Previously, we reported that M-CSF induced monocyte survival through the activation of Akt, p38MAPK and Erk1/2 kinases. Here, we found that Src family kinases were upstream of these kinases and played a central role i...Previously, we reported that M-CSF induced monocyte survival through the activation of Akt, p38MAPK and Erk1/2 kinases. Here, we found that Src family kinases were upstream of these kinases and played a central role in regulating M-CSF-induced monocyte survival. We observed that M-CSF promoted c-Src activation in monocytes and MDMs in a time-dependent manner. Src inhibitors reduced M-CSF-mediated phosphorylation of the M-CSF receptor (M-CSFR), Akt, Erk1/2, and p38 MAPK. We also observed that Src directly phosphorylated the M-CSFR. Notably, the inhibitors blocked phosphorylation of specific tyrosine residues within the M-CSFR. We further demonstrated that the Src inhibitor, PP2, attenuated M-CSF-induced NF-κB activation and M-CSF-induced monocyte survival. These findings indicated that Src family kinases mediate monocyte survival through the regulation of receptor phosphorylation and modulation of downstream signaling events. Thus, we predict that targeting Src family kinases may have therapeutic implication in inflammatory diseases.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
ABC immunoperoxidase was used to test the effects of rhTGF-β1 and rhGM-CSF on receptor expressions in J6-1 and J6-2 leukemic cell lines. Computer assisted image analysis system was introduced to evaluate positive ind...ABC immunoperoxidase was used to test the effects of rhTGF-β1 and rhGM-CSF on receptor expressions in J6-1 and J6-2 leukemic cell lines. Computer assisted image analysis system was introduced to evaluate positive index of time-and dose-dependent specimens. The expression of c-kit was elevated both in positive rate and positive index by TGF-01 in both time- and dose-dependent manners. Ing/ml rhTGF-β1 simultaneously enhanced the expression of c-fms and PDGF-R which is not detected in 50 ng / ml GM-CSF treatment. Endoglin was down-regulated after TGF-β treatment and up-regulated in J6-2 cells after GM-CSF treatment, c-kit Expression was elevated by TGF-β in J6-1 cells while decreased by both in J6-2 cells.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
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
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
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
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
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
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
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
Punicalagin has been demonstrated to exhibit anti-oxidant and anti-inflammatory properties,but whether and how it could impact hypercholesterolemia remains not fully explored.The aim of this study was to investigate t...Punicalagin has been demonstrated to exhibit anti-oxidant and anti-inflammatory properties,but whether and how it could impact hypercholesterolemia remains not fully explored.The aim of this study was to investigate the influence of punicalagin on hypercholesterolemia in mice and its related mechanisms.After 6 weeks'intervention,punicalagin significantly reduced serum total cholesterol and low-density lipoprotein cholesterol(LDL-C)levels in mice fed a high-fat high-cholesterol(HFHC)diet.Meanwhile,punicalagin supplementation lowered hepatic cholesterol level,which corresponded to the down-regulation of cholesterol synthesis genes(Fdps,Cyp51)and up-regulated bile acid synthesis genes(Cyp7a1,Cyp27a1).In addition,bile acid reabsorption was retarded in punicalagin-fed mice through down-regulating ileal apical sodium-dependent BA transporter(ASBT).Furthermore,intestinal farnesoid X receptor(FXR)-fibroblast growth factor 15(Fgf15)pathway was inhibited while hepatic FXR-small heterodimeric partner(SHP)pathway was activated in punicalagin group.Microbiota analysis and targeted metabolomics showed that punicalagin decreased the abundance of bile-salt hydrolase(BSH)-producing bacteria(Clostridiaceae and Bifidobacteriaceae)and the ratio of primary BAs to secondary BAs.In conclusion,the cholesterol-lowering effect of punicalagin partly through down-regulating cholesterol synthesis and increasing cholesterol catabolism,which could be achieved by regulating gut microbiota,altering bile acid composition and modulating FXR signaling pathway.These findings indicate the potential application of punicalagin-related products as an alternative strategy for hypercholesterolemia prevention and mitigation.展开更多
OBJECTIVE:To explore if Hewei Jiangni granule(和胃降逆颗粒,HWJNG)could regulate esophageal hypersensitivity via stromal interaction molecule 1(STIM1)/transient receptor potential vanilloid subfamily member 1(TRPV1)pat...OBJECTIVE:To explore if Hewei Jiangni granule(和胃降逆颗粒,HWJNG)could regulate esophageal hypersensitivity via stromal interaction molecule 1(STIM1)/transient receptor potential vanilloid subfamily member 1(TRPV1)pathway.METHODS:Qualitative analysis of HWJNG was analysis by high performance of liquid and gas chromatography.In vivo,animal model of non-erosive reflux disease(NERD)was established by fructose intake and restraint stress.HWJNG and Omeprazole were administered by gavage to the drug intervention group.Reflux and visceral hypersensitivity were analyzed by pathological changes,PH value test,mechanical paw withdrawal threshold,thermal withdrawal latency and mast cells(MCs)degranulation.In vitro,substance P(SP)-induced P815 cells and dorsal root ganglion(DRG)cells were cocultured.Expression in both mice and cells of STIM1,TRPV1,and esophageal visceral hypersensitivity-related gastrointestinal neurochemicals were validated by enzyme linked immunosorbent assays,quantitative realtime polymerase chain reaction(qRT-PCR)and Western blot.Moreover,overexpression and small interfering RNA against STIM1 were utilized to verify of the role of HWJNG in DRG cells.RESULTS:HWJNG significantly suppressed intercellular space widening,injury of mitochondrial,MCs degranulation,mechanical allodynia and heat neuropathic sensory and increased pH value of esophageal mucosa in NERD mice.HWJNG inhibited expression of visceral hypersensitivityrelated gastrointestinal neurochemicals in esophageal mucosa and activated P815 cells,and expression of the STIM1,TRPV1 and related neurotransmitters in DRG and DRG cells.STIM1 siRNA and HWJNG both reduced P815 cells adhesion to DRGs cells and Ca2+flow into the cytoplasmic space of DRG cells.Furthermore,HWJNG could reversed STIM1 overexpression induced upregulation of TRPV1.CONCLUSION:HWJNG suppressed intercellular space widening in NERD mice,stabilized MCs and restored neuronal hyperexcitability by regulating visceral hypersensitivity via STIM1/TRPV1 pathway.展开更多
Objective To evaluate the association of GGN repeat polymorphism of androgen receptor(AR)with ovarian reserve and ovarian response in controlled ovarian stimulation(COS).Methods This genetic association study was cond...Objective To evaluate the association of GGN repeat polymorphism of androgen receptor(AR)with ovarian reserve and ovarian response in controlled ovarian stimulation(COS).Methods This genetic association study was conducted among a total of 361 women aged≤40 years with basal FSH≤12 U/L undergoing the GnRH-agonist long protocol for COS in a university affiliated IVF center.GGN repeat in the AR gene was analyzed with Sanger sequencing.The primary endpoint was the number of antral follicle counts(AFCs),and the secondary endpoints were stimulation days,total dose of gonadotropin(Gn)used,total number of retrieved oocytes,ovarian sensitivity index,and follicular output rate.Results The GGN repeat in exon 1 of the AR gene ranged from 13 to 24,and the median repeat length was 22.Based on the genotypes(S for GGN repeats<22,L for GGN repeats≥22),the patients were divided into 3 groups:SS,SL,and LL.Generalized regression analysis indicated that the number of AFCs in group SS was significantly lower than those in group SL(adjusted β=1.8,95%CI:0.2-3.4,P=0.024)and group LL(adjusted β=1.5,95%CI:0.2-2.7,P=0.021).No significant difference was observed in the number of AFCs between group SL and group LL(P>0.05).Generalized regression analysis indicated no significant differences in ovarian stimulation parameters among the 3 groups,either before or after adjusting for confounding factors(P>0.05).Conclusion GGN repeat length on the AR gene is associated with AFC but not with ovarian response in Chinese women,indicating that AR gene polymorphisms may affect ovarian reserve.展开更多
BACKGROUND C-X-C chemokine receptor type 5(CXCR5)^(+)CD8^(+)T cells represent a unique immune subset with dual roles,functioning as cytotoxic cells in persistent viral infections while promoting B cell responses.Despi...BACKGROUND C-X-C chemokine receptor type 5(CXCR5)^(+)CD8^(+)T cells represent a unique immune subset with dual roles,functioning as cytotoxic cells in persistent viral infections while promoting B cell responses.Despite their importance,the specific role of CXCR5^(+)CD8^(+)T cells in chronic hepatitis B(CHB),particularly during interferon-alpha(IFN-α)treatment,is not fully understood.This study aims to elucidate the relationship between CXCR5^(+)CD8^(+)T cells and sustained serologic response(SR)in patients undergoing 48 weeks of pegylated IFN-α(peg-IFN-α)treatment for CHB.AIM To elucidate the relationship between CXCR5^(+)CD8^(+)T cells and sustained SR in patients undergoing 48 weeks of peg-IFN-αtreatment for CHB.METHODS This study enrolled 60 patients with hepatitis Be antigen(HBeAg)-positive CHB undergoing 48 weeks of peg-IFN-αtreatment.Participants were assessed for eligibility based on criteria such as persistent HBsAg-positive status for at least six months,HBeAb-negative,hepatitis B virus DNA levels exceeding 2×10^(4) copies/mL,and alanine aminotransferase(ALT)levels between 2 and 10 times the upper limit of normal.Blood samples were collected at baseline and at weeks 12,24,48,and a 24-week treatment-free follow-up(week 72)to measure serum interleukin(IL)-21 concentration via ELISA and to analyze CXCR5 and programmed death-ligand 1(PD-L1)expression on CD8^(+)T cells by flow cytometry,CXCR5 is a chemokine receptor that directs immune cells to specific tissues,while PD-L1 is a protein that regulates immune responses by inhibiting T cell activity.RESULTS Patients with CHB exhibited significantly lower levels of circulating CXCR5^(+)CD8^(+)T cells compared to healthy controls(P<0.01).Notably,CXCR5^(+)CD8^(+)T cells were prominently expressed in patients who achieved sustained SR compared to non-SR(NSR).A significant correlation was observed between CXCR5 and PD-L1 expression(r=-0.189,P=0.002).However,there was no significant correlation between serum IL-21 levels and CXCR5+CD8+lymphocytes(r=-0.03,P=0.625)or serum ALT levels(r=0.026,P=0.678).CONCLUSION The enhanced expression of CXCR5^(+)CD8^(+)T cells in patients achieving HBeAg seroconversion during IFN-αtreatment suggests that these cells play a crucial role in antiviral immune responses against hepatitis B.This study highlights the potential of CXCR5^(+)CD8^(+)T cells as immune regulators in CHB,which may inform future therapeutic strategies to optimize antiviral treatments.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
Neuron-derived clone 77 (Nur77) is a member of the NR4A subfamily that plays critical roles in apoptosis, survival, proliferation, autophagy, angiogenesis, inflammatory responses, DNA repair, glycolipid metabolism and...Neuron-derived clone 77 (Nur77) is a member of the NR4A subfamily that plays critical roles in apoptosis, survival, proliferation, autophagy, angiogenesis, inflammatory responses, DNA repair, glycolipid metabolism and energy consumption. The deregulation of Nur77 signalling often relates to various serious diseases, including cancer and non-cancer diseases. A systematic review is necessary for the better understanding of Nur77 in clinical treatment. In this article, we comprehensively conclude the lipid regulation function and expression of Nur77, and its role in COPD. Finally, we prospect that development of drugs and clinical biochemical investigations targeting of Nur77 has considerable potential within healthcare.展开更多
BACKGROUND The classification of uterine sarcomas is based on distinctive morphological and immunophenotypic characteristics,increasingly supported by molecular genetic diagnostics.Data on neurotrophic tyrosine recept...BACKGROUND The classification of uterine sarcomas is based on distinctive morphological and immunophenotypic characteristics,increasingly supported by molecular genetic diagnostics.Data on neurotrophic tyrosine receptor kinase(NTRK)gene fusionpositive uterine sarcoma,potentially aggressive and morphologically similar to fibrosarcoma,are limited due to its recent recognition.Pan-TRK immunohistochemistry(IHC)analysis serves as an effective screening tool with high sensitivity and specificity for NTRK-fusion malignancies.CASE SUMMARY We report a case of a malignant mesenchymal tumor originating from the uterine cervix,which was pan-TRK IHC-positive but lacked NTRK gene fusions,accompanied by a brief literature review.A 55-year-old woman presented to the emergency department with abdominal pain and distension,exhibiting significant ascites and multiple solid pelvic masses.Pelvic examination revealed a tumor encompassing the uterine cervix,extending to the vagina and uterine corpus.A punch biopsy of the cervix indicated NTRK sarcoma with positive immunochemical pan-TRK stain.However,subsequent next generation sequencing revealed no NTRK gene fusion,leading to a diagnosis of poorly differentiated,advanced-stage sarcoma.CONCLUSION The clinical significance of NTRK gene fusion lies in potential treatment with TRK inhibitors for positive sarcomas.Identifying such rare tumors is crucial due to the potential applicability of tropomyosin receptor kinase inhibitor treatment.展开更多
文摘Previously, we reported that M-CSF induced monocyte survival through the activation of Akt, p38MAPK and Erk1/2 kinases. Here, we found that Src family kinases were upstream of these kinases and played a central role in regulating M-CSF-induced monocyte survival. We observed that M-CSF promoted c-Src activation in monocytes and MDMs in a time-dependent manner. Src inhibitors reduced M-CSF-mediated phosphorylation of the M-CSF receptor (M-CSFR), Akt, Erk1/2, and p38 MAPK. We also observed that Src directly phosphorylated the M-CSFR. Notably, the inhibitors blocked phosphorylation of specific tyrosine residues within the M-CSFR. We further demonstrated that the Src inhibitor, PP2, attenuated M-CSF-induced NF-κB activation and M-CSF-induced monocyte survival. These findings indicated that Src family kinases mediate monocyte survival through the regulation of receptor phosphorylation and modulation of downstream signaling events. Thus, we predict that targeting Src family kinases may have therapeutic implication in inflammatory diseases.
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 National Natural Sciences Foundation. The abstract of this work was published in Exp Hematol (1994:22:743)
文摘ABC immunoperoxidase was used to test the effects of rhTGF-β1 and rhGM-CSF on receptor expressions in J6-1 and J6-2 leukemic cell lines. Computer assisted image analysis system was introduced to evaluate positive index of time-and dose-dependent specimens. The expression of c-kit was elevated both in positive rate and positive index by TGF-01 in both time- and dose-dependent manners. Ing/ml rhTGF-β1 simultaneously enhanced the expression of c-fms and PDGF-R which is not detected in 50 ng / ml GM-CSF treatment. Endoglin was down-regulated after TGF-β treatment and up-regulated in J6-2 cells after GM-CSF treatment, c-kit Expression was elevated by TGF-β in J6-1 cells while decreased by both in J6-2 cells.
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 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.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 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 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 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.
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.
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 in part by the National Key Research and Development Program of China(2022YFD2100104)the Science and Technology Program of Shaanxi Province,China(2022JM-111)Graduate Innovation Fund of Dalian Polytechnic University。
文摘Punicalagin has been demonstrated to exhibit anti-oxidant and anti-inflammatory properties,but whether and how it could impact hypercholesterolemia remains not fully explored.The aim of this study was to investigate the influence of punicalagin on hypercholesterolemia in mice and its related mechanisms.After 6 weeks'intervention,punicalagin significantly reduced serum total cholesterol and low-density lipoprotein cholesterol(LDL-C)levels in mice fed a high-fat high-cholesterol(HFHC)diet.Meanwhile,punicalagin supplementation lowered hepatic cholesterol level,which corresponded to the down-regulation of cholesterol synthesis genes(Fdps,Cyp51)and up-regulated bile acid synthesis genes(Cyp7a1,Cyp27a1).In addition,bile acid reabsorption was retarded in punicalagin-fed mice through down-regulating ileal apical sodium-dependent BA transporter(ASBT).Furthermore,intestinal farnesoid X receptor(FXR)-fibroblast growth factor 15(Fgf15)pathway was inhibited while hepatic FXR-small heterodimeric partner(SHP)pathway was activated in punicalagin group.Microbiota analysis and targeted metabolomics showed that punicalagin decreased the abundance of bile-salt hydrolase(BSH)-producing bacteria(Clostridiaceae and Bifidobacteriaceae)and the ratio of primary BAs to secondary BAs.In conclusion,the cholesterol-lowering effect of punicalagin partly through down-regulating cholesterol synthesis and increasing cholesterol catabolism,which could be achieved by regulating gut microbiota,altering bile acid composition and modulating FXR signaling pathway.These findings indicate the potential application of punicalagin-related products as an alternative strategy for hypercholesterolemia prevention and mitigation.
基金National Natural Science Foundation of China:Study on the Molecular Mechanism of the Regulation of Crypt Goblet Cell Pyroptosis and Exocytosis to Repair Ulcerative Colitis Mucus Barrier by the Method of Clearing and Opening the Xuanfu from the Perspective of"Xuanfu-Crypt"(No.82305143),and National Natural Science Foundation of China:Exploring the Molecular Mechanism of"Hewei Jiangni Fang"Intervention in Non-erosive Reflux Disease Esophageal Hypersensitivity from the Perspective of Mas-related Gene X2/Stromal Interaction Molecule 1/Cell Adhesion Molecule 1 Pathway Regulation of Mast Cell/Dorsal Root Ganglion Communication based on the"Xinkai-Kujiang"Method(No.82374401)。
文摘OBJECTIVE:To explore if Hewei Jiangni granule(和胃降逆颗粒,HWJNG)could regulate esophageal hypersensitivity via stromal interaction molecule 1(STIM1)/transient receptor potential vanilloid subfamily member 1(TRPV1)pathway.METHODS:Qualitative analysis of HWJNG was analysis by high performance of liquid and gas chromatography.In vivo,animal model of non-erosive reflux disease(NERD)was established by fructose intake and restraint stress.HWJNG and Omeprazole were administered by gavage to the drug intervention group.Reflux and visceral hypersensitivity were analyzed by pathological changes,PH value test,mechanical paw withdrawal threshold,thermal withdrawal latency and mast cells(MCs)degranulation.In vitro,substance P(SP)-induced P815 cells and dorsal root ganglion(DRG)cells were cocultured.Expression in both mice and cells of STIM1,TRPV1,and esophageal visceral hypersensitivity-related gastrointestinal neurochemicals were validated by enzyme linked immunosorbent assays,quantitative realtime polymerase chain reaction(qRT-PCR)and Western blot.Moreover,overexpression and small interfering RNA against STIM1 were utilized to verify of the role of HWJNG in DRG cells.RESULTS:HWJNG significantly suppressed intercellular space widening,injury of mitochondrial,MCs degranulation,mechanical allodynia and heat neuropathic sensory and increased pH value of esophageal mucosa in NERD mice.HWJNG inhibited expression of visceral hypersensitivityrelated gastrointestinal neurochemicals in esophageal mucosa and activated P815 cells,and expression of the STIM1,TRPV1 and related neurotransmitters in DRG and DRG cells.STIM1 siRNA and HWJNG both reduced P815 cells adhesion to DRGs cells and Ca2+flow into the cytoplasmic space of DRG cells.Furthermore,HWJNG could reversed STIM1 overexpression induced upregulation of TRPV1.CONCLUSION:HWJNG suppressed intercellular space widening in NERD mice,stabilized MCs and restored neuronal hyperexcitability by regulating visceral hypersensitivity via STIM1/TRPV1 pathway.
文摘Objective To evaluate the association of GGN repeat polymorphism of androgen receptor(AR)with ovarian reserve and ovarian response in controlled ovarian stimulation(COS).Methods This genetic association study was conducted among a total of 361 women aged≤40 years with basal FSH≤12 U/L undergoing the GnRH-agonist long protocol for COS in a university affiliated IVF center.GGN repeat in the AR gene was analyzed with Sanger sequencing.The primary endpoint was the number of antral follicle counts(AFCs),and the secondary endpoints were stimulation days,total dose of gonadotropin(Gn)used,total number of retrieved oocytes,ovarian sensitivity index,and follicular output rate.Results The GGN repeat in exon 1 of the AR gene ranged from 13 to 24,and the median repeat length was 22.Based on the genotypes(S for GGN repeats<22,L for GGN repeats≥22),the patients were divided into 3 groups:SS,SL,and LL.Generalized regression analysis indicated that the number of AFCs in group SS was significantly lower than those in group SL(adjusted β=1.8,95%CI:0.2-3.4,P=0.024)and group LL(adjusted β=1.5,95%CI:0.2-2.7,P=0.021).No significant difference was observed in the number of AFCs between group SL and group LL(P>0.05).Generalized regression analysis indicated no significant differences in ovarian stimulation parameters among the 3 groups,either before or after adjusting for confounding factors(P>0.05).Conclusion GGN repeat length on the AR gene is associated with AFC but not with ovarian response in Chinese women,indicating that AR gene polymorphisms may affect ovarian reserve.
基金Supported by Changsha Science and Technology Program,No.kq2022397Natural Science Foundation of Hunan Province(Departmental Joint Fund),No.2023JJ60440+2 种基金Research Program of Health Commission of Hunan Province,No.202303088786Clinical Medical Research Center for Viral Hepatitis of Hunan Province,No.2023SK4009the Scientific Research Program of FuRong Laboratory,No.2023SK2108.
文摘BACKGROUND C-X-C chemokine receptor type 5(CXCR5)^(+)CD8^(+)T cells represent a unique immune subset with dual roles,functioning as cytotoxic cells in persistent viral infections while promoting B cell responses.Despite their importance,the specific role of CXCR5^(+)CD8^(+)T cells in chronic hepatitis B(CHB),particularly during interferon-alpha(IFN-α)treatment,is not fully understood.This study aims to elucidate the relationship between CXCR5^(+)CD8^(+)T cells and sustained serologic response(SR)in patients undergoing 48 weeks of pegylated IFN-α(peg-IFN-α)treatment for CHB.AIM To elucidate the relationship between CXCR5^(+)CD8^(+)T cells and sustained SR in patients undergoing 48 weeks of peg-IFN-αtreatment for CHB.METHODS This study enrolled 60 patients with hepatitis Be antigen(HBeAg)-positive CHB undergoing 48 weeks of peg-IFN-αtreatment.Participants were assessed for eligibility based on criteria such as persistent HBsAg-positive status for at least six months,HBeAb-negative,hepatitis B virus DNA levels exceeding 2×10^(4) copies/mL,and alanine aminotransferase(ALT)levels between 2 and 10 times the upper limit of normal.Blood samples were collected at baseline and at weeks 12,24,48,and a 24-week treatment-free follow-up(week 72)to measure serum interleukin(IL)-21 concentration via ELISA and to analyze CXCR5 and programmed death-ligand 1(PD-L1)expression on CD8^(+)T cells by flow cytometry,CXCR5 is a chemokine receptor that directs immune cells to specific tissues,while PD-L1 is a protein that regulates immune responses by inhibiting T cell activity.RESULTS Patients with CHB exhibited significantly lower levels of circulating CXCR5^(+)CD8^(+)T cells compared to healthy controls(P<0.01).Notably,CXCR5^(+)CD8^(+)T cells were prominently expressed in patients who achieved sustained SR compared to non-SR(NSR).A significant correlation was observed between CXCR5 and PD-L1 expression(r=-0.189,P=0.002).However,there was no significant correlation between serum IL-21 levels and CXCR5+CD8+lymphocytes(r=-0.03,P=0.625)or serum ALT levels(r=0.026,P=0.678).CONCLUSION The enhanced expression of CXCR5^(+)CD8^(+)T cells in patients achieving HBeAg seroconversion during IFN-αtreatment suggests that these cells play a crucial role in antiviral immune responses against hepatitis B.This study highlights the potential of CXCR5^(+)CD8^(+)T cells as immune regulators in CHB,which may inform future therapeutic strategies to optimize antiviral treatments.
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Neuron-derived clone 77 (Nur77) is a member of the NR4A subfamily that plays critical roles in apoptosis, survival, proliferation, autophagy, angiogenesis, inflammatory responses, DNA repair, glycolipid metabolism and energy consumption. The deregulation of Nur77 signalling often relates to various serious diseases, including cancer and non-cancer diseases. A systematic review is necessary for the better understanding of Nur77 in clinical treatment. In this article, we comprehensively conclude the lipid regulation function and expression of Nur77, and its role in COPD. Finally, we prospect that development of drugs and clinical biochemical investigations targeting of Nur77 has considerable potential within healthcare.
基金Supported by Grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute,funded by the Ministry of Health&Welfare,Republic of Korea,No.RS-2022-KH129889.
文摘BACKGROUND The classification of uterine sarcomas is based on distinctive morphological and immunophenotypic characteristics,increasingly supported by molecular genetic diagnostics.Data on neurotrophic tyrosine receptor kinase(NTRK)gene fusionpositive uterine sarcoma,potentially aggressive and morphologically similar to fibrosarcoma,are limited due to its recent recognition.Pan-TRK immunohistochemistry(IHC)analysis serves as an effective screening tool with high sensitivity and specificity for NTRK-fusion malignancies.CASE SUMMARY We report a case of a malignant mesenchymal tumor originating from the uterine cervix,which was pan-TRK IHC-positive but lacked NTRK gene fusions,accompanied by a brief literature review.A 55-year-old woman presented to the emergency department with abdominal pain and distension,exhibiting significant ascites and multiple solid pelvic masses.Pelvic examination revealed a tumor encompassing the uterine cervix,extending to the vagina and uterine corpus.A punch biopsy of the cervix indicated NTRK sarcoma with positive immunochemical pan-TRK stain.However,subsequent next generation sequencing revealed no NTRK gene fusion,leading to a diagnosis of poorly differentiated,advanced-stage sarcoma.CONCLUSION The clinical significance of NTRK gene fusion lies in potential treatment with TRK inhibitors for positive sarcomas.Identifying such rare tumors is crucial due to the potential applicability of tropomyosin receptor kinase inhibitor treatment.
