This article comments on the work by Soresi and Giannitrapani.The authors have stated that one of the most novel and promising treatments for metabolic dysfunction-associated steatotic liver disease(MASLD)is the use o...This article comments on the work by Soresi and Giannitrapani.The authors have stated that one of the most novel and promising treatments for metabolic dysfunction-associated steatotic liver disease(MASLD)is the use of glucagon-like peptide 1 receptor agonists,especially when used in combination therapy.However,despite their notable efficacy,these drugs were not initially designed to target MASLD directly.In a groundbreaking development,the Food and Drug Administration has recently approved resmetirom,the first treatment specifically aimed at reducing liver fibrosis in metabolic-associated steatohepatitis.Resmetirom,an orally administered,liver-directed thyroid hormone beta-selective agonist,acts directly on intrahepatic pathways,enhancing its therapeutic potential and marking the beginning of a new era in the treatment of MASLD.Furthermore,the integration of lifestyle modifications into liver disease management is an essential component that should be considered and reinforced.By incorporating dietary changes and regular physical exercise into treatment,patients may achieve improved outcomes,reducing the need for pharmacological interventions and/or improving treatment efficacy.As a complement to medical therapies,lifestyle factors should not be overlooked in the broader strategy for managing MASLD.展开更多
In the quest for novel PPARα/γ dual agonists as putative drugs for the treatment of type 2 diabetes and dyslipidemia, we designed and synthesized a series of urea acetates as potential PPARα/γ dual agonists. The s...In the quest for novel PPARα/γ dual agonists as putative drugs for the treatment of type 2 diabetes and dyslipidemia, we designed and synthesized a series of urea acetates as potential PPARα/γ dual agonists. The structure of the target compounds, intermediates were characterized by ^1H N-MR, HRMS.展开更多
A new series of compounds, 2-（benzodioxol-2-yl）acetic acids, have been synthesized. Their structures were confirmed by MS and 1H-NMR. The preliminary pharmacological screening showed that these compounds exhibited p...A new series of compounds, 2-（benzodioxol-2-yl）acetic acids, have been synthesized. Their structures were confirmed by MS and 1H-NMR. The preliminary pharmacological screening showed that these compounds exhibited potent human PPARδ agonist activities.展开更多
Aim Activation of peroxisome proliferator-activated receptor δ (PPARδ) subtypes increases expression of genes involved in fatty acid transport and oxidation and alters adiposity in animal models of obesity and type-...Aim Activation of peroxisome proliferator-activated receptor δ (PPARδ) subtypes increases expression of genes involved in fatty acid transport and oxidation and alters adiposity in animal models of obesity and type-2 diabetes. We aim to explore the effects of peroxisome proliferator-activated receptor δ (PPARδ) subtypes on serum lipid profiles in obese rhesus monkey, especially evaluate the efficacy of investigational new drug (HS00098). Methods: First, a prototype of obese rhesus monkey was established by continuously feeding test animals a high fat diet for 2 months. Fifteen obese rhesus monkeys were randomly divided into 3 groups, and the 2 test groups were treated with GW 501516 and HS00098. The test groups were administered doses of 0.3 mg/kg for 1 month, then with 1 mg/kg for 1 month, and finally with 3 mg/kg for 1 month. The control group received placebo treatment. In each experiment, the body weight of each animal was measured and recorded initially and prior to changing the dose of the drug each month. The total cholesterol, blood glucose, triglyceride, high density lipoprotein cholesterol, low-density lipoprotein cholesterol, serum Apo-A1, Apo-B100 and insulin were tested. Results: The average body weight gain of the GW501516 and HS00098 groups was significantly lower than that of the control group. The group receiving the HS00098 treatment had a higher signifycant increase in high density lipoprotein and apo-A1 (P < 0.05) than the control monkeys, while the total cholesterol, triglycerides, low density lipoproteins, apo-B100, and insulin (P < 0.05 or P < 0.01) were significantly decreased. Compared with GW50-1516, the effects of HS00098 on serum lipid profiles in diet-induced obese rhesus monkeys are more obvious. Conclusion: These results suggested that the investigational drug (HS00098) can effectively reduce body weight, blood lipid and blood sugar levels of diet-induced obese rhesus monkeys.展开更多
Obesity is a global pandemic that has been threatening the worldwide population.It has been reported to be associated with an increase in the risk of chronic diseases such as type 2 diabetes mellitus(T2DM),cardiovascu...Obesity is a global pandemic that has been threatening the worldwide population.It has been reported to be associated with an increase in the risk of chronic diseases such as type 2 diabetes mellitus(T2DM),cardiovascular disease,and other diseases,including some malignancies.Currently,the first line of management includes lifestyle modifications.However,recently,bariatric surgeries were introduced to combat obesity.The previous modalities of management are always challenging since lifestyle could have limited long-term effectiveness and difficulty to achieve,and surgeries are invasive and also require a lifestyle modification and commitment.Glucagon-like peptide-1 receptor agonists(GLP-1RAs)were initially introduced as a rising star for managing T2DM,with patients benefiting from the control of blood sugar and weight loss.These medications work by enhancing feelings of fullness,slowing down digestion,and ultimately reducing calorie intake.However,GLP-1RAs are not without side effects and have some costs.Common side effects include gastrointestinal(GI)adverse events such as nausea,vomiting,diarrhea,and a lack of GI motility,which is the main mechanism through which the drug induces a feeling of fullness and promotes weight loss,potentially resulting in treatment discontinuation.More serious,though less frequent,risks include pancreatitis,gallbladder diseases,and,rarely,thyroid Ccell cancers.This review aimed to discuss the globally emerging role of GLP-1RAs in obesity management and highlight some safety considerations for patients taking these drugs.展开更多
Glucagon-like peptide-1 (GLP-1) and its receptor agonists (GLP-1RAs) are wellestablishedtherapies for metabolic conditions such as type 2 diabetes and obesitydue to their ability to enhance insulin secretion, promote ...Glucagon-like peptide-1 (GLP-1) and its receptor agonists (GLP-1RAs) are wellestablishedtherapies for metabolic conditions such as type 2 diabetes and obesitydue to their ability to enhance insulin secretion, promote weight loss, and regulateblood glucose levels. Emerging evidence, however, indicates that GLP-1RAs mayalso have therapeutic potential in inflammatory and autoimmune conditions. Thisreview explores the evolving role of GLP-1RAs in managing rheumatic diseases,including osteoarthritis, rheumatoid arthritis, psoriatic arthritis, and systemiclupus erythematosus. Studies suggest that GLP-1RAs reduce inflammation bymodulating immune cell activity, increasing anti-inflammatory cytokine production,shifting macrophage polarization toward an anti-inflammatory phenotype,and enhancing regulatory T-cell function to maintain immune homeostasis. Theseimmunomodulatory effects point toward a promising adjunctive strategy incurrent clinical practice for patients with rheumatic diseases, particularly thosewith metabolic comorbidities. Further clinical trials are warranted to validatethese findings, clarify underlying mechanisms, and assess long-term safety,ultimately paving the way for novel treatment approaches in rheumatology.展开更多
BACKGROUND Atrial fibrillation(AF)stands as the most prevalent type of arrhythmia,affecting approximately 60 million individuals world-wide.Although antiarrhythmic drugs(AADs)remain the gold standard for AF treatment,...BACKGROUND Atrial fibrillation(AF)stands as the most prevalent type of arrhythmia,affecting approximately 60 million individuals world-wide.Although antiarrhythmic drugs(AADs)remain the gold standard for AF treatment,glucagon-like peptide-1 receptor agonists(GLP-1 RAs)are arising as potential therapeutic alternatives.AIM To evaluate the impact of GLP-1 RAs on the incidence of AF.METHODS Inclusion criteria included systematic reviews(SRs)that based their analyses on clinical trials,observational studies,controlled trials and network meta-analyses.A total of 8 SRs were selected for data extraction,focusing on semaglutide,liraglutide and dulaglutide.Additionally,the effects of GLP-1 RAs on AF incidence were compared with those of sodium-glucose co-transporter 2(SGLT2)inhibitors.RESULTS Findings indicate that semaglutide,evaluated in the largest patient cohort across the 8 SRs,consistently reduced AF incidence.However,dulaglutide and liraglutide exhibited inconsistent effects.Notably,as opposed to variable outcomes associated with GLP-1 RAs,SGLT2 inhibitors a class of antidiabetic agents with weight-reducing properties exhibit significant cardiovascular benefits,including reductions in both AF and atrial flutter.CONCLUSION GLP-1 RAs emerge as a promising and potential alternative for AADs in reduction of incidence of AF.However,further research is required to fully determine their therapeutic potential and long-term cardiovascular effects.展开更多
BACKGROUND Glucagon-like peptide-1 receptor agonists(GLP-1RAs)are increasingly being used to treat type 2 diabetes mellitus(T2DM)and obesity.Although GLP-1RAs delay gastric emptying,their impact on gastric mucosal vis...BACKGROUND Glucagon-like peptide-1 receptor agonists(GLP-1RAs)are increasingly being used to treat type 2 diabetes mellitus(T2DM)and obesity.Although GLP-1RAs delay gastric emptying,their impact on gastric mucosal visibility during upper endoscopy remains uncertain,especially in Asian patients.AIM To investigate the association between GLP-1RA treatment and gastric mucosal visibility during upper endoscopy in Asian patients with T2DM.METHODS The study population included Korean patients who underwent esophagogastroduodenoscopy(EGD)with concomitant GLP-1RA or dipeptidyl peptidase 4 inhibitor(DPP4i)for the treatment of T2DM.A 1:2 propensity score matching between GLP-1RA and DPP4i users resulted in 198 matched patients and 295 matched patients in each group,respectively.Gastric mucosal visibility was assessed by reviewing endoscopy images with a validated scale(POLPREP).In addition,the rates of aborted and repeat EGD and pulmonary aspiration were also assessed.RESULTS Of the 493 matched patients,mean body mass index was 26.0 kg/m^(2).The rate of inadequate gastric mucosal visibility(gastric POLPREP score 0 or 1)was significantly higher in GLP-1RA group than matched DPP4i group(8.6%vs 1.4%,P=0.0007).The rates of aborted EGD and repeat EGD were also significantly higher in GLP-1RA than DPP4i group(7.6%vs 0.7%in both aborted and repeat EGD,P=0.0011).Multivariable logistic regression revealed GLP-1RA use as an independent risk factor for both inadequate gastric mucosal visibility(odds ratio=6.143,95%confidence interval:2.289,20.318,P=0.0008)and aborted EGD(odds ratio=11.099,95%confidence interval:3.172,63.760,P=0.0010).Despite gastric residue,no pulmonary aspiration was reported in either group.CONCLUSION GLP-1RA use was associated with a higher risk of inadequate gastric mucosal visibility and aborted and repeat procedures during upper gastrointestinal endoscopy in Korean patients with T2DM while pulmonary aspiration was not observed.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
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
Type 2 diabetes mellitus(T2DM)is one of the most prevalent chronic metabolic disorder characterized by insulin resistance and relative insulin deficiency.PPARδactivation has been reported to have several beneficial e...Type 2 diabetes mellitus(T2DM)is one of the most prevalent chronic metabolic disorder characterized by insulin resistance and relative insulin deficiency.PPARδactivation has been reported to have several beneficial effects in alleviating dyslipidemia and insulin resistance.GW501516,a synthetic PPARδagonist,was developed to target hyperlipidemia and reported to alleviating insulin resistance in T2DM.Studies indicate that PPARδactivation by GW501516 can reduce adiposity,enhanceβ-oxidation of fatty acids,and improve insulin sensitivity in T2DM animal models.Despite its therapeutic promise,potential carcinogenic effects also have been reported.Therefore,a comprehensive non-targeted and targeted lipidomics study was carried out to evaluate the regulatory effect of GW501516 in the plasma of db/db mice.The results revealed that GW501516 is effective in reducing the accumulation of lipids in the fatty acid metabolism pathway and lipid classes including triglycerides and phosphatidylglycerols.Furthermore,activation of PPARδby GW501516 demonstrated a beneficial effect on improving circulating cholesterol homeostasis.However,while the levels of hexosylceramides and sphingomyelin were partially reversed,ceramide levels,which are negatively associated with insulin sensitivity,were significantly elevated by GW501516.Despite these mixed outcomes,the study highlights both the promising therapeutic potential of PPARδactivation in metabolic disorders and the safety concerns regarding long-term clinical use.The findings provide valuable insights into the impact of GW501516-induced PPARδactivation on lipid metabolism in T2DM,contributing to a better understanding of its therapeutic potential and risks.展开更多
Metabolic dysfunction-associated steatotic liver disease(MASLD)is a highly prevalent liver pathology in need of novel pharmacological treatments to complement lifestyle-based interventions.Nuclear receptor agonists ha...Metabolic dysfunction-associated steatotic liver disease(MASLD)is a highly prevalent liver pathology in need of novel pharmacological treatments to complement lifestyle-based interventions.Nuclear receptor agonists have been under scrutiny as potential pharmacological targets and as of today,resmetirom,a thyroid hormone receptor b agonist,is the only approved agent.The dual PPARαandδagonist elafibranor has also undergone extensive clinical testing,which reached the phase III clinical trial but failed to demonstrate a beneficial effect on MASLD.As alcohol-associated liver disease and MASLD can be interconnected,whether elafibranor might be affective against liver disease caused by alcohol consumption is worth investigating.Writing recently in the World Journal of Gastroenterology,Koizumi et al reported using a mouse model of alcoholassociated liver disease and found that hepatic steatosis,liver fibrosis,and hepatocyte apoptosis were alleviated by administration of elafibranor.Although preclinical in nature,these data support the potential beneficial action of elafibranor in alcohol-induced MASLD,warranting the testing of this molecule in patients with steatotic liver disease caused by alcohol consumption.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
Aim: We aimed to investigate whether the agonists for liver X receptor (LXR) ameliorate lupus-like phenotypes in mice mediated by the clearance of apoptotic cells, and compare with peroxisome proliferator-activated re...Aim: We aimed to investigate whether the agonists for liver X receptor (LXR) ameliorate lupus-like phenotypes in mice mediated by the clearance of apoptotic cells, and compare with peroxisome proliferator-activated receptor (PPAR) γ plus PPARδ agonists, which also facilitate the clearance of apoptotic cells and exert anti-inflammatory effects in systemic lupus erythematosus (SLE). Methods: We investigated the efficacy of LXR agonist (GW3965) or dual treatment of PPARγ (pioglitazone) and PPARδ (GW0742) agonists in SLE animal models, female MRL/MpJ-Fas/J mice and BALB/cAJcl mice treated with pristane. The data were analyzed with one-way analysis of variance and Tukey’s honestly significant difference tests. Results: The treatment with LXR or PPARγ/δ agonists did not significantly alter the swelling of lymph nodes, ds-DNA production, albuminuria, histological score of glomerular lesions, and mRNA expression of target genes including Abca1, C1qa, Icam1, Mertk and Tnf. Conclusion: LXR or PPARγ/δ agonists targeting the impaired clearance for apoptosis cells may not be efficient in the remission induction therapy in SLE.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
Introduction Nonarteritic anterior ischemic optic neuropathy(NAION)is the most common acute optic neuropathy in patients over the age of 50 years(1).It is characterized by acute,painless vision loss in one eye which i...Introduction Nonarteritic anterior ischemic optic neuropathy(NAION)is the most common acute optic neuropathy in patients over the age of 50 years(1).It is characterized by acute,painless vision loss in one eye which is often noticed upon awakening.Commonly,there is an altitudinal visual field defect,though this can be variable(1).展开更多
Background and Objective:Idiopathic intracranial hypertension(IIH)is a disorder of raised intracranial pressure(ICP)associated with overweight and obesity,with weight loss being the mainstay of management.Diet and lif...Background and Objective:Idiopathic intracranial hypertension(IIH)is a disorder of raised intracranial pressure(ICP)associated with overweight and obesity,with weight loss being the mainstay of management.Diet and lifestyle changes alone are often unsuccessful at achieving meaningful or sustained weight loss.Glucagon-like peptide-1 receptor agonists(GLP-1RA)are a class of medications developed for the treatment of diabetes but are also highly effective for weight reduction.The objective of this narrative review is to present the current evidence for GLP-1RAs in the management of IIH.Methods:Articles were searched for inclusion through OVID using the following terms:[papilledema OR intracranial hypertension OR idiopathic intracranial hypertension OR brain pseudotumor]and[glucagon like peptide 1 OR glucagon like peptide 1 receptor agonist OR semaglutide OR exendin 4 OR liraglutide OR tirzepatide].Titles and abstracts were screened manually for relevance.There were no exclusion criteria for time frame,language,population or article type,although conference abstracts were not included.An illustrative case of a patient with IIH treated with tirzepatide and semaglutide is also presented.Key Content and Findings:GLP-1RAs have demonstrated the potential for significantly greater weight loss in patients with IIH,with a reduced requirement for IIH medications and improved symptoms,compared to conventional weight management.Treatment with GLP-1RAs has also been shown to result in a rapid and persistent reduction in ICP in both rat and human studies.The side effects of GLP-1RAs are generally well-tolerated,with low rates of discontinuation in clinical trials.However,continuous treatment is likely required to avoid weight rebound and symptom recurrence after cessation.Conclusions:Despite highly promising preliminary evidence,further clinical trials are needed to determine the most effective GLP-1RA medications within this class,appropriate dosing regimens and treatment duration.展开更多
Debates regarding the specific effects of general anesthesia on developing brains have persisted for over 30 years.A consensus has been reached that prolonged,repeated,high-dose exposure to anesthetics is associated w...Debates regarding the specific effects of general anesthesia on developing brains have persisted for over 30 years.A consensus has been reached that prolonged,repeated,high-dose exposure to anesthetics is associated with a higher incidence of deficits in behavior and executive function,while single exposure has a relatively minor effect on long-term neurological function.In this review,we summarize the dose-dependent neuroprotective or neurotoxic effects of gamma-aminobutyric acid type A receptor agonists,a representative group of sedatives,on developing brains or central nervous system diseases.Most preclinical research indicates that anesthetics have neurotoxic effects on the developing brain through various signal pathways.However,recent studies on low-dose anesthetics suggest that they may promote neurodevelopment during this critical period.These findings are incomprehensible for the general“dose-effect”principles of pharmacological research,which has attracted researchers'interest and led to the following questions:What is the threshold for the dual effects exerted by anesthetics such as propofol and sevoflurane on the developing brain?To what extent can their protective effects be maximized?What are the underlying mechanisms involved in these effects?Consequently,this issue has essentially become a“mathematical problem.”After summarizing the dose-dependent effects of gamma-aminobutyric acid type A receptor agonist sedatives in both the developing brain and the brains of patients with central nervous system diseases,we believe that all such anesthetics exhibit specific threshold effects unique to each drug.These effects range from neuroprotection to neurotoxicity,depending on different brain functional states.However,the exact values of the specific thresholds for different drugs in various brain states,as well as the underlying mechanisms explaining why these thresholds exist,remain unclear.Further in-depth exploration of these issues could significantly enhance the therapeutic translational value of these anesthetics.展开更多
Background:To determine whether initiating a glucagon-like peptide-1 receptor agonist(GLP-1 RA)within 3 months of type 2 diabetes(T2DM)diagnosis alters the subsequent risk of overall and site-specific cancer and wheth...Background:To determine whether initiating a glucagon-like peptide-1 receptor agonist(GLP-1 RA)within 3 months of type 2 diabetes(T2DM)diagnosis alters the subsequent risk of overall and site-specific cancer and whether this association differs by baseline body-mass index(BMI).Methods:This retrospective cohort study used electronic health records from the TriNetX U.S.research network.Adults aged 20 years or older diagnosed with T2DM between 2016 and 2024 were included if they received any hypoglycemic agents within 3 months before and after diagnosis.Following 1:1 propensity score matching,both the GLP-1 RA user and non-user groups included 183,264 patients.The study outcome was defined as a diagnosis of malignant neoplasms.Hazard ratios(HRs)for overall and site-specific cancer risk were estimated using Cox proportional hazards models.Kaplan–Meier analysis and stratified analysis by BMI were performed.Results:Early GLP-1 RA use demonstrated a modest but significant association with reduced overall cancer risk(HR 0.93;95%CI:0.90–0.96).Reduced risks were noted for cancers of the digestive(HR 0.81),respiratory(HR 0.66),and female genital(HR 0.87)systems.In stratified analysis,benefits were more pronounced in patients with BMI≥30,particularly for pancreatic and colorectal cancers.Conclusion:Early initiation of GLP-1 receptor agonists in patients with diagnosed T2DM was associated with a modest reduction in overall cancer risk,particularly among individuals with obesity.These findings highlight the dual metabolic and oncologic value of prompt GLP-1 RA therapy.展开更多
文摘This article comments on the work by Soresi and Giannitrapani.The authors have stated that one of the most novel and promising treatments for metabolic dysfunction-associated steatotic liver disease(MASLD)is the use of glucagon-like peptide 1 receptor agonists,especially when used in combination therapy.However,despite their notable efficacy,these drugs were not initially designed to target MASLD directly.In a groundbreaking development,the Food and Drug Administration has recently approved resmetirom,the first treatment specifically aimed at reducing liver fibrosis in metabolic-associated steatohepatitis.Resmetirom,an orally administered,liver-directed thyroid hormone beta-selective agonist,acts directly on intrahepatic pathways,enhancing its therapeutic potential and marking the beginning of a new era in the treatment of MASLD.Furthermore,the integration of lifestyle modifications into liver disease management is an essential component that should be considered and reinforced.By incorporating dietary changes and regular physical exercise into treatment,patients may achieve improved outcomes,reducing the need for pharmacological interventions and/or improving treatment efficacy.As a complement to medical therapies,lifestyle factors should not be overlooked in the broader strategy for managing MASLD.
文摘In the quest for novel PPARα/γ dual agonists as putative drugs for the treatment of type 2 diabetes and dyslipidemia, we designed and synthesized a series of urea acetates as potential PPARα/γ dual agonists. The structure of the target compounds, intermediates were characterized by ^1H N-MR, HRMS.
基金supported by the National High Technology Research and Development Program of China(863 project:2003AA235010)the National Natural Science Foundation of China(No.30472092).
文摘A new series of compounds, 2-（benzodioxol-2-yl）acetic acids, have been synthesized. Their structures were confirmed by MS and 1H-NMR. The preliminary pharmacological screening showed that these compounds exhibited potent human PPARδ agonist activities.
文摘Aim Activation of peroxisome proliferator-activated receptor δ (PPARδ) subtypes increases expression of genes involved in fatty acid transport and oxidation and alters adiposity in animal models of obesity and type-2 diabetes. We aim to explore the effects of peroxisome proliferator-activated receptor δ (PPARδ) subtypes on serum lipid profiles in obese rhesus monkey, especially evaluate the efficacy of investigational new drug (HS00098). Methods: First, a prototype of obese rhesus monkey was established by continuously feeding test animals a high fat diet for 2 months. Fifteen obese rhesus monkeys were randomly divided into 3 groups, and the 2 test groups were treated with GW 501516 and HS00098. The test groups were administered doses of 0.3 mg/kg for 1 month, then with 1 mg/kg for 1 month, and finally with 3 mg/kg for 1 month. The control group received placebo treatment. In each experiment, the body weight of each animal was measured and recorded initially and prior to changing the dose of the drug each month. The total cholesterol, blood glucose, triglyceride, high density lipoprotein cholesterol, low-density lipoprotein cholesterol, serum Apo-A1, Apo-B100 and insulin were tested. Results: The average body weight gain of the GW501516 and HS00098 groups was significantly lower than that of the control group. The group receiving the HS00098 treatment had a higher signifycant increase in high density lipoprotein and apo-A1 (P < 0.05) than the control monkeys, while the total cholesterol, triglycerides, low density lipoproteins, apo-B100, and insulin (P < 0.05 or P < 0.01) were significantly decreased. Compared with GW50-1516, the effects of HS00098 on serum lipid profiles in diet-induced obese rhesus monkeys are more obvious. Conclusion: These results suggested that the investigational drug (HS00098) can effectively reduce body weight, blood lipid and blood sugar levels of diet-induced obese rhesus monkeys.
文摘Obesity is a global pandemic that has been threatening the worldwide population.It has been reported to be associated with an increase in the risk of chronic diseases such as type 2 diabetes mellitus(T2DM),cardiovascular disease,and other diseases,including some malignancies.Currently,the first line of management includes lifestyle modifications.However,recently,bariatric surgeries were introduced to combat obesity.The previous modalities of management are always challenging since lifestyle could have limited long-term effectiveness and difficulty to achieve,and surgeries are invasive and also require a lifestyle modification and commitment.Glucagon-like peptide-1 receptor agonists(GLP-1RAs)were initially introduced as a rising star for managing T2DM,with patients benefiting from the control of blood sugar and weight loss.These medications work by enhancing feelings of fullness,slowing down digestion,and ultimately reducing calorie intake.However,GLP-1RAs are not without side effects and have some costs.Common side effects include gastrointestinal(GI)adverse events such as nausea,vomiting,diarrhea,and a lack of GI motility,which is the main mechanism through which the drug induces a feeling of fullness and promotes weight loss,potentially resulting in treatment discontinuation.More serious,though less frequent,risks include pancreatitis,gallbladder diseases,and,rarely,thyroid Ccell cancers.This review aimed to discuss the globally emerging role of GLP-1RAs in obesity management and highlight some safety considerations for patients taking these drugs.
文摘Glucagon-like peptide-1 (GLP-1) and its receptor agonists (GLP-1RAs) are wellestablishedtherapies for metabolic conditions such as type 2 diabetes and obesitydue to their ability to enhance insulin secretion, promote weight loss, and regulateblood glucose levels. Emerging evidence, however, indicates that GLP-1RAs mayalso have therapeutic potential in inflammatory and autoimmune conditions. Thisreview explores the evolving role of GLP-1RAs in managing rheumatic diseases,including osteoarthritis, rheumatoid arthritis, psoriatic arthritis, and systemiclupus erythematosus. Studies suggest that GLP-1RAs reduce inflammation bymodulating immune cell activity, increasing anti-inflammatory cytokine production,shifting macrophage polarization toward an anti-inflammatory phenotype,and enhancing regulatory T-cell function to maintain immune homeostasis. Theseimmunomodulatory effects point toward a promising adjunctive strategy incurrent clinical practice for patients with rheumatic diseases, particularly thosewith metabolic comorbidities. Further clinical trials are warranted to validatethese findings, clarify underlying mechanisms, and assess long-term safety,ultimately paving the way for novel treatment approaches in rheumatology.
文摘BACKGROUND Atrial fibrillation(AF)stands as the most prevalent type of arrhythmia,affecting approximately 60 million individuals world-wide.Although antiarrhythmic drugs(AADs)remain the gold standard for AF treatment,glucagon-like peptide-1 receptor agonists(GLP-1 RAs)are arising as potential therapeutic alternatives.AIM To evaluate the impact of GLP-1 RAs on the incidence of AF.METHODS Inclusion criteria included systematic reviews(SRs)that based their analyses on clinical trials,observational studies,controlled trials and network meta-analyses.A total of 8 SRs were selected for data extraction,focusing on semaglutide,liraglutide and dulaglutide.Additionally,the effects of GLP-1 RAs on AF incidence were compared with those of sodium-glucose co-transporter 2(SGLT2)inhibitors.RESULTS Findings indicate that semaglutide,evaluated in the largest patient cohort across the 8 SRs,consistently reduced AF incidence.However,dulaglutide and liraglutide exhibited inconsistent effects.Notably,as opposed to variable outcomes associated with GLP-1 RAs,SGLT2 inhibitors a class of antidiabetic agents with weight-reducing properties exhibit significant cardiovascular benefits,including reductions in both AF and atrial flutter.CONCLUSION GLP-1 RAs emerge as a promising and potential alternative for AADs in reduction of incidence of AF.However,further research is required to fully determine their therapeutic potential and long-term cardiovascular effects.
文摘BACKGROUND Glucagon-like peptide-1 receptor agonists(GLP-1RAs)are increasingly being used to treat type 2 diabetes mellitus(T2DM)and obesity.Although GLP-1RAs delay gastric emptying,their impact on gastric mucosal visibility during upper endoscopy remains uncertain,especially in Asian patients.AIM To investigate the association between GLP-1RA treatment and gastric mucosal visibility during upper endoscopy in Asian patients with T2DM.METHODS The study population included Korean patients who underwent esophagogastroduodenoscopy(EGD)with concomitant GLP-1RA or dipeptidyl peptidase 4 inhibitor(DPP4i)for the treatment of T2DM.A 1:2 propensity score matching between GLP-1RA and DPP4i users resulted in 198 matched patients and 295 matched patients in each group,respectively.Gastric mucosal visibility was assessed by reviewing endoscopy images with a validated scale(POLPREP).In addition,the rates of aborted and repeat EGD and pulmonary aspiration were also assessed.RESULTS Of the 493 matched patients,mean body mass index was 26.0 kg/m^(2).The rate of inadequate gastric mucosal visibility(gastric POLPREP score 0 or 1)was significantly higher in GLP-1RA group than matched DPP4i group(8.6%vs 1.4%,P=0.0007).The rates of aborted EGD and repeat EGD were also significantly higher in GLP-1RA than DPP4i group(7.6%vs 0.7%in both aborted and repeat EGD,P=0.0011).Multivariable logistic regression revealed GLP-1RA use as an independent risk factor for both inadequate gastric mucosal visibility(odds ratio=6.143,95%confidence interval:2.289,20.318,P=0.0008)and aborted EGD(odds ratio=11.099,95%confidence interval:3.172,63.760,P=0.0010).Despite gastric residue,no pulmonary aspiration was reported in either group.CONCLUSION GLP-1RA use was associated with a higher risk of inadequate gastric mucosal visibility and aborted and repeat procedures during upper gastrointestinal endoscopy in Korean patients with T2DM while pulmonary aspiration was not observed.
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.
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the financial support by Hong Kong Research Grants Council(No.T12-101/23-N)National Natural Science Foundation of China(No.22206160)。
文摘Type 2 diabetes mellitus(T2DM)is one of the most prevalent chronic metabolic disorder characterized by insulin resistance and relative insulin deficiency.PPARδactivation has been reported to have several beneficial effects in alleviating dyslipidemia and insulin resistance.GW501516,a synthetic PPARδagonist,was developed to target hyperlipidemia and reported to alleviating insulin resistance in T2DM.Studies indicate that PPARδactivation by GW501516 can reduce adiposity,enhanceβ-oxidation of fatty acids,and improve insulin sensitivity in T2DM animal models.Despite its therapeutic promise,potential carcinogenic effects also have been reported.Therefore,a comprehensive non-targeted and targeted lipidomics study was carried out to evaluate the regulatory effect of GW501516 in the plasma of db/db mice.The results revealed that GW501516 is effective in reducing the accumulation of lipids in the fatty acid metabolism pathway and lipid classes including triglycerides and phosphatidylglycerols.Furthermore,activation of PPARδby GW501516 demonstrated a beneficial effect on improving circulating cholesterol homeostasis.However,while the levels of hexosylceramides and sphingomyelin were partially reversed,ceramide levels,which are negatively associated with insulin sensitivity,were significantly elevated by GW501516.Despite these mixed outcomes,the study highlights both the promising therapeutic potential of PPARδactivation in metabolic disorders and the safety concerns regarding long-term clinical use.The findings provide valuable insights into the impact of GW501516-induced PPARδactivation on lipid metabolism in T2DM,contributing to a better understanding of its therapeutic potential and risks.
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD)is a highly prevalent liver pathology in need of novel pharmacological treatments to complement lifestyle-based interventions.Nuclear receptor agonists have been under scrutiny as potential pharmacological targets and as of today,resmetirom,a thyroid hormone receptor b agonist,is the only approved agent.The dual PPARαandδagonist elafibranor has also undergone extensive clinical testing,which reached the phase III clinical trial but failed to demonstrate a beneficial effect on MASLD.As alcohol-associated liver disease and MASLD can be interconnected,whether elafibranor might be affective against liver disease caused by alcohol consumption is worth investigating.Writing recently in the World Journal of Gastroenterology,Koizumi et al reported using a mouse model of alcoholassociated liver disease and found that hepatic steatosis,liver fibrosis,and hepatocyte apoptosis were alleviated by administration of elafibranor.Although preclinical in nature,these data support the potential beneficial action of elafibranor in alcohol-induced MASLD,warranting the testing of this molecule in patients with steatotic liver disease caused by alcohol consumption.
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.
文摘Aim: We aimed to investigate whether the agonists for liver X receptor (LXR) ameliorate lupus-like phenotypes in mice mediated by the clearance of apoptotic cells, and compare with peroxisome proliferator-activated receptor (PPAR) γ plus PPARδ agonists, which also facilitate the clearance of apoptotic cells and exert anti-inflammatory effects in systemic lupus erythematosus (SLE). Methods: We investigated the efficacy of LXR agonist (GW3965) or dual treatment of PPARγ (pioglitazone) and PPARδ (GW0742) agonists in SLE animal models, female MRL/MpJ-Fas/J mice and BALB/cAJcl mice treated with pristane. The data were analyzed with one-way analysis of variance and Tukey’s honestly significant difference tests. Results: The treatment with LXR or PPARγ/δ agonists did not significantly alter the swelling of lymph nodes, ds-DNA production, albuminuria, histological score of glomerular lesions, and mRNA expression of target genes including Abca1, C1qa, Icam1, Mertk and Tnf. Conclusion: LXR or PPARγ/δ agonists targeting the impaired clearance for apoptosis cells may not be efficient in the remission induction therapy in SLE.
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.
文摘Introduction Nonarteritic anterior ischemic optic neuropathy(NAION)is the most common acute optic neuropathy in patients over the age of 50 years(1).It is characterized by acute,painless vision loss in one eye which is often noticed upon awakening.Commonly,there is an altitudinal visual field defect,though this can be variable(1).
文摘Background and Objective:Idiopathic intracranial hypertension(IIH)is a disorder of raised intracranial pressure(ICP)associated with overweight and obesity,with weight loss being the mainstay of management.Diet and lifestyle changes alone are often unsuccessful at achieving meaningful or sustained weight loss.Glucagon-like peptide-1 receptor agonists(GLP-1RA)are a class of medications developed for the treatment of diabetes but are also highly effective for weight reduction.The objective of this narrative review is to present the current evidence for GLP-1RAs in the management of IIH.Methods:Articles were searched for inclusion through OVID using the following terms:[papilledema OR intracranial hypertension OR idiopathic intracranial hypertension OR brain pseudotumor]and[glucagon like peptide 1 OR glucagon like peptide 1 receptor agonist OR semaglutide OR exendin 4 OR liraglutide OR tirzepatide].Titles and abstracts were screened manually for relevance.There were no exclusion criteria for time frame,language,population or article type,although conference abstracts were not included.An illustrative case of a patient with IIH treated with tirzepatide and semaglutide is also presented.Key Content and Findings:GLP-1RAs have demonstrated the potential for significantly greater weight loss in patients with IIH,with a reduced requirement for IIH medications and improved symptoms,compared to conventional weight management.Treatment with GLP-1RAs has also been shown to result in a rapid and persistent reduction in ICP in both rat and human studies.The side effects of GLP-1RAs are generally well-tolerated,with low rates of discontinuation in clinical trials.However,continuous treatment is likely required to avoid weight rebound and symptom recurrence after cessation.Conclusions:Despite highly promising preliminary evidence,further clinical trials are needed to determine the most effective GLP-1RA medications within this class,appropriate dosing regimens and treatment duration.
文摘Debates regarding the specific effects of general anesthesia on developing brains have persisted for over 30 years.A consensus has been reached that prolonged,repeated,high-dose exposure to anesthetics is associated with a higher incidence of deficits in behavior and executive function,while single exposure has a relatively minor effect on long-term neurological function.In this review,we summarize the dose-dependent neuroprotective or neurotoxic effects of gamma-aminobutyric acid type A receptor agonists,a representative group of sedatives,on developing brains or central nervous system diseases.Most preclinical research indicates that anesthetics have neurotoxic effects on the developing brain through various signal pathways.However,recent studies on low-dose anesthetics suggest that they may promote neurodevelopment during this critical period.These findings are incomprehensible for the general“dose-effect”principles of pharmacological research,which has attracted researchers'interest and led to the following questions:What is the threshold for the dual effects exerted by anesthetics such as propofol and sevoflurane on the developing brain?To what extent can their protective effects be maximized?What are the underlying mechanisms involved in these effects?Consequently,this issue has essentially become a“mathematical problem.”After summarizing the dose-dependent effects of gamma-aminobutyric acid type A receptor agonist sedatives in both the developing brain and the brains of patients with central nervous system diseases,we believe that all such anesthetics exhibit specific threshold effects unique to each drug.These effects range from neuroprotection to neurotoxicity,depending on different brain functional states.However,the exact values of the specific thresholds for different drugs in various brain states,as well as the underlying mechanisms explaining why these thresholds exist,remain unclear.Further in-depth exploration of these issues could significantly enhance the therapeutic translational value of these anesthetics.
基金financial support fromthe Chung Shan Medical University Hospital,Taiwan(CSH-2022-A-009).
文摘Background:To determine whether initiating a glucagon-like peptide-1 receptor agonist(GLP-1 RA)within 3 months of type 2 diabetes(T2DM)diagnosis alters the subsequent risk of overall and site-specific cancer and whether this association differs by baseline body-mass index(BMI).Methods:This retrospective cohort study used electronic health records from the TriNetX U.S.research network.Adults aged 20 years or older diagnosed with T2DM between 2016 and 2024 were included if they received any hypoglycemic agents within 3 months before and after diagnosis.Following 1:1 propensity score matching,both the GLP-1 RA user and non-user groups included 183,264 patients.The study outcome was defined as a diagnosis of malignant neoplasms.Hazard ratios(HRs)for overall and site-specific cancer risk were estimated using Cox proportional hazards models.Kaplan–Meier analysis and stratified analysis by BMI were performed.Results:Early GLP-1 RA use demonstrated a modest but significant association with reduced overall cancer risk(HR 0.93;95%CI:0.90–0.96).Reduced risks were noted for cancers of the digestive(HR 0.81),respiratory(HR 0.66),and female genital(HR 0.87)systems.In stratified analysis,benefits were more pronounced in patients with BMI≥30,particularly for pancreatic and colorectal cancers.Conclusion:Early initiation of GLP-1 receptor agonists in patients with diagnosed T2DM was associated with a modest reduction in overall cancer risk,particularly among individuals with obesity.These findings highlight the dual metabolic and oncologic value of prompt GLP-1 RA therapy.
