Sugars are one of the major metabolites and are essential for nucleic acid synthesis and energy production.In addition,sugars can act as signaling molecules.To study sugar signaling at the systemic level,there is an u...Sugars are one of the major metabolites and are essential for nucleic acid synthesis and energy production.In addition,sugars can act as signaling molecules.To study sugar signaling at the systemic level,there is an urgent need to systematically identify sugar-sensing proteins and nucleic acids.I propose the terms“swodkoreceptor”and“swodkocrine signaling,”derived from the Polish word“slodki”meaning“sweet,”to comprise all sugar-sensing proteins and signaling events,respectively,regardless of their cellular location and signaling domains.This proposal is intended to facilitate the inclusion of proteins such as the Escherichia coli Lac I repressor as an allolactose receptor,human glucokinase regulatory protein(GCKR)as a fructose receptor,and other sugar-binding based allosterically regulated enzymes and transcription factors as sugar-sensing receptors.In addition,enzyme-interacting proteins whose interaction state is regulated by sugar binding have also been proposed as sugar receptors.The systemic study of protein-and nucleic-acid-based swodkoreceptors may help to identify organelle-specific swodkoreceptors and to also address receptor duality.The study of intra-and inter-organism swodkocrine signaling and its crosstalk with gasocrine signaling may help to understand the etiology of diseases due to dysregulation in sugar homeostasis and signaling.展开更多
Olfactory receptors are crucial for detecting odors and play a vital role in our sense of smell,influencing behaviors from food choices to emotional memories.These receptors also contribute to our perception of flavor...Olfactory receptors are crucial for detecting odors and play a vital role in our sense of smell,influencing behaviors from food choices to emotional memories.These receptors also contribute to our perception of flavor and have potential applications in medical diagnostics and environmental monitoring.The ability of the olfactory system to regenerate its sensory neurons provides a unique model to study neural regeneration,a phenomenon largely absent in the central nervous system.Insights gained from how olfactory neurons continuously replace themselves and reestablish functional connections can provide strategies to promote similar regenerative processes in the central nervous system,where damage often results in permanent deficits.Understanding the molecular and cellular mechanisms underpinning olfactory neuron regeneration could pave the way for developing therapeutic approaches to treat spinal co rd injuries and neurodegenerative diseases like Alzheimer's disease.Olfa ctory receptors are found in almost any cell of eve ry orga n/tissue of the mammalian body.This ectopic expression provides insights into the chemical structures that can activate olfactory receptors.In addition to odors,olfactory receptors in ectopic expression may respond to endogenous compounds and molecules produced by mucosal colonizing microbiota.The analysis of the function of olfactory receptors in ectopic expression provides valuable information on the signaling pathway engaged upon receptor activation and the receptor's role in proliferation and cell differentiation mechanisms.This review explo res the ectopic expression of olfa ctory receptors and the role they may play in neural regeneration within the central nervous system,with particular attention to compounds that can activate these receptors to initiate regenerative processes.Evidence suggests that olfactory receptors could serve as potential therapeutic targets for enhancing neural repair and recovery following central nervous system injuries.展开更多
Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand...Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis exhibits significant differences before and after injury.Recent studies have revealed that the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis is closely associated with secondary inflammatory responses and the recruitment of immune cells following spinal cord injury,suggesting that this axis is a novel target and regulatory control point for treatment.This review comprehensively examines the therapeutic strategies targeting the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis,along with the regenerative and repair mechanisms linking the axis to spinal cord injury.Additionally,we summarize the upstream and downstream inflammatory signaling pathways associated with spinal cord injury and the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review primarily elaborates on therapeutic strategies that target the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the latest progress of research on antagonistic drugs,along with the approaches used to exploit new therapeutic targets within the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the development of targeted drugs.Nevertheless,there are presently no clinical studies relating to spinal cord injury that are focusing on the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review aims to provide new ideas and therapeutic strategies for the future treatment of spinal cord injury.展开更多
The delicate balance between bone formation by osteoblasts and bone resorption by osteoclasts maintains bone homeostasis.Nuclear receptors(NRs)are now understood to be crucial in bone physiology and pathology.However,...The delicate balance between bone formation by osteoblasts and bone resorption by osteoclasts maintains bone homeostasis.Nuclear receptors(NRs)are now understood to be crucial in bone physiology and pathology.However,the function of the Farnesoid X receptor(FXR),a member of the NR family,in regulating bone homeostasis remains incompletely understood.In this study,in vitro and in vivo models revealed delayed bone development and an osteoporosis phenotype in mice lacking FXR in bone marrow mesenchymal stem cells(BMSCs)and osteoblasts due to impaired osteoblast differentiation.Mechanistically,FXR could stabilize RUNX2 by inhibiting Thoc6-mediated ubiquitination,thereby promoting osteogenic activity in BMSCs.Moreover,activated FXR could directly bind to the Thoc6 promoter,suppressing its expression.The interaction between RUNX2 and Thoc6 was mediated by the Runt domain of RUNX2 and the WD repeat of Thoc6.Additionally,Obeticholic acid(OCA),an orally available FXR agonist,could ameliorate bone loss in an ovariectomy(OVX)-induced osteoporotic mouse model.Taken together,our findings suggest that FXR plays pivotal roles in osteoblast differentiation by regulating RUNX2 stability and that targeting FXR may be a promising therapeutic approach for osteoporosis.展开更多
Epidermal growth factor receptor(EGFR)is one of the most important tyrosine kinase receptor families,which plays a pivotal role in cell signaling transduction and physiological processes.Studies on the EGFR gene in hu...Epidermal growth factor receptor(EGFR)is one of the most important tyrosine kinase receptor families,which plays a pivotal role in cell signaling transduction and physiological processes.Studies on the EGFR gene in humans and other species have demonstrated its pivotal role in regulating the sodium ion balance and mediating sodium and water reabsorption in the kidney's proximal tubules.However,the impact of EGFR gene in how the Yarkand hare(Lepus yarkandensis)adapts to extreme environmental habitat remains unclear,The Yarkand hare is a desert-dwelling animal with multiple adaptations to cope with drought.Given the important physiological function of EGFR gene,we strived to understand its role in arid environment and explore the molecular mechanism of drought tolerance in the Yarkand hare.We first performed segmental cloning of the CDS of the Yarkand hare EGFR gene.Then,We constructed the phylogenetic tree of the Yarkand hare's EGFR gene and compared it with that of other species.The results showed that the Yarkand hare was most closely related to the Tolai hare(Lepus tolai).Through quantitative reverse transcription polymerase chain reaction(RT-qPCR),we discovered that EGFR expression in the kidneys of the Yarkand hare was higher than in the allopatric Tolai hare from non-arid areas.Therefore,we hypothesized that EGFR gene overexpression in the kidney of the Yarkand hare may play a crucial role in drought adaptability.Subsequently,we inserted CDS of EGFR gene into a pcDNA3.1-EGFP expression vector to construct recombinant plasmid,which was transfected into HeLa cells and overexpressed.RT-qPCR demonstrated a notable and statistically significant increase in EGFR mRNA expression and western blot proved stable expression of this protein in HeLa cells.Through cell experiments,EGFR gene overexpression markedly enhanced the survival of Hela cells subjected to NaCl,H_(2)O_(2),and heat stresses,increased superoxide dismutase activity,and decreased malondialdehyde content.In conclusion,these findings preliminarily suggest that EGFR might help the Yarkand hare adapt to extreme environmental conditions.EGFR manipulation in vivo could be a promising strategy to enhance the resilience of animals to extreme conditions.展开更多
Chimeric antigen receptor T(CAR-T)cell therapy represents a major advance in cancer immunotherapy,offering targeted treatment options,particularly for hematologic malignancies.This review comprehensively explores the ...Chimeric antigen receptor T(CAR-T)cell therapy represents a major advance in cancer immunotherapy,offering targeted treatment options,particularly for hematologic malignancies.This review comprehensively explores the structural evolution,production processes,and cytotoxic mechanisms underlying CAR-T function.Therapy involves engineering autologous T cells with synthetic receptors that allow major histocompatibility complex-independent recognition of tumor-associated antigens.Key structural components such as antigen recognition domains,spacers,transmembrane,and intracellular domains are optimized to enhance specificity,persistence,and cytotoxicity.CAR-T therapy exerts antitumor effects via granzyme-perforin degranulation,Fas/Fas ligand signaling,and cytokine secretion.Over time,the development of second-to fifth-generation CARs has incorporated costimulatory molecules,transcriptional regulation,and logic-gated control to improve efficacy and safety.Additionally,novel engineering strategies such as dual CARs,tandem CARs,SynNotch systems,and universal or inhibitory CARs have expanded antigen targeting and reduced offtumor toxicity.Emerging gene delivery technologies,including viral vectors,transposons,CRISPR/Cas9,and RNA-based electroporation,are improving CART production.Despite notable clinical success,particularly in CD19-and B-cell maturation antigen-targeted therapies,CAR-T applications face challenges,including cell exhaustion,antigen escape,and therapy-induced toxicities,such as cytokine release syndrome and neurotoxicity.Ongoing efforts in engineering innovation,clinical trials,and regulatory support continue to shape CAR-T therapy into a safer,more precise tool for cancer treatment.This review highlights current advances while outlining the barriers and future prospects of CAR-T immunotherapy.展开更多
BACKGROUND Colony-stimulating factor 3(CSF3)and its receptor(CSF3R)are known to promote gastric cancer(GC)growth and metastasis.However,their effects on the immune microenvironment remain unclear.Our analysis indicate...BACKGROUND Colony-stimulating factor 3(CSF3)and its receptor(CSF3R)are known to promote gastric cancer(GC)growth and metastasis.However,their effects on the immune microenvironment remain unclear.Our analysis indicated a potential link between CSF3R expression and the immunosuppressive receptor leukocyte immunoglobulin-like receptor B2(LILRB2)in GC.We hypothesized that CSF3/CSF3R may regulate LILRB2 and its ligands,angiopoietin-like protein 2(ANGPTL2)and human leukocyte antigen-G(HLA-G),contributing to immunosuppression.AIM To investigate the relationship between CSF3/CSF3R and LILRB2,as well as its ligands ANGPTL2 and HLA-G,in GC.METHODS Transcriptome sequencing data from The Cancer Genome Atlas were analyzed,stratifying patients by CSF3R expression.Differentially expressed genes and immune checkpoints were evaluated.Immunohistochemistry(IHC)was performed on GC tissues.Correlation analyses of CSF3R,LILRB2,ANGPTL2,and HLA-G were conducted using The Cancer Genome Atlas data and IHC results.GC cells were treated with CSF3,and expression levels of LILRB2,ANGPTL2,and HLA-G were measured by quantitative reverse transcriptase-polymerase chain reaction and western blotting.RESULTS Among 122 upregulated genes in high CSF3R expression groups,LILRB2 showed the most significant increase.IHC results indicated high expression of LILRB2(63.0%),ANGPTL2(56.5%),and HLA-G(73.9%)in GC tissues.Strong positive correlations existed between CSF3R and LILRB2,ANGPTL2,and HLA-G mRNA levels(P<0.001).IHC confirmed positive correlations between CSF3R and LILRB2(P<0.001),and HLA-G(P=0.010),but not ANGPTL2(P>0.05).CSF3 increased LILRB2,ANGPTL2,and HLA-G expression in GC cells.Heterogeneous nuclear ribonucleoprotein H1 modulation significantly altered their expression,impacting CSF3’s regulatory effects.CONCLUSION The CSF3/CSF3R pathway may contribute to immunosuppression in GC by upregulating LILRB2 and its ligands,with heterogeneous nuclear ribonucleoprotein H1 playing a regulatory role.展开更多
AMPA Receptor and PET Tracer Limitation.The alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid receptor(AMPAR)is a subtype of ionotropic glutamate receptor.It functions as a ligand-gated ion channel and is primar...AMPA Receptor and PET Tracer Limitation.The alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid receptor(AMPAR)is a subtype of ionotropic glutamate receptor.It functions as a ligand-gated ion channel and is primarily responsible for rapidly transmitting the signal from glutamate in the central nervous system[1].This receptor plays a crucial role in various cognitive functions including learning,memory,cognition,synaptic plasticity,and neurodevelopment.AMPARs are typically composed of four subunits,namely GluA1,GluA2,GluA3,and GluA4,which can form homo-or hetero-tetramers.These subunits bind directly or indirectly to various scaffolding proteins such as transmembrane AMPA receptor regulatory proteins(TARPs).展开更多
Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has b...Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer’s disease treatments in the last decades.However,existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic,necessitating the exploration of alternative therapeutic strategies.Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer’s disease patients,with dysregulated astrocytic purinergic receptors,particularly the P2Y1 receptor,all of which constitute the pathophysiology of Alzheimer’s disease.These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer’s disease.This review delves into recent insights into the association between P2Y1 receptor and Alzheimer’s disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer’s disease by mitigating neuroinflammation,thus offering promising avenues for developing drugs for Alzheimer’s disease and potentially contributing to the development of more effective treatments.展开更多
Western equine encephalitis virus(WEEV)is an arbovirus that historically caused large outbreaks of encephalitis throughout the Americas.WEEV binds protocadherin 10(PCDH10)as a receptor,and highly virulent ancestral WE...Western equine encephalitis virus(WEEV)is an arbovirus that historically caused large outbreaks of encephalitis throughout the Americas.WEEV binds protocadherin 10(PCDH10)as a receptor,and highly virulent ancestral WEEV strains also bind low-density lipoprotein receptor(LDLR)-related proteins.As WEEV declined as a human pathogen in North America over the past century,isolates have lost the ability to bind mammalian receptors while still recognizing avian receptors.To explain shifts in receptor dependencies and assess the risk of WEEV re-emergence,we determined cryoelectron microscopy structures of WEEV bound to human PCDH10,avian PCDH10,and human very-low-density lipoprotein receptor(VLDLR).We show that one to three E2 glycoprotein substitutions are sufficient for a nonpathogenic strain to regain the ability to bind mammalian receptors.A soluble VLDLR fragment protects mice from lethal challenge by a virulent ancestral WEEV strain.Because WEEV recently re-emerged in South America after decades of inactivity,our findings have important implications for outbreak preparedness.展开更多
Sex hormones,including androgens and estrogens,are known to have widespread physiological actions beyond the reproductive system via binding to their cognitive receptors,members of the nuclear receptor superfamily tha...Sex hormones,including androgens and estrogens,are known to have widespread physiological actions beyond the reproductive system via binding to their cognitive receptors,members of the nuclear receptor superfamily that function as ligand-inducible transcription factors.Meanwhile,a growing body of evidence has indicated the involvement of androgen receptor,as well as estrogen receptors such as estrogen receptor-αand estrogen receptor-β,in the pathogenesis and growth of various types of malignancies,including urothelial cancer.Additionally,in bladder cancer,the activity of sex hormone receptors has been implicated in modulating sensitivity to conventional non-surgical therapy.These may clearly explain sex-related differences in the incidence and prognosis of bladder cancer.This article focuses on summarizing the recent progress on understanding the role of sex hormones and their receptors in urothelial tumorigenesis,urothelial cancer progression,and resistance to non-surgical therapy for bladder cancer.Specifically,potential downstream effectors of sex hormone receptors have been newly identified.Thus,most of previous and subsequent data have indicated that activation of the androgen receptor or estrogen receptor-βpathway is favorable for urothelial cancer,while conflicting data exist especially on estrogen receptor-αfunctions.展开更多
BACKGROUND Yinchenhao decoction(YCHD)is a traditional Chinese medicine widely used to treat liver damage caused by obstructive jaundice(OJ).Although YCHD has demonstrated protective effects against liver damage,reduce...BACKGROUND Yinchenhao decoction(YCHD)is a traditional Chinese medicine widely used to treat liver damage caused by obstructive jaundice(OJ).Although YCHD has demonstrated protective effects against liver damage,reduced apoptosis,and mitigated oxidative stress in OJ,the precise molecular mechanisms involved remain poorly understood.AIM To investigate the beneficial effects of YCHD on OJ and elucidate the underlying mechanisms.METHODS The active constituents of YCHD were identified using liquid chromatography tandem mass spectrometry,and their potential targets for OJ treatment were predicted through network pharmacology.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed.An OJ rat model was established by common bile duct ligation.Rats were divided into three groups:Sham surgery(S Group),model(O Group),and YCHD(Y Group).YCHD was administered to Group Y for one week.Bilirubin levels,liver function parameters,and bile acid concentrations in blood and urine were measured by enzyme-linked immunosorbent assay.The bile acid renal clearance rate(Clr)was calculated.Histopathological evaluation of liver and kidney tissues was performed using hematoxylin-eosin staining.Western blotting was utilized to assess the expression of key bile acid metabolism and transport proteins in both liver and kidney tissues.The expression of the constitutive androstane receptor(CAR)and its nuclear localization were evaluated by immunohistochemistry.Molecular docking studies identified the epidermal growth factor receptor(EGFR)as a potential target of YCHD's active components.An OJ cell model was created using human liver(L02)and renal tubular epithelial(HK-2)cells,which were treated with YCHD-containing serum.Western blotting and immunofluorescence assays were employed to evaluate CAR expression and its nuclear localization in relation to EGFR activation.RESULTS Network analysis identified the EGFR signaling pathway as a key mechanism through which YCHD exerts its effects on OJ.In vivo experiments showed that YCHD improved liver function,reduced OJ-induced pathology in liver and kidney tissues,and decreased serum bile acid content by enhancing bile acid Clr and urine output.YCHD also increased CAR expression and nuclear heterotopy,upregulating proteins involved in bile acid metabolism and transport,including CYP3A4,UGT1A1,MRP3,and MRP4 in the liver,and MRP2 and MRP4 in the kidneys.In vitro,YCHD increased CAR expression and nuclear heterotopy in L02 and HK-2 cells,an effect that was reversed by EGFR agonists.CONCLUSION YCHD enhances bile acid metabolism in the liver and promotes bile acid excretion in the kidneys,ameliorating liver damage caused by OJ.These effects are likely mediated by the upregulation of CAR and its nuclear translocation.展开更多
Different from reversible agonist-stimulated receptor activation,singlet oxygen oxidation activates permanently G protein-coupled receptor(GPCR)cholecystokinin 1(CCK1R)in type II photodynamic action,with soluble photo...Different from reversible agonist-stimulated receptor activation,singlet oxygen oxidation activates permanently G protein-coupled receptor(GPCR)cholecystokinin 1(CCK1R)in type II photodynamic action,with soluble photosensitizer dyes(sulphonated aluminum phthalocyanine,λmax 675 nm)or genetically encoded protein photosensitizers(KillerRedλmax 585 nm;mini singlet oxygen generatorλmax 450 nm),together with a pulse of light(37 mW/cm2,1-2 minutes).Three lines of evidence shed light on the mechanism of GPCR activated by singlet oxygen(GPCR-ABSO):(1)CCK1R is quantitatively converted from dimer to monomer;(2)Transmembrane domain 3,a pharmacophore for permanent photodynamic CCK1R activation,can be transplanted to non-susceptible M3 acetylcholine receptor;and(3)Larger size of disordered region in intracellular loop 3 correlates with higher sensitivity to photodynamic CCK1R activation.GPCR-ABSO will add to the arsenal of engineered designer GPCR such as receptors activated solely by synthetic ligands and designer receptors exclusively activated by designer drugs,but show some clear advantages:Enhanced selectivity(double selectivity of localized photosensitizer and light illumination),long-lasting activation with no need for repeated drug administration,antagonist-binding site remains intact when needed,ease to apply to multiple GPCR.This type of permanent photodynamic activation may be applied to functional proteins other than GPCR.展开更多
BACKGROUND Epidermal growth factor receptor(EGFR)is a transmembrane protein that is differentially expressed in gestational diabetes mellitus(GDM).Endothelial dy-sfunction is a hallmark of GDM and plays a key role in ...BACKGROUND Epidermal growth factor receptor(EGFR)is a transmembrane protein that is differentially expressed in gestational diabetes mellitus(GDM).Endothelial dy-sfunction is a hallmark of GDM and plays a key role in its pathogenesis.EGFR is associated with endothelial dysfunction in the context of various diseases.How-ever,the exact mechanism by which EGFR causes endothelial dysfunction in GDM is unknown,particularly its regulation at the transcriptional and protein levels.METHODS Quantitative real-time polymerase chain reaction was used to detect the ex-pression of EGFR and H19.Western blotting was used to detect the expression of endothelial cell dysfunction markers.A cell counting kit 8 assay was used to assess cell viability,flow cytometry was used to assess apoptosis,scratch and Transwell assays were used to assess cell migration,and a tube formation assay was used to assess cell vascular formation.Hematoxylin-eosin staining was used to observe histopathological changes in the placentas of the mice.RESULTS In this study,EGFR was upregulated in clinical samples,GDM animal models and GDM cell models,and the knockdown of EGFR could mitigate the effect of streptozotocin(STZ)and high glucose(HG);promoted the proliferation,migration and vascularization of human umbilical vein endothelial cells(HUVECs);inhibited cell apoptosis and the expression of endothelial cell dysfunction markers(vascular cell adhesion molecule-1,tumor necrosis factor-α,vascular endothelial growth factor-A,and intercellular cell adhesion molecule-1);and alleviated the process of GDM in vivo.Mechanistically,EIF4A3 binding to long noncoding RNA H19 increased the stability of EGFR messenger RNA,thereby promoting HG-induced HUVECs dysfunction or STZ-induced endothelial cell dysfunction in GDM mice.In addition,ERRFI1 also regulated the expression of EGFR,and ERRFI1 inhibited EGFR activity by binding to EGFR,thereby inhibiting HG-induced HUVECs dysfunction.CONCLUSION Our study revealed that EGFR can accelerate the development of GDM by promoting endothelial cell dysfunction.展开更多
Colorectal cancer(CRC)is the third most common cancer worldwide and remains a major treatment challenge,particularly in advanced and metastatic stages.Current standard treatments have limited efficacy,underscoring the...Colorectal cancer(CRC)is the third most common cancer worldwide and remains a major treatment challenge,particularly in advanced and metastatic stages.Current standard treatments have limited efficacy,underscoring the urgent need for innovative strategies.Adoptive cell therapy(ACT),which involves in vitro expansion or genetic engineering of immune cells,is a promising approach to bolster anti-tumor immune responses.Key ACT modalities include chimeric antigen receptor(CAR)T cells,tumor-infiltrating lymphocytes(TILs),and T cell receptor(TCR)-engineered T cells.CAR-T cell therapy has shown success in hematological malignancies but faces significant challenges in solid tumors like CRC.These challenges include antigen heterogeneity,an immunosuppressive tumor microenvironment,on-target off-tumor toxicity,among other factors.To address these limitations,combinatorial approaches,such as immune checkpoint inhibitors,cytokines,and advanced gene-editing tools like CRISPR/Cas9,are being actively explored.These strategies aim to enhance CAR-T cell specificity,improve resistance to immunosuppressive signals,and optimize in vivo functionality.This review summarizes ACT approaches for CRC,with a focus on CAR-T therapy.It briefly introduces TILs and TCR-T cells,while emphasizing the major challenges faced by CAR-T therapy in solid tumors and discusses potential strategies to improve therapeutic outcomes.展开更多
Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit...Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit NLR family pyrin domain containing protein 3(NLRP3)inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease.However,little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke.To address this issue in the present study,we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models.First,we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis.We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation.Second,we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus.Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype.Finally,we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin,an NLRP3 agonist,restored the neurotoxic astrocyte phenotype.These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.展开更多
BACKGROUND Transforming growth factor-β(TGF-β)superfamily plays an important role in tumor progression and metastasis.Activin A receptor type 1C(ACVR1C)is a TGF-βtype I receptor that is involved in tumorigenesis th...BACKGROUND Transforming growth factor-β(TGF-β)superfamily plays an important role in tumor progression and metastasis.Activin A receptor type 1C(ACVR1C)is a TGF-βtype I receptor that is involved in tumorigenesis through binding to dif-ferent ligands.AIM To evaluate the correlation between single nucleotide polymorphisms(SNPs)of ACVR1C and susceptibility to esophageal squamous cell carcinoma(ESCC)in Chinese Han population.METHODS In this hospital-based cohort study,1043 ESCC patients and 1143 healthy controls were enrolled.Five SNPs(rs4664229,rs4556933,rs77886248,rs77263459,rs6734630)of ACVR1C were assessed by the ligation detection reaction method.Hardy-Weinberg equilibrium test,genetic model analysis,stratified analysis,linkage disequi-librium test,and haplotype analysis were conducted.RESULTS Participants carrying ACVR1C rs4556933 GA mutant had significantly decreased risk of ESCC,and those with rs77886248 TA mutant were related with higher risk,especially in older male smokers.In the haplotype analysis,ACVR1C Trs4664229Ars4556933Trs77886248Crs77263459Ars6734630 increased risk of ESCC,while Trs4664229Grs4556933Trs77886248Crs77263459Ars6734630 was associated with lower susceptibility to ESCC.CONCLUSION ACVR1C rs4556933 and rs77886248 SNPs were associated with the susceptibility to ESCC,which could provide a potential target for early diagnosis and treatment of ESCC in Chinese Han population.展开更多
Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0...Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain injury.Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema.Next,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells.Finally,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema.Furthermore,YL-0919 effectively combated oxidative stress both in vivo and in vitro.The protective effects of YL-0919 were partially inhibited by BD-1047.These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047.YL-0919 may have potential as a new treatment for traumatic brain injury.展开更多
The hypothalamic-pituitary-adrenal axis regulates the secretion of glucoco rticoids in response to environmental challenges.In the brain,a nuclear receptor transcription fa ctor,the glucocorticoid recepto r,is an impo...The hypothalamic-pituitary-adrenal axis regulates the secretion of glucoco rticoids in response to environmental challenges.In the brain,a nuclear receptor transcription fa ctor,the glucocorticoid recepto r,is an important component of the hypothalamicpituitary-a d renal axis's negative feedback loop and plays a key role in regulating cognitive equilibrium and neuroplasticity.The glucoco rticoid receptor influences cognitive processes,including glutamate neurotransmission,calcium signaling,and the activation of brain-derived neurotrophic factor-mediated pathways,through a combination of genomic and non-genomic mechanisms.Protein interactions within the central nervous system can alter the expression and activity of the glucocorticoid receptor,there by affecting the hypothalamic-pituitary-a d renal axis and stress-related cognitive functions.An appropriate level of glucocorticoid receptor expression can improve cognitive function,while excessive glucocorticoid receptors or long-term exposure to glucoco rticoids may lead to cognitive impairment.Patients with cognitive impairment-associated diseases,such as Alzheimer's disease,aging,depression,Parkinson's disease,Huntington's disease,stroke,and addiction,often present with dysregulation of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor expression.This review provides a comprehensive overview of the functions of the glucoco rticoid receptor in the hypothalamic-pituitary-a d renal axis and cognitive activities.It emphasizes that appropriate glucocorticoid receptor signaling fa cilitates learning and memory,while its dysregulation can lead to cognitive impairment.This provides clues about how glucocorticoid receptor signaling can be targeted to ove rcome cognitive disability-related disorders.展开更多
Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen r...Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.展开更多
基金supported by the National Science Centre grants,Grant/Award Number:SONATA-BIS 2020/38/E/NZ3/00090 and SONATA 2021/43/D/NZ3/01798。
文摘Sugars are one of the major metabolites and are essential for nucleic acid synthesis and energy production.In addition,sugars can act as signaling molecules.To study sugar signaling at the systemic level,there is an urgent need to systematically identify sugar-sensing proteins and nucleic acids.I propose the terms“swodkoreceptor”and“swodkocrine signaling,”derived from the Polish word“slodki”meaning“sweet,”to comprise all sugar-sensing proteins and signaling events,respectively,regardless of their cellular location and signaling domains.This proposal is intended to facilitate the inclusion of proteins such as the Escherichia coli Lac I repressor as an allolactose receptor,human glucokinase regulatory protein(GCKR)as a fructose receptor,and other sugar-binding based allosterically regulated enzymes and transcription factors as sugar-sensing receptors.In addition,enzyme-interacting proteins whose interaction state is regulated by sugar binding have also been proposed as sugar receptors.The systemic study of protein-and nucleic-acid-based swodkoreceptors may help to identify organelle-specific swodkoreceptors and to also address receptor duality.The study of intra-and inter-organism swodkocrine signaling and its crosstalk with gasocrine signaling may help to understand the etiology of diseases due to dysregulation in sugar homeostasis and signaling.
文摘Olfactory receptors are crucial for detecting odors and play a vital role in our sense of smell,influencing behaviors from food choices to emotional memories.These receptors also contribute to our perception of flavor and have potential applications in medical diagnostics and environmental monitoring.The ability of the olfactory system to regenerate its sensory neurons provides a unique model to study neural regeneration,a phenomenon largely absent in the central nervous system.Insights gained from how olfactory neurons continuously replace themselves and reestablish functional connections can provide strategies to promote similar regenerative processes in the central nervous system,where damage often results in permanent deficits.Understanding the molecular and cellular mechanisms underpinning olfactory neuron regeneration could pave the way for developing therapeutic approaches to treat spinal co rd injuries and neurodegenerative diseases like Alzheimer's disease.Olfa ctory receptors are found in almost any cell of eve ry orga n/tissue of the mammalian body.This ectopic expression provides insights into the chemical structures that can activate olfactory receptors.In addition to odors,olfactory receptors in ectopic expression may respond to endogenous compounds and molecules produced by mucosal colonizing microbiota.The analysis of the function of olfactory receptors in ectopic expression provides valuable information on the signaling pathway engaged upon receptor activation and the receptor's role in proliferation and cell differentiation mechanisms.This review explo res the ectopic expression of olfa ctory receptors and the role they may play in neural regeneration within the central nervous system,with particular attention to compounds that can activate these receptors to initiate regenerative processes.Evidence suggests that olfactory receptors could serve as potential therapeutic targets for enhancing neural repair and recovery following central nervous system injuries.
基金supported by the National Natural Science Foundation of China(Key Program),No.11932013the National Natural Science Foundation of China(General Program),No.82272255+2 种基金Armed Police Force High-Level Science and Technology Personnel ProjectThe Armed Police Force Focuses on Supporting Scientific and Technological Innovation TeamsKey Project of Tianjin Science and Technology Plan,No.20JCZDJC00570(all to XC)。
文摘Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis exhibits significant differences before and after injury.Recent studies have revealed that the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis is closely associated with secondary inflammatory responses and the recruitment of immune cells following spinal cord injury,suggesting that this axis is a novel target and regulatory control point for treatment.This review comprehensively examines the therapeutic strategies targeting the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis,along with the regenerative and repair mechanisms linking the axis to spinal cord injury.Additionally,we summarize the upstream and downstream inflammatory signaling pathways associated with spinal cord injury and the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review primarily elaborates on therapeutic strategies that target the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the latest progress of research on antagonistic drugs,along with the approaches used to exploit new therapeutic targets within the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the development of targeted drugs.Nevertheless,there are presently no clinical studies relating to spinal cord injury that are focusing on the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review aims to provide new ideas and therapeutic strategies for the future treatment of spinal cord injury.
基金supported by National Natural Science Foundation of China(grant numbers 82072523 to Zhiyong Hou)Postdoctoral program of Clinical medicine of Hebei Medical University(grant numbers PD2023012 to Sujuan Xu)+2 种基金Excellent postdoctoral research funding project of Hebei Province(grant numbers B2023005011 to Sujuan Xu)The 16th special grant of China Postdoctoral Science Foundation(grant numbers 2023T160182 to Sujuan Xu)Natural Science Foundation of Hebei Province,China(grant numbers H2023206230 to Yingchao Yin,H2024206186 to Sujuan Xu).
文摘The delicate balance between bone formation by osteoblasts and bone resorption by osteoclasts maintains bone homeostasis.Nuclear receptors(NRs)are now understood to be crucial in bone physiology and pathology.However,the function of the Farnesoid X receptor(FXR),a member of the NR family,in regulating bone homeostasis remains incompletely understood.In this study,in vitro and in vivo models revealed delayed bone development and an osteoporosis phenotype in mice lacking FXR in bone marrow mesenchymal stem cells(BMSCs)and osteoblasts due to impaired osteoblast differentiation.Mechanistically,FXR could stabilize RUNX2 by inhibiting Thoc6-mediated ubiquitination,thereby promoting osteogenic activity in BMSCs.Moreover,activated FXR could directly bind to the Thoc6 promoter,suppressing its expression.The interaction between RUNX2 and Thoc6 was mediated by the Runt domain of RUNX2 and the WD repeat of Thoc6.Additionally,Obeticholic acid(OCA),an orally available FXR agonist,could ameliorate bone loss in an ovariectomy(OVX)-induced osteoporotic mouse model.Taken together,our findings suggest that FXR plays pivotal roles in osteoblast differentiation by regulating RUNX2 stability and that targeting FXR may be a promising therapeutic approach for osteoporosis.
基金supported by the Central Guidance for Local Projects of Xinjiang(ZYYD2024ZY04)the National Natural Science Foundation of China(32260116).
文摘Epidermal growth factor receptor(EGFR)is one of the most important tyrosine kinase receptor families,which plays a pivotal role in cell signaling transduction and physiological processes.Studies on the EGFR gene in humans and other species have demonstrated its pivotal role in regulating the sodium ion balance and mediating sodium and water reabsorption in the kidney's proximal tubules.However,the impact of EGFR gene in how the Yarkand hare(Lepus yarkandensis)adapts to extreme environmental habitat remains unclear,The Yarkand hare is a desert-dwelling animal with multiple adaptations to cope with drought.Given the important physiological function of EGFR gene,we strived to understand its role in arid environment and explore the molecular mechanism of drought tolerance in the Yarkand hare.We first performed segmental cloning of the CDS of the Yarkand hare EGFR gene.Then,We constructed the phylogenetic tree of the Yarkand hare's EGFR gene and compared it with that of other species.The results showed that the Yarkand hare was most closely related to the Tolai hare(Lepus tolai).Through quantitative reverse transcription polymerase chain reaction(RT-qPCR),we discovered that EGFR expression in the kidneys of the Yarkand hare was higher than in the allopatric Tolai hare from non-arid areas.Therefore,we hypothesized that EGFR gene overexpression in the kidney of the Yarkand hare may play a crucial role in drought adaptability.Subsequently,we inserted CDS of EGFR gene into a pcDNA3.1-EGFP expression vector to construct recombinant plasmid,which was transfected into HeLa cells and overexpressed.RT-qPCR demonstrated a notable and statistically significant increase in EGFR mRNA expression and western blot proved stable expression of this protein in HeLa cells.Through cell experiments,EGFR gene overexpression markedly enhanced the survival of Hela cells subjected to NaCl,H_(2)O_(2),and heat stresses,increased superoxide dismutase activity,and decreased malondialdehyde content.In conclusion,these findings preliminarily suggest that EGFR might help the Yarkand hare adapt to extreme environmental conditions.EGFR manipulation in vivo could be a promising strategy to enhance the resilience of animals to extreme conditions.
文摘Chimeric antigen receptor T(CAR-T)cell therapy represents a major advance in cancer immunotherapy,offering targeted treatment options,particularly for hematologic malignancies.This review comprehensively explores the structural evolution,production processes,and cytotoxic mechanisms underlying CAR-T function.Therapy involves engineering autologous T cells with synthetic receptors that allow major histocompatibility complex-independent recognition of tumor-associated antigens.Key structural components such as antigen recognition domains,spacers,transmembrane,and intracellular domains are optimized to enhance specificity,persistence,and cytotoxicity.CAR-T therapy exerts antitumor effects via granzyme-perforin degranulation,Fas/Fas ligand signaling,and cytokine secretion.Over time,the development of second-to fifth-generation CARs has incorporated costimulatory molecules,transcriptional regulation,and logic-gated control to improve efficacy and safety.Additionally,novel engineering strategies such as dual CARs,tandem CARs,SynNotch systems,and universal or inhibitory CARs have expanded antigen targeting and reduced offtumor toxicity.Emerging gene delivery technologies,including viral vectors,transposons,CRISPR/Cas9,and RNA-based electroporation,are improving CART production.Despite notable clinical success,particularly in CD19-and B-cell maturation antigen-targeted therapies,CAR-T applications face challenges,including cell exhaustion,antigen escape,and therapy-induced toxicities,such as cytokine release syndrome and neurotoxicity.Ongoing efforts in engineering innovation,clinical trials,and regulatory support continue to shape CAR-T therapy into a safer,more precise tool for cancer treatment.This review highlights current advances while outlining the barriers and future prospects of CAR-T immunotherapy.
基金Supported by Hebei Province Medical Science Research Project Plan,No.20230755.
文摘BACKGROUND Colony-stimulating factor 3(CSF3)and its receptor(CSF3R)are known to promote gastric cancer(GC)growth and metastasis.However,their effects on the immune microenvironment remain unclear.Our analysis indicated a potential link between CSF3R expression and the immunosuppressive receptor leukocyte immunoglobulin-like receptor B2(LILRB2)in GC.We hypothesized that CSF3/CSF3R may regulate LILRB2 and its ligands,angiopoietin-like protein 2(ANGPTL2)and human leukocyte antigen-G(HLA-G),contributing to immunosuppression.AIM To investigate the relationship between CSF3/CSF3R and LILRB2,as well as its ligands ANGPTL2 and HLA-G,in GC.METHODS Transcriptome sequencing data from The Cancer Genome Atlas were analyzed,stratifying patients by CSF3R expression.Differentially expressed genes and immune checkpoints were evaluated.Immunohistochemistry(IHC)was performed on GC tissues.Correlation analyses of CSF3R,LILRB2,ANGPTL2,and HLA-G were conducted using The Cancer Genome Atlas data and IHC results.GC cells were treated with CSF3,and expression levels of LILRB2,ANGPTL2,and HLA-G were measured by quantitative reverse transcriptase-polymerase chain reaction and western blotting.RESULTS Among 122 upregulated genes in high CSF3R expression groups,LILRB2 showed the most significant increase.IHC results indicated high expression of LILRB2(63.0%),ANGPTL2(56.5%),and HLA-G(73.9%)in GC tissues.Strong positive correlations existed between CSF3R and LILRB2,ANGPTL2,and HLA-G mRNA levels(P<0.001).IHC confirmed positive correlations between CSF3R and LILRB2(P<0.001),and HLA-G(P=0.010),but not ANGPTL2(P>0.05).CSF3 increased LILRB2,ANGPTL2,and HLA-G expression in GC cells.Heterogeneous nuclear ribonucleoprotein H1 modulation significantly altered their expression,impacting CSF3’s regulatory effects.CONCLUSION The CSF3/CSF3R pathway may contribute to immunosuppression in GC by upregulating LILRB2 and its ligands,with heterogeneous nuclear ribonucleoprotein H1 playing a regulatory role.
基金supported by the National Natural Science Foundation of China(32371066)the Guangdong Basic and Applied Basic Research Foundation(2022A1515010134)+1 种基金the Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions(NYKFKT2019009)the Shenzhen Technological Research Center for Primate Translational Medicine(XMHT20220104005).
文摘AMPA Receptor and PET Tracer Limitation.The alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid receptor(AMPAR)is a subtype of ionotropic glutamate receptor.It functions as a ligand-gated ion channel and is primarily responsible for rapidly transmitting the signal from glutamate in the central nervous system[1].This receptor plays a crucial role in various cognitive functions including learning,memory,cognition,synaptic plasticity,and neurodevelopment.AMPARs are typically composed of four subunits,namely GluA1,GluA2,GluA3,and GluA4,which can form homo-or hetero-tetramers.These subunits bind directly or indirectly to various scaffolding proteins such as transmembrane AMPA receptor regulatory proteins(TARPs).
文摘Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer’s disease treatments in the last decades.However,existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic,necessitating the exploration of alternative therapeutic strategies.Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer’s disease patients,with dysregulated astrocytic purinergic receptors,particularly the P2Y1 receptor,all of which constitute the pathophysiology of Alzheimer’s disease.These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer’s disease.This review delves into recent insights into the association between P2Y1 receptor and Alzheimer’s disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer’s disease by mitigating neuroinflammation,thus offering promising avenues for developing drugs for Alzheimer’s disease and potentially contributing to the development of more effective treatments.
文摘Western equine encephalitis virus(WEEV)is an arbovirus that historically caused large outbreaks of encephalitis throughout the Americas.WEEV binds protocadherin 10(PCDH10)as a receptor,and highly virulent ancestral WEEV strains also bind low-density lipoprotein receptor(LDLR)-related proteins.As WEEV declined as a human pathogen in North America over the past century,isolates have lost the ability to bind mammalian receptors while still recognizing avian receptors.To explain shifts in receptor dependencies and assess the risk of WEEV re-emergence,we determined cryoelectron microscopy structures of WEEV bound to human PCDH10,avian PCDH10,and human very-low-density lipoprotein receptor(VLDLR).We show that one to three E2 glycoprotein substitutions are sufficient for a nonpathogenic strain to regain the ability to bind mammalian receptors.A soluble VLDLR fragment protects mice from lethal challenge by a virulent ancestral WEEV strain.Because WEEV recently re-emerged in South America after decades of inactivity,our findings have important implications for outbreak preparedness.
文摘Sex hormones,including androgens and estrogens,are known to have widespread physiological actions beyond the reproductive system via binding to their cognitive receptors,members of the nuclear receptor superfamily that function as ligand-inducible transcription factors.Meanwhile,a growing body of evidence has indicated the involvement of androgen receptor,as well as estrogen receptors such as estrogen receptor-αand estrogen receptor-β,in the pathogenesis and growth of various types of malignancies,including urothelial cancer.Additionally,in bladder cancer,the activity of sex hormone receptors has been implicated in modulating sensitivity to conventional non-surgical therapy.These may clearly explain sex-related differences in the incidence and prognosis of bladder cancer.This article focuses on summarizing the recent progress on understanding the role of sex hormones and their receptors in urothelial tumorigenesis,urothelial cancer progression,and resistance to non-surgical therapy for bladder cancer.Specifically,potential downstream effectors of sex hormone receptors have been newly identified.Thus,most of previous and subsequent data have indicated that activation of the androgen receptor or estrogen receptor-βpathway is favorable for urothelial cancer,while conflicting data exist especially on estrogen receptor-αfunctions.
基金Supported by Tianjin Municipal Education Commission Scientific Research Program,China,No.2022KJ271.
文摘BACKGROUND Yinchenhao decoction(YCHD)is a traditional Chinese medicine widely used to treat liver damage caused by obstructive jaundice(OJ).Although YCHD has demonstrated protective effects against liver damage,reduced apoptosis,and mitigated oxidative stress in OJ,the precise molecular mechanisms involved remain poorly understood.AIM To investigate the beneficial effects of YCHD on OJ and elucidate the underlying mechanisms.METHODS The active constituents of YCHD were identified using liquid chromatography tandem mass spectrometry,and their potential targets for OJ treatment were predicted through network pharmacology.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed.An OJ rat model was established by common bile duct ligation.Rats were divided into three groups:Sham surgery(S Group),model(O Group),and YCHD(Y Group).YCHD was administered to Group Y for one week.Bilirubin levels,liver function parameters,and bile acid concentrations in blood and urine were measured by enzyme-linked immunosorbent assay.The bile acid renal clearance rate(Clr)was calculated.Histopathological evaluation of liver and kidney tissues was performed using hematoxylin-eosin staining.Western blotting was utilized to assess the expression of key bile acid metabolism and transport proteins in both liver and kidney tissues.The expression of the constitutive androstane receptor(CAR)and its nuclear localization were evaluated by immunohistochemistry.Molecular docking studies identified the epidermal growth factor receptor(EGFR)as a potential target of YCHD's active components.An OJ cell model was created using human liver(L02)and renal tubular epithelial(HK-2)cells,which were treated with YCHD-containing serum.Western blotting and immunofluorescence assays were employed to evaluate CAR expression and its nuclear localization in relation to EGFR activation.RESULTS Network analysis identified the EGFR signaling pathway as a key mechanism through which YCHD exerts its effects on OJ.In vivo experiments showed that YCHD improved liver function,reduced OJ-induced pathology in liver and kidney tissues,and decreased serum bile acid content by enhancing bile acid Clr and urine output.YCHD also increased CAR expression and nuclear heterotopy,upregulating proteins involved in bile acid metabolism and transport,including CYP3A4,UGT1A1,MRP3,and MRP4 in the liver,and MRP2 and MRP4 in the kidneys.In vitro,YCHD increased CAR expression and nuclear heterotopy in L02 and HK-2 cells,an effect that was reversed by EGFR agonists.CONCLUSION YCHD enhances bile acid metabolism in the liver and promotes bile acid excretion in the kidneys,ameliorating liver damage caused by OJ.These effects are likely mediated by the upregulation of CAR and its nuclear translocation.
基金Supported by the National Natural Science Foundation of China,No.32271278 and No.31971170.
文摘Different from reversible agonist-stimulated receptor activation,singlet oxygen oxidation activates permanently G protein-coupled receptor(GPCR)cholecystokinin 1(CCK1R)in type II photodynamic action,with soluble photosensitizer dyes(sulphonated aluminum phthalocyanine,λmax 675 nm)or genetically encoded protein photosensitizers(KillerRedλmax 585 nm;mini singlet oxygen generatorλmax 450 nm),together with a pulse of light(37 mW/cm2,1-2 minutes).Three lines of evidence shed light on the mechanism of GPCR activated by singlet oxygen(GPCR-ABSO):(1)CCK1R is quantitatively converted from dimer to monomer;(2)Transmembrane domain 3,a pharmacophore for permanent photodynamic CCK1R activation,can be transplanted to non-susceptible M3 acetylcholine receptor;and(3)Larger size of disordered region in intracellular loop 3 correlates with higher sensitivity to photodynamic CCK1R activation.GPCR-ABSO will add to the arsenal of engineered designer GPCR such as receptors activated solely by synthetic ligands and designer receptors exclusively activated by designer drugs,but show some clear advantages:Enhanced selectivity(double selectivity of localized photosensitizer and light illumination),long-lasting activation with no need for repeated drug administration,antagonist-binding site remains intact when needed,ease to apply to multiple GPCR.This type of permanent photodynamic activation may be applied to functional proteins other than GPCR.
基金Supported by the Youth Talent Program of Yunnan“Ten-thousand Talents Program”,No.YNWR-QNBJ-2018-169the Science Project of Yunnan Science and Technology Department,No.202201AY070001-068.
文摘BACKGROUND Epidermal growth factor receptor(EGFR)is a transmembrane protein that is differentially expressed in gestational diabetes mellitus(GDM).Endothelial dy-sfunction is a hallmark of GDM and plays a key role in its pathogenesis.EGFR is associated with endothelial dysfunction in the context of various diseases.How-ever,the exact mechanism by which EGFR causes endothelial dysfunction in GDM is unknown,particularly its regulation at the transcriptional and protein levels.METHODS Quantitative real-time polymerase chain reaction was used to detect the ex-pression of EGFR and H19.Western blotting was used to detect the expression of endothelial cell dysfunction markers.A cell counting kit 8 assay was used to assess cell viability,flow cytometry was used to assess apoptosis,scratch and Transwell assays were used to assess cell migration,and a tube formation assay was used to assess cell vascular formation.Hematoxylin-eosin staining was used to observe histopathological changes in the placentas of the mice.RESULTS In this study,EGFR was upregulated in clinical samples,GDM animal models and GDM cell models,and the knockdown of EGFR could mitigate the effect of streptozotocin(STZ)and high glucose(HG);promoted the proliferation,migration and vascularization of human umbilical vein endothelial cells(HUVECs);inhibited cell apoptosis and the expression of endothelial cell dysfunction markers(vascular cell adhesion molecule-1,tumor necrosis factor-α,vascular endothelial growth factor-A,and intercellular cell adhesion molecule-1);and alleviated the process of GDM in vivo.Mechanistically,EIF4A3 binding to long noncoding RNA H19 increased the stability of EGFR messenger RNA,thereby promoting HG-induced HUVECs dysfunction or STZ-induced endothelial cell dysfunction in GDM mice.In addition,ERRFI1 also regulated the expression of EGFR,and ERRFI1 inhibited EGFR activity by binding to EGFR,thereby inhibiting HG-induced HUVECs dysfunction.CONCLUSION Our study revealed that EGFR can accelerate the development of GDM by promoting endothelial cell dysfunction.
基金Supported by the Natural Science Foundation of the Science and Technology Commission of Shanghai Municipality,China,No.23ZR1458300Key Discipline Project of Shanghai Municipal Health System,China,No.2024ZDXK0004+1 种基金Doctoral Innovation Talent Base Project for Diagnosis and Treatment of Chronic Liver Diseases,China,No.RCJD2021B02Pujiang Project of Shanghai Magnolia Talent Plan,China,No.24PJD098.
文摘Colorectal cancer(CRC)is the third most common cancer worldwide and remains a major treatment challenge,particularly in advanced and metastatic stages.Current standard treatments have limited efficacy,underscoring the urgent need for innovative strategies.Adoptive cell therapy(ACT),which involves in vitro expansion or genetic engineering of immune cells,is a promising approach to bolster anti-tumor immune responses.Key ACT modalities include chimeric antigen receptor(CAR)T cells,tumor-infiltrating lymphocytes(TILs),and T cell receptor(TCR)-engineered T cells.CAR-T cell therapy has shown success in hematological malignancies but faces significant challenges in solid tumors like CRC.These challenges include antigen heterogeneity,an immunosuppressive tumor microenvironment,on-target off-tumor toxicity,among other factors.To address these limitations,combinatorial approaches,such as immune checkpoint inhibitors,cytokines,and advanced gene-editing tools like CRISPR/Cas9,are being actively explored.These strategies aim to enhance CAR-T cell specificity,improve resistance to immunosuppressive signals,and optimize in vivo functionality.This review summarizes ACT approaches for CRC,with a focus on CAR-T therapy.It briefly introduces TILs and TCR-T cells,while emphasizing the major challenges faced by CAR-T therapy in solid tumors and discusses potential strategies to improve therapeutic outcomes.
基金supported by the National Natural Science Foundation of China,No.82201460(to YH)Nanjing Medical University Science and Technology Development Fund,No.NMUB20210202(to YH).
文摘Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit NLR family pyrin domain containing protein 3(NLRP3)inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease.However,little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke.To address this issue in the present study,we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models.First,we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis.We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation.Second,we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus.Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype.Finally,we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin,an NLRP3 agonist,restored the neurotoxic astrocyte phenotype.These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.
基金Supported by The National Natural Science Foundation of China,No.82350127 and No.82241013the Shanghai Natural Science Foundation,No.20ZR1411600+2 种基金the Shanghai Shenkang Hospital Development Center,No.SHDC2020CR4039the Bethune Ethicon Excellent Surgery Foundation,No.CESS2021TC04Xuhui District Medical Research Project of Shanghai,No.SHXH201805.
文摘BACKGROUND Transforming growth factor-β(TGF-β)superfamily plays an important role in tumor progression and metastasis.Activin A receptor type 1C(ACVR1C)is a TGF-βtype I receptor that is involved in tumorigenesis through binding to dif-ferent ligands.AIM To evaluate the correlation between single nucleotide polymorphisms(SNPs)of ACVR1C and susceptibility to esophageal squamous cell carcinoma(ESCC)in Chinese Han population.METHODS In this hospital-based cohort study,1043 ESCC patients and 1143 healthy controls were enrolled.Five SNPs(rs4664229,rs4556933,rs77886248,rs77263459,rs6734630)of ACVR1C were assessed by the ligation detection reaction method.Hardy-Weinberg equilibrium test,genetic model analysis,stratified analysis,linkage disequi-librium test,and haplotype analysis were conducted.RESULTS Participants carrying ACVR1C rs4556933 GA mutant had significantly decreased risk of ESCC,and those with rs77886248 TA mutant were related with higher risk,especially in older male smokers.In the haplotype analysis,ACVR1C Trs4664229Ars4556933Trs77886248Crs77263459Ars6734630 increased risk of ESCC,while Trs4664229Grs4556933Trs77886248Crs77263459Ars6734630 was associated with lower susceptibility to ESCC.CONCLUSION ACVR1C rs4556933 and rs77886248 SNPs were associated with the susceptibility to ESCC,which could provide a potential target for early diagnosis and treatment of ESCC in Chinese Han population.
基金supported by the National Natural Science Foundation of China,Nos.82204360(to HM)and 82270411(to GW)National Science and Technology Innovation 2030 Major Program,No.2021ZD0200900(to YL)。
文摘Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain injury.Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema.Next,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells.Finally,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema.Furthermore,YL-0919 effectively combated oxidative stress both in vivo and in vitro.The protective effects of YL-0919 were partially inhibited by BD-1047.These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047.YL-0919 may have potential as a new treatment for traumatic brain injury.
基金supported by the National Natural Science Foundation of China,No.82371444(to YZ)the Natural Science Foundation of Hubei Province,No.2022CFB216(to XC)the Key Research Project of Ministry of Science and Technology of China,No.2022ZD021160(to YZ)。
文摘The hypothalamic-pituitary-adrenal axis regulates the secretion of glucoco rticoids in response to environmental challenges.In the brain,a nuclear receptor transcription fa ctor,the glucocorticoid recepto r,is an important component of the hypothalamicpituitary-a d renal axis's negative feedback loop and plays a key role in regulating cognitive equilibrium and neuroplasticity.The glucoco rticoid receptor influences cognitive processes,including glutamate neurotransmission,calcium signaling,and the activation of brain-derived neurotrophic factor-mediated pathways,through a combination of genomic and non-genomic mechanisms.Protein interactions within the central nervous system can alter the expression and activity of the glucocorticoid receptor,there by affecting the hypothalamic-pituitary-a d renal axis and stress-related cognitive functions.An appropriate level of glucocorticoid receptor expression can improve cognitive function,while excessive glucocorticoid receptors or long-term exposure to glucoco rticoids may lead to cognitive impairment.Patients with cognitive impairment-associated diseases,such as Alzheimer's disease,aging,depression,Parkinson's disease,Huntington's disease,stroke,and addiction,often present with dysregulation of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor expression.This review provides a comprehensive overview of the functions of the glucoco rticoid receptor in the hypothalamic-pituitary-a d renal axis and cognitive activities.It emphasizes that appropriate glucocorticoid receptor signaling fa cilitates learning and memory,while its dysregulation can lead to cognitive impairment.This provides clues about how glucocorticoid receptor signaling can be targeted to ove rcome cognitive disability-related disorders.
基金supported by the National Key R&D Program of China,No.2021YFA0805200(to SY)the National Natural Science Foundation of China,No.31970954(to SY)two grants from the Department of Science and Technology of Guangdong Province,Nos.2021ZT09Y007,2020B121201006(both to XJL)。
文摘Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.
