Selection against hybridization can cause mating traits to diverge between species in sympatry via reproductive character displacement （RCD）. Additionally, selection against interspecific fighting can cause aggressi...Selection against hybridization can cause mating traits to diverge between species in sympatry via reproductive character displacement （RCD）. Additionally, selection against interspecific fighting can cause aggressive traits to diverge between sympatric species via agonistic character displacement （ACD）. By directly affecting conspecific recognition traits, RCD and ACD between species can also incidentally cause divergence in mating and fighting traits among populations within a species [termed cascade RCD （CRCD） and cascade ACD]. Here, we demonstrate patterns consistent with male-driven RCD and ACD in 2 groups of darters （orangethroat darter clade Ceasia and rainbow darter Etheostoma caeruleum）. In both groups, males that occur in sympatry （between Ceasia and E. caeruleum） have higher levels of preference for mating and fighting with conspecifics over heterospecifics than do males from allopatry. This is consistent with RCD and ACD. We also found patterns consistent with CRCD and cascade ACD among species of Ceasia. Ceasia males that are sympatric to E. caeruleum （but allopatric to one another） also have heightened preferences for mat- ing and fighting with conspecific versus heterospecific Ceasia. In contrast, Ceasia males that are allopatric to E. caeruleum readily mate and fight with heterospecific Ceasia. We suggest that RCD and ACD between Ceasia and E. caeruleum has incidentally led to divergence in mating and fighting traits among Ceasia species. This study is unique in that male preferences evolve via both RCD （male preference for conspecific females） and ACD （male preference to fight conspecific males） which leads to subsequent divergence among allopatric lineages.展开更多
To assess the potential endocrine disruptive effects through multiple nuclear receptors （NRs）, especially non-steroidal NRs, in municipal wastewater, we examined the agonistic activities on four NRs （estrogen recep...To assess the potential endocrine disruptive effects through multiple nuclear receptors （NRs）, especially non-steroidal NRs, in municipal wastewater, we examined the agonistic activities on four NRs （estrogen receptor α, thyroid hormone receptor α, retinoic acid receptor ct and retinoid X receptor α） of untreated and treated wastewater from municipal wastewater treatment plants （WWTPs） in Japan using a yeast two-hybrid assay. Investigation of the influent and effluent of seven WWTPs revealed that agonistic activities against steroidal and non-steroidal NRs were always detected in the influents and partially remained in the effluents. Further investigation of four WWTPs employing conventional activated sludge, pseudo-anoxic-oxic, anoxic-oxic and anaerobic-anoxic-oxic processes revealed that the ability to reduce the agonistic activity against each of the four NRs varies depending on the treatment process. These results indicated that municipal wastewater in Japan commonly contains endocrine disrupting chemicals that exert agonistic activities on steroidal and non-steroidal NRs, and that some of these chemicals are released into the natural aquatic environment. Although the results obtained in yeast assays suggested that measured levels of non-steroidal NR agonists in the effluent of WWTPs were not likely to cause any biological effect, further study is required to assess their possible risks in detail.展开更多
In many species, agonistic interactions result in social relationships that are stable over time. In Syrian hamsters, two unfamiliar males that are placed together will fight vigorously and a clear winner/loser relati...In many species, agonistic interactions result in social relationships that are stable over time. In Syrian hamsters, two unfamiliar males that are placed together will fight vigorously and a clear winner/loser relationship is usually established. In subsequent interactions, the loser will flee soon after detecting the familiar winner. Here we tested the hypothesis that losing a fight with a conspecific will affect future agonistic interactions not only toward that individual （i.e., the familiar winner） but also toward unfamiliar conspecifics. To test this hypothesis we paired two Syrian hamster males in three trials on one day in which the loser had tile opportunity to escape the winner. The next day the loser was paired with an unfarniliar male, also for three trials. If he lost again, he was tested on a third day with a third unfamiliar male. Subjects were those males that were losers on all three days. The latency to escape on the first trial on Days 2 and 3 was significantly shorter than on the first trial on Day l, indicating that losing against the first male affected the response toward unfamiliar males. However, the latency to escape on the first trial on Days 2 and 3 was significantly longer than that on the third trial on the preceding day, indicating that a loser treats unfamiliar males differently than a familiar winner. These results suggest that a defeat during an interaction with one male affects later agonistic behavior towards other, unfamiliar males [Current Zoology 57 （4）： 449-452, 2011].展开更多
In comparison to studies investigating the roles of 5-HT1, 5-HT2 and 5-HT3 receptors in aggressive behaviour there is a dearth of material examining the function of 5-HT4 receptors in this behaviour. In view of this, ...In comparison to studies investigating the roles of 5-HT1, 5-HT2 and 5-HT3 receptors in aggressive behaviour there is a dearth of material examining the function of 5-HT4 receptors in this behaviour. In view of this, the current study examined the effects of the 5-HT4 receptor partial agonist RS 67333 and antagonist RS 39604 in murine agonistic behaviour. RS 67333 failed to produce any significant changes in the offensive. Significant variation in the frequency of evade behaviour was detected but this occurred between treatment groups rather than with controls. Interestingly, both the frequency and duration of stretched attend behaviour were increased by RS 67333 0.1 mg/kg, a result indicative of increased risk assessment. The administration of RS 39604 (0.01 - 1 mg/kg) produced significant variation in the fre-quency and duration of following, and aggressive grooming. Frozen crouch behaviour was also increased significantly at 0.1 mg/kg. It is concluded that since the 5-HT4 receptor ligands employed in this study produced very few significant behavioural effects across the treatment groups, 5-HT4 receptors do not play a role in the modulation of murine aggressive behaviour.展开更多
An agonistic display by a white shark was observed and photographed during a cage dive at Guadalupe Island in November 2015. Exhibiting exaggerated pectoral fin depression, agonistic behaviors have been previously obs...An agonistic display by a white shark was observed and photographed during a cage dive at Guadalupe Island in November 2015. Exhibiting exaggerated pectoral fin depression, agonistic behaviors have been previously observed and described in several shark species. This account may be the first record of a white shark in close proximity to a caged diver, exhibiting strong pectoral fin depression significantly dipped, in the mid-agonistic display. Such displays should be considered as aggressive and potentially life-threatening by those using the ocean for recreational or professional purposes.展开更多
The commercially available drug-eluting stent with limus (rapamycin, everolimus, etc.) or paclitaxel inhibits smooth muscle cell (SMC), reducing the in-stent restenosis, whereas damages endothelial cell (EC) and delay...The commercially available drug-eluting stent with limus (rapamycin, everolimus, etc.) or paclitaxel inhibits smooth muscle cell (SMC), reducing the in-stent restenosis, whereas damages endothelial cell (EC) and delays stent reendothelialization, increasing the risk of stent thrombosis (ST) and sudden cardiac death. Here we present a new strategy for promoting stent reendothelialization and preventing ST by exploring the application of precise molecular targets with EC specificity. Proteomics was used to investigate the molecular mechanism of EC injury caused by rapamycin. Endothelial protein C receptor (EPCR) was screened out as a crucial EC-specific effector. Limus and paclitaxel repressed the EPCR expression, while overexpression of EPCR protected EC from coating (eluting) drug-induced injury. Furthermore, the ligand activated protein C (APC), polypeptide TR47, and compound parmodulin 2, which activated the target EPCR, promoted EC functions and inhibited platelet or neutrophil adhesion, and enhanced rapamycin stent reendothelialization in the simulated stent environment and in vitro. In vivo, the APC/rapamycin-coating promoted reendothelialization rapidly and prevented ST more effectively than rapamycin-coating alone, in both traditional metal stents and biodegradable stents. Additionally, overexpression or activation of the target EPCR did not affect the cellular behavior of SMC or the inhibitory effect of rapamycin on SMC. In conclusion, EPCR is a promising therapeutical agonistic target for pro-reendothelialization and anti-thrombosis of eluting stent. Activation of EPCR protects against coating drugs-induced EC injury, inflammatory cell, or platelet adhesion onto the stent. The novel application formula for APC/rapamycin-combined eluting promotes stent reendothelialization and prevents ST.展开更多
CD137 (4-1BB),a member of the TNF receptor superfamily,is an inducible T cell costimulatory receptor primarily expressed on activated CD4^+ and CD8^+ T cells.Agonistic monoclonal antibodies (mAbs) against CD137 greatl...CD137 (4-1BB),a member of the TNF receptor superfamily,is an inducible T cell costimulatory receptor primarily expressed on activated CD4^+ and CD8^+ T cells.Agonistic monoclonal antibodies (mAbs) against CD137 greatly enhance T cell-mediated immune responses against many types of tumors and viruses.Surprisingly,these agonists also showed therapeutic effects in several autoimmune diseases.These findings suggest that in different disease environments,CD137 engagement with agonist mAb in vivo can diametrically modulate immune response outcomes.Therefore,CD137 agonists represent a promising immunotherapeutic approach to a wide array of disparate immune disorders.However,CD137's potency in modulating immune response necessitates caution when targeting CD137 clinically.Cellular & Molecular Immunology.2004;1(1):31-36.展开更多
The investigation of Morinda officinalis led to the isolation of twelve compounds(1-12),including three new iridoid glycosides morindallns A-C(1-3)and nine known compounds(4-12).Their structural identifications were c...The investigation of Morinda officinalis led to the isolation of twelve compounds(1-12),including three new iridoid glycosides morindallns A-C(1-3)and nine known compounds(4-12).Their structural identifications were conducted using HRMS,1D and 2D NMR,and electronic circular dichroism(ECD)spectra as well as quantum chemical computations.Compound 6 displayed the most significantly agonistic activity against farnesoid X receptor(FXR)with an EC_(50) value of 7.18 μM,and its agonistic effect was verified through the investigation of FXR downstream target genes including small heterodimer partner 1(SHP1),bile salt export pump(BSEP),and organic solute transporter subunit alpha and beta(OSTα and OSTβ).The potential interaction of compound 6 with FXR was analyzed by molecular docking and molecular dynamics stimulation,revealing that amino acid residues Leu287;Thr288,and Ser332 played a crucial role in the activation of compound 6 towards FXR.These findings suggested that compound 6 could be regarded as a potential candidate for the development of FXR agonists.展开更多
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
Type 2 diabetes mellitus and Parkinson's disease are chronic diseases linked to a growing pandemic that affects older adults and causes significant socio-economic burden.Epidemiological data supporting a close rel...Type 2 diabetes mellitus and Parkinson's disease are chronic diseases linked to a growing pandemic that affects older adults and causes significant socio-economic burden.Epidemiological data supporting a close relationship between these two aging-related diseases have resulted in the investigation of shared pathophysiological molecular mechanisms.Impaired insulin signaling in the brain has gained increasing attention during the last decade and has been suggested to contribute to the development of Parkinson's disease through the dysregulation of several pathological processes.The contribution of type 2 diabetes mellitus and insulin resistance in neurodegeneration in Parkinson's disease,with emphasis on brain insulin resistance,is extensively discussed in this article and new therapeutic strategies targeting this pathological link are presented and reviewed.展开更多
This article discusses the recent study written by Koizumi et al.Alcohol-associated liver disease(ALD)is a major cause of liver-related morbidity and mortality,which is driven by complex mechanisms,including lipid acc...This article discusses the recent study written by Koizumi et al.Alcohol-associated liver disease(ALD)is a major cause of liver-related morbidity and mortality,which is driven by complex mechanisms,including lipid accumulation,apoptosis,and inflammatory responses exacerbated by gut barrier dysfunction.The study explored the therapeutic potential of elafibranor,a dual peroxisome proliferatoractivated receptor alpha/delta agonist.In clinical trials,elafibranor has shown promise for the treatment of other liver conditions;however,its effects on ALD remain unclear.The authors’findings indicate that elafibranor significantly reduced liver fibrosis and enhanced gut barrier integrity in patients with ALD.These positive effects of elafibranor are mediated through multiple pathways.Elafibranor promotes lipid metabolism,reduces oxidative stress,and inhibits inflammatory responses by restoring gut barrier function.Specifically,it improves hepatocyte function by enhancing autophagic and antioxidant capacity,and it mitigates inflammation by suppressing the lipopolysaccharide/toll-like receptor 4/nuclear factor kappa B signaling pathway.These findings indicate that elafibranor has promising clinical applications.In addition,the study highlights elafibranor’s potential as a therapeutic agent for liver diseases,particularly ALD.This article underscores the importance of understanding the mechanistic pathways underlying ALD and suggests directions for future research aimed at elucidating the benefits and limitations of elafibranor.展开更多
Cardiovascular disease(CVD)remains one of the leading causes of mortality among adults globally,with continuously rising morbidity and mortality rates.Metabolic disorders are closely linked to various cardiovascular d...Cardiovascular disease(CVD)remains one of the leading causes of mortality among adults globally,with continuously rising morbidity and mortality rates.Metabolic disorders are closely linked to various cardiovascular diseases and play a critical role in their pathogenesis and progression,involving multifaceted mechanisms such as altered substrate utilization,mitochondrial structural and functional dysfunction,and impaired ATP synthesis and transport.In recent years,the potential role of peroxisome proliferator-activated receptors(PPARs)in cardiovascular diseases has garnered significant attention,particularly peroxisome proliferator-activated receptor alpha(PPARα),which is recognized as a highly promising therapeutic target for CVD.PPARαregulates cardiovascular physiological and pathological processes through fatty acid metabolism.As a ligand-activated receptor within the nuclear hormone receptor family,PPARαis highly expressed in multiple organs,including skeletal muscle,liver,intestine,kidney,and heart,where it governs the metabolism of diverse substrates.Functioning as a key transcription factor in maintaining metabolic homeostasis and catalyzing or regulating biochemical reactions,PPARαexerts its cardioprotective effects through multiple pathways:modulating lipid metabolism,participating in cardiac energy metabolism,enhancing insulin sensitivity,suppressing inflammatory responses,improving vascular endothelial function,and inhibiting smooth muscle cell proliferation and migration.These mechanisms collectively reduce the risk of cardiovascular disease development.Thus,PPARαplays a pivotal role in various pathological processes via mechanisms such as lipid metabolism regulation,anti-inflammatory actions,and anti-apoptotic effects.PPARαis activated by binding to natural or synthetic lipophilic ligands,including endogenous fatty acids and their derivatives(e.g.,linoleic acid,oleic acid,and arachidonic acid)as well as synthetic peroxisome proliferators.Upon ligand binding,PPARαactivates the nuclear receptor retinoid X receptor(RXR),forming a PPARα-RXR heterodimer.This heterodimer,in conjunction with coactivators,undergoes further activation and subsequently binds to peroxisome proliferator response elements(PPREs),thereby regulating the transcription of target genes critical for lipid and glucose homeostasis.Key genes include fatty acid translocase(FAT/CD36),diacylglycerol acyltransferase(DGAT),carnitine palmitoyltransferase I(CPT1),and glucose transporter(GLUT),which are primarily involved in fatty acid uptake,storage,oxidation,and glucose utilization processes.Advancing research on PPARαas a therapeutic target for cardiovascular diseases has underscored its growing clinical significance.Currently,PPARαactivators/agonists,such as fibrates(e.g.,fenofibrate and bezafibrate)and thiazolidinediones,have been extensively studied in clinical trials for CVD prevention.Traditional PPARαagonists,including fenofibrate and bezafibrate,are widely used in clinical practice to treat hypertriglyceridemia and low high-density lipoprotein cholesterol(HDL-C)levels.These fibrates enhance fatty acid metabolism in the liver and skeletal muscle by activating PPARα,and their cardioprotective effects have been validated in numerous clinical studies.Recent research highlights that fibrates improve insulin resistance,regulate lipid metabolism,correct energy metabolism imbalances,and inhibit the proliferation and migration of vascular smooth muscle and endothelial cells,thereby ameliorating pathological remodeling of the cardiovascular system and reducing blood pressure.Given the substantial attention to PPARα-targeted interventions in both basic research and clinical applications,activating PPARαmay serve as a key therapeutic strategy for managing cardiovascular conditions such as myocardial hypertrophy,atherosclerosis,ischemic cardiomyopathy,myocardial infarction,diabetic cardiomyopathy,and heart failure.This review comprehensively examines the regulatory roles of PPARαin cardiovascular diseases and evaluates its clinical application value,aiming to provide a theoretical foundation for further development and utilization of PPARα-related therapies in CVD treatment.展开更多
t OX40 is a costimulatory receptor that is expressed primarily on activated CD4+,CD8+,and regulatory T cells.The ligation of OX40 to its sole ligand OX40L potentiates T cell expansion,differentiation,and activation an...t OX40 is a costimulatory receptor that is expressed primarily on activated CD4+,CD8+,and regulatory T cells.The ligation of OX40 to its sole ligand OX40L potentiates T cell expansion,differentiation,and activation and also promotes dendritic cells to mature to enhance their cytokine production.Therefore,the use of agonistic anti-Ox40 antibodies for cancer immunotherapy has gained great interest.However,most of the agonistic anti-OX40 antibodies in the clinic are OX40L-competitive and show limited efficacy.Here,we discovered that BGB-A445,a non-ligand-competitive agonistic anti-OX40 antibody currently under clinical investigation,induced optimal T cell activation without impairing dendritic cell function.In addition,BGB-A445 dose-dependently and significantly depleted regulatory T cells in vitro and in vivo via antibody-dependent cellular cytotoxicity.In the MC38 syngeneic model established in humanized OX40 knock-in mice,BGB-A445 demonstrated robust and dose-dependent antitumor efficacy,whereas the ligand-competitive anti-Ox40 antibody showed antitumor efficacy characterized by a hook effect.Furthermore,BGB-A445 demonstrated a strong combination antitumor effect with an anti-PD-1 antibody.Taken together,our findings show that BGB-A445,which does not block OX40-OX40L interaction in contrast to clinical-stage anti-OX40 antibodies,shows superior immune-stimulating effects and antitumor efficacy and thus warrants further clinical investigation.展开更多
Anemia is a common yet often overlooked complication in patients with type 2 diabetes mellitus(T2DM),particularly those with chronic kidney disease.It significantly impacts patients'quality of life,cardiovascular ...Anemia is a common yet often overlooked complication in patients with type 2 diabetes mellitus(T2DM),particularly those with chronic kidney disease.It significantly impacts patients'quality of life,cardiovascular health,and treatment outcomes.Despite its high prevalence,current clinical guidelines lack specific recommendations for anemia prevention and management in T2DM,especially in the context of newer antidiabetic therapies.This review explores the potential of emerging antidiabetic medications,such as sodium-glucose cotransporter-2 inhibitors,glucagon-like peptide-1 receptor agonists(GLP-1 RAs),and combined GLP-1-RA/GIP to mitigate anemia risk.Early detection and management of anemia in T2DM patients are crucial for improving glycemic control,reducing cardiovascular morbidity,and enhancing overall treatment outcomes.This review underscores the need for further research to better understand the mechanisms by which these novel therapies influence anemia risk and to integrate these findings into clinical practice.展开更多
A recent article highlighted the hepatic benefits of intermittent fasting,particularly during Ramadan.However,the rising use of glucagon-like peptide-1(GLP-1)/glucose-dependent insulinotropic polypeptide(GIP)receptor ...A recent article highlighted the hepatic benefits of intermittent fasting,particularly during Ramadan.However,the rising use of glucagon-like peptide-1(GLP-1)/glucose-dependent insulinotropic polypeptide(GIP)receptor agonists(RAs)is altering public behavior,leading to decreased interest in diet and exercise.With a focus on hepatic health,we analyzed global search trends using Google Trends™data from January 1,2022 to December 31,2024,focusing on the keywords"fasting","intermittent fasting","diet","nutrition","liver",Semaglutide("Ozempic"™,the most widely known GLP-1 RA)and Tirzepatide("Mounjaro"™,a newer dual GLP-1 and GIP RA).Search interest for"intermittent fasting"and"diet"showed a significant decline over time(Spearman's rho:-0.582 and-0.605,respectively,both P<0.001),while interest in"fasting"and"nutrition"remained stable.Search interest for Semaglutide,Tirzepatide,"fasting and liver","diet and liver"and Semaglutide and"liver"increased(Spearman's rho:+0.914,+0.936,+0.369,+0.297 and+0.808,respectively,all P<0.001).These findings suggest a trend of shifting away from traditional dieting toward broader health concerns,likely influenced by the increasing use of GLP-1/GIP RAs.展开更多
The cyclic guanosine monophosphate-adenosine monophosphate synthase and the stimulator of interferon genes(cGAS-STING)has emerged as a promising target for cancer immunotherapy.However,the development of natural STING...The cyclic guanosine monophosphate-adenosine monophosphate synthase and the stimulator of interferon genes(cGAS-STING)has emerged as a promising target for cancer immunotherapy.However,the development of natural STING agonists is impeded by several challenges,including limited biostability,poor pharmacokinetics,and inefficient cytosolic delivery.Herein,we meticulously designed a doublelayer polyethylenimine(PEI)modified nanoscale covalent organic polymer(CPGP)for efficient delivery of 23cyclic guanosine monophosphate-adenosine monophosphate(cGAMP),a natural STING agonist.The double-layer PEI structured CPGP enhanced both the loading capacity and stability of cGAMP.Furthermore,CPGP improved the intracellular delivery efficiency and amplified the activation of STING pathway for the secretion of type-I interferon and pro-inflammatory cytokines.In contrast,single-layered nanoparticles failed to permit stable loading and intracellular delivery of cGAMP for immune response.The nano-STING agonist also mitigated the immunosuppressive tumor microenvironment(TME)by reducing regulatory T cells and polarizing M2 macrophages to the M1 phenotype,thereby creating an immune-supportive TME to enhance adaptive immune responses.The combination of CPGP and immune checkpoint blockers showed synergistic effect,further enhancing the inhibition effect on tumor growth.This double-layer PEI modified CPGP may offer a generalizable platform for other natural dinucleotide STING agonists to overcome the cascade delivery barriers,augmenting immune activation for tumor immunotherapy.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
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
基金This work was supported by the Cooperative State Research, Education, and Extension Service, US Department of Agriculture, under project number ILLU 875-952, the National Science Foundation （DEB 0953716 and IOS 1701676）, and the University of IlLinois. The treatment of animals was approved by the Institutional Animal Care and Use Committee under protocol No. 14097.
文摘Selection against hybridization can cause mating traits to diverge between species in sympatry via reproductive character displacement （RCD）. Additionally, selection against interspecific fighting can cause aggressive traits to diverge between sympatric species via agonistic character displacement （ACD）. By directly affecting conspecific recognition traits, RCD and ACD between species can also incidentally cause divergence in mating and fighting traits among populations within a species [termed cascade RCD （CRCD） and cascade ACD]. Here, we demonstrate patterns consistent with male-driven RCD and ACD in 2 groups of darters （orangethroat darter clade Ceasia and rainbow darter Etheostoma caeruleum）. In both groups, males that occur in sympatry （between Ceasia and E. caeruleum） have higher levels of preference for mating and fighting with conspecifics over heterospecifics than do males from allopatry. This is consistent with RCD and ACD. We also found patterns consistent with CRCD and cascade ACD among species of Ceasia. Ceasia males that are sympatric to E. caeruleum （but allopatric to one another） also have heightened preferences for mat- ing and fighting with conspecific versus heterospecific Ceasia. In contrast, Ceasia males that are allopatric to E. caeruleum readily mate and fight with heterospecific Ceasia. We suggest that RCD and ACD between Ceasia and E. caeruleum has incidentally led to divergence in mating and fighting traits among Ceasia species. This study is unique in that male preferences evolve via both RCD （male preference for conspecific females） and ACD （male preference to fight conspecific males） which leads to subsequent divergence among allopatric lineages.
基金supported in part by the Environment Research and Technology Development Fund (C-0802) of the Ministry of the Environment,Japanthe Grant-in-Aid for Young Scientists (B) 20760362 from the Ministry of Education,Culture,Sports,Science and Technology,Japan
文摘To assess the potential endocrine disruptive effects through multiple nuclear receptors （NRs）, especially non-steroidal NRs, in municipal wastewater, we examined the agonistic activities on four NRs （estrogen receptor α, thyroid hormone receptor α, retinoic acid receptor ct and retinoid X receptor α） of untreated and treated wastewater from municipal wastewater treatment plants （WWTPs） in Japan using a yeast two-hybrid assay. Investigation of the influent and effluent of seven WWTPs revealed that agonistic activities against steroidal and non-steroidal NRs were always detected in the influents and partially remained in the effluents. Further investigation of four WWTPs employing conventional activated sludge, pseudo-anoxic-oxic, anoxic-oxic and anaerobic-anoxic-oxic processes revealed that the ability to reduce the agonistic activity against each of the four NRs varies depending on the treatment process. These results indicated that municipal wastewater in Japan commonly contains endocrine disrupting chemicals that exert agonistic activities on steroidal and non-steroidal NRs, and that some of these chemicals are released into the natural aquatic environment. Although the results obtained in yeast assays suggested that measured levels of non-steroidal NR agonists in the effluent of WWTPs were not likely to cause any biological effect, further study is required to assess their possible risks in detail.
文摘In many species, agonistic interactions result in social relationships that are stable over time. In Syrian hamsters, two unfamiliar males that are placed together will fight vigorously and a clear winner/loser relationship is usually established. In subsequent interactions, the loser will flee soon after detecting the familiar winner. Here we tested the hypothesis that losing a fight with a conspecific will affect future agonistic interactions not only toward that individual （i.e., the familiar winner） but also toward unfamiliar conspecifics. To test this hypothesis we paired two Syrian hamster males in three trials on one day in which the loser had tile opportunity to escape the winner. The next day the loser was paired with an unfarniliar male, also for three trials. If he lost again, he was tested on a third day with a third unfamiliar male. Subjects were those males that were losers on all three days. The latency to escape on the first trial on Days 2 and 3 was significantly shorter than on the first trial on Day l, indicating that losing against the first male affected the response toward unfamiliar males. However, the latency to escape on the first trial on Days 2 and 3 was significantly longer than that on the third trial on the preceding day, indicating that a loser treats unfamiliar males differently than a familiar winner. These results suggest that a defeat during an interaction with one male affects later agonistic behavior towards other, unfamiliar males [Current Zoology 57 （4）： 449-452, 2011].
文摘In comparison to studies investigating the roles of 5-HT1, 5-HT2 and 5-HT3 receptors in aggressive behaviour there is a dearth of material examining the function of 5-HT4 receptors in this behaviour. In view of this, the current study examined the effects of the 5-HT4 receptor partial agonist RS 67333 and antagonist RS 39604 in murine agonistic behaviour. RS 67333 failed to produce any significant changes in the offensive. Significant variation in the frequency of evade behaviour was detected but this occurred between treatment groups rather than with controls. Interestingly, both the frequency and duration of stretched attend behaviour were increased by RS 67333 0.1 mg/kg, a result indicative of increased risk assessment. The administration of RS 39604 (0.01 - 1 mg/kg) produced significant variation in the fre-quency and duration of following, and aggressive grooming. Frozen crouch behaviour was also increased significantly at 0.1 mg/kg. It is concluded that since the 5-HT4 receptor ligands employed in this study produced very few significant behavioural effects across the treatment groups, 5-HT4 receptors do not play a role in the modulation of murine aggressive behaviour.
文摘An agonistic display by a white shark was observed and photographed during a cage dive at Guadalupe Island in November 2015. Exhibiting exaggerated pectoral fin depression, agonistic behaviors have been previously observed and described in several shark species. This account may be the first record of a white shark in close proximity to a caged diver, exhibiting strong pectoral fin depression significantly dipped, in the mid-agonistic display. Such displays should be considered as aggressive and potentially life-threatening by those using the ocean for recreational or professional purposes.
基金National Natural Science Foundation of China(82170413,82170342,82200377)Guangdong Basic and Applied Basic Research Foundation(2021A1515012546,2022A1515012474)+3 种基金Shanghai Yangfan Project(21YF1440000)Innovation Team of General Universities in Guangdong Province(2023KCXTD025)Guangzhou Science and Technology Plan(202102010101,202201020220)Student Innovation Program of Guangzhou Medical University(to S.J.L.).
文摘The commercially available drug-eluting stent with limus (rapamycin, everolimus, etc.) or paclitaxel inhibits smooth muscle cell (SMC), reducing the in-stent restenosis, whereas damages endothelial cell (EC) and delays stent reendothelialization, increasing the risk of stent thrombosis (ST) and sudden cardiac death. Here we present a new strategy for promoting stent reendothelialization and preventing ST by exploring the application of precise molecular targets with EC specificity. Proteomics was used to investigate the molecular mechanism of EC injury caused by rapamycin. Endothelial protein C receptor (EPCR) was screened out as a crucial EC-specific effector. Limus and paclitaxel repressed the EPCR expression, while overexpression of EPCR protected EC from coating (eluting) drug-induced injury. Furthermore, the ligand activated protein C (APC), polypeptide TR47, and compound parmodulin 2, which activated the target EPCR, promoted EC functions and inhibited platelet or neutrophil adhesion, and enhanced rapamycin stent reendothelialization in the simulated stent environment and in vitro. In vivo, the APC/rapamycin-coating promoted reendothelialization rapidly and prevented ST more effectively than rapamycin-coating alone, in both traditional metal stents and biodegradable stents. Additionally, overexpression or activation of the target EPCR did not affect the cellular behavior of SMC or the inhibitory effect of rapamycin on SMC. In conclusion, EPCR is a promising therapeutical agonistic target for pro-reendothelialization and anti-thrombosis of eluting stent. Activation of EPCR protects against coating drugs-induced EC injury, inflammatory cell, or platelet adhesion onto the stent. The novel application formula for APC/rapamycin-combined eluting promotes stent reendothelialization and prevents ST.
文摘CD137 (4-1BB),a member of the TNF receptor superfamily,is an inducible T cell costimulatory receptor primarily expressed on activated CD4^+ and CD8^+ T cells.Agonistic monoclonal antibodies (mAbs) against CD137 greatly enhance T cell-mediated immune responses against many types of tumors and viruses.Surprisingly,these agonists also showed therapeutic effects in several autoimmune diseases.These findings suggest that in different disease environments,CD137 engagement with agonist mAb in vivo can diametrically modulate immune response outcomes.Therefore,CD137 agonists represent a promising immunotherapeutic approach to a wide array of disparate immune disorders.However,CD137's potency in modulating immune response necessitates caution when targeting CD137 clinically.Cellular & Molecular Immunology.2004;1(1):31-36.
基金the National Natural Science Foundation of China(No.81703679)the Liaoning Provincial Key Research and Development Program(No.2019JH2/10300022)+1 种基金the Natural Science Foundation of Liaoning Province(No.2020-MS-256)the Dalian Young Star of Science and Tech nology(Nos.2019RQ123 and 2019RQ116).
文摘The investigation of Morinda officinalis led to the isolation of twelve compounds(1-12),including three new iridoid glycosides morindallns A-C(1-3)and nine known compounds(4-12).Their structural identifications were conducted using HRMS,1D and 2D NMR,and electronic circular dichroism(ECD)spectra as well as quantum chemical computations.Compound 6 displayed the most significantly agonistic activity against farnesoid X receptor(FXR)with an EC_(50) value of 7.18 μM,and its agonistic effect was verified through the investigation of FXR downstream target genes including small heterodimer partner 1(SHP1),bile salt export pump(BSEP),and organic solute transporter subunit alpha and beta(OSTα and OSTβ).The potential interaction of compound 6 with FXR was analyzed by molecular docking and molecular dynamics stimulation,revealing that amino acid residues Leu287;Thr288,and Ser332 played a crucial role in the activation of compound 6 towards FXR.These findings suggested that compound 6 could be regarded as a potential candidate for the development of FXR agonists.
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.
基金support from Region Stockholm,ALF-project(FoUI-960041)Open Access funding is provided by Karolinska Institute(both to IM)。
文摘Type 2 diabetes mellitus and Parkinson's disease are chronic diseases linked to a growing pandemic that affects older adults and causes significant socio-economic burden.Epidemiological data supporting a close relationship between these two aging-related diseases have resulted in the investigation of shared pathophysiological molecular mechanisms.Impaired insulin signaling in the brain has gained increasing attention during the last decade and has been suggested to contribute to the development of Parkinson's disease through the dysregulation of several pathological processes.The contribution of type 2 diabetes mellitus and insulin resistance in neurodegeneration in Parkinson's disease,with emphasis on brain insulin resistance,is extensively discussed in this article and new therapeutic strategies targeting this pathological link are presented and reviewed.
文摘This article discusses the recent study written by Koizumi et al.Alcohol-associated liver disease(ALD)is a major cause of liver-related morbidity and mortality,which is driven by complex mechanisms,including lipid accumulation,apoptosis,and inflammatory responses exacerbated by gut barrier dysfunction.The study explored the therapeutic potential of elafibranor,a dual peroxisome proliferatoractivated receptor alpha/delta agonist.In clinical trials,elafibranor has shown promise for the treatment of other liver conditions;however,its effects on ALD remain unclear.The authors’findings indicate that elafibranor significantly reduced liver fibrosis and enhanced gut barrier integrity in patients with ALD.These positive effects of elafibranor are mediated through multiple pathways.Elafibranor promotes lipid metabolism,reduces oxidative stress,and inhibits inflammatory responses by restoring gut barrier function.Specifically,it improves hepatocyte function by enhancing autophagic and antioxidant capacity,and it mitigates inflammation by suppressing the lipopolysaccharide/toll-like receptor 4/nuclear factor kappa B signaling pathway.These findings indicate that elafibranor has promising clinical applications.In addition,the study highlights elafibranor’s potential as a therapeutic agent for liver diseases,particularly ALD.This article underscores the importance of understanding the mechanistic pathways underlying ALD and suggests directions for future research aimed at elucidating the benefits and limitations of elafibranor.
文摘Cardiovascular disease(CVD)remains one of the leading causes of mortality among adults globally,with continuously rising morbidity and mortality rates.Metabolic disorders are closely linked to various cardiovascular diseases and play a critical role in their pathogenesis and progression,involving multifaceted mechanisms such as altered substrate utilization,mitochondrial structural and functional dysfunction,and impaired ATP synthesis and transport.In recent years,the potential role of peroxisome proliferator-activated receptors(PPARs)in cardiovascular diseases has garnered significant attention,particularly peroxisome proliferator-activated receptor alpha(PPARα),which is recognized as a highly promising therapeutic target for CVD.PPARαregulates cardiovascular physiological and pathological processes through fatty acid metabolism.As a ligand-activated receptor within the nuclear hormone receptor family,PPARαis highly expressed in multiple organs,including skeletal muscle,liver,intestine,kidney,and heart,where it governs the metabolism of diverse substrates.Functioning as a key transcription factor in maintaining metabolic homeostasis and catalyzing or regulating biochemical reactions,PPARαexerts its cardioprotective effects through multiple pathways:modulating lipid metabolism,participating in cardiac energy metabolism,enhancing insulin sensitivity,suppressing inflammatory responses,improving vascular endothelial function,and inhibiting smooth muscle cell proliferation and migration.These mechanisms collectively reduce the risk of cardiovascular disease development.Thus,PPARαplays a pivotal role in various pathological processes via mechanisms such as lipid metabolism regulation,anti-inflammatory actions,and anti-apoptotic effects.PPARαis activated by binding to natural or synthetic lipophilic ligands,including endogenous fatty acids and their derivatives(e.g.,linoleic acid,oleic acid,and arachidonic acid)as well as synthetic peroxisome proliferators.Upon ligand binding,PPARαactivates the nuclear receptor retinoid X receptor(RXR),forming a PPARα-RXR heterodimer.This heterodimer,in conjunction with coactivators,undergoes further activation and subsequently binds to peroxisome proliferator response elements(PPREs),thereby regulating the transcription of target genes critical for lipid and glucose homeostasis.Key genes include fatty acid translocase(FAT/CD36),diacylglycerol acyltransferase(DGAT),carnitine palmitoyltransferase I(CPT1),and glucose transporter(GLUT),which are primarily involved in fatty acid uptake,storage,oxidation,and glucose utilization processes.Advancing research on PPARαas a therapeutic target for cardiovascular diseases has underscored its growing clinical significance.Currently,PPARαactivators/agonists,such as fibrates(e.g.,fenofibrate and bezafibrate)and thiazolidinediones,have been extensively studied in clinical trials for CVD prevention.Traditional PPARαagonists,including fenofibrate and bezafibrate,are widely used in clinical practice to treat hypertriglyceridemia and low high-density lipoprotein cholesterol(HDL-C)levels.These fibrates enhance fatty acid metabolism in the liver and skeletal muscle by activating PPARα,and their cardioprotective effects have been validated in numerous clinical studies.Recent research highlights that fibrates improve insulin resistance,regulate lipid metabolism,correct energy metabolism imbalances,and inhibit the proliferation and migration of vascular smooth muscle and endothelial cells,thereby ameliorating pathological remodeling of the cardiovascular system and reducing blood pressure.Given the substantial attention to PPARα-targeted interventions in both basic research and clinical applications,activating PPARαmay serve as a key therapeutic strategy for managing cardiovascular conditions such as myocardial hypertrophy,atherosclerosis,ischemic cardiomyopathy,myocardial infarction,diabetic cardiomyopathy,and heart failure.This review comprehensively examines the regulatory roles of PPARαin cardiovascular diseases and evaluates its clinical application value,aiming to provide a theoretical foundation for further development and utilization of PPARα-related therapies in CVD treatment.
文摘t OX40 is a costimulatory receptor that is expressed primarily on activated CD4+,CD8+,and regulatory T cells.The ligation of OX40 to its sole ligand OX40L potentiates T cell expansion,differentiation,and activation and also promotes dendritic cells to mature to enhance their cytokine production.Therefore,the use of agonistic anti-Ox40 antibodies for cancer immunotherapy has gained great interest.However,most of the agonistic anti-OX40 antibodies in the clinic are OX40L-competitive and show limited efficacy.Here,we discovered that BGB-A445,a non-ligand-competitive agonistic anti-OX40 antibody currently under clinical investigation,induced optimal T cell activation without impairing dendritic cell function.In addition,BGB-A445 dose-dependently and significantly depleted regulatory T cells in vitro and in vivo via antibody-dependent cellular cytotoxicity.In the MC38 syngeneic model established in humanized OX40 knock-in mice,BGB-A445 demonstrated robust and dose-dependent antitumor efficacy,whereas the ligand-competitive anti-Ox40 antibody showed antitumor efficacy characterized by a hook effect.Furthermore,BGB-A445 demonstrated a strong combination antitumor effect with an anti-PD-1 antibody.Taken together,our findings show that BGB-A445,which does not block OX40-OX40L interaction in contrast to clinical-stage anti-OX40 antibodies,shows superior immune-stimulating effects and antitumor efficacy and thus warrants further clinical investigation.
文摘Anemia is a common yet often overlooked complication in patients with type 2 diabetes mellitus(T2DM),particularly those with chronic kidney disease.It significantly impacts patients'quality of life,cardiovascular health,and treatment outcomes.Despite its high prevalence,current clinical guidelines lack specific recommendations for anemia prevention and management in T2DM,especially in the context of newer antidiabetic therapies.This review explores the potential of emerging antidiabetic medications,such as sodium-glucose cotransporter-2 inhibitors,glucagon-like peptide-1 receptor agonists(GLP-1 RAs),and combined GLP-1-RA/GIP to mitigate anemia risk.Early detection and management of anemia in T2DM patients are crucial for improving glycemic control,reducing cardiovascular morbidity,and enhancing overall treatment outcomes.This review underscores the need for further research to better understand the mechanisms by which these novel therapies influence anemia risk and to integrate these findings into clinical practice.
文摘A recent article highlighted the hepatic benefits of intermittent fasting,particularly during Ramadan.However,the rising use of glucagon-like peptide-1(GLP-1)/glucose-dependent insulinotropic polypeptide(GIP)receptor agonists(RAs)is altering public behavior,leading to decreased interest in diet and exercise.With a focus on hepatic health,we analyzed global search trends using Google Trends™data from January 1,2022 to December 31,2024,focusing on the keywords"fasting","intermittent fasting","diet","nutrition","liver",Semaglutide("Ozempic"™,the most widely known GLP-1 RA)and Tirzepatide("Mounjaro"™,a newer dual GLP-1 and GIP RA).Search interest for"intermittent fasting"and"diet"showed a significant decline over time(Spearman's rho:-0.582 and-0.605,respectively,both P<0.001),while interest in"fasting"and"nutrition"remained stable.Search interest for Semaglutide,Tirzepatide,"fasting and liver","diet and liver"and Semaglutide and"liver"increased(Spearman's rho:+0.914,+0.936,+0.369,+0.297 and+0.808,respectively,all P<0.001).These findings suggest a trend of shifting away from traditional dieting toward broader health concerns,likely influenced by the increasing use of GLP-1/GIP RAs.
基金supported by the Beijing Natural Science Foundation(No.Z230021)the National Natural Science Foundation of China(No.52202356)+1 种基金the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(No.2021-RC350-001)the CAMS Innovation Fund for Medical Sciences(No.2022-I2M-1-013).
文摘The cyclic guanosine monophosphate-adenosine monophosphate synthase and the stimulator of interferon genes(cGAS-STING)has emerged as a promising target for cancer immunotherapy.However,the development of natural STING agonists is impeded by several challenges,including limited biostability,poor pharmacokinetics,and inefficient cytosolic delivery.Herein,we meticulously designed a doublelayer polyethylenimine(PEI)modified nanoscale covalent organic polymer(CPGP)for efficient delivery of 23cyclic guanosine monophosphate-adenosine monophosphate(cGAMP),a natural STING agonist.The double-layer PEI structured CPGP enhanced both the loading capacity and stability of cGAMP.Furthermore,CPGP improved the intracellular delivery efficiency and amplified the activation of STING pathway for the secretion of type-I interferon and pro-inflammatory cytokines.In contrast,single-layered nanoparticles failed to permit stable loading and intracellular delivery of cGAMP for immune response.The nano-STING agonist also mitigated the immunosuppressive tumor microenvironment(TME)by reducing regulatory T cells and polarizing M2 macrophages to the M1 phenotype,thereby creating an immune-supportive TME to enhance adaptive immune responses.The combination of CPGP and immune checkpoint blockers showed synergistic effect,further enhancing the inhibition effect on tumor growth.This double-layer PEI modified CPGP may offer a generalizable platform for other natural dinucleotide STING agonists to overcome the cascade delivery barriers,augmenting immune activation for tumor immunotherapy.
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.
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.
