Neutrophils,macrophages,CD3^(+),CD4^(+),and CD8^(+)T lymphocytes expressμ-,δ-,andκ-opioid receptors(ORs)with varying affinities for opioids.Mast cells express the atypical OR Mas-related G-protein-coupled receptor ...Neutrophils,macrophages,CD3^(+),CD4^(+),and CD8^(+)T lymphocytes expressμ-,δ-,andκ-opioid receptors(ORs)with varying affinities for opioids.Mast cells express the atypical OR Mas-related G-protein-coupled receptor X2(MRGPRX2),which has a low affinity for morphine.Neutrophils and macrophages can synthesize and release endogenous opioid peptides.Activation of ORs enhances the synthesis of proinflammatory cytokines and the production of reactive oxygen species(ROS)in unstimulated leukocytes.Conversely,OR activation reduces proinflammatory cytokine synthesis in stimulated neutrophils and macrophages.Morphine inhibits Toll-like receptor 4(TLR4)expression in macrophages,thereby attenuating inflammation,whereas methadone induces ROS production in mast cells through TLR4 activation.Stimulation of TLR4 triggersβ-endorphin synthesis in macrophages.The production of proinflammatory cytokines and ROS contributes to cardiac reperfusion injury.Importantly,activation ofκ1-andμ-ORs suppresses proinflammatory cytokine production by leukocytes,thereby mitigating inflammatory injury to the heart and other organs.展开更多
Accumulating evidence has highlighted the functional role of the endogenous nociceptin/orphanin FQ peptide(N/OFQ)and its nociceptin opioid receptor(NOP)in alcohol and cocaine reward.However,the effects of NOP agonists...Accumulating evidence has highlighted the functional role of the endogenous nociceptin/orphanin FQ peptide(N/OFQ)and its nociceptin opioid receptor(NOP)in alcohol and cocaine reward.However,the effects of NOP agonists on methamphetamine(MAP)reinforcement,motivation,and relapse remain uncertain.In this study,we evaluated the effects of Ro 64-6198,a selective NOP agonist,on MAP reinforcement,motivation,and relapse in rats.Rats underwent a fixed-ratio 1(FR1)training to establish stable MAP intravenous self-administration(0.05 mg/kg/infusion)for 12 days,and the motivation for MAP was quantified using a progressive-ratio(PR)schedule,while the relapse was assessed through cue-and MAP-primed reinstatement after abstinence.Western blot analysis was employed to measure the relative expression of phosphorylated CREB,ERK,and Akt in the nucleus accumbens(NAc)following drug priming.Acute treatment of Ro 64-6198(1 mg/kg)significantly reduced the motivated behavior for MAP under PR testing(P<0.05 vs.vehicle).Ro 64-6198 at doses of 0.3 and 1 mg/kg could suppress the drug-seeking behavior induced by extinction or cues,respectively(P<0.05),whereas only the higher dose(1 mg/kg)could attenuate MAP primed drug-seeking(P<0.05).These behavioral effects were related to the upregulated phosphorylation of CREB and Akt in the NAc.Our results provide preclinical evidence that NOP activation disrupts multiple addiction-relevant behaviors,positioning Ro 64-6198 as a potential therapeutic candidate for treating MAP use disorders.展开更多
G protein-coupled receptor 37(GPR37)is an orphan receptor predominantly expressed in the brain,particularly in oligodendrocytes and certain types of neurons.Notably,it has been shown that the N-terminal domain of GPR3...G protein-coupled receptor 37(GPR37)is an orphan receptor predominantly expressed in the brain,particularly in oligodendrocytes and certain types of neurons.Notably,it has been shown that the N-terminal domain of GPR37 undergoes proteolysis under normal physiological conditions,resulting in the formation of cleaved receptor forms and the release of its ectodomain(ecto-GPR37)into the extracellular milieu(Mattila et al.,2021).Importantly,ecto-GPR37 density is increased in cerebrospinal fluid(CSF)of patients suffering from sporadic Parkinson’s disease(PD),together with an abnormal GPR37 processing in post-mortem PD substantia nigra(Moratóet al.,2021;Figure 1A).展开更多
Glutamate receptors and schizophrenia:Schizophrenia is a chronic mental disorder affecting approximately 1%of the global population,with 70%-80%heritability.It has a multifactorial etiology involving both environmenta...Glutamate receptors and schizophrenia:Schizophrenia is a chronic mental disorder affecting approximately 1%of the global population,with 70%-80%heritability.It has a multifactorial etiology involving both environmental factors and a complex polygenic genetic architecture.Over the last two decades,large-scale genome-wide approaches revealed contributions of common variants with individually small effect sizes and of rare copy number variants with a large effect size.N-methy l-D-a spar tat e receptor(NMDAR)hypofunction has been implicated as a central mechanism in the pathophysiology of schizophrenia(Coyle et al.,2020).展开更多
Objectives:Permanent middle cerebral artery occlusion(pMCAO)can lead to hippocampal damage through multiple linked pathways such as reactive oxidative stress(ROS),neuroinflammation mediated by NOD-,LRR-and pyrin domai...Objectives:Permanent middle cerebral artery occlusion(pMCAO)can lead to hippocampal damage through multiple linked pathways such as reactive oxidative stress(ROS),neuroinflammation mediated by NOD-,LRR-and pyrin domain-containing protein 3(NLRP3),tumour necrosis factor-alpha(TNF-α),and nuclear factor kappa-light-chain-enhancer of activated B cells(NF-κB),and glutamate excitotoxicity involving N-methyl-D-aspartate receptor subunits 2a and 2b(NR2a/NR2b)and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor(AMPAR/GluR1).The hippocampus,which is essential for memory and cognition,is at a substantial risk of ischemic degeneration.The aim of this study was to investigate the neuroprotective potential of melatonin in regulating these pathways.Method:Male adult rats were subjected to pMCAO,and melatonin(5 mg/kg)was administered just prior to ischemia,while sham-operated animals underwent surgery without nylon insertion.Hippocampal samples were collected 24 h after ischemia,Results:Hippocampal tissues showed NLRP3 inflammasome activation,increased TNF-α and p-NF-κB,and decreased peroxisome proliferator-activated receptor(PPARγ)after pMCAO.Melatonin-modulated ischemia-induced glutamatergic receptor subunits(NR2a,NR2b,GluR1)dysregulation,which possibly stimulated the prosurvival pathways and reduced collagen response-mediated protein(CRMP2)and its phosphorylation.Melatonin also modulated the expression of the postsynaptic protein(PSD95)and inhibited inflammatory cascades while upregulating antioxidant proteins.Further,melatonin reduced inflammation triggered by NLRP3,restored synaptic integrity,possibly by enhancing nuclear factor erythroid 2-related factor 2(Nrf2)expression.Conclusion:These results demonstrated the dual role ofmelatonin by protecting ischemic brain damage both as amodulator of excitotoxicity and neuroinflammation/oxidative stress.展开更多
Brassinosteroids(BRs)are essential phytohormones that broadly regulate plant growth,development,and adaptation to biotic and abiotic stresses.In Arabidopsis,apoplastic BR molecules are perceived by a plasma membrane-l...Brassinosteroids(BRs)are essential phytohormones that broadly regulate plant growth,development,and adaptation to biotic and abiotic stresses.In Arabidopsis,apoplastic BR molecules are perceived by a plasma membrane-localized receptor complex comprising the ligand-binding receptor BRI1 and the co-receptor BAK1.While negative regulators of the BR receptor complex,such as BKI1,BIR3,and PUB12/13,have been well characterized,how BRI1 and BAK1 are positively modulated in the BR pathway remains largely unknown.In this study,a genetic screen involving overexpression of RLP genes in the bak1-3 bkk1-1 double mutant reveals that enhanced RLP51 expression partially suppresses the BR-deficient phenotypes of bak1-3 bkk1-1.RLP51 overexpression also partially rescues the weak bri1 mutant allele,bri1-301.Although the rlp51 single mutant exhibits wild-type-like phenotypes,it enhances BR-defective phenotypes in bri1-301 and bak1 serk1 mutants.RLP51 is next found to interact with both BRI1 and BAK1 without affecting BRI1–BAK1 interaction.Critically,co-expression of RLP51 with BRI1 or BAK1 significantly increases BRI1 and BAK1 protein abundances.RLP51 appears to promote protein synthesis rather than stabilize BRI1 and BAK1 proteins.Thus,our study identifies RLP51 as a positive regulator of BR signaling that enhances the protein levels of BRI1 and BAK1.展开更多
Brain insulin resistance(BIR)is a prevalent detrimental feature of Alzheimer’s disease(AD)and all-cause dementia.Therapies designed to activate insulin signaling and enhance insulin receptor sensitivity have proven b...Brain insulin resistance(BIR)is a prevalent detrimental feature of Alzheimer’s disease(AD)and all-cause dementia.Therapies designed to activate insulin signaling and enhance insulin receptor sensitivity have proven beneficial for cognitive enhancement in pre-clinical models,non-human primates,and humans.BIR encompasses dysregulated brain insulin signaling,which is either due to insulin receptor resistance,reduced insulin receptor levels,or reduced levels of insulin in the brain,affecting processes involved in AD development and progression.展开更多
Diapause is a programmed developmental arrest process in insects.Diapause can occur at various stages of insect development and is frequently restricted to a specific developmental stage within a single species.In Bom...Diapause is a programmed developmental arrest process in insects.Diapause can occur at various stages of insect development and is frequently restricted to a specific developmental stage within a single species.In Bombyx mori,embryonic diapause is elicited by the diapause hormone(DH)and DH receptor(DHR)in diapause strains.Nevertheless,the regulatory mechanism through which BmDHR functions as a G protein-coupled receptor(GPCR),to exert other physiological functions in nondiapause silkworms,remains unclear.In this study,we found that BmDHR had 7 alternative splice isoforms.A knockout experiment confirmed that BmDHR mediated the transduction of diapause signals.Interestingly,the loss of BmDHR caused partial precocious metamorphosis and an embryo-lethal phenotype in nondiapause silkworms.An assessment of global transcriptional patterns revealed that BmDHR knockout affected physiological responses induced by manifold cellular processes,including the Toll/immune deficiency(Imd),Wnt,insulin-like growth factor,Hedgehog and P38/mitogen-activated protein kinase(MAPK)signaling pathways.This study expands our knowledge of the physiological roles for DHR in insect growth and development.展开更多
Aberrant activation of Receptor Tyrosine Kinases(RTKs)is a well-established trigger of tumorigenesis,and the over-use of RTK inhibitors often leads to drug resistance and tumor recurrence.While current Drug-Target Int...Aberrant activation of Receptor Tyrosine Kinases(RTKs)is a well-established trigger of tumorigenesis,and the over-use of RTK inhibitors often leads to drug resistance and tumor recurrence.While current Drug-Target Interaction(DTI)prediction methods(including those based on heterogeneous information networks)have shown promise,they remain limited in their ability to fully capture the nature of DTIs and often lack interpretability.To overcome these limitations,this study introduces a novel hybrid optimization model termed MDBO-RF,which integrates a Modified Dung Beetle Optimizer(MDBO)with Random Forest(RF).The key innovation lies in the enhancement of the DBO algorithm through a quaternion-based learning mechanism and the Cauchy mutation strategy,specifically designed to overcome the slow convergence and susceptibility to local optima that plague traditional metaheuristic algorithms used for hyperparameter tuning.The model leverages commonly used molecular descriptors to enhance the prediction of Tyrosine Kinase(TK)inhibitory activity and enable efficient compound screening.Our results demonstrate that MDBO-RF achieves a 3.41%increase in prediction accuracy compared to the standard RF model and outperforms several other contemporary machine learning approaches.The model effectively streamlines the RTK inhibitor screening process by improving prediction accuracy in multi-target competitive binding scenarios and reducing false-positive screening due to off-target effects.This work underscores the value of hybrid optimization strategies in bioinformatics and provides a robust,interpretable tool for accelerating drug discovery.展开更多
Pancreatic ductal adenocarcinoma(PDAC)remains one of the most lethal malignancies,characterized by a highly immunosuppressive tumor microenvironment(TME),dense stromal architecture,and limited response to conventional...Pancreatic ductal adenocarcinoma(PDAC)remains one of the most lethal malignancies,characterized by a highly immunosuppressive tumor microenvironment(TME),dense stromal architecture,and limited response to conventional therapies.This review comprehensively examines the emerging role of chimeric antigen receptor(CAR)-engineered immune cells,including chimeric antigen receptor-T(CAR-T),CAR-macrophages(CAR-M),and CAR-natural killer(CAR-NK)cells,as innovative immunotherapeutic strategies for PDAC.We delve into the mechanistic foundations of these platforms,highlighting their unique abilities to target tumor-associated antigens,overcome stromal barriers,and remodel the immunosuppressive TME.Recent preclinical and clinical advances demonstrate promising antitumor activity,particularly with targets such as mesothelin,claudin18.2,and human epidermal growth factor 2(HER2),though challenges related to antigen heterogeneity,TME suppression,and cell persistence remain.We further discuss synergistic approaches involving genetic engineering,microenvironment modulation,and combination therapies aimed at enhancing efficacy.Finally,we offer perspectives on the future direction of CARbased therapies,including the development of next-generation constructs,allogeneic“off-the-shelf”products,and personalized combination regimens,underscoring their potential in pancreatic cancer.展开更多
Cortico-thalamic projections(the hyper-direct pathway)are implicated in levodopa-induced dyskinesia(LID),a challenging complication in the advanced stages of Parkinson’s disease(PD).Excessive beta and gamma activity ...Cortico-thalamic projections(the hyper-direct pathway)are implicated in levodopa-induced dyskinesia(LID),a challenging complication in the advanced stages of Parkinson’s disease(PD).Excessive beta and gamma activity in PD and LID has frequently been reported in recent cross-sectional studies.We aimed to investigate the temporal features of beta and gamma activity in the hyper-direct pathway during the development of PD and LID in rats,as well as the regulatory role of the dopamine receptors DI(D1Rs)and DIII(D3Rs)in these disorders.We recorded motor behavior and electrophysiological data during the development of PD and LID,and after interventions with D1R and D3R antagonists and agonists.We demonstrated exaggerated beta-band activity in the PD state and excessive gamma-band activity during on-state dyskinesia.Subsequently,process-dependent increased beta activity correlated with bradykinesia during PD modeling,while process-dependent increased gamma activity correlated with dyskinesia under the cumulative effects of levodopa during on-state dyskinesia.Finally,both D1Rs and D3Rs were found to be involved in regulating dyskinesia and gamma activity.Dynamic oscillations are closely associated with motor behavior,and mapping dynamic oscillations may be associated with optimizing deep brain stimulation parameters and developing personalized neurotherapeutic targeting.Moreover,D1Rs and D3Rs may ameliorate dyskinesia by mediating gamma oscillations.展开更多
Hemorrhagic shock(HS)is a leading cause of death worldwide,particularly within the first 24 h post-injury.Current treatments are limited,especially in low-resource settings.Therapeutic hypothermia(TH)offers potential ...Hemorrhagic shock(HS)is a leading cause of death worldwide,particularly within the first 24 h post-injury.Current treatments are limited,especially in low-resource settings.Therapeutic hypothermia(TH)offers potential benefits by reducing metabolic demands and protecting organs,but its application in HS is challenged by cooling difficulties and side effects.This study introduces a novel nasal gel formulation of N6-cyclohexyladenosine(CHA),an adenosine A1 receptor agonist,designed to enhance brain delivery while minimizing peripheral side effects.In a mouse model of HS,administration of CHA nasal gel significantly improved survival rates,reduced metabolic rates,and protected major organs without worsening coagulopathy.Metabolomics analysis revealed a shift towards fatty acid oxidation and increased antioxidant capacity.These findings demonstrate that CHA nasal gel effectively induces TH,offering a safe and innovative treatment strategy for HS,particularly in resource-limited environments.展开更多
Background:This study investigated the role of polydatin in regulating macrophage-epithelial cell(EC)interactions during asthma.An asthma model was induced in BALB/c mice using ovalbumin(20μg).Methods:The therapeutic...Background:This study investigated the role of polydatin in regulating macrophage-epithelial cell(EC)interactions during asthma.An asthma model was induced in BALB/c mice using ovalbumin(20μg).Methods:The therapeutic effects of polydatin(20 and 40 mg/kg)were evaluated in this asthmatic mouse model.To assess the underlying mechanisms,Bronchial Epithelium Adenovirus 12-SV402B(BEAS-2B)cells were cocultured with Tohoku Hospital for Pediatrics-1(THP-1)macrophages,in which toll-like receptor 4(TLR4)was either overexpressed or knocked down,and subsequently stimulated with lipopoly-saccharide(LPS)and ATP.THP-1 cells underwent a 1-h pretreatment with polydatin(50 and 100μmol/L),Class Lipid Inhibitor-095(CLI-095,TLR4 inhibitor,1μg/mL),or A438079(P2X7R antagonist,10μmol/L)prior to LPS/ATP challenge.Results:Findings from Western blotting,enzyme-linked immunosorbent assay,flow cytometry,real-time polymerase chain reaction,and immunofluorescence assays demonstrated that modulating TLR4 expression significantly altered interleukin-1β(IL-1β)secretion from THP-1 macrophages and mitochondrial reactive oxygen species(mtROS)production in BEAS-2B ECs.In the mouse asthma model,polydatin significantly alleviated airway inflammation,oxidative stress,and apoptosis,likely by interfering with TLR4/P2X7R-mediated signaling and suppressing the activation of the NOD-like receptor protein inflammasome.Additionally,polydatin significantly reduced IL-1βand IL-18 levels and inhibited the infiltration of macrophages and eosinophils.Correspondingly,polydatin significantly attenuated TLR4/P2X7R signaling in THP-1 cells stimulated with ATP and LPS,thereby reducing IL-1βand IL-18 secretion,calcium influx,mtROS production,and apoptosis in BEAS-2B ECs.Conclusions:Polydatin is a promising therapeutic candidate for asthma,possibly by targeting macrophage-epithelium cross-talk via the TLR4/P2X7R axis.Future formulations as capsules or sprays may effectively alleviate airway inflammation and remodeling.展开更多
Retinal ganglion cells are susceptible to neurodegenerative conditions and their death drives common forms of irreversible vision loss.In mice,there are 46 transcriptionally unique retinal ganglion cell types that dem...Retinal ganglion cells are susceptible to neurodegenerative conditions and their death drives common forms of irreversible vision loss.In mice,there are 46 transcriptionally unique retinal ganglion cell types that demonstrate different susceptibilities to degeneration.Recent transcriptional experiments defined a novel retinal ganglion cell type that survives particularly well and uniquely expresses high levels of the orphan G-protein-coupled receptor 88.Motivated to study this retinal ganglion cell type,we obtained GPR88-Cre transgenic mice to identify the novel well-surviving retinal ganglion cells and examine their survival and regenerative potential.Our experiments demonstrate that this unidentified retinal ganglion cell type is likely accordant with previously described ON-direction-selective retinal ganglion cells.Interestingly,we find that ON-direction-selective retinal ganglion cells are resilient,but demonstrate limited potential to regenerate their axons in response to well-characterized regenerative treatments.Studying the molecular properties of the ON-direction-selective retinal ganglion cells could unlock new therapeutics to preserve retinal ganglion cells in patients.展开更多
Objectives:Cholecystokinin A receptor(CCKAR)has been linked to poor prognosis in colon cancer patients,but the role of CCKAR in colon cancer cell invasiveness and the underlying mechanisms remain elusive.This study ai...Objectives:Cholecystokinin A receptor(CCKAR)has been linked to poor prognosis in colon cancer patients,but the role of CCKAR in colon cancer cell invasiveness and the underlying mechanisms remain elusive.This study aimed to explore the effect of CCKAR on the invasive potential of colon cancer cells.Methods:Different human colon cancer cell lines were used.Gene expression was evaluated by reverse transcription polymerase chain reaction(RT-PCR)and quantitative real-time RT-PCR(qPCR),while protein expression and phosphorylation were assessed by Western blotting.Cell motility and invasiveness were examined through wound healing and invasion assays,respectively.Results:Our results showed that CCKAR expression levels varied across colon cancer cell lines,with DLD-1 and LoVo cells showing high expression.Knockdown of CCKAR significantly impaired the cell motility and invasiveness of DLD-1 and LoVo cells,downregulated integrinβ3 expression,and diminished the phosphorylation levels of focal adhesion kinase(FAK),Src,and paxillin.In addition,CCKAR knockdown modulated epithelialmesenchymal transition(EMT)markers ZO-1,E-cadherin,and vimentin and reduced urokinase-type plasminogen activator(uPA),uPA receptor(uPAR),Rho GTPase cell division control protein 42(CDC42)and RhoA,and matrix metalloproteinase-2(MMP-2).Conclusions:These findings indicate that CCKAR knockdown impairs the invasiveness of colon cancer cells,which may be attributed to modulating integrin/FAK/Rho GTPases,EMT markers,and the uPA/uPAR axis.It suggests that targeting CCKAR may represent a potential therapeutic strategy for colon cancer treatment.展开更多
The arginine-phenylalanine-amide neuropeptide receptor family comprises a subclass within the G protein-coupled receptor superfamily with crucial roles in physiological regulation.These receptors recognize and bind ne...The arginine-phenylalanine-amide neuropeptide receptor family comprises a subclass within the G protein-coupled receptor superfamily with crucial roles in physiological regulation.These receptors recognize and bind neuropeptides with an arginine-phenylalanine-amide motif,thereby participating in a variety of biological processes such as energy metabolism,pain perception,and reproductive functions.In this review,we explore the physiological and pathological processes involving these receptors and delve into the structure-activity relationships of their ligand peptides,clarifying the key structural motifs within these neuropeptides that determine their biological activity,pharmacological potency,and receptor selectivity.Particular emphasis is placed on their roles in modulating nociception,regulating appetite,and maintaining reproductive health.Additionally,we discuss the therapeutic potential of structure-based drug design targeting these receptors based on existing cryo-electron microscopy structures.The available structural insights into ligand-binding pockets and G protein-receptor interaction interfaces provide a clear perspective and valuable complement to ligand optimization.展开更多
OBJECTIVE:To investigate the effects of optimizing Qinggan Jieyu decoction(清肝解郁方)on purinergic receptor P2X ligand-gated ion channel 7(P2X7R)and autophagy in migraine model rats based on molecular biology and his...OBJECTIVE:To investigate the effects of optimizing Qinggan Jieyu decoction(清肝解郁方)on purinergic receptor P2X ligand-gated ion channel 7(P2X7R)and autophagy in migraine model rats based on molecular biology and histopathology.METHODS:A migraine rat model was established by a single subcutaneous nitroglycerin(NTG)injection into the posterior neck.QGJY was administered via gavage for 7 d prior to NTG induction.Behavioral changes,central sensitization biomarkers,and inflammatory cytokine levels were analyzed to evaluate migraine severity.Western blot,immunofluorescence,quantitative real-time PCR,and transmission electron microscopy were employed to assess P2X7R expression and autophagy activity in trigeminal nucleus caudalis(TNC)tissues.The P2X7R agonist 2'(3')-O-(4-Benzoylbenzoyl)adenosine-5'-triphosphate(Bz ATP)was further utilized to validate QGJY's regulatory effects.RESULTS:QGJY significantly reduced cage-climbing and head-scratching frequencies in NTG-induced migraine rats,downregulated serum and TNC levels of interleukin-1 beta,interleukin-6,and tumor necrosis factor-alpha,and suppressed central sensitization markers(substance P;calcitonin gene-related peptide;and c-fos induced growth factor)in TNC tissues(P<0.05).QGJY markedly decreased microglial cell counts and average immunofluorescence intensity in TNC tissues and promoted elongation of microglial protrusions(P<0.05).Concurrently,QGJY downregulated P2X7R protein and m RNA expression,reduced the light chain 3(LC3)-II/LC3-I ratio,elevated ubiquitin-binding protein p62 levels,and diminished autophagosome numbers in TNC tissues(P<0.05).Furthermore,QGJY reversed Bz ATP-induced P2X7R upregulation(P<0.05).CONCLUSIONS:QGJY alleviates migraine and inhibits central sensitization in rats,potentially by downregulating P2X7R expression,concomitantly suppressing autophagy,attenuating microglial activation,and reducing pro-inflammatory cytokine release.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
Phytomelatonin,an emerging plant hormone,plays vital roles in plant growth,development,and stress adaptation(Arnao et al.,2022;Ullah et al.,2024).It acts both as a direct antioxidant and a signaling molecule,engaging ...Phytomelatonin,an emerging plant hormone,plays vital roles in plant growth,development,and stress adaptation(Arnao et al.,2022;Ullah et al.,2024).It acts both as a direct antioxidant and a signaling molecule,engaging complex networks and interacting with other phytohormones(Liu et al.,2022;Khan et al.,2023).Although phytomelatonin receptors(PMTRs)have been identified in many plants(Wei et al.,2018;Wang et al.,2022;Liu et al.,2025),the downstream signaling mechanisms,particularly receptor-mediated protein modifications and transcriptional regulation,remain poorly characterized.展开更多
The delta-opioid receptor was previously viewed as a mediator in pain regulation.Recent data shed light on its specific role in neural protection and regeneration.An up-regulation of delta-opioid receptor expression a...The delta-opioid receptor was previously viewed as a mediator in pain regulation.Recent data shed light on its specific role in neural protection and regeneration.An up-regulation of delta-opioid receptor expression and/or activity protects neuronal cells/tissues against various injuries and promotes neural regeneration.This review focuses on these new findings and the underlying mechanisms.In particular,we summarize the following key points:(1)the role of delta-opioid receptor in neuroprotection across various models and conditions;(2)the mechanisms of delta-opioid receptor neuroprotection against acute injury;(3)the neuroprotective mechanisms of delta-opioid receptor during prolonged injury;(4)delta-opioid receptor protection against ischemic and degenerative brain diseases and the underlying mechanisms;and(5)the regulation of delta-opioid receptor in neural regeneration.This article aims to provide an overview of delta-opioid receptor-mediated neural protection and regeneration,as well as its potential in treating neurological diseases.展开更多
基金supported by the Russian Science Foundation(Grant No.23-65-10017 to B.K.K.and M.K.)The Ministry of Science and Higher Education of the Russian Federation(Grant No.122020300042-4 to L.N.M.)supported the preparation of the minichapter titled"Opioids reduce inflammatory injury of the heart".
文摘Neutrophils,macrophages,CD3^(+),CD4^(+),and CD8^(+)T lymphocytes expressμ-,δ-,andκ-opioid receptors(ORs)with varying affinities for opioids.Mast cells express the atypical OR Mas-related G-protein-coupled receptor X2(MRGPRX2),which has a low affinity for morphine.Neutrophils and macrophages can synthesize and release endogenous opioid peptides.Activation of ORs enhances the synthesis of proinflammatory cytokines and the production of reactive oxygen species(ROS)in unstimulated leukocytes.Conversely,OR activation reduces proinflammatory cytokine synthesis in stimulated neutrophils and macrophages.Morphine inhibits Toll-like receptor 4(TLR4)expression in macrophages,thereby attenuating inflammation,whereas methadone induces ROS production in mast cells through TLR4 activation.Stimulation of TLR4 triggersβ-endorphin synthesis in macrophages.The production of proinflammatory cytokines and ROS contributes to cardiac reperfusion injury.Importantly,activation ofκ1-andμ-ORs suppresses proinflammatory cytokine production by leukocytes,thereby mitigating inflammatory injury to the heart and other organs.
基金supported by Ningbo Top Medical and Health Research Program(No.2022030410)National Key Research and Development Program of China(No.2022YFC3300905,2023YFC3304202).
文摘Accumulating evidence has highlighted the functional role of the endogenous nociceptin/orphanin FQ peptide(N/OFQ)and its nociceptin opioid receptor(NOP)in alcohol and cocaine reward.However,the effects of NOP agonists on methamphetamine(MAP)reinforcement,motivation,and relapse remain uncertain.In this study,we evaluated the effects of Ro 64-6198,a selective NOP agonist,on MAP reinforcement,motivation,and relapse in rats.Rats underwent a fixed-ratio 1(FR1)training to establish stable MAP intravenous self-administration(0.05 mg/kg/infusion)for 12 days,and the motivation for MAP was quantified using a progressive-ratio(PR)schedule,while the relapse was assessed through cue-and MAP-primed reinstatement after abstinence.Western blot analysis was employed to measure the relative expression of phosphorylated CREB,ERK,and Akt in the nucleus accumbens(NAc)following drug priming.Acute treatment of Ro 64-6198(1 mg/kg)significantly reduced the motivated behavior for MAP under PR testing(P<0.05 vs.vehicle).Ro 64-6198 at doses of 0.3 and 1 mg/kg could suppress the drug-seeking behavior induced by extinction or cues,respectively(P<0.05),whereas only the higher dose(1 mg/kg)could attenuate MAP primed drug-seeking(P<0.05).These behavioral effects were related to the upregulated phosphorylation of CREB and Akt in the NAc.Our results provide preclinical evidence that NOP activation disrupts multiple addiction-relevant behaviors,positioning Ro 64-6198 as a potential therapeutic candidate for treating MAP use disorders.
基金FEDER/Ministerio de Ciencia,Innovacióny Universidades-Agencia Estatal de Investigación(PID2023-147425OB-I00 to FC)Agència de Gestiód’Ajuts Universitaris i de Recerca(AGAUR)-Generalitat de Catalunya(2021 SGR 00698 to FC).
文摘G protein-coupled receptor 37(GPR37)is an orphan receptor predominantly expressed in the brain,particularly in oligodendrocytes and certain types of neurons.Notably,it has been shown that the N-terminal domain of GPR37 undergoes proteolysis under normal physiological conditions,resulting in the formation of cleaved receptor forms and the release of its ectodomain(ecto-GPR37)into the extracellular milieu(Mattila et al.,2021).Importantly,ecto-GPR37 density is increased in cerebrospinal fluid(CSF)of patients suffering from sporadic Parkinson’s disease(PD),together with an abnormal GPR37 processing in post-mortem PD substantia nigra(Moratóet al.,2021;Figure 1A).
文摘Glutamate receptors and schizophrenia:Schizophrenia is a chronic mental disorder affecting approximately 1%of the global population,with 70%-80%heritability.It has a multifactorial etiology involving both environmental factors and a complex polygenic genetic architecture.Over the last two decades,large-scale genome-wide approaches revealed contributions of common variants with individually small effect sizes and of rare copy number variants with a large effect size.N-methy l-D-a spar tat e receptor(NMDAR)hypofunction has been implicated as a central mechanism in the pathophysiology of schizophrenia(Coyle et al.,2020).
基金the financial support for this work from the Deanship of Scientific Research(DSR)at the University of Tabuk,Tabuk,Saudi Arabia(grant No.S-1442-0164).
文摘Objectives:Permanent middle cerebral artery occlusion(pMCAO)can lead to hippocampal damage through multiple linked pathways such as reactive oxidative stress(ROS),neuroinflammation mediated by NOD-,LRR-and pyrin domain-containing protein 3(NLRP3),tumour necrosis factor-alpha(TNF-α),and nuclear factor kappa-light-chain-enhancer of activated B cells(NF-κB),and glutamate excitotoxicity involving N-methyl-D-aspartate receptor subunits 2a and 2b(NR2a/NR2b)and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor(AMPAR/GluR1).The hippocampus,which is essential for memory and cognition,is at a substantial risk of ischemic degeneration.The aim of this study was to investigate the neuroprotective potential of melatonin in regulating these pathways.Method:Male adult rats were subjected to pMCAO,and melatonin(5 mg/kg)was administered just prior to ischemia,while sham-operated animals underwent surgery without nylon insertion.Hippocampal samples were collected 24 h after ischemia,Results:Hippocampal tissues showed NLRP3 inflammasome activation,increased TNF-α and p-NF-κB,and decreased peroxisome proliferator-activated receptor(PPARγ)after pMCAO.Melatonin-modulated ischemia-induced glutamatergic receptor subunits(NR2a,NR2b,GluR1)dysregulation,which possibly stimulated the prosurvival pathways and reduced collagen response-mediated protein(CRMP2)and its phosphorylation.Melatonin also modulated the expression of the postsynaptic protein(PSD95)and inhibited inflammatory cascades while upregulating antioxidant proteins.Further,melatonin reduced inflammation triggered by NLRP3,restored synaptic integrity,possibly by enhancing nuclear factor erythroid 2-related factor 2(Nrf2)expression.Conclusion:These results demonstrated the dual role ofmelatonin by protecting ischemic brain damage both as amodulator of excitotoxicity and neuroinflammation/oxidative stress.
基金supported by the National Natural Science Foundation of China(32370295 and 32170280 to K.H.)Foundation of Science and Technology of Gansu Province(22ZD6NA049)+3 种基金the Fundamental Research Funds for the Central Universities(lzujbky-2021-kb05 to Y.F.and lzujbky-2023-kb05 to P.L.)the Science and Technology Department of Gansu Province(24JRRA392 to K.H.and 23JRRA1132 to C.X.)China Postdoctoral Science Foundation(2024M751259 and GZB20240285 to B.L.)Science and Technology Program of Gansu Province(25JRRA718 to B.L.).
文摘Brassinosteroids(BRs)are essential phytohormones that broadly regulate plant growth,development,and adaptation to biotic and abiotic stresses.In Arabidopsis,apoplastic BR molecules are perceived by a plasma membrane-localized receptor complex comprising the ligand-binding receptor BRI1 and the co-receptor BAK1.While negative regulators of the BR receptor complex,such as BKI1,BIR3,and PUB12/13,have been well characterized,how BRI1 and BAK1 are positively modulated in the BR pathway remains largely unknown.In this study,a genetic screen involving overexpression of RLP genes in the bak1-3 bkk1-1 double mutant reveals that enhanced RLP51 expression partially suppresses the BR-deficient phenotypes of bak1-3 bkk1-1.RLP51 overexpression also partially rescues the weak bri1 mutant allele,bri1-301.Although the rlp51 single mutant exhibits wild-type-like phenotypes,it enhances BR-defective phenotypes in bri1-301 and bak1 serk1 mutants.RLP51 is next found to interact with both BRI1 and BAK1 without affecting BRI1–BAK1 interaction.Critically,co-expression of RLP51 with BRI1 or BAK1 significantly increases BRI1 and BAK1 protein abundances.RLP51 appears to promote protein synthesis rather than stabilize BRI1 and BAK1 proteins.Thus,our study identifies RLP51 as a positive regulator of BR signaling that enhances the protein levels of BRI1 and BAK1.
文摘Brain insulin resistance(BIR)is a prevalent detrimental feature of Alzheimer’s disease(AD)and all-cause dementia.Therapies designed to activate insulin signaling and enhance insulin receptor sensitivity have proven beneficial for cognitive enhancement in pre-clinical models,non-human primates,and humans.BIR encompasses dysregulated brain insulin signaling,which is either due to insulin receptor resistance,reduced insulin receptor levels,or reduced levels of insulin in the brain,affecting processes involved in AD development and progression.
基金supported by the National Natural Science Foundation of China(32170483 and 31970460)the Natural Science Foundation of Zhejiang Province(LR22C040001 and LQ23C040001)the Zhejiang Province Agricultural Technology Major Collaborative Promotion Project(2024ZDXT09).
文摘Diapause is a programmed developmental arrest process in insects.Diapause can occur at various stages of insect development and is frequently restricted to a specific developmental stage within a single species.In Bombyx mori,embryonic diapause is elicited by the diapause hormone(DH)and DH receptor(DHR)in diapause strains.Nevertheless,the regulatory mechanism through which BmDHR functions as a G protein-coupled receptor(GPCR),to exert other physiological functions in nondiapause silkworms,remains unclear.In this study,we found that BmDHR had 7 alternative splice isoforms.A knockout experiment confirmed that BmDHR mediated the transduction of diapause signals.Interestingly,the loss of BmDHR caused partial precocious metamorphosis and an embryo-lethal phenotype in nondiapause silkworms.An assessment of global transcriptional patterns revealed that BmDHR knockout affected physiological responses induced by manifold cellular processes,including the Toll/immune deficiency(Imd),Wnt,insulin-like growth factor,Hedgehog and P38/mitogen-activated protein kinase(MAPK)signaling pathways.This study expands our knowledge of the physiological roles for DHR in insect growth and development.
基金National Key Research and Development Program of China(No.2022YFD1802104).
文摘Aberrant activation of Receptor Tyrosine Kinases(RTKs)is a well-established trigger of tumorigenesis,and the over-use of RTK inhibitors often leads to drug resistance and tumor recurrence.While current Drug-Target Interaction(DTI)prediction methods(including those based on heterogeneous information networks)have shown promise,they remain limited in their ability to fully capture the nature of DTIs and often lack interpretability.To overcome these limitations,this study introduces a novel hybrid optimization model termed MDBO-RF,which integrates a Modified Dung Beetle Optimizer(MDBO)with Random Forest(RF).The key innovation lies in the enhancement of the DBO algorithm through a quaternion-based learning mechanism and the Cauchy mutation strategy,specifically designed to overcome the slow convergence and susceptibility to local optima that plague traditional metaheuristic algorithms used for hyperparameter tuning.The model leverages commonly used molecular descriptors to enhance the prediction of Tyrosine Kinase(TK)inhibitory activity and enable efficient compound screening.Our results demonstrate that MDBO-RF achieves a 3.41%increase in prediction accuracy compared to the standard RF model and outperforms several other contemporary machine learning approaches.The model effectively streamlines the RTK inhibitor screening process by improving prediction accuracy in multi-target competitive binding scenarios and reducing false-positive screening due to off-target effects.This work underscores the value of hybrid optimization strategies in bioinformatics and provides a robust,interpretable tool for accelerating drug discovery.
文摘Pancreatic ductal adenocarcinoma(PDAC)remains one of the most lethal malignancies,characterized by a highly immunosuppressive tumor microenvironment(TME),dense stromal architecture,and limited response to conventional therapies.This review comprehensively examines the emerging role of chimeric antigen receptor(CAR)-engineered immune cells,including chimeric antigen receptor-T(CAR-T),CAR-macrophages(CAR-M),and CAR-natural killer(CAR-NK)cells,as innovative immunotherapeutic strategies for PDAC.We delve into the mechanistic foundations of these platforms,highlighting their unique abilities to target tumor-associated antigens,overcome stromal barriers,and remodel the immunosuppressive TME.Recent preclinical and clinical advances demonstrate promising antitumor activity,particularly with targets such as mesothelin,claudin18.2,and human epidermal growth factor 2(HER2),though challenges related to antigen heterogeneity,TME suppression,and cell persistence remain.We further discuss synergistic approaches involving genetic engineering,microenvironment modulation,and combination therapies aimed at enhancing efficacy.Finally,we offer perspectives on the future direction of CARbased therapies,including the development of next-generation constructs,allogeneic“off-the-shelf”products,and personalized combination regimens,underscoring their potential in pancreatic cancer.
基金supported by the Non-profit Central Research Institute Fund of the Chinese Academy of Medical Sciences(2020-PT310-01).
文摘Cortico-thalamic projections(the hyper-direct pathway)are implicated in levodopa-induced dyskinesia(LID),a challenging complication in the advanced stages of Parkinson’s disease(PD).Excessive beta and gamma activity in PD and LID has frequently been reported in recent cross-sectional studies.We aimed to investigate the temporal features of beta and gamma activity in the hyper-direct pathway during the development of PD and LID in rats,as well as the regulatory role of the dopamine receptors DI(D1Rs)and DIII(D3Rs)in these disorders.We recorded motor behavior and electrophysiological data during the development of PD and LID,and after interventions with D1R and D3R antagonists and agonists.We demonstrated exaggerated beta-band activity in the PD state and excessive gamma-band activity during on-state dyskinesia.Subsequently,process-dependent increased beta activity correlated with bradykinesia during PD modeling,while process-dependent increased gamma activity correlated with dyskinesia under the cumulative effects of levodopa during on-state dyskinesia.Finally,both D1Rs and D3Rs were found to be involved in regulating dyskinesia and gamma activity.Dynamic oscillations are closely associated with motor behavior,and mapping dynamic oscillations may be associated with optimizing deep brain stimulation parameters and developing personalized neurotherapeutic targeting.Moreover,D1Rs and D3Rs may ameliorate dyskinesia by mediating gamma oscillations.
基金supported by grants from the National Natural Science Foundation of China(No.81981340417 to LiSu)Natural Science Foundation of Jiangsu Province Outstanding Youth Fund(No.BK20240134 to Yuanqing Gao).
文摘Hemorrhagic shock(HS)is a leading cause of death worldwide,particularly within the first 24 h post-injury.Current treatments are limited,especially in low-resource settings.Therapeutic hypothermia(TH)offers potential benefits by reducing metabolic demands and protecting organs,but its application in HS is challenged by cooling difficulties and side effects.This study introduces a novel nasal gel formulation of N6-cyclohexyladenosine(CHA),an adenosine A1 receptor agonist,designed to enhance brain delivery while minimizing peripheral side effects.In a mouse model of HS,administration of CHA nasal gel significantly improved survival rates,reduced metabolic rates,and protected major organs without worsening coagulopathy.Metabolomics analysis revealed a shift towards fatty acid oxidation and increased antioxidant capacity.These findings demonstrate that CHA nasal gel effectively induces TH,offering a safe and innovative treatment strategy for HS,particularly in resource-limited environments.
基金National Natural Science Foundation of China,Grant/Award Number:82260007Jilin Province Health Commission,Grant/Award Number:2024A062+1 种基金Jilin Provincial Department of Education,Grant/Award Number:JJKH20240698KJJilin Province Science and Technology Department,Grant/Award Number:20240404025ZP and 20240602100RC。
文摘Background:This study investigated the role of polydatin in regulating macrophage-epithelial cell(EC)interactions during asthma.An asthma model was induced in BALB/c mice using ovalbumin(20μg).Methods:The therapeutic effects of polydatin(20 and 40 mg/kg)were evaluated in this asthmatic mouse model.To assess the underlying mechanisms,Bronchial Epithelium Adenovirus 12-SV402B(BEAS-2B)cells were cocultured with Tohoku Hospital for Pediatrics-1(THP-1)macrophages,in which toll-like receptor 4(TLR4)was either overexpressed or knocked down,and subsequently stimulated with lipopoly-saccharide(LPS)and ATP.THP-1 cells underwent a 1-h pretreatment with polydatin(50 and 100μmol/L),Class Lipid Inhibitor-095(CLI-095,TLR4 inhibitor,1μg/mL),or A438079(P2X7R antagonist,10μmol/L)prior to LPS/ATP challenge.Results:Findings from Western blotting,enzyme-linked immunosorbent assay,flow cytometry,real-time polymerase chain reaction,and immunofluorescence assays demonstrated that modulating TLR4 expression significantly altered interleukin-1β(IL-1β)secretion from THP-1 macrophages and mitochondrial reactive oxygen species(mtROS)production in BEAS-2B ECs.In the mouse asthma model,polydatin significantly alleviated airway inflammation,oxidative stress,and apoptosis,likely by interfering with TLR4/P2X7R-mediated signaling and suppressing the activation of the NOD-like receptor protein inflammasome.Additionally,polydatin significantly reduced IL-1βand IL-18 levels and inhibited the infiltration of macrophages and eosinophils.Correspondingly,polydatin significantly attenuated TLR4/P2X7R signaling in THP-1 cells stimulated with ATP and LPS,thereby reducing IL-1βand IL-18 secretion,calcium influx,mtROS production,and apoptosis in BEAS-2B ECs.Conclusions:Polydatin is a promising therapeutic candidate for asthma,possibly by targeting macrophage-epithelium cross-talk via the TLR4/P2X7R axis.Future formulations as capsules or sprays may effectively alleviate airway inflammation and remodeling.
基金Institutional National Research Service Award T32 EY013360(to SM and SW)Research to Prevent Blindness(Career Development Award+8 种基金to PRW)BrightFocus Foundation(National Glaucoma Researchto PRW)Alcon Research Institute(Young Investigator Awardto PRW),and NIH Grants(EY032908,EY035684,EY036111to PRW)the Jefferey T.Fort Innovation Fund and Siteman Retina Research Fund(to RSA)the Hope Center Viral Vectors Core at Washington University School of Medicine,an unrestricted grant(to the Department of Ophthalmology and Visual Sciences)from Research to Prevent BlindnessVision Core Grant(P30 EY002687).
文摘Retinal ganglion cells are susceptible to neurodegenerative conditions and their death drives common forms of irreversible vision loss.In mice,there are 46 transcriptionally unique retinal ganglion cell types that demonstrate different susceptibilities to degeneration.Recent transcriptional experiments defined a novel retinal ganglion cell type that survives particularly well and uniquely expresses high levels of the orphan G-protein-coupled receptor 88.Motivated to study this retinal ganglion cell type,we obtained GPR88-Cre transgenic mice to identify the novel well-surviving retinal ganglion cells and examine their survival and regenerative potential.Our experiments demonstrate that this unidentified retinal ganglion cell type is likely accordant with previously described ON-direction-selective retinal ganglion cells.Interestingly,we find that ON-direction-selective retinal ganglion cells are resilient,but demonstrate limited potential to regenerate their axons in response to well-characterized regenerative treatments.Studying the molecular properties of the ON-direction-selective retinal ganglion cells could unlock new therapeutics to preserve retinal ganglion cells in patients.
基金funded by Chung Shan Medical University Hospital(grant number CSH 2023-C-010)Buddhist Tzu Chi Medical Foundation,Dalin Tzu Chi Hospital(grant number DTCRD112(2)-I-24).
文摘Objectives:Cholecystokinin A receptor(CCKAR)has been linked to poor prognosis in colon cancer patients,but the role of CCKAR in colon cancer cell invasiveness and the underlying mechanisms remain elusive.This study aimed to explore the effect of CCKAR on the invasive potential of colon cancer cells.Methods:Different human colon cancer cell lines were used.Gene expression was evaluated by reverse transcription polymerase chain reaction(RT-PCR)and quantitative real-time RT-PCR(qPCR),while protein expression and phosphorylation were assessed by Western blotting.Cell motility and invasiveness were examined through wound healing and invasion assays,respectively.Results:Our results showed that CCKAR expression levels varied across colon cancer cell lines,with DLD-1 and LoVo cells showing high expression.Knockdown of CCKAR significantly impaired the cell motility and invasiveness of DLD-1 and LoVo cells,downregulated integrinβ3 expression,and diminished the phosphorylation levels of focal adhesion kinase(FAK),Src,and paxillin.In addition,CCKAR knockdown modulated epithelialmesenchymal transition(EMT)markers ZO-1,E-cadherin,and vimentin and reduced urokinase-type plasminogen activator(uPA),uPA receptor(uPAR),Rho GTPase cell division control protein 42(CDC42)and RhoA,and matrix metalloproteinase-2(MMP-2).Conclusions:These findings indicate that CCKAR knockdown impairs the invasiveness of colon cancer cells,which may be attributed to modulating integrin/FAK/Rho GTPases,EMT markers,and the uPA/uPAR axis.It suggests that targeting CCKAR may represent a potential therapeutic strategy for colon cancer treatment.
基金supported by the Shenzhen Science and Technology Innovation Commission,No.JCYJ20220818103009018(to YD).
文摘The arginine-phenylalanine-amide neuropeptide receptor family comprises a subclass within the G protein-coupled receptor superfamily with crucial roles in physiological regulation.These receptors recognize and bind neuropeptides with an arginine-phenylalanine-amide motif,thereby participating in a variety of biological processes such as energy metabolism,pain perception,and reproductive functions.In this review,we explore the physiological and pathological processes involving these receptors and delve into the structure-activity relationships of their ligand peptides,clarifying the key structural motifs within these neuropeptides that determine their biological activity,pharmacological potency,and receptor selectivity.Particular emphasis is placed on their roles in modulating nociception,regulating appetite,and maintaining reproductive health.Additionally,we discuss the therapeutic potential of structure-based drug design targeting these receptors based on existing cryo-electron microscopy structures.The available structural insights into ligand-binding pockets and G protein-receptor interaction interfaces provide a clear perspective and valuable complement to ligand optimization.
基金Supported by the China Academy of Chinese Medical Sciences Innovation Fund:Multicenter Randomized Controlled Study on the Intervention of Yiqi Huoxue Huatan Tongluo decoction in Post-Stent Restenosis of Vertebral Arteries(No.CI2021A01308)In-Hospital Mentorship Program of Xiyuan Hospital,China Academy of Chinese Medical Sciences-Zhou Shaohua(No.0203055)。
文摘OBJECTIVE:To investigate the effects of optimizing Qinggan Jieyu decoction(清肝解郁方)on purinergic receptor P2X ligand-gated ion channel 7(P2X7R)and autophagy in migraine model rats based on molecular biology and histopathology.METHODS:A migraine rat model was established by a single subcutaneous nitroglycerin(NTG)injection into the posterior neck.QGJY was administered via gavage for 7 d prior to NTG induction.Behavioral changes,central sensitization biomarkers,and inflammatory cytokine levels were analyzed to evaluate migraine severity.Western blot,immunofluorescence,quantitative real-time PCR,and transmission electron microscopy were employed to assess P2X7R expression and autophagy activity in trigeminal nucleus caudalis(TNC)tissues.The P2X7R agonist 2'(3')-O-(4-Benzoylbenzoyl)adenosine-5'-triphosphate(Bz ATP)was further utilized to validate QGJY's regulatory effects.RESULTS:QGJY significantly reduced cage-climbing and head-scratching frequencies in NTG-induced migraine rats,downregulated serum and TNC levels of interleukin-1 beta,interleukin-6,and tumor necrosis factor-alpha,and suppressed central sensitization markers(substance P;calcitonin gene-related peptide;and c-fos induced growth factor)in TNC tissues(P<0.05).QGJY markedly decreased microglial cell counts and average immunofluorescence intensity in TNC tissues and promoted elongation of microglial protrusions(P<0.05).Concurrently,QGJY downregulated P2X7R protein and m RNA expression,reduced the light chain 3(LC3)-II/LC3-I ratio,elevated ubiquitin-binding protein p62 levels,and diminished autophagosome numbers in TNC tissues(P<0.05).Furthermore,QGJY reversed Bz ATP-induced P2X7R upregulation(P<0.05).CONCLUSIONS:QGJY alleviates migraine and inhibits central sensitization in rats,potentially by downregulating P2X7R expression,concomitantly suppressing autophagy,attenuating microglial activation,and reducing pro-inflammatory cytokine release.
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 grants from the Key Research and Development Program of Xinjiang Uygur autonomous region in China(Grant No.2023B02017)the National Key Research and Development Program of China(Grant No.2024YFD2300703)+1 种基金the financial support from the Beijing Rural Revitalization Agricultural Science and Technology Project(Grant No.NY2401080000),BAIC01-2025the 2115 Talent Development Program of China Agricultural University.
文摘Phytomelatonin,an emerging plant hormone,plays vital roles in plant growth,development,and stress adaptation(Arnao et al.,2022;Ullah et al.,2024).It acts both as a direct antioxidant and a signaling molecule,engaging complex networks and interacting with other phytohormones(Liu et al.,2022;Khan et al.,2023).Although phytomelatonin receptors(PMTRs)have been identified in many plants(Wei et al.,2018;Wang et al.,2022;Liu et al.,2025),the downstream signaling mechanisms,particularly receptor-mediated protein modifications and transcriptional regulation,remain poorly characterized.
基金supported by the National Natural Science Foundation of China,Nos.81873361(to YXia),82101533(to YXu)a grant from Science and Technology Commission of Shanghai Municipality,No.18401970100(to YXia)+1 种基金Top Talent of Changzhou“The 14th Five-Year Plan”High-Level Health Talents Training Project,No.2022CZBJ047(to YXu)Young Talent Development Plan Project of Changzhou Health Commission,No.CZQM2020043(to YXu).
文摘The delta-opioid receptor was previously viewed as a mediator in pain regulation.Recent data shed light on its specific role in neural protection and regeneration.An up-regulation of delta-opioid receptor expression and/or activity protects neuronal cells/tissues against various injuries and promotes neural regeneration.This review focuses on these new findings and the underlying mechanisms.In particular,we summarize the following key points:(1)the role of delta-opioid receptor in neuroprotection across various models and conditions;(2)the mechanisms of delta-opioid receptor neuroprotection against acute injury;(3)the neuroprotective mechanisms of delta-opioid receptor during prolonged injury;(4)delta-opioid receptor protection against ischemic and degenerative brain diseases and the underlying mechanisms;and(5)the regulation of delta-opioid receptor in neural regeneration.This article aims to provide an overview of delta-opioid receptor-mediated neural protection and regeneration,as well as its potential in treating neurological diseases.
