONCLUSION The investigation underscored a tentative causal relationship between IL6R blockade and decreased epilepsy incidence,likely mediated via complex neuroinflammatory pathways.These results encouraged further in-depth studies involving larger cohorts and multifaceted psychiatric assessments to corroborate these findings and more thoroughly delineate the neuro-psychiatric implications of IL-6 signaling in epilepsy.The exploration of IL6R blockade could herald a novel therapeutic avenue not just for seizure management but also for addressing the broader psychiatric and cognitive disturbances often associated with epilepsy.

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.