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
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
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
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
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
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
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
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
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
Skeletal muscle alterations(SMA)are increasingly recognized as both contributors and consequences of metabolic dysfunction-associated steatotic liver disease(MASLD),affecting disease progression and outcomes.Sarcopeni...Skeletal muscle alterations(SMA)are increasingly recognized as both contributors and consequences of metabolic dysfunction-associated steatotic liver disease(MASLD),affecting disease progression and outcomes.Sarcopenia is common in patients with MASLD,with a prevalence ranging from 20%to 40%depending on the population and diagnostic criteria used.In advanced stages,such as metabolic dysfunction-associated steatohepatitis and fibrosis,its prevalence is even higher.Sarcopenia exacerbates insulin resistance,systemic inflammation,and oxidative stress,all of which worsen MASLD.It is an independent risk factor for fibrosis progression and poor outcomes including mortality.Myosteatosis refers to the abnormal accumulation of fat within muscle tissue,leading to decreased muscle quality.Myosteatosis is prevalent(>30%)in patients with MASLD,especially those with obesity or type 2 diabetes,although this can vary with the imaging techniques used.It reduces muscle strength and metabolic efficiency,further contributing to insulin resistance and is usually associated with advanced liver disease,cardiovascular complications,and lower levels of physical activity.Altered muscle metabolism,which includes mitochondrial dysfunction and impaired amino acid metabolism,has been reported in metabolic syndromes,including MASLD,although its actual prevalence is unknown.Altered muscle metabolism limits glucose uptake and oxidation,worsening hyperglycemia and lipotoxicity.Reduced muscle perfusion and oxygenation due to endothelial dysfunction and systemic metabolic alterations are common in MASLD associated with comorbidities,such as obesity,hypertension,and atherosclerosis.It decrea-ses the muscle capacity for aerobic metabolism,leading to fatigue and reduced physical activity in patients with MASLD,aggravating metabolic dysfunction.Various SMA in MASLD worsen insulin resistance and hepatic fat accumulation,may accelerate progression to fibrosis and cirrhosis,and increase the risk of cardiovascular disease and mortality.Management strategies for SMA include resistance training,aerobic exercise,and nutritional support(e.g.,high-protein diets,vitamin D,and omega-3 fatty acids),which are essential for mitigating skeletal muscle loss and improving outcomes.However,pharmacological agents that target the muscle and liver(such as glucagon-like peptide-1 receptor agonists)show promise but have not yet been approved for the treatment of MASLD.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
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
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
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.
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.
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.
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 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.
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Supported by Russian Science Foundation,No.19-76-30014.
文摘Skeletal muscle alterations(SMA)are increasingly recognized as both contributors and consequences of metabolic dysfunction-associated steatotic liver disease(MASLD),affecting disease progression and outcomes.Sarcopenia is common in patients with MASLD,with a prevalence ranging from 20%to 40%depending on the population and diagnostic criteria used.In advanced stages,such as metabolic dysfunction-associated steatohepatitis and fibrosis,its prevalence is even higher.Sarcopenia exacerbates insulin resistance,systemic inflammation,and oxidative stress,all of which worsen MASLD.It is an independent risk factor for fibrosis progression and poor outcomes including mortality.Myosteatosis refers to the abnormal accumulation of fat within muscle tissue,leading to decreased muscle quality.Myosteatosis is prevalent(>30%)in patients with MASLD,especially those with obesity or type 2 diabetes,although this can vary with the imaging techniques used.It reduces muscle strength and metabolic efficiency,further contributing to insulin resistance and is usually associated with advanced liver disease,cardiovascular complications,and lower levels of physical activity.Altered muscle metabolism,which includes mitochondrial dysfunction and impaired amino acid metabolism,has been reported in metabolic syndromes,including MASLD,although its actual prevalence is unknown.Altered muscle metabolism limits glucose uptake and oxidation,worsening hyperglycemia and lipotoxicity.Reduced muscle perfusion and oxygenation due to endothelial dysfunction and systemic metabolic alterations are common in MASLD associated with comorbidities,such as obesity,hypertension,and atherosclerosis.It decrea-ses the muscle capacity for aerobic metabolism,leading to fatigue and reduced physical activity in patients with MASLD,aggravating metabolic dysfunction.Various SMA in MASLD worsen insulin resistance and hepatic fat accumulation,may accelerate progression to fibrosis and cirrhosis,and increase the risk of cardiovascular disease and mortality.Management strategies for SMA include resistance training,aerobic exercise,and nutritional support(e.g.,high-protein diets,vitamin D,and omega-3 fatty acids),which are essential for mitigating skeletal muscle loss and improving outcomes.However,pharmacological agents that target the muscle and liver(such as glucagon-like peptide-1 receptor agonists)show promise but have not yet been approved for the treatment of MASLD.
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.
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.
