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
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
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
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)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 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
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 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 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
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
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
Toll-like receptor 7 （TLR7）, the best known TLRs, has been demonstrated to be useful in fighting against infectious disease. In our study, three-dimensional （3D） pharmacophore models were constructed from a set of...Toll-like receptor 7 （TLR7）, the best known TLRs, has been demonstrated to be useful in fighting against infectious disease. In our study, three-dimensional （3D） pharmacophore models were constructed from a set of 5 TLR7 agonists. Among the 10 common-featured models generated by program Discovery Studio/HipHop, a hypothesis （Hypo2） including one hydrogen-bond donor （D）, one hydrogen-bond acceptor （A）, and two hydrophobic （H） features was considered to be important in evaluating the ligands with TLR7 agonistic activity. The obtained pharmacophore model was further validated using a set of test molecules and the Catalyst TLR7-agonist-subset database. Hypo2 has been shown to identify a range of highly potent TLR7 agonists. Finally, the obtained pharmacophore was further validated using docking studies. Taken together, this model can be utilized as a guide for future studies to design the structurally novel TLR7 agonists.展开更多
Alzheimer's disease is the primary cause of dementia and imposes a significant socioeconomic burden globally.Physical exercise,as an effective strategy for improving general health,has been largely reported for it...Alzheimer's disease is the primary cause of dementia and imposes a significant socioeconomic burden globally.Physical exercise,as an effective strategy for improving general health,has been largely reported for its effectiveness in slowing neurodegeneration and increasing brain functional plasticity,particularly in aging brains.However,the underlying mechanisms of exercise in cognitive aging remain largely unclear.Adiponectin,a cell-secreted protein hormone,has recently been found to regulate synaptic plasticity and mediate the antidepressant effects of physical exercise.Studies on the neuroprotective effects of adiponectin have revealed potential innovative treatments for Alzheimer's disease.Here,we reviewed the functions of adiponectin and its receptor in the brains of human and animal models of cognitive impairment.We summarized the role of adiponectin in Alzheimer's disease,focusing on its impact on energy metabolism,insulin resistance,and inflammation.We also discuss how exercise increases adiponectin secretion and its potential benefits for learning and memory.Finally,we highlight the latest research on chemical compounds that mimic exerciseenhanced secretion of adiponectin and its receptor in Alzheimer's disease.展开更多
Peroxisome proliferator-activated receptor alpha is a member of the nuclear hormone receptor superfamily and functions as a transcription factor involved in regulating cellular metabolism.Previous studies have shown t...Peroxisome proliferator-activated receptor alpha is a member of the nuclear hormone receptor superfamily and functions as a transcription factor involved in regulating cellular metabolism.Previous studies have shown that PPARαplays a key role in the onset and progression of neurodegenerative diseases.Consequently,peroxisome proliferator-activated receptor alpha agonists have garnered increasing attention as potential treatments for neurological disorders.This review aims to clarify the research progress regarding peroxisome proliferator-activated receptor alpha in nervous system diseases.Peroxisome proliferator-activated receptor alpha is present in all cell types within adult mouse and adult neural tissues.Although it is conventionally believed to be primarily localized in the nucleus,its function may be regulated by a dynamic balance between cytoplasmic and nuclear shuttling.Both endogenous and exogenous peroxisome proliferator-activated receptor alpha agonists bind to the peroxisome proliferator-activated response element to exert their biological effects.Peroxisome proliferator-activated receptor alpha plays a significant therapeutic role in neurodegenerative diseases.For instance,peroxisome proliferator-activated receptor alpha agonist gemfibrozil has been shown to reduce levels of soluble and insoluble amyloid-beta in the hippocampus of Alzheimer's disease mouse models through the autophagy-lysosomal pathway.Additionally,peroxisome proliferator-activated receptor alpha is essential for the normal development and functional maintenance of the substantia nigra,and it can mitigate motor dysfunction in Parkinson's disease mouse models.Furthermore,peroxisome proliferator-activated receptor alpha has been found to reduce neuroinflammation and oxidative stress in various neurological diseases.In summary,peroxisome proliferator-activated receptor alpha plays a crucial role in the onset and progression of multiple nervous system diseases,and peroxisome proliferator-activated receptor alpha agonists hold promise as new therapeutic agents for the treatment of neurodegenerative diseases,providing new options for patient care.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
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
Lysophosphatidic acid(LPA)is a pleiotropic lipid agonist essential for functions of the central nervous system(CNS).It is abundant in the developing and adult brain while its concentration in biological fluids,includi...Lysophosphatidic acid(LPA)is a pleiotropic lipid agonist essential for functions of the central nervous system(CNS).It is abundant in the developing and adult brain while its concentration in biological fluids,including cerebrospinal fluid,varies significantly(Figure 1Α;Yung et al.,2014).LPA actually corresponds to a variety of lipid species that include different stereoisomers with either saturated or unsaturated fatty acids bearing likely differentiated biological activities(Figure 1Α;Yung et al.,2014;Hernández-Araiza et al.,2018).展开更多
Neural machine interface technology is a pioneering approach that aims to address the complex challenges of neurological dysfunctions and disabilities resulting from conditions such as congenital disorders,traumatic i...Neural machine interface technology is a pioneering approach that aims to address the complex challenges of neurological dysfunctions and disabilities resulting from conditions such as congenital disorders,traumatic injuries,and neurological diseases.Neural machine interface technology establishes direct connections with the brain or peripheral nervous system to restore impaired motor,sensory,and cognitive functions,significantly improving patients'quality of life.This review analyzes the chronological development and integration of various neural machine interface technologies,including regenerative peripheral nerve interfaces,targeted muscle and sensory reinnervation,agonist–antagonist myoneural interfaces,and brain–machine interfaces.Recent advancements in flexible electronics and bioengineering have led to the development of more biocompatible and highresolution electrodes,which enhance the performance and longevity of neural machine interface technology.However,significant challenges remain,such as signal interference,fibrous tissue encapsulation,and the need for precise anatomical localization and reconstruction.The integration of advanced signal processing algorithms,particularly those utilizing artificial intelligence and machine learning,has the potential to improve the accuracy and reliability of neural signal interpretation,which will make neural machine interface technologies more intuitive and effective.These technologies have broad,impactful clinical applications,ranging from motor restoration and sensory feedback in prosthetics to neurological disorder treatment and neurorehabilitation.This review suggests that multidisciplinary collaboration will play a critical role in advancing neural machine interface technologies by combining insights from biomedical engineering,clinical surgery,and neuroengineering to develop more sophisticated and reliable interfaces.By addressing existing limitations and exploring new technological frontiers,neural machine interface technologies have the potential to revolutionize neuroprosthetics and neurorehabilitation,promising enhanced mobility,independence,and quality of life for individuals with neurological impairments.By leveraging detailed anatomical knowledge and integrating cutting-edge neuroengineering principles,researchers and clinicians can push the boundaries of what is possible and create increasingly sophisticated and long-lasting prosthetic devices that provide sustained benefits for users.展开更多
Human nAChR u7 is the potential target for schizophrenia cognitive disorders, and it is meaningful to develop selective human nAChR α7 agonists for the clinical treatment of the disease. Because the crystal structure...Human nAChR u7 is the potential target for schizophrenia cognitive disorders, and it is meaningful to develop selective human nAChR α7 agonists for the clinical treatment of the disease. Because the crystal structure ofα7 receptor has not been resolved, ligand-based drug design strategy was took in this work. A 3D QSAR pharmacophore model was built by HypoGen method, and its quality was evaluated by cost function. Furthermore, the pharmacophore model was validated with activity prediction of test set and was cross-validated based on Fisher＇s Randomization Method. By Enrichment Factor and AU-ROC analysis, the final pharmacophore, which is consisted of one HBA, two Hydrophobic and one PosIonizable, was selected and it fitted well with the docking result of α7 homology model and the ligand. The pharmacophore is expected for the following virtual screening and lead optimization of human nAChR α7 agonists, which is important for the development and discovery of novel antipsychotics.展开更多
Glucagon-like peptide1 (GLP-1) is secreted from Langerhans cells in response to oral nutrient intake. Glucagon- like peptide-1 receptor agonists (GLP-1RAs) are a new class of incretin-based anti-diabetic drugs. They f...Glucagon-like peptide1 (GLP-1) is secreted from Langerhans cells in response to oral nutrient intake. Glucagon- like peptide-1 receptor agonists (GLP-1RAs) are a new class of incretin-based anti-diabetic drugs. They function to stimulate insulin secretion while suppressing glucagon secretion. GLP-1-based therapies are now well established in the management of type 2 diabetes mellitus (T2DM), and recent literature has suggested potential applications of these drugs in the treatment of obesity and for protection against cardiovascular and neurological diseases. As we know, along with change in lifestyles, the prevalence of non-alcoholic fatty liver disease (NAFLD) in China is rising more than that of viral hepatitis and alcoholic fatty liver disease, and NAFLD has become the most common chronic liver disease in recent years. Recent studies further suggest that GLP-1RAs can reduce transaminase levels to improve NAFLD by improving blood lipid levels, cutting down the fat content to promote fat redistribution, directly decreasing fatty degeneration of the liver, reducing the degree of liver fibrosis and improving inflammation. This review shows the NAFLD-associated effects of GLP-1RAs in animal models and in patients with T2DM or obesity who are participants in clinical trials. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.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)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.
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.
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).
基金supported by the National Natural Science Foundation of China(Grant No.20902068)Natural Science Foundation of Inner Mongolia Autonomous Region,China(Grant No.2011BS1201)+1 种基金Program for Young Talents of ScienceTechnology in Universities of Inner Mongolia Autonomous Region,China
文摘Toll-like receptor 7 （TLR7）, the best known TLRs, has been demonstrated to be useful in fighting against infectious disease. In our study, three-dimensional （3D） pharmacophore models were constructed from a set of 5 TLR7 agonists. Among the 10 common-featured models generated by program Discovery Studio/HipHop, a hypothesis （Hypo2） including one hydrogen-bond donor （D）, one hydrogen-bond acceptor （A）, and two hydrophobic （H） features was considered to be important in evaluating the ligands with TLR7 agonistic activity. The obtained pharmacophore model was further validated using a set of test molecules and the Catalyst TLR7-agonist-subset database. Hypo2 has been shown to identify a range of highly potent TLR7 agonists. Finally, the obtained pharmacophore was further validated using docking studies. Taken together, this model can be utilized as a guide for future studies to design the structurally novel TLR7 agonists.
基金supported by the National Natural Science Foundation of China,No.82072529(to HWHT)Key Laboratory of Guangdong Higher Education Institutes,No.2021KSYS009(to HWHT)the China Postdoctoral Science Foundation,No.2022M720907(to HHG)。
文摘Alzheimer's disease is the primary cause of dementia and imposes a significant socioeconomic burden globally.Physical exercise,as an effective strategy for improving general health,has been largely reported for its effectiveness in slowing neurodegeneration and increasing brain functional plasticity,particularly in aging brains.However,the underlying mechanisms of exercise in cognitive aging remain largely unclear.Adiponectin,a cell-secreted protein hormone,has recently been found to regulate synaptic plasticity and mediate the antidepressant effects of physical exercise.Studies on the neuroprotective effects of adiponectin have revealed potential innovative treatments for Alzheimer's disease.Here,we reviewed the functions of adiponectin and its receptor in the brains of human and animal models of cognitive impairment.We summarized the role of adiponectin in Alzheimer's disease,focusing on its impact on energy metabolism,insulin resistance,and inflammation.We also discuss how exercise increases adiponectin secretion and its potential benefits for learning and memory.Finally,we highlight the latest research on chemical compounds that mimic exerciseenhanced secretion of adiponectin and its receptor in Alzheimer's disease.
基金supported by grants from Tianjin Scientific Research Project in Key Areas of Traditional Chinese Medicine,Tianjin Municipal Health Commission,No.2024012(to JL)Tianjin Municipal Education Commission Project,No.2021KJ217(to CS)。
文摘Peroxisome proliferator-activated receptor alpha is a member of the nuclear hormone receptor superfamily and functions as a transcription factor involved in regulating cellular metabolism.Previous studies have shown that PPARαplays a key role in the onset and progression of neurodegenerative diseases.Consequently,peroxisome proliferator-activated receptor alpha agonists have garnered increasing attention as potential treatments for neurological disorders.This review aims to clarify the research progress regarding peroxisome proliferator-activated receptor alpha in nervous system diseases.Peroxisome proliferator-activated receptor alpha is present in all cell types within adult mouse and adult neural tissues.Although it is conventionally believed to be primarily localized in the nucleus,its function may be regulated by a dynamic balance between cytoplasmic and nuclear shuttling.Both endogenous and exogenous peroxisome proliferator-activated receptor alpha agonists bind to the peroxisome proliferator-activated response element to exert their biological effects.Peroxisome proliferator-activated receptor alpha plays a significant therapeutic role in neurodegenerative diseases.For instance,peroxisome proliferator-activated receptor alpha agonist gemfibrozil has been shown to reduce levels of soluble and insoluble amyloid-beta in the hippocampus of Alzheimer's disease mouse models through the autophagy-lysosomal pathway.Additionally,peroxisome proliferator-activated receptor alpha is essential for the normal development and functional maintenance of the substantia nigra,and it can mitigate motor dysfunction in Parkinson's disease mouse models.Furthermore,peroxisome proliferator-activated receptor alpha has been found to reduce neuroinflammation and oxidative stress in various neurological diseases.In summary,peroxisome proliferator-activated receptor alpha plays a crucial role in the onset and progression of multiple nervous system diseases,and peroxisome proliferator-activated receptor alpha agonists hold promise as new therapeutic agents for the treatment of neurodegenerative diseases,providing new options for patient care.
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.
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supported by the Hellenic Foundation for Research and Innovation,HFRI,“2nd Call for HFRI Research Projects to support Faculty Members&Researchers”Project 02667 to GL.
文摘Lysophosphatidic acid(LPA)is a pleiotropic lipid agonist essential for functions of the central nervous system(CNS).It is abundant in the developing and adult brain while its concentration in biological fluids,including cerebrospinal fluid,varies significantly(Figure 1Α;Yung et al.,2014).LPA actually corresponds to a variety of lipid species that include different stereoisomers with either saturated or unsaturated fatty acids bearing likely differentiated biological activities(Figure 1Α;Yung et al.,2014;Hernández-Araiza et al.,2018).
基金supported in part by the National Natural Science Foundation of China,Nos.81927804(to GL),82260456(to LY),U21A20479(to LY)Science and Technology Planning Project of Shenzhen,No.JCYJ20230807140559047(to LY)+3 种基金Key-Area Research and Development Program of Guangdong Province,No.2020B0909020004(to GL)Guangdong Basic and Applied Research Foundation,No.2023A1515011478(to LY)the Science and Technology Program of Guangdong Province,No.2022A0505090007(to GL)Ministry of Science and Technology,Shenzhen,No.QN2022032013L(to LY)。
文摘Neural machine interface technology is a pioneering approach that aims to address the complex challenges of neurological dysfunctions and disabilities resulting from conditions such as congenital disorders,traumatic injuries,and neurological diseases.Neural machine interface technology establishes direct connections with the brain or peripheral nervous system to restore impaired motor,sensory,and cognitive functions,significantly improving patients'quality of life.This review analyzes the chronological development and integration of various neural machine interface technologies,including regenerative peripheral nerve interfaces,targeted muscle and sensory reinnervation,agonist–antagonist myoneural interfaces,and brain–machine interfaces.Recent advancements in flexible electronics and bioengineering have led to the development of more biocompatible and highresolution electrodes,which enhance the performance and longevity of neural machine interface technology.However,significant challenges remain,such as signal interference,fibrous tissue encapsulation,and the need for precise anatomical localization and reconstruction.The integration of advanced signal processing algorithms,particularly those utilizing artificial intelligence and machine learning,has the potential to improve the accuracy and reliability of neural signal interpretation,which will make neural machine interface technologies more intuitive and effective.These technologies have broad,impactful clinical applications,ranging from motor restoration and sensory feedback in prosthetics to neurological disorder treatment and neurorehabilitation.This review suggests that multidisciplinary collaboration will play a critical role in advancing neural machine interface technologies by combining insights from biomedical engineering,clinical surgery,and neuroengineering to develop more sophisticated and reliable interfaces.By addressing existing limitations and exploring new technological frontiers,neural machine interface technologies have the potential to revolutionize neuroprosthetics and neurorehabilitation,promising enhanced mobility,independence,and quality of life for individuals with neurological impairments.By leveraging detailed anatomical knowledge and integrating cutting-edge neuroengineering principles,researchers and clinicians can push the boundaries of what is possible and create increasingly sophisticated and long-lasting prosthetic devices that provide sustained benefits for users.
基金National Natural Science Foundation of China(Grant No.81373272)
文摘Human nAChR u7 is the potential target for schizophrenia cognitive disorders, and it is meaningful to develop selective human nAChR α7 agonists for the clinical treatment of the disease. Because the crystal structure ofα7 receptor has not been resolved, ligand-based drug design strategy was took in this work. A 3D QSAR pharmacophore model was built by HypoGen method, and its quality was evaluated by cost function. Furthermore, the pharmacophore model was validated with activity prediction of test set and was cross-validated based on Fisher＇s Randomization Method. By Enrichment Factor and AU-ROC analysis, the final pharmacophore, which is consisted of one HBA, two Hydrophobic and one PosIonizable, was selected and it fitted well with the docking result of α7 homology model and the ligand. The pharmacophore is expected for the following virtual screening and lead optimization of human nAChR α7 agonists, which is important for the development and discovery of novel antipsychotics.
文摘Glucagon-like peptide1 (GLP-1) is secreted from Langerhans cells in response to oral nutrient intake. Glucagon- like peptide-1 receptor agonists (GLP-1RAs) are a new class of incretin-based anti-diabetic drugs. They function to stimulate insulin secretion while suppressing glucagon secretion. GLP-1-based therapies are now well established in the management of type 2 diabetes mellitus (T2DM), and recent literature has suggested potential applications of these drugs in the treatment of obesity and for protection against cardiovascular and neurological diseases. As we know, along with change in lifestyles, the prevalence of non-alcoholic fatty liver disease (NAFLD) in China is rising more than that of viral hepatitis and alcoholic fatty liver disease, and NAFLD has become the most common chronic liver disease in recent years. Recent studies further suggest that GLP-1RAs can reduce transaminase levels to improve NAFLD by improving blood lipid levels, cutting down the fat content to promote fat redistribution, directly decreasing fatty degeneration of the liver, reducing the degree of liver fibrosis and improving inflammation. This review shows the NAFLD-associated effects of GLP-1RAs in animal models and in patients with T2DM or obesity who are participants in clinical trials. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.
