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...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.展开更多
Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0...Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain injury.Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema.Next,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells.Finally,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema.Furthermore,YL-0919 effectively combated oxidative stress both in vivo and in vitro.The protective effects of YL-0919 were partially inhibited by BD-1047.These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047.YL-0919 may have potential as a new treatment for traumatic brain injury.展开更多
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 b...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.展开更多
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...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.展开更多
BACKGROUND Colony-stimulating factor 3(CSF3)and its receptor(CSF3R)are known to promote gastric cancer(GC)growth and metastasis.However,their effects on the immune microenvironment remain unclear.Our analysis indicate...BACKGROUND Colony-stimulating factor 3(CSF3)and its receptor(CSF3R)are known to promote gastric cancer(GC)growth and metastasis.However,their effects on the immune microenvironment remain unclear.Our analysis indicated a potential link between CSF3R expression and the immunosuppressive receptor leukocyte immunoglobulin-like receptor B2(LILRB2)in GC.We hypothesized that CSF3/CSF3R may regulate LILRB2 and its ligands,angiopoietin-like protein 2(ANGPTL2)and human leukocyte antigen-G(HLA-G),contributing to immunosuppression.AIM To investigate the relationship between CSF3/CSF3R and LILRB2,as well as its ligands ANGPTL2 and HLA-G,in GC.METHODS Transcriptome sequencing data from The Cancer Genome Atlas were analyzed,stratifying patients by CSF3R expression.Differentially expressed genes and immune checkpoints were evaluated.Immunohistochemistry(IHC)was performed on GC tissues.Correlation analyses of CSF3R,LILRB2,ANGPTL2,and HLA-G were conducted using The Cancer Genome Atlas data and IHC results.GC cells were treated with CSF3,and expression levels of LILRB2,ANGPTL2,and HLA-G were measured by quantitative reverse transcriptase-polymerase chain reaction and western blotting.RESULTS Among 122 upregulated genes in high CSF3R expression groups,LILRB2 showed the most significant increase.IHC results indicated high expression of LILRB2(63.0%),ANGPTL2(56.5%),and HLA-G(73.9%)in GC tissues.Strong positive correlations existed between CSF3R and LILRB2,ANGPTL2,and HLA-G mRNA levels(P<0.001).IHC confirmed positive correlations between CSF3R and LILRB2(P<0.001),and HLA-G(P=0.010),but not ANGPTL2(P>0.05).CSF3 increased LILRB2,ANGPTL2,and HLA-G expression in GC cells.Heterogeneous nuclear ribonucleoprotein H1 modulation significantly altered their expression,impacting CSF3’s regulatory effects.CONCLUSION The CSF3/CSF3R pathway may contribute to immunosuppression in GC by upregulating LILRB2 and its ligands,with heterogeneous nuclear ribonucleoprotein H1 playing a regulatory role.展开更多
Familial androgen insensitivity syndrome (AIS), resulting from inherited mutations in the androgen receptor (AR)gene, has traditionally been examined within the framework of disorders of sex development. However, grow...Familial androgen insensitivity syndrome (AIS), resulting from inherited mutations in the androgen receptor (AR)gene, has traditionally been examined within the framework of disorders of sex development. However, growingevidence indicates that AR dysfunction also disrupts systemic metabolic homeostasis, predisposing affectedindividuals to insulin resistance and type 2 diabetes mellitus. This article synthesizes recent advances in genetics,transcriptomics, and physiology to elucidate how AR mutations drive tissue-specific metabolic reprogramming inkey organs, including pancreatic β-cells, skeletal muscle, liver, and adipose tissue. Particular attention is given to anewly identified familial AR variant (c.2117A>G;p.Asn706Ser), which not only broadens the known mutationalspectrum of AIS but also underscores the clinical importance of early metabolic risk screening in this population.We further examine how pubertal stage, hormone replacement therapy, and sex-specific signaling pathwaysinteract to influence long-term metabolic outcomes. Lastly, we propose an integrative management framework thatincorporates genetic diagnosis, endocrine surveillance, and personalized pharmacological strategies aimed atreducing the risk of type 2 diabetes mellitus and cardiometabolic complications in individuals with AIS. Distinctfrom previous AIS-centered reviews, this work integrates metabolic and endocrine perspectives into the traditionaldevelopmental paradigm, offering a more comprehensive understanding of disease risk and translational management.展开更多
BACKGROUND Beinaglutide,a short-acting glucagon-like polypeptide-1 receptor agonist,has shown variable efficacy in weight reduction and metabolic control in randomized controlled trials(RCTs).AIM To summarize the ther...BACKGROUND Beinaglutide,a short-acting glucagon-like polypeptide-1 receptor agonist,has shown variable efficacy in weight reduction and metabolic control in randomized controlled trials(RCTs).AIM To summarize the therapeutic effects of beinaglutide in patients with overweight/obesity with/without type 2 diabetes.METHODS RCTs involving patients receiving beinaglutide in the intervention arm and placebo or active comparator in the control arm were searched through multiple electronic databases.The change from baseline in body weight was the primary outcome;secondary outcomes included changes in body mass index(BMI),waist circumference(WC),blood pressure,glycemic parameters,lipids,and adverse events(AEs).RevMan web was used to conduct meta-analysis using random-effects models.Outcomes were presented as mean differences(MDs),odds ratios(ORs),or risk ratios(RRs)with 95%confidence intervals(95%CIs).RESULTS Six RCTs(n=800)with mostly some concerns about the risk of bias were included.Over 12-24 weeks,beinaglutide 0.1-0.2 mg thrice daily was superior to the control group in reducing total(MD=-3.25 kg,95%CI:-4.52 to-1.98,I^(2)=84%,P<0.00001)and percent(MD=-4.13%,95%CI:-4.87 to-3.39,I^(2)=54%,P<0.00001)body weight reduction.Beinaglutide also outperformed the control group in achieving weight loss by 5%(OR 4.61)and 10%(OR=5.34).The superiority of beinaglutide vs the control group was also found in reducing BMI(MD=-1.22 kg/m^(2),95%CI:-1.67 to-0.77)and WC(MD=-2.47 cm,95%CI:-3.74 to-1.19]).Beinaglutide and the control group had comparable impacts on blood pressure,glycemic parameters,insulin resistance,hepatic transaminases,and lipid profile.Beinaglutide posed higher risks of treatment discontinuation due to AEs(RR=3.15),nausea(RR=4.51),vomiting(RR=8.19),palpitation(RR=3.95),headache(RR=2.87),and dizziness(RR=6.07)than the control.However,the two groups had identical risks of total and serious AEs,diarrhea,fatigue,and hypoglycemia.CONCLUSION Short-term data from RCTs suggested that beinaglutide causes modest benefits in reducing body weight,BMI,and WC,with no significant difference in glycemic and other metabolic endpoints compared to the control arm.Safety data were consistent with those of the other drugs in the glucagon-like polypeptide-1 receptor agonist class.Larger RCTs are warranted to prove the longer-term metabolic benefits of beinaglutide.展开更多
BACKGROUND With accumulating evidence showing a benefit in the renal and cardiovascular systems,diabetes guidelines recommend that patients with diabetes and chronic kidney disease(CKD)be treated with sodium-glucose c...BACKGROUND With accumulating evidence showing a benefit in the renal and cardiovascular systems,diabetes guidelines recommend that patients with diabetes and chronic kidney disease(CKD)be treated with sodium-glucose cotransporter-2 inhibitor(SGLT2i)and/or glucagon like peptide-1 receptor agonists(GLP-1RAs)for renal protection.The real-world efficacy of the two medications on the urinary albumin-creatinine ratio(UACR)and estimated glomerular filtration rate(eGFR)remains to be explored.AIM To evaluate the SGLT2i and GLP-1RA application rates and UACR alterations after intervention in a real-world cohort of patients with diabetes.METHODS A cohort of 5482 patients with type 2 diabetes were enrolled and followed up at the Integrated Care Clinic for Diabetes of Peking University First Hospital for at least 6 months.Propensity score matching was performed,and patients who were not recommended for GLP-1RA or SGLT2i with comparable sex categories and ages were assigned to the control group at a 1:2 ratio.Blood glucose,body weight,UACR and eGFR were evaluated after 6 months of treatment in real-world clinical practice.RESULTS A total of 139(2.54%)patients started GLP-1RA,and 387(7.06%)received SGLT2i.After 6 months,the variations in fasting blood glucose,prandial blood glucose,and glycosylated hemoglobin between the GLP-1RA group and the SGLT2i and control groups were not significantly different.UACR showed a tendency toward a greater reduction compared with the control group,although this difference was not statistically significant(GLP-1RA vs control,-2.20 vs 30.16 mg/g,P=0.812;SGLT2i vs control,-20.61 vs 12.01 mg/g,P=0.327);eGFR alteration also showed no significant differences.Significant weight loss was observed in the GLP-1RA group compared with the control group(GLP-1RA vs control,-0.90 vs 0.27 kg,P<0.001),as well as in the SGLT2i group(SGLT2i vs control,-0.59 vs-0.03 kg,P=0.010).CONCLUSION Compared with patients who received other glucose-lowering drugs,patients receiving SGLT2i or GLP-1RAs presented significant weight loss,a decreasing trend in UACR and comparable glucose-lowering effects in realworld settings.展开更多
BACKGROUND Magnesium(Mg^(2+))plays a fundamental role in numerous cellular processes,including enzymatic reactions,DNA replication,oxidative stress response,and cytoskeletal dynamics.In fact,dysregulation of Mg^(2+)ho...BACKGROUND Magnesium(Mg^(2+))plays a fundamental role in numerous cellular processes,including enzymatic reactions,DNA replication,oxidative stress response,and cytoskeletal dynamics.In fact,dysregulation of Mg^(2+)homeostasis has been increasingly associated with the development and progression of cancer,particularly colorectal cancer(CRC).Transient receptor potential melastatin(TRPM)channels,especially TRPM6 and TRPM7,are essential regulators of epithelial Mg^(2+)influx.While TRPM7 promotes CRC progression,the role of TRPM6 and TRPM6/7 channels remains unclear.AIM To investigate the role of membrane-localized TRPM6 and TRPM6/7 channels in Mg^(2+)influx,spheroid(SP)formation,stemness,and migration.METHODS We used parental and SP-derived HT-29 cells at comparable passages as in vitro models.Mass spectrometry confirmed full-length sequences,phosphorylation,and methionine oxidation of TRPM6 and TRPM7.Mg^(2+)influx,total and free Mg^(2+)levels were measured by fluorescence imaging and biochemical assays.TRPM6/TRPM7 expression and markers were analyzed by western blot.Func-tional assays,including secondary SP formation and wound healing,assessed stemness and migration.Cells were treated with Mg^(2+)transport inhibitors:Co(III)hexamine,2-aminoethyl diphenylborinate(TRPM6/7 blocker),and Mesendogen(TRPM6 inhibitor).RESULTS The expression of membrane-bound TRPM6,TRPM7,and TRPM6/7 was significantly higher in SP cells than in parental cells.Mass spectrometric analysis confirmed the presence of full-length TRPM6 and TRPM7 with increased phosphorylation and oxidation in SP cells.Enhanced Mg^(2+)influx and total intracellular Mg^(2+)levels were observed in SP cells.Free ionized intracellular Mg^(2+)levels remained comparable across all experimental groups.Pharmacological inhibition of TRPM6 and TRPM6/7 significantly reduced Mg^(2+)influx,decreased total Mg^(2+)content,compromised CRC SP stability,abolished cancer stem-like properties,impaired cell migration,and downregulated pro-tumorigenic markers,including Nanog,cyclooxygenase-2,and matrix metalloproteinase-9.CONCLUSION Membrane-localized TRPM6 and TRPM6/7 channels regulate Mg^(2+)influx and promote CRC stemness,SP stability,and migration,highlighting their potential as therapeutic targets to inhibit CRC progression and metastasis.展开更多
BACKGROUND Data on the use of glucagon-like peptide-1 receptor agonists(GLP-1RAs)in individuals with type 2 diabetes mellitus(T2DM)during Ramadan fasting is limited.No meta-analysis has summarized the safety and effec...BACKGROUND Data on the use of glucagon-like peptide-1 receptor agonists(GLP-1RAs)in individuals with type 2 diabetes mellitus(T2DM)during Ramadan fasting is limited.No meta-analysis has summarized the safety and effectiveness of GLP-1RAs in these situations.AIM To evaluate the safety and efficacy of GLP-1RA in patients with T2DM fasting during Ramadan.METHODS Electronic databases were systematically searched for relevant studies that featured GLP-1RA in the intervention arm and other glucose-lowering medications in the control arm.The primary outcome was adverse events(AEs)during Ramadan for both groups;other outcomes included changes in glycemic and anthropometric measures during the peri-Ramadan period.RESULTS Four studies[three randomized-controlled trials with low risk of bias(RoB)and one prospective observational study with serious RoB]involving 754 subjects were analyzed.GLP-1RA group achieved greater glycated hemoglobin reduction than the non-GLP-1RA group[mean difference(MD):-0.31%,95%CI:-0.61 to-0.01,P=0.04,I2=77%]with a lower risk of documented symptomatic hypoglycemia(risk ratio=0.38,95%CI:0.16 to 0.88,P=0.02).Any AEs,serious AEs,or AEs that led to treatment discontinuation were comparable between the two groups.The GLP-1RA group experienced greater weight loss compared to the non-GLP-1RA group(MD:-2.0 kg,95%CI:-3.37 to-0.63,P=0.004,I2=95%).There were comparable changes in blood pressure and lipid profile between the two groups.GLP-1RA users experienced higher risks of gastrointestinal AEs,nausea,and vomiting;however,the risks of heartburn,abdominal pain,and diarrhea were similar in both groups.CONCLUSION Limited evidence suggests that GLP-1RAs are safe for T2DM management during Ramadan,offering modest benefits in blood sugar control and weight loss.Large multicenter trials are needed to confirm their safety and efficacy in at-risk populations,improving clinical practice decision-making.展开更多
The global prevalence of diabetes has surged in recent years,with diabetic kidney disease(DKD)emerging as a major complication.Traditional therapies have had limited success in slowing progression to end-stage kidney ...The global prevalence of diabetes has surged in recent years,with diabetic kidney disease(DKD)emerging as a major complication.Traditional therapies have had limited success in slowing progression to end-stage kidney disease.However,novel therapies,particularly sodium-glucose cotransporter 2(SGLT2)inhibitors and glucagon-like peptide-1(GLP-1)receptor agonists,which were initially developed for hyperglycemia management,have transformed the treatment of obesity,heart failure,cardiovascular disease,and more recently,DKD.SGLT2 inhibitors have consistently and significantly reduced cardiovascular events,albuminuria,and glomerular filtration rate,highlighting their efficacy across diverse clinical presentations for patients with kidney impairment.Although fewer studies have specifically investigated GLP-1 receptor agonists in patients with kidney disease,existing evidence underscores their potential to slow renal disease progression,reduce albuminuria,and improve clinically relevant outcomes.However,further research is needed to better identify patients most likely to benefit from treatment.Together,these therapies represent valuable advancements for DKD,offering significant reductions in morbidity and mortality and shifting the management of the disease by becoming essential pillars for the treatment of these patients.展开更多
BACKGROUND Although targeted therapy provides survival benefits for patients with metastatic colorectal cancer,some patients develop resistance to these treatments.Human epidermal growth factor receptor 2(HER2)is over...BACKGROUND Although targeted therapy provides survival benefits for patients with metastatic colorectal cancer,some patients develop resistance to these treatments.Human epidermal growth factor receptor 2(HER2)is overexpressed in a subset of pa-tients with colorectal cancer and has been established as a therapeutic target.CASE SUMMARY This case report describes a Chinese patient with HER2-amplified advanced rectal cancer who showed no response to chemotherapy and targeted therapies against epidermal growth factor receptor and vascular endothelial growth factor but achieved a remarkable response following treatment with immune checkpoint inhibitors(ICIs)in combination with pyrotinib.The combination of oxaliplatin and ICIs with pyrotinib demonstrates synergistic effects after late-stage disease progression.CONCLUSION ICIs and pyrotinib may be effective in treating HER2-amplified advanced rectal cancer.Chemotherapy following disease progression could enhance efficacy synergistically.展开更多
BACKGROUND Human epidermal growth factor receptor 2(HER2)plays pivotal roles in cellular proliferation,survival,and differentiation of several malignancies.Upper tract urothelial carcinoma(UTUC)is a relatively rare ma...BACKGROUND Human epidermal growth factor receptor 2(HER2)plays pivotal roles in cellular proliferation,survival,and differentiation of several malignancies.Upper tract urothelial carcinoma(UTUC)is a relatively rare malignancy.The clinical and molecular significance of HER2 expression level in UTUC remains poorly characterized vs bladder cancer.AIM To comprehensively evaluate HER2 expression patterns and their association with UTUC patients’clinicopathological features.METHODS Data were retrospectively collected from patients diagnosed with UTUC at The First Affiliated Hospital of Guangxi Medical University between January 2023 and December 2024.HER2 status was evaluated by immunohistochemistry in 145 UTUC patients who met the inclusion criteria.Its associations with tumor grade,tumor stage,and other clinicopathological parameters were assessed.Theχ2 test or Fisher’s exact test,along with univariate and multivariate logistic regression analyses,were performed to determine the influences of clinicopathological factors on HER2 expression.RESULTS HER2 positivity was significantly associated with high tumor grade(P=0.003),while other variables,including sex,anatomical tumor location,pathological T stage,Ki-67 proliferation index,nodal metastasis status,lymphovascular invasion,and tumor laterality failed to demonstrate statistically significant correlations.These findings were further substantiated through univariate logistic regression modeling,yielding an odds ratio of 3.56[95%confidence interval(CI):1.30-9.75;P=0.013]for the association between high tumor grade and HER2 positivity.Importantly,this relationship remained robust(hazard ratio=3.42,95%CI:1.22-9.60;P=0.019)even after implementing multivariate logistic regression analysis.With a median follow-up time of 8 months(interquartile range,4-14)months,14 patients experienced intravesical recurrence after radical nephroureterectomy.Certain patient characteristics,such as HER2-negative,male sex,high-grade tumors,and luminal phenotype,were associated with a higher risk of intravesical recurrence.CONCLUSION In UTUC,HER2 overexpression is closely associated with tumor dedifferentiation(high grade),while it does not correlate with conventional indicators of disease progression,indicating that HER2 may serve a distinct biological function in this cancer type.展开更多
BACKGROUND Human epidermal growth factor receptor 2(HER2)-positive gastric cancer(GC)represents a distinct molecular cancer subtype that is often associated with a poor prognosis.While perioperative chemotherapy regim...BACKGROUND Human epidermal growth factor receptor 2(HER2)-positive gastric cancer(GC)represents a distinct molecular cancer subtype that is often associated with a poor prognosis.While perioperative chemotherapy regimens are currently the primary recommendation for locally advanced HER2-positive GC,combination therapies incorporating immune checkpoint inhibitors are under active investigation.CASE SUMMARY The present case describes a patient with locally advanced HER2-positive GC who underwent perioperative treatment with chemotherapy combined with trastuzumab.Although significant tumor shrinkage was observed,surgical pathology results did not confirm the achievement of a pathological complete response.The current treatment strategies for advanced GC were also reviewed.Relevant case reports,retrospective studies,and prospective clinical trials were retrieved for analysis after searching the PubMed/MEDLINE,EMBASE,Cochrane Library,Web of Science,and American Society of Clinical Oncology/European Society for Medical Oncology conference abstracts between 2014 and 2024.CONCLUSION Large-scale phase Ⅲ clinical trials are needed to verify the efficacy of combined neoadjuvant treatment application for GC.展开更多
OBJECTIVE:to investigate the anti-arthritic effects of lappaconitine(LA)on adjuvant-induced arthritis in Sprague-Dawley rats and its possible involvement in the regulation of M1/M2 macrophage balance through the P2X7 ...OBJECTIVE:to investigate the anti-arthritic effects of lappaconitine(LA)on adjuvant-induced arthritis in Sprague-Dawley rats and its possible involvement in the regulation of M1/M2 macrophage balance through the P2X7 receptor(P2X7r).METHODS:Rats were immunized with complete Freund's adjuvant and then intraperitoneally administered LA(2,4,or 8 mg·kg^(-1)·d^(-1))or methotrexate(0.5 mg/kg per 3 d)for 14 d.The anti-arthritic effects of LA were evaluated through arthritis index(AI)assessment,ankle diameter measurement,and histopathological staining analysis.The analgesic effect of LA on arthritis was measured using mechanical withdrawal threshold testing and gait scoring.The impacts of LA on macrophage polarization,the expression of pro-/anti-inflammatory cytokines and P2X7r were analyzed using quantitative real-time polymerase chain reaction,enzyme-linked immunosorbent assay,and Western blotting.RESULTS:LA treatment significantly reduced AI scores,paw swelling,joint destruction,and inflammatory cell infiltration,and alleviated arthritis pain.Additionally,LA promoted a balanced M1/M2 ratio by increasing the m RNA expression level of M2 marker arginase 1 and decreasing those of M1 markers inducible nitric oxide synthase and interleukin(IL)-1βin synovial tissues.Furthermore,LA lowered the levels of three M1-related cytokines,namely tumor necrosis factor-α,IL-1βand IL-18,and raised the level of the M2-related cytokine IL-10.Further research showed that treatment with LA inhibited the expression of P2X7r.CONCLUSION:Our findings indicate that the notable therapeutic and analgesic effects of LA on AIA rats are exerted through balancing the M1/M2 ratio,probably via P2X7r.展开更多
Non-alcoholic fatty liver disease(NAFLD)is a progressive disease.Without effective interventions,NAFLD can gradually develop to non-alcoholic steatohepatitis,fatty liver fibrosis,liver cirrhosis and even hepatocellula...Non-alcoholic fatty liver disease(NAFLD)is a progressive disease.Without effective interventions,NAFLD can gradually develop to non-alcoholic steatohepatitis,fatty liver fibrosis,liver cirrhosis and even hepatocellular carcinoma.It is still to investigate the precise molecular mechanism behind the pathophysiology of NAFLD.Triggering receptor expressed on myeloid cells 2(TREM2)can sense tissue injury and mediate immune remodeling,thereby inducing phagocytosis,lipid metabolism,and metabolic transfer,promoting cell survival and combating inflammatory activation.NAFLD might develop as a result of TREM2's regulatory role.We here briefly summarize the biological characteristics of TREM2 and its functions in the disease progression of NAFLD.Moreover,we propose to broaden the therapeutic strategy for NAFLD by targeting TREM2.展开更多
BACKGROUND Glucagon-like peptide-1 receptor agonists(GLP-1RAs)play a key role in managing type 2 diabetes mellitus(T2DM).Transitioning between different GLP-1RA has been proposed as a treatment strategy.AIM To investi...BACKGROUND Glucagon-like peptide-1 receptor agonists(GLP-1RAs)play a key role in managing type 2 diabetes mellitus(T2DM).Transitioning between different GLP-1RA has been proposed as a treatment strategy.AIM To investigate switching patterns between GLP-1RA and their impact on glycemic control.METHODS A retrospective study involving patients with T2DM who initiated GLP-1RA therapy between 2009 and 2021 and transitioned to another GLP-1RA.Baseline glycated hemoglobin(HbA1c)was defined as the most recent measurement within 1 year prior to switching,and follow-up HbA1c was the first measurement recorded 4-15 months post-switch.RESULTS Among 70654 patients initiating GLP-1RA therapy,18047(25.5%)switched regimens.In the 13970 patients with available HbA1c,levels decreased from 8.5%±1.6%to 7.6%±1.4%(P<0.001).HbA1c decreased in 78.3%(10943/13970)of these patients,with the most frequent improvement observed in those switching from daily to weekly GLP-1RA(81%,5582/6890).CONCLUSION Switching between GLP-1RAs can serve as a practical alternative to treatment intensification for effectively managing T2DM.展开更多
BACKGROUND Traditional Chinese medicine offers many valuable remedies for maintaining blood glucose homeostasis in patients with type 2 diabetes mellitus.Bile powder(BP)is a powdered form of bile derived from pigs.It ...BACKGROUND Traditional Chinese medicine offers many valuable remedies for maintaining blood glucose homeostasis in patients with type 2 diabetes mellitus.Bile powder(BP)is a powdered form of bile derived from pigs.It has been used historically in various medicinal applications.Currently,the therapeutic potential of BP in regulating glucose homeostasis remains unclear.Bile acids(BAs)are increasingly recognized for their role in glucose metabolism particularly through the modu-lation of glucagon-like peptide-1(GLP-1).AIM To investigate BP effects on glucose homeostasis and elucidate its mechanistic role through GLP-1 and farnesoid X receptor(FXR)signaling.METHODS A diabetic mouse model was established using a high-fat diet and streptozotocin administration.Mice were treated with BP at doses of 25,50,or 75 mg/kg/day for 45 days.Glucose homeostasis was assessed via the oral glucose tolerance test and insulin tolerance test.Serum GLP-1 levels were measured by enzyme-linked immunosorbent assay.A GLP-1 receptor antagonist and an FXR agonist were used to clarify the underlying mechanisms.In vitro STC-1 murine enteroendocrine cells were treated with a BP-mimicking BA mixture to assess GLP-1 secretion and proglucagon gene expression.RESULTS BP treatment significantly improved glucose homeostasis in the diabetic mouse model as indicated by lower blood glucose(P<0.05)and improved insulin sensitivity.BP enhanced GLP-1 secretion(P<0.05),which was an effect abolished by the GLP-1 receptor antagonist.This observation confirmed its dependence on GLP-1 signaling.In STC-1 cells,BP-derived BA mixtures stimulated GLP-1 secretion and upregulated proglucagon expression(P<0.05).Mechanistically,BP inhibited FXR signaling as evidenced by the reversal of its effects upon fexaramine administration.In addition,long-term BP treatment suppressed FXR signaling,resulting in elevated GLP-1 levels and preventing glucose dysregulation.CONCLUSION BP improved glucose homeostasis by promoting GLP-1 secretion via FXR inhibition,highlighting its potential as a therapeutic strategy for metabolic disorders.展开更多
A switch from avian-typeα-2,3 to human-typeα-2,6 receptors is an essential element for the initiation of a pandemic from an avian influenza virus.Some H9N2 viruses exhibit a preference for binding to human-typeα-2,...A switch from avian-typeα-2,3 to human-typeα-2,6 receptors is an essential element for the initiation of a pandemic from an avian influenza virus.Some H9N2 viruses exhibit a preference for binding to human-typeα-2,6 receptors.This identifies their potential threat to public health.However,our understanding of the molecular basis for the switch of receptor preference is still limited.In this study,we employed the random forest algorithm to identify the potentially key amino acid sites within hemagglutinin(HA),which are associated with the receptor binding ability of H9N2 avian influenza virus(AIV).Subsequently,these sites were further verified by receptor binding assays.A total of 12 substitutions in the HA protein(N158D,N158S,A160 N,A160D,A160T,T163I,T163V,V190T,V190A,D193 N,D193G,and N231D)were predicted to prefer binding toα-2,6 receptors.Except for the V190T substitution,the other substitutions were demonstrated to display an affinity for preferential binding toα-2,6 receptors by receptor binding assays.Especially,the A160T substitution caused a significant upregulation of immune-response genes and an increased mortality rate in mice.Our findings provide novel insights into understanding the genetic basis of receptor preference of the H9N2 AIV.展开更多
Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsol...Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsolved issue in pain medicine.Our previous study,using protein kinase C gamma(PKCγ)-tdTomato mice,highlights the spinal feedforward inhibitory circuit involving PKCγ neurons in gating neuropathic allodynia.However,the regulatory mechanisms governing this circuit necessitate further elucidation.We used diverse transgenic mice and advanced techniques to uncover the regulatory role of the descending serotonin(5-HT)facilitation system on spinal PKCγ neurons.Our findings revealed that 5-HT neurons from the rostral ventromedial medulla hyperpolarize spinal inhibitory interneurons via 5-HT_(2C) receptors,disinhibiting the feedforward inhibitory circuit involving PKCγ neurons and exacerbating allodynia.Inhibiting spinal 5-HT_(2C) receptors restored the feedforward inhibitory circuit,effectively preventing neuropathic allodynia.These insights offer promising therapeutic targets for neuropathic allodynia management,emphasizing the potential of spinal 5-HT_(2C) receptors as a novel avenue for intervention.展开更多
基金supported by the National Natural Science Foundation of China(Key Program),No.11932013the National Natural Science Foundation of China(General Program),No.82272255+2 种基金Armed Police Force High-Level Science and Technology Personnel ProjectThe Armed Police Force Focuses on Supporting Scientific and Technological Innovation TeamsKey Project of Tianjin Science and Technology Plan,No.20JCZDJC00570(all to XC)。
文摘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.
基金supported by the National Natural Science Foundation of China,Nos.82204360(to HM)and 82270411(to GW)National Science and Technology Innovation 2030 Major Program,No.2021ZD0200900(to YL)。
文摘Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain injury.Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema.Next,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells.Finally,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema.Furthermore,YL-0919 effectively combated oxidative stress both in vivo and in vitro.The protective effects of YL-0919 were partially inhibited by BD-1047.These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047.YL-0919 may have potential as a new treatment for traumatic brain injury.
文摘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.
基金Supported by Shanxi Provincial Key Research and Development Plan Project,No.2020ZDLSF01-02Doctor Foundation of the Second Affiliated Hospital of Xi’an Medical University,No.X2Y-R11.
文摘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.
基金Supported by Hebei Province Medical Science Research Project Plan,No.20230755.
文摘BACKGROUND Colony-stimulating factor 3(CSF3)and its receptor(CSF3R)are known to promote gastric cancer(GC)growth and metastasis.However,their effects on the immune microenvironment remain unclear.Our analysis indicated a potential link between CSF3R expression and the immunosuppressive receptor leukocyte immunoglobulin-like receptor B2(LILRB2)in GC.We hypothesized that CSF3/CSF3R may regulate LILRB2 and its ligands,angiopoietin-like protein 2(ANGPTL2)and human leukocyte antigen-G(HLA-G),contributing to immunosuppression.AIM To investigate the relationship between CSF3/CSF3R and LILRB2,as well as its ligands ANGPTL2 and HLA-G,in GC.METHODS Transcriptome sequencing data from The Cancer Genome Atlas were analyzed,stratifying patients by CSF3R expression.Differentially expressed genes and immune checkpoints were evaluated.Immunohistochemistry(IHC)was performed on GC tissues.Correlation analyses of CSF3R,LILRB2,ANGPTL2,and HLA-G were conducted using The Cancer Genome Atlas data and IHC results.GC cells were treated with CSF3,and expression levels of LILRB2,ANGPTL2,and HLA-G were measured by quantitative reverse transcriptase-polymerase chain reaction and western blotting.RESULTS Among 122 upregulated genes in high CSF3R expression groups,LILRB2 showed the most significant increase.IHC results indicated high expression of LILRB2(63.0%),ANGPTL2(56.5%),and HLA-G(73.9%)in GC tissues.Strong positive correlations existed between CSF3R and LILRB2,ANGPTL2,and HLA-G mRNA levels(P<0.001).IHC confirmed positive correlations between CSF3R and LILRB2(P<0.001),and HLA-G(P=0.010),but not ANGPTL2(P>0.05).CSF3 increased LILRB2,ANGPTL2,and HLA-G expression in GC cells.Heterogeneous nuclear ribonucleoprotein H1 modulation significantly altered their expression,impacting CSF3’s regulatory effects.CONCLUSION The CSF3/CSF3R pathway may contribute to immunosuppression in GC by upregulating LILRB2 and its ligands,with heterogeneous nuclear ribonucleoprotein H1 playing a regulatory role.
基金Supported by the Quzhou Science and Technology Plan Project,No.2022K69.
文摘Familial androgen insensitivity syndrome (AIS), resulting from inherited mutations in the androgen receptor (AR)gene, has traditionally been examined within the framework of disorders of sex development. However, growingevidence indicates that AR dysfunction also disrupts systemic metabolic homeostasis, predisposing affectedindividuals to insulin resistance and type 2 diabetes mellitus. This article synthesizes recent advances in genetics,transcriptomics, and physiology to elucidate how AR mutations drive tissue-specific metabolic reprogramming inkey organs, including pancreatic β-cells, skeletal muscle, liver, and adipose tissue. Particular attention is given to anewly identified familial AR variant (c.2117A>G;p.Asn706Ser), which not only broadens the known mutationalspectrum of AIS but also underscores the clinical importance of early metabolic risk screening in this population.We further examine how pubertal stage, hormone replacement therapy, and sex-specific signaling pathwaysinteract to influence long-term metabolic outcomes. Lastly, we propose an integrative management framework thatincorporates genetic diagnosis, endocrine surveillance, and personalized pharmacological strategies aimed atreducing the risk of type 2 diabetes mellitus and cardiometabolic complications in individuals with AIS. Distinctfrom previous AIS-centered reviews, this work integrates metabolic and endocrine perspectives into the traditionaldevelopmental paradigm, offering a more comprehensive understanding of disease risk and translational management.
文摘BACKGROUND Beinaglutide,a short-acting glucagon-like polypeptide-1 receptor agonist,has shown variable efficacy in weight reduction and metabolic control in randomized controlled trials(RCTs).AIM To summarize the therapeutic effects of beinaglutide in patients with overweight/obesity with/without type 2 diabetes.METHODS RCTs involving patients receiving beinaglutide in the intervention arm and placebo or active comparator in the control arm were searched through multiple electronic databases.The change from baseline in body weight was the primary outcome;secondary outcomes included changes in body mass index(BMI),waist circumference(WC),blood pressure,glycemic parameters,lipids,and adverse events(AEs).RevMan web was used to conduct meta-analysis using random-effects models.Outcomes were presented as mean differences(MDs),odds ratios(ORs),or risk ratios(RRs)with 95%confidence intervals(95%CIs).RESULTS Six RCTs(n=800)with mostly some concerns about the risk of bias were included.Over 12-24 weeks,beinaglutide 0.1-0.2 mg thrice daily was superior to the control group in reducing total(MD=-3.25 kg,95%CI:-4.52 to-1.98,I^(2)=84%,P<0.00001)and percent(MD=-4.13%,95%CI:-4.87 to-3.39,I^(2)=54%,P<0.00001)body weight reduction.Beinaglutide also outperformed the control group in achieving weight loss by 5%(OR 4.61)and 10%(OR=5.34).The superiority of beinaglutide vs the control group was also found in reducing BMI(MD=-1.22 kg/m^(2),95%CI:-1.67 to-0.77)and WC(MD=-2.47 cm,95%CI:-3.74 to-1.19]).Beinaglutide and the control group had comparable impacts on blood pressure,glycemic parameters,insulin resistance,hepatic transaminases,and lipid profile.Beinaglutide posed higher risks of treatment discontinuation due to AEs(RR=3.15),nausea(RR=4.51),vomiting(RR=8.19),palpitation(RR=3.95),headache(RR=2.87),and dizziness(RR=6.07)than the control.However,the two groups had identical risks of total and serious AEs,diarrhea,fatigue,and hypoglycemia.CONCLUSION Short-term data from RCTs suggested that beinaglutide causes modest benefits in reducing body weight,BMI,and WC,with no significant difference in glycemic and other metabolic endpoints compared to the control arm.Safety data were consistent with those of the other drugs in the glucagon-like polypeptide-1 receptor agonist class.Larger RCTs are warranted to prove the longer-term metabolic benefits of beinaglutide.
基金Peking University First Hospital Institutional Review Board(No.2018104).
文摘BACKGROUND With accumulating evidence showing a benefit in the renal and cardiovascular systems,diabetes guidelines recommend that patients with diabetes and chronic kidney disease(CKD)be treated with sodium-glucose cotransporter-2 inhibitor(SGLT2i)and/or glucagon like peptide-1 receptor agonists(GLP-1RAs)for renal protection.The real-world efficacy of the two medications on the urinary albumin-creatinine ratio(UACR)and estimated glomerular filtration rate(eGFR)remains to be explored.AIM To evaluate the SGLT2i and GLP-1RA application rates and UACR alterations after intervention in a real-world cohort of patients with diabetes.METHODS A cohort of 5482 patients with type 2 diabetes were enrolled and followed up at the Integrated Care Clinic for Diabetes of Peking University First Hospital for at least 6 months.Propensity score matching was performed,and patients who were not recommended for GLP-1RA or SGLT2i with comparable sex categories and ages were assigned to the control group at a 1:2 ratio.Blood glucose,body weight,UACR and eGFR were evaluated after 6 months of treatment in real-world clinical practice.RESULTS A total of 139(2.54%)patients started GLP-1RA,and 387(7.06%)received SGLT2i.After 6 months,the variations in fasting blood glucose,prandial blood glucose,and glycosylated hemoglobin between the GLP-1RA group and the SGLT2i and control groups were not significantly different.UACR showed a tendency toward a greater reduction compared with the control group,although this difference was not statistically significant(GLP-1RA vs control,-2.20 vs 30.16 mg/g,P=0.812;SGLT2i vs control,-20.61 vs 12.01 mg/g,P=0.327);eGFR alteration also showed no significant differences.Significant weight loss was observed in the GLP-1RA group compared with the control group(GLP-1RA vs control,-0.90 vs 0.27 kg,P<0.001),as well as in the SGLT2i group(SGLT2i vs control,-0.59 vs-0.03 kg,P=0.010).CONCLUSION Compared with patients who received other glucose-lowering drugs,patients receiving SGLT2i or GLP-1RAs presented significant weight loss,a decreasing trend in UACR and comparable glucose-lowering effects in realworld settings.
基金Supported by Burapha University,Thailand Science Research and Innovation,and National Science Research and Innovation Fund,No.53/2567.
文摘BACKGROUND Magnesium(Mg^(2+))plays a fundamental role in numerous cellular processes,including enzymatic reactions,DNA replication,oxidative stress response,and cytoskeletal dynamics.In fact,dysregulation of Mg^(2+)homeostasis has been increasingly associated with the development and progression of cancer,particularly colorectal cancer(CRC).Transient receptor potential melastatin(TRPM)channels,especially TRPM6 and TRPM7,are essential regulators of epithelial Mg^(2+)influx.While TRPM7 promotes CRC progression,the role of TRPM6 and TRPM6/7 channels remains unclear.AIM To investigate the role of membrane-localized TRPM6 and TRPM6/7 channels in Mg^(2+)influx,spheroid(SP)formation,stemness,and migration.METHODS We used parental and SP-derived HT-29 cells at comparable passages as in vitro models.Mass spectrometry confirmed full-length sequences,phosphorylation,and methionine oxidation of TRPM6 and TRPM7.Mg^(2+)influx,total and free Mg^(2+)levels were measured by fluorescence imaging and biochemical assays.TRPM6/TRPM7 expression and markers were analyzed by western blot.Func-tional assays,including secondary SP formation and wound healing,assessed stemness and migration.Cells were treated with Mg^(2+)transport inhibitors:Co(III)hexamine,2-aminoethyl diphenylborinate(TRPM6/7 blocker),and Mesendogen(TRPM6 inhibitor).RESULTS The expression of membrane-bound TRPM6,TRPM7,and TRPM6/7 was significantly higher in SP cells than in parental cells.Mass spectrometric analysis confirmed the presence of full-length TRPM6 and TRPM7 with increased phosphorylation and oxidation in SP cells.Enhanced Mg^(2+)influx and total intracellular Mg^(2+)levels were observed in SP cells.Free ionized intracellular Mg^(2+)levels remained comparable across all experimental groups.Pharmacological inhibition of TRPM6 and TRPM6/7 significantly reduced Mg^(2+)influx,decreased total Mg^(2+)content,compromised CRC SP stability,abolished cancer stem-like properties,impaired cell migration,and downregulated pro-tumorigenic markers,including Nanog,cyclooxygenase-2,and matrix metalloproteinase-9.CONCLUSION Membrane-localized TRPM6 and TRPM6/7 channels regulate Mg^(2+)influx and promote CRC stemness,SP stability,and migration,highlighting their potential as therapeutic targets to inhibit CRC progression and metastasis.
基金thankful to Dr.Marina George Kudiyirickal MSc,MJDF-RCS,PhD for providing us the audio core tip of this article.
文摘BACKGROUND Data on the use of glucagon-like peptide-1 receptor agonists(GLP-1RAs)in individuals with type 2 diabetes mellitus(T2DM)during Ramadan fasting is limited.No meta-analysis has summarized the safety and effectiveness of GLP-1RAs in these situations.AIM To evaluate the safety and efficacy of GLP-1RA in patients with T2DM fasting during Ramadan.METHODS Electronic databases were systematically searched for relevant studies that featured GLP-1RA in the intervention arm and other glucose-lowering medications in the control arm.The primary outcome was adverse events(AEs)during Ramadan for both groups;other outcomes included changes in glycemic and anthropometric measures during the peri-Ramadan period.RESULTS Four studies[three randomized-controlled trials with low risk of bias(RoB)and one prospective observational study with serious RoB]involving 754 subjects were analyzed.GLP-1RA group achieved greater glycated hemoglobin reduction than the non-GLP-1RA group[mean difference(MD):-0.31%,95%CI:-0.61 to-0.01,P=0.04,I2=77%]with a lower risk of documented symptomatic hypoglycemia(risk ratio=0.38,95%CI:0.16 to 0.88,P=0.02).Any AEs,serious AEs,or AEs that led to treatment discontinuation were comparable between the two groups.The GLP-1RA group experienced greater weight loss compared to the non-GLP-1RA group(MD:-2.0 kg,95%CI:-3.37 to-0.63,P=0.004,I2=95%).There were comparable changes in blood pressure and lipid profile between the two groups.GLP-1RA users experienced higher risks of gastrointestinal AEs,nausea,and vomiting;however,the risks of heartburn,abdominal pain,and diarrhea were similar in both groups.CONCLUSION Limited evidence suggests that GLP-1RAs are safe for T2DM management during Ramadan,offering modest benefits in blood sugar control and weight loss.Large multicenter trials are needed to confirm their safety and efficacy in at-risk populations,improving clinical practice decision-making.
基金Supported by Industrial Technological Initiation Scholarship of National Council for Scientific and Technological Development,CNPq,Brazil,No.0932204294929829 and No.7414780530977345the Scientific Initiation Scholarship Programme(PIBIC)of National Council for Scientific and Technological Development,CNPq,Brazil,No.5763023359532159,No.6472982965854452,and No.7340128440641417the CNPq Research Productivity Fellow,No.4357511882624145.
文摘The global prevalence of diabetes has surged in recent years,with diabetic kidney disease(DKD)emerging as a major complication.Traditional therapies have had limited success in slowing progression to end-stage kidney disease.However,novel therapies,particularly sodium-glucose cotransporter 2(SGLT2)inhibitors and glucagon-like peptide-1(GLP-1)receptor agonists,which were initially developed for hyperglycemia management,have transformed the treatment of obesity,heart failure,cardiovascular disease,and more recently,DKD.SGLT2 inhibitors have consistently and significantly reduced cardiovascular events,albuminuria,and glomerular filtration rate,highlighting their efficacy across diverse clinical presentations for patients with kidney impairment.Although fewer studies have specifically investigated GLP-1 receptor agonists in patients with kidney disease,existing evidence underscores their potential to slow renal disease progression,reduce albuminuria,and improve clinically relevant outcomes.However,further research is needed to better identify patients most likely to benefit from treatment.Together,these therapies represent valuable advancements for DKD,offering significant reductions in morbidity and mortality and shifting the management of the disease by becoming essential pillars for the treatment of these patients.
基金Supported by the Jiangsu Provincial Health and Family Planning Commission Personnel Talent Project,No.R2017005.
文摘BACKGROUND Although targeted therapy provides survival benefits for patients with metastatic colorectal cancer,some patients develop resistance to these treatments.Human epidermal growth factor receptor 2(HER2)is overexpressed in a subset of pa-tients with colorectal cancer and has been established as a therapeutic target.CASE SUMMARY This case report describes a Chinese patient with HER2-amplified advanced rectal cancer who showed no response to chemotherapy and targeted therapies against epidermal growth factor receptor and vascular endothelial growth factor but achieved a remarkable response following treatment with immune checkpoint inhibitors(ICIs)in combination with pyrotinib.The combination of oxaliplatin and ICIs with pyrotinib demonstrates synergistic effects after late-stage disease progression.CONCLUSION ICIs and pyrotinib may be effective in treating HER2-amplified advanced rectal cancer.Chemotherapy following disease progression could enhance efficacy synergistically.
基金Supported by Scientific Research Project of Health Commission of Guangxi Zhuang Autonomous Region,No.Z-A20240546Undergraduate Education and Teaching Reform Project of Guangxi Medical University,No.2025XJGYC38and Key Textbook Construction Project of Guangxi Medical University,No.Gxmuzdjc2417。
文摘BACKGROUND Human epidermal growth factor receptor 2(HER2)plays pivotal roles in cellular proliferation,survival,and differentiation of several malignancies.Upper tract urothelial carcinoma(UTUC)is a relatively rare malignancy.The clinical and molecular significance of HER2 expression level in UTUC remains poorly characterized vs bladder cancer.AIM To comprehensively evaluate HER2 expression patterns and their association with UTUC patients’clinicopathological features.METHODS Data were retrospectively collected from patients diagnosed with UTUC at The First Affiliated Hospital of Guangxi Medical University between January 2023 and December 2024.HER2 status was evaluated by immunohistochemistry in 145 UTUC patients who met the inclusion criteria.Its associations with tumor grade,tumor stage,and other clinicopathological parameters were assessed.Theχ2 test or Fisher’s exact test,along with univariate and multivariate logistic regression analyses,were performed to determine the influences of clinicopathological factors on HER2 expression.RESULTS HER2 positivity was significantly associated with high tumor grade(P=0.003),while other variables,including sex,anatomical tumor location,pathological T stage,Ki-67 proliferation index,nodal metastasis status,lymphovascular invasion,and tumor laterality failed to demonstrate statistically significant correlations.These findings were further substantiated through univariate logistic regression modeling,yielding an odds ratio of 3.56[95%confidence interval(CI):1.30-9.75;P=0.013]for the association between high tumor grade and HER2 positivity.Importantly,this relationship remained robust(hazard ratio=3.42,95%CI:1.22-9.60;P=0.019)even after implementing multivariate logistic regression analysis.With a median follow-up time of 8 months(interquartile range,4-14)months,14 patients experienced intravesical recurrence after radical nephroureterectomy.Certain patient characteristics,such as HER2-negative,male sex,high-grade tumors,and luminal phenotype,were associated with a higher risk of intravesical recurrence.CONCLUSION In UTUC,HER2 overexpression is closely associated with tumor dedifferentiation(high grade),while it does not correlate with conventional indicators of disease progression,indicating that HER2 may serve a distinct biological function in this cancer type.
基金Supported by CAMS Innovation Fund for Medical Sciences CIFMS,No.2023-I2M-3-012.
文摘BACKGROUND Human epidermal growth factor receptor 2(HER2)-positive gastric cancer(GC)represents a distinct molecular cancer subtype that is often associated with a poor prognosis.While perioperative chemotherapy regimens are currently the primary recommendation for locally advanced HER2-positive GC,combination therapies incorporating immune checkpoint inhibitors are under active investigation.CASE SUMMARY The present case describes a patient with locally advanced HER2-positive GC who underwent perioperative treatment with chemotherapy combined with trastuzumab.Although significant tumor shrinkage was observed,surgical pathology results did not confirm the achievement of a pathological complete response.The current treatment strategies for advanced GC were also reviewed.Relevant case reports,retrospective studies,and prospective clinical trials were retrieved for analysis after searching the PubMed/MEDLINE,EMBASE,Cochrane Library,Web of Science,and American Society of Clinical Oncology/European Society for Medical Oncology conference abstracts between 2014 and 2024.CONCLUSION Large-scale phase Ⅲ clinical trials are needed to verify the efficacy of combined neoadjuvant treatment application for GC.
文摘OBJECTIVE:to investigate the anti-arthritic effects of lappaconitine(LA)on adjuvant-induced arthritis in Sprague-Dawley rats and its possible involvement in the regulation of M1/M2 macrophage balance through the P2X7 receptor(P2X7r).METHODS:Rats were immunized with complete Freund's adjuvant and then intraperitoneally administered LA(2,4,or 8 mg·kg^(-1)·d^(-1))or methotrexate(0.5 mg/kg per 3 d)for 14 d.The anti-arthritic effects of LA were evaluated through arthritis index(AI)assessment,ankle diameter measurement,and histopathological staining analysis.The analgesic effect of LA on arthritis was measured using mechanical withdrawal threshold testing and gait scoring.The impacts of LA on macrophage polarization,the expression of pro-/anti-inflammatory cytokines and P2X7r were analyzed using quantitative real-time polymerase chain reaction,enzyme-linked immunosorbent assay,and Western blotting.RESULTS:LA treatment significantly reduced AI scores,paw swelling,joint destruction,and inflammatory cell infiltration,and alleviated arthritis pain.Additionally,LA promoted a balanced M1/M2 ratio by increasing the m RNA expression level of M2 marker arginase 1 and decreasing those of M1 markers inducible nitric oxide synthase and interleukin(IL)-1βin synovial tissues.Furthermore,LA lowered the levels of three M1-related cytokines,namely tumor necrosis factor-α,IL-1βand IL-18,and raised the level of the M2-related cytokine IL-10.Further research showed that treatment with LA inhibited the expression of P2X7r.CONCLUSION:Our findings indicate that the notable therapeutic and analgesic effects of LA on AIA rats are exerted through balancing the M1/M2 ratio,probably via P2X7r.
基金Supported by Henan Province's"Double First-Class"Creation of Scientific Research in Traditional Chinese Medicine,No.HSRPDFCTCM-2023-7-23 and No.STG-ZYX02-202117National Traditional Chinese Medicine Clinical Research Base Scientific Research Special Project,No.2022JDZX098 and No.2022JDZX114+1 种基金National Natural Science Foundation of China,No.82205086The 9th China Association for Science and Technology Young Talent Support Project,No.2023QNRC001.
文摘Non-alcoholic fatty liver disease(NAFLD)is a progressive disease.Without effective interventions,NAFLD can gradually develop to non-alcoholic steatohepatitis,fatty liver fibrosis,liver cirrhosis and even hepatocellular carcinoma.It is still to investigate the precise molecular mechanism behind the pathophysiology of NAFLD.Triggering receptor expressed on myeloid cells 2(TREM2)can sense tissue injury and mediate immune remodeling,thereby inducing phagocytosis,lipid metabolism,and metabolic transfer,promoting cell survival and combating inflammatory activation.NAFLD might develop as a result of TREM2's regulatory role.We here briefly summarize the biological characteristics of TREM2 and its functions in the disease progression of NAFLD.Moreover,we propose to broaden the therapeutic strategy for NAFLD by targeting TREM2.
文摘BACKGROUND Glucagon-like peptide-1 receptor agonists(GLP-1RAs)play a key role in managing type 2 diabetes mellitus(T2DM).Transitioning between different GLP-1RA has been proposed as a treatment strategy.AIM To investigate switching patterns between GLP-1RA and their impact on glycemic control.METHODS A retrospective study involving patients with T2DM who initiated GLP-1RA therapy between 2009 and 2021 and transitioned to another GLP-1RA.Baseline glycated hemoglobin(HbA1c)was defined as the most recent measurement within 1 year prior to switching,and follow-up HbA1c was the first measurement recorded 4-15 months post-switch.RESULTS Among 70654 patients initiating GLP-1RA therapy,18047(25.5%)switched regimens.In the 13970 patients with available HbA1c,levels decreased from 8.5%±1.6%to 7.6%±1.4%(P<0.001).HbA1c decreased in 78.3%(10943/13970)of these patients,with the most frequent improvement observed in those switching from daily to weekly GLP-1RA(81%,5582/6890).CONCLUSION Switching between GLP-1RAs can serve as a practical alternative to treatment intensification for effectively managing T2DM.
基金Supported by the National Natural Science Foundation of China,No.82122012,No.82270917,No.82170833 and No.82170601Shanghai Sixth People’s Hospital Project,No.ynjq202401 and No.ynms202117Shanghai Research Center for Endocrine and Metabolic Diseases,No.2022ZZ01002.
文摘BACKGROUND Traditional Chinese medicine offers many valuable remedies for maintaining blood glucose homeostasis in patients with type 2 diabetes mellitus.Bile powder(BP)is a powdered form of bile derived from pigs.It has been used historically in various medicinal applications.Currently,the therapeutic potential of BP in regulating glucose homeostasis remains unclear.Bile acids(BAs)are increasingly recognized for their role in glucose metabolism particularly through the modu-lation of glucagon-like peptide-1(GLP-1).AIM To investigate BP effects on glucose homeostasis and elucidate its mechanistic role through GLP-1 and farnesoid X receptor(FXR)signaling.METHODS A diabetic mouse model was established using a high-fat diet and streptozotocin administration.Mice were treated with BP at doses of 25,50,or 75 mg/kg/day for 45 days.Glucose homeostasis was assessed via the oral glucose tolerance test and insulin tolerance test.Serum GLP-1 levels were measured by enzyme-linked immunosorbent assay.A GLP-1 receptor antagonist and an FXR agonist were used to clarify the underlying mechanisms.In vitro STC-1 murine enteroendocrine cells were treated with a BP-mimicking BA mixture to assess GLP-1 secretion and proglucagon gene expression.RESULTS BP treatment significantly improved glucose homeostasis in the diabetic mouse model as indicated by lower blood glucose(P<0.05)and improved insulin sensitivity.BP enhanced GLP-1 secretion(P<0.05),which was an effect abolished by the GLP-1 receptor antagonist.This observation confirmed its dependence on GLP-1 signaling.In STC-1 cells,BP-derived BA mixtures stimulated GLP-1 secretion and upregulated proglucagon expression(P<0.05).Mechanistically,BP inhibited FXR signaling as evidenced by the reversal of its effects upon fexaramine administration.In addition,long-term BP treatment suppressed FXR signaling,resulting in elevated GLP-1 levels and preventing glucose dysregulation.CONCLUSION BP improved glucose homeostasis by promoting GLP-1 secretion via FXR inhibition,highlighting its potential as a therapeutic strategy for metabolic disorders.
基金supported by the National Natural Science Foundation of China(32273037 and 32102636)the Guangdong Major Project of Basic and Applied Basic Research(2020B0301030007)+4 种基金Laboratory of Lingnan Modern Agriculture Project(NT2021007)the Guangdong Science and Technology Innovation Leading Talent Program(2019TX05N098)the 111 Center(D20008)the double first-class discipline promotion project(2023B10564003)the Department of Education of Guangdong Province(2019KZDXM004 and 2019KCXTD001).
文摘A switch from avian-typeα-2,3 to human-typeα-2,6 receptors is an essential element for the initiation of a pandemic from an avian influenza virus.Some H9N2 viruses exhibit a preference for binding to human-typeα-2,6 receptors.This identifies their potential threat to public health.However,our understanding of the molecular basis for the switch of receptor preference is still limited.In this study,we employed the random forest algorithm to identify the potentially key amino acid sites within hemagglutinin(HA),which are associated with the receptor binding ability of H9N2 avian influenza virus(AIV).Subsequently,these sites were further verified by receptor binding assays.A total of 12 substitutions in the HA protein(N158D,N158S,A160 N,A160D,A160T,T163I,T163V,V190T,V190A,D193 N,D193G,and N231D)were predicted to prefer binding toα-2,6 receptors.Except for the V190T substitution,the other substitutions were demonstrated to display an affinity for preferential binding toα-2,6 receptors by receptor binding assays.Especially,the A160T substitution caused a significant upregulation of immune-response genes and an increased mortality rate in mice.Our findings provide novel insights into understanding the genetic basis of receptor preference of the H9N2 AIV.
基金supported by the National Natural Science Foundation of China(81971058,82371226,82101295,82301398)the National Funded Postdoctoral Researcher Program(GZC20233585)The Boost Plan of Xijing Hospital(XJZT24QN25,XJZT25CX22).
文摘Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsolved issue in pain medicine.Our previous study,using protein kinase C gamma(PKCγ)-tdTomato mice,highlights the spinal feedforward inhibitory circuit involving PKCγ neurons in gating neuropathic allodynia.However,the regulatory mechanisms governing this circuit necessitate further elucidation.We used diverse transgenic mice and advanced techniques to uncover the regulatory role of the descending serotonin(5-HT)facilitation system on spinal PKCγ neurons.Our findings revealed that 5-HT neurons from the rostral ventromedial medulla hyperpolarize spinal inhibitory interneurons via 5-HT_(2C) receptors,disinhibiting the feedforward inhibitory circuit involving PKCγ neurons and exacerbating allodynia.Inhibiting spinal 5-HT_(2C) receptors restored the feedforward inhibitory circuit,effectively preventing neuropathic allodynia.These insights offer promising therapeutic targets for neuropathic allodynia management,emphasizing the potential of spinal 5-HT_(2C) receptors as a novel avenue for intervention.
