In order to investigate the mechanism of progestin and antiprogestin in the regulation of ovarian steroidogenesis, a dual chamber culture system was prepared with the amnion membrane of human placenta. Isolated porci...In order to investigate the mechanism of progestin and antiprogestin in the regulation of ovarian steroidogenesis, a dual chamber culture system was prepared with the amnion membrane of human placenta. Isolated porcine granulosa and thecal cells from 4~6 mm diameter follicles were grown on both sides of the amnion, respectively, and co cultured with or without LNG and RU486. After 48 h incubation, the mRNAs of FSH receptor (FSH R) and LH receptor (LH R) of both cells were observed by in situ hybridization. The results showed that granulosa cells expressed both FSH R mRNA and LH R mRNA, while thecal cells expressed LH R mRNA only. Under the stimulation of FSH, both LNG and RU486 increased FSH R mRNA expression of granulosa cells. Under the stimulation of LH, LNG enhanced LH R mRNA expression of thecal cells; while RU486 decreased its expression. When granulosa and thecal cells were exposed to FSH and LH both, the actions of LNG and RU486 in thecal cells showed the same result as that stimulated by LH alone. In granulosa cells LNG decreased LH R mRNA expression, while RU486 increased its expression. These data suggest that: (1) granulosa cells expressed FSH R mRNA significantly; (2) both the progestin and antiprogestin directly acted on the mRNA expression of gonadotropin receptors of ovarian cells, but effects were different; (3) the response of granulosa or thecal cells to the action of LNG and RU486 was not the same. The mechanism needs to be further investigated.展开更多
Bone morphogenetic proteins（BMPs） play critical roles in follicle growth and development.BMPs initiate signaling by assembling BMP receptors and activating Smads,which in turn alter expression of target genes.The me...Bone morphogenetic proteins（BMPs） play critical roles in follicle growth and development.BMPs initiate signaling by assembling BMP receptors and activating Smads,which in turn alter expression of target genes.The mechanism underlying the regulation of the expression of BMP receptors and Smads during follicle development in pigs is still unknown.By quantitative real-time PCR,the mRNA expression of BMP receptors and Smads in granulosa cells（GC） was investigated.Cells were obtained from small porcine follicles（SF;3 mm diameter） and dominant follicles（DF;6 mm diameter）;ActR1A and BMPR2 mRNA levels in DF were significantly higher（P0.05） than that in SF,whereas BMPR1B,Smad4 and Smad7 expression tended to decrease（P0.05）.The levels of BMPR1A,ActR2,Smad1,Smad5,and Smad8 mRNA did not differ between DFs and SFs.To investigate the effect of LH on BMP receptors in GC,cells obtained from porcine DFs were cultured in medium supplemented with different doses of luteinizing hormone（LH）.High doses of LH（4 IU mL-1） significantly decreased the concentration of estradiol（E2） and progesterone（P4） in medium and the expression of Cyp19a1（P450 aromatase,P450arom） and Cyp11a1（cholesterol side-chain cleavage enzyme P450,P450scc）,while significantly increased viable cell numbers and up-regulated expression of cyclin dependent kinase-4（CDK4） and cyclin D2.However,LH had no effect on the expression of BMP receptor genes.Thus,the present study indicates that the expression of members of the BMP signaling pathway in porcine GC is regulated during follicle development and the expression of BMP receptors are not regulated by LH in porcine GCs.展开更多
The functional significance of the endometrial hCG/ LH receptors has been related to a rapid release of prostaglandins. However, as compared to gonads and myometrium, in-endometrium mechanisms of transmembrane signall...The functional significance of the endometrial hCG/ LH receptors has been related to a rapid release of prostaglandins. However, as compared to gonads and myometrium, in-endometrium mechanisms of transmembrane signalling of the hCG/LH receptors are probably not conventional and remain unclear. Here we investigated, in vivo, the potential of hCG to interact with, and stimulate the membrane effector enzyme, adenylyl cyclase (AC), in human endometrium. Hormonal and nonhormonal activation of AC was tested in membrane fractions prepared from endometrial biopsies obtained from patients undergoing evaluation cycles for hormone replacement therapy (HRT) and controlled ovarian hyperstimulation (COH). AC activity was determined by the direct conversion of the substrate ATP into cAMP under unstimulated conditions and in the presence of the non-hormonal activators guanyl nucleotide and forskolin. Also AC activity was tested in the presence of hCG under conditions allowing maximal enzyme stimulation. Isoproterenol and prostaglandin E2 (PGE2) were included for comparison. Immunoblot analyses demonstrated the presence of hCG/LH receptors and Gsα protein and other members of the G protein family in the membrane fractions. Endometrial membranes also exhibited high levels of AC activity compared to luteal membranes used as control. Stimulation by GMP-P(NH)P alone was 196 ± 63 (n = 8) (pmol/mg/ min ± SD). Neither hCG nor isoproterenol showed stimulation of endometrial AC (210 ± 65, and 197 ± 53, respectively;n = 66 assays). But PGE2 stimulated the enzyme system significantly (264 ± 63, p < 0.05;n = 66 assays). These data show that membrane fractions from human endometrium express all the AC system components, namely, hCG/LH receptors, Gsα protein and AC;however, hCG does not stimulate the endometrial AC system. Our data indicate that, in great contrast to gonadal receptors, endometrial hCG/ LH receptors are not coupled to the transmembrane AC effector. The well known release of eicosanoids in response to hCG suggests that these receptors are functional in human endometrium but throughout a signalling system different from AC. This enzyme is certainly coupled to and directly activated by eicosanoids and other embryonic signals.展开更多
Objective:To investigate the potential of N-acetylcysteine(NAC)and zinc sulphate(ZnSO_(4))in mitigating reproductive dysfunction caused by di-2-ethylhexyl phthalate(DEHP)in rats and to understand the underlying mechan...Objective:To investigate the potential of N-acetylcysteine(NAC)and zinc sulphate(ZnSO_(4))in mitigating reproductive dysfunction caused by di-2-ethylhexyl phthalate(DEHP)in rats and to understand the underlying mechanisms,specifically oxidative stress and sex hormone receptor activity.Methods:Thirty-five male Wistar rats were randomly divided into five equal groups(n=7 per group).Group 1 was administered 0.5 mL of distilled water and served as the control group.Group 2 was given only DEHP(750 mg/kg/day),while group 3,4 and 5 were given DEHP(750 mg/kg/day)plus NAC(100 mg/kg/day),DEHP(750 mg/kg/day)plus ZnSO_(4)(0.5 mg/kg/day),and DEHP(750 mg/kg/day)plus NAC(100 mg/kg/day)as well as ZnSO_(4)(0.5 mg/kg/day),respectively.All treatments lasted for 21 days.Samples were obtained after the rats were sacrificed,and hormones levels in the serum and markers of oxidative stress in the testicles were analyzed using the enzyme-linked immunosorbent assay.The amount of androgen receptors in the testicles was determined by immunohistochemistry,and the susceptibility of testosterone and DEHP to bind to androgen receptor and 5α-reductase was determined by molecular docking studies.Results:DEHP decreased reproductive hormones,testicular antioxidant enzymes,increased malondialdehyde levels,and negatively impacted histology of the pituitary and testes.NAC or ZnSO_(4) treatment showed a marked improvement in testicular antioxidant status and hormone levels,as well as a positive effect on the histology of the pituitary and testes.The combination of both treatments appeared to be more effective.The affinity of DEHP to bind to androgen receptors may lead to disruption of androgen receptor signaling,which can further result in dysfunction of hormones related to androgen.However,NAC is more likely to form stronger binding interactions with follicle stimulating hormone and luteinizing hormone receptors,as well as gonadotropin-releasing hormone receptors,when compared to DEHP.Conclusions:The possibility that NAC and ZnSO_(4) could downregulate DEHP-induced sex hormone changes is suggested by their potential to reduce toxicity.展开更多
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
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
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well ...Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease. However, due to the its subtle nature and concurring events PDAC cure remains elusive. Nuclear receptors (NR) are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism, to growth and development. Given the nature of their ligands, NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases. There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages; nonetheless many aspects of their role are not fully understood. The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors, retinoic acid receptors, retinoid X receptor, androgen receptor, estrogen receptors and the orphan NR Nur, chicken ovalbumin upstream promoter transcription factor II and the liver receptor homologue-1 receptor to PDAC development, connections that could lead to the identification of novel therapies for this disease.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
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
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
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
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
In recent years,the field of neuroimmunology has witnessed a profound paradigm shift.Research has expanded beyond the traditional focus on the central nervous system to unravel the dynamic interplay between peripheral...In recent years,the field of neuroimmunology has witnessed a profound paradigm shift.Research has expanded beyond the traditional focus on the central nervous system to unravel the dynamic interplay between peripheral immunity and neural networks.Cutting-edge methodologies have unmasked a tripartite communication axis enabling peripheral immune signals to mediate the CNS:(1)neural communication via vagal afferents,(2)humoral signaling through circumventricular organ cytokine diffusion,and(3)cellular interactions involving bone marrow-derived macrophages[1].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
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
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
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
文摘In order to investigate the mechanism of progestin and antiprogestin in the regulation of ovarian steroidogenesis, a dual chamber culture system was prepared with the amnion membrane of human placenta. Isolated porcine granulosa and thecal cells from 4~6 mm diameter follicles were grown on both sides of the amnion, respectively, and co cultured with or without LNG and RU486. After 48 h incubation, the mRNAs of FSH receptor (FSH R) and LH receptor (LH R) of both cells were observed by in situ hybridization. The results showed that granulosa cells expressed both FSH R mRNA and LH R mRNA, while thecal cells expressed LH R mRNA only. Under the stimulation of FSH, both LNG and RU486 increased FSH R mRNA expression of granulosa cells. Under the stimulation of LH, LNG enhanced LH R mRNA expression of thecal cells; while RU486 decreased its expression. When granulosa and thecal cells were exposed to FSH and LH both, the actions of LNG and RU486 in thecal cells showed the same result as that stimulated by LH alone. In granulosa cells LNG decreased LH R mRNA expression, while RU486 increased its expression. These data suggest that: (1) granulosa cells expressed FSH R mRNA significantly; (2) both the progestin and antiprogestin directly acted on the mRNA expression of gonadotropin receptors of ovarian cells, but effects were different; (3) the response of granulosa or thecal cells to the action of LNG and RU486 was not the same. The mechanism needs to be further investigated.
基金supported by the National High Tech-nology Research & Development Program of China(2006AA10Z136)
文摘Bone morphogenetic proteins（BMPs） play critical roles in follicle growth and development.BMPs initiate signaling by assembling BMP receptors and activating Smads,which in turn alter expression of target genes.The mechanism underlying the regulation of the expression of BMP receptors and Smads during follicle development in pigs is still unknown.By quantitative real-time PCR,the mRNA expression of BMP receptors and Smads in granulosa cells（GC） was investigated.Cells were obtained from small porcine follicles（SF;3 mm diameter） and dominant follicles（DF;6 mm diameter）;ActR1A and BMPR2 mRNA levels in DF were significantly higher（P0.05） than that in SF,whereas BMPR1B,Smad4 and Smad7 expression tended to decrease（P0.05）.The levels of BMPR1A,ActR2,Smad1,Smad5,and Smad8 mRNA did not differ between DFs and SFs.To investigate the effect of LH on BMP receptors in GC,cells obtained from porcine DFs were cultured in medium supplemented with different doses of luteinizing hormone（LH）.High doses of LH（4 IU mL-1） significantly decreased the concentration of estradiol（E2） and progesterone（P4） in medium and the expression of Cyp19a1（P450 aromatase,P450arom） and Cyp11a1（cholesterol side-chain cleavage enzyme P450,P450scc）,while significantly increased viable cell numbers and up-regulated expression of cyclin dependent kinase-4（CDK4） and cyclin D2.However,LH had no effect on the expression of BMP receptor genes.Thus,the present study indicates that the expression of members of the BMP signaling pathway in porcine GC is regulated during follicle development and the expression of BMP receptors are not regulated by LH in porcine GCs.
文摘The functional significance of the endometrial hCG/ LH receptors has been related to a rapid release of prostaglandins. However, as compared to gonads and myometrium, in-endometrium mechanisms of transmembrane signalling of the hCG/LH receptors are probably not conventional and remain unclear. Here we investigated, in vivo, the potential of hCG to interact with, and stimulate the membrane effector enzyme, adenylyl cyclase (AC), in human endometrium. Hormonal and nonhormonal activation of AC was tested in membrane fractions prepared from endometrial biopsies obtained from patients undergoing evaluation cycles for hormone replacement therapy (HRT) and controlled ovarian hyperstimulation (COH). AC activity was determined by the direct conversion of the substrate ATP into cAMP under unstimulated conditions and in the presence of the non-hormonal activators guanyl nucleotide and forskolin. Also AC activity was tested in the presence of hCG under conditions allowing maximal enzyme stimulation. Isoproterenol and prostaglandin E2 (PGE2) were included for comparison. Immunoblot analyses demonstrated the presence of hCG/LH receptors and Gsα protein and other members of the G protein family in the membrane fractions. Endometrial membranes also exhibited high levels of AC activity compared to luteal membranes used as control. Stimulation by GMP-P(NH)P alone was 196 ± 63 (n = 8) (pmol/mg/ min ± SD). Neither hCG nor isoproterenol showed stimulation of endometrial AC (210 ± 65, and 197 ± 53, respectively;n = 66 assays). But PGE2 stimulated the enzyme system significantly (264 ± 63, p < 0.05;n = 66 assays). These data show that membrane fractions from human endometrium express all the AC system components, namely, hCG/LH receptors, Gsα protein and AC;however, hCG does not stimulate the endometrial AC system. Our data indicate that, in great contrast to gonadal receptors, endometrial hCG/ LH receptors are not coupled to the transmembrane AC effector. The well known release of eicosanoids in response to hCG suggests that these receptors are functional in human endometrium but throughout a signalling system different from AC. This enzyme is certainly coupled to and directly activated by eicosanoids and other embryonic signals.
文摘Objective:To investigate the potential of N-acetylcysteine(NAC)and zinc sulphate(ZnSO_(4))in mitigating reproductive dysfunction caused by di-2-ethylhexyl phthalate(DEHP)in rats and to understand the underlying mechanisms,specifically oxidative stress and sex hormone receptor activity.Methods:Thirty-five male Wistar rats were randomly divided into five equal groups(n=7 per group).Group 1 was administered 0.5 mL of distilled water and served as the control group.Group 2 was given only DEHP(750 mg/kg/day),while group 3,4 and 5 were given DEHP(750 mg/kg/day)plus NAC(100 mg/kg/day),DEHP(750 mg/kg/day)plus ZnSO_(4)(0.5 mg/kg/day),and DEHP(750 mg/kg/day)plus NAC(100 mg/kg/day)as well as ZnSO_(4)(0.5 mg/kg/day),respectively.All treatments lasted for 21 days.Samples were obtained after the rats were sacrificed,and hormones levels in the serum and markers of oxidative stress in the testicles were analyzed using the enzyme-linked immunosorbent assay.The amount of androgen receptors in the testicles was determined by immunohistochemistry,and the susceptibility of testosterone and DEHP to bind to androgen receptor and 5α-reductase was determined by molecular docking studies.Results:DEHP decreased reproductive hormones,testicular antioxidant enzymes,increased malondialdehyde levels,and negatively impacted histology of the pituitary and testes.NAC or ZnSO_(4) treatment showed a marked improvement in testicular antioxidant status and hormone levels,as well as a positive effect on the histology of the pituitary and testes.The combination of both treatments appeared to be more effective.The affinity of DEHP to bind to androgen receptors may lead to disruption of androgen receptor signaling,which can further result in dysfunction of hormones related to androgen.However,NAC is more likely to form stronger binding interactions with follicle stimulating hormone and luteinizing hormone receptors,as well as gonadotropin-releasing hormone receptors,when compared to DEHP.Conclusions:The possibility that NAC and ZnSO_(4) could downregulate DEHP-induced sex hormone changes is suggested by their potential to reduce toxicity.
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.
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Supported by Fondo per gli Investimenti della Ricerca di Base(FIRB)(RBAP10MY35_002)by Ente Cassa di Risparmio di Firenzeby FiorGen ONLUS to Galli A
文摘Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease. However, due to the its subtle nature and concurring events PDAC cure remains elusive. Nuclear receptors (NR) are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism, to growth and development. Given the nature of their ligands, NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases. There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages; nonetheless many aspects of their role are not fully understood. The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors, retinoic acid receptors, retinoid X receptor, androgen receptor, estrogen receptors and the orphan NR Nur, chicken ovalbumin upstream promoter transcription factor II and the liver receptor homologue-1 receptor to PDAC development, connections that could lead to the identification of novel therapies for this disease.
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.
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.
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 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 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 STI2030-Major Projects(2021ZD0200600)the National Natural Science Foundation of China(81971269).
文摘In recent years,the field of neuroimmunology has witnessed a profound paradigm shift.Research has expanded beyond the traditional focus on the central nervous system to unravel the dynamic interplay between peripheral immunity and neural networks.Cutting-edge methodologies have unmasked a tripartite communication axis enabling peripheral immune signals to mediate the CNS:(1)neural communication via vagal afferents,(2)humoral signaling through circumventricular organ cytokine diffusion,and(3)cellular interactions involving bone marrow-derived macrophages[1].
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.
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 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.
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.
