In the present article, we report that DR4 or DR5 overexpression dramatically activates the release of the inflammatory cytokines IL-8, TNF-α, CCL20, MIP-2 and MIP-1β in an NF-κB-dependent manner in 293T, MDA-MB-23...In the present article, we report that DR4 or DR5 overexpression dramatically activates the release of the inflammatory cytokines IL-8, TNF-α, CCL20, MIP-2 and MIP-1β in an NF-κB-dependent manner in 293T, MDA-MB-231 and HCT-116 cells. We showed that death receptor-mediated signals were extracellular domain-independent, whereas the effect of overexpression of the DR4 intracellular domain was much less potent. The TRADD-TRAF2-NIK- IKKα/β signaling cascade, which plays an essential role in TNF-induced NF-κB activation, was found to be involved in tumor necrosis factor-related apoptosis-inducing ligand （TRAIL） receptor-mediated signal transduction. The FADD-caspase signaling pathway, which has been reported to be mostly related to apoptosis, was identified as being essential for DR4 or DR5 overexpression-mediated NF-κB activation and cytokine secretion and crosstalks with the TRADD-TRAF2-NIK-IKKα/β signaling cascade. Furthermore, a DR5 agonistic antibody （AD5-10） triggered the inflammatory cytokine release. These data, together with previous reports, provide strong evidence that TRAIL and TRAIL receptors play an important role in inflammation.展开更多
This present study was aimed to investigate the roles of the receptors of Thl/Th2 cytokines and chemokines in lhe pathogenesis of chronic idiopathic urticaria （CIU）. Thirty patients with CIU, 30 patients with dermog...This present study was aimed to investigate the roles of the receptors of Thl/Th2 cytokines and chemokines in lhe pathogenesis of chronic idiopathic urticaria （CIU）. Thirty patients with CIU, 30 patients with dermographism and 30 healthy controls were randomly enrolled. Reverse transcription-PCR （RT-PCR） was used to analyze the mRNA of cytokine receptors in peripheral blood mononuclear cells （PBMCs）. The mRNA levels of tumor necro- sis factor receptor （TNFR）, interferon-7 receptor （IFN-yR）, and interleukin-10 receptor （IL-IOR） were statistically increased in the CIU group （P 〈 0.05）, while IL-2R, IL-4R, IL-6R, and IL-13R showed no significant differences between the CIU and other groups. The mRNA levels of CCR3 and CCR6 were statistically increased in the CIU group （P 〈 0.05）. The toll-like receptor 2 （TLR2） mRNA level was significantly lower in the CIU group than the healthy control group （P 〈 0.05）. These findings indicate that the regulation of mRNA of TNFR, IFN-γR, IL-IOR, CCR3, CCR6 and TLR2 may be involved in the pathogenesis of CIU.展开更多
Cytokine release syndrome(CRS)is a major obstacle to the widespread clinical application of chimeric antigen receptor(CAR)T cell therapies.CRS can also be induced by infections(such as SARS-CoV-2),drugs(such as therap...Cytokine release syndrome(CRS)is a major obstacle to the widespread clinical application of chimeric antigen receptor(CAR)T cell therapies.CRS can also be induced by infections(such as SARS-CoV-2),drugs(such as therapeutic antibodies),and some autoimmune diseases.Myeloid-derived macrophages play key roles in the pathogenesis of CRS,and participate in the production and release of the core CRS cytokines,including interleukin(IL)-1,IL-6,and interferon-γ.In this review,we summarize the roles of macrophages in CRS and discuss new developments in macrophage activation and the related mechanisms of cytokine regulation in CRS.展开更多
Background: Chemokines are small proteins that activate immune system in normal and pathological conditions. The induction of chemotaxis is a well-established role of chemokines. Moreover chemokines are important medi...Background: Chemokines are small proteins that activate immune system in normal and pathological conditions. The induction of chemotaxis is a well-established role of chemokines. Moreover chemokines are important mediators of angiogenesis, implantation of fetus, and maturation of immune cells. In human body many types of cells express chemokines and cytokines at level of gene and protein. In blood cells chemokine and chemokine receptors mRNA level is a one of crucial points of chemokine system condition. The aim of the study was to evaluate the relationship between plasma concentration of cyto- kines and chemokines/chemokine receptors mRNA level in blood of healthy volunteers. Results: Gene expression of eotaxin, eotaxin-2, IL-8, MIP-1α, MIP- 1β, RANTES, CCR1, CCR3, CCR5, CXCR1, and CXCR2 was measured in peripheral blood cells, as well as the concentration of IL-1β, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, eotaxin, FGF-2, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, and VEGF was evaluated in the plasma of 19 healthy individuals. We studied rela- tionship between mRNA levels of chemokines/recaptors and cytokine concentration in blood of healthy volunteers. Conclusion: These data are allowed to assess chemokines impact in the cytokine regulation of healthy subjects. These results indicate that chemokines and their receptors is diverse and redundant system of immune reactivity in response to internal and external challenges.展开更多
Objective:To assess the association between genetic variants of transferrin receptor 2(TFR2)exon 4 and anemia status and to describe the expression levels of several cytokines,hepcidin,soluble transferrin receptor and...Objective:To assess the association between genetic variants of transferrin receptor 2(TFR2)exon 4 and anemia status and to describe the expression levels of several cytokines,hepcidin,soluble transferrin receptor and erythropoietin.Methods:Institutional based comparative study was done randomly to recruit 106 pregnant women who attended antenatal care in three different health centers in Boyolali Regency,Central Java from May 2015 to September 2015.DNA was extracted from peripheral blood samples of selected pregnant women and sequencing was done for TFR2 exon 4.Furthermore,enzyme-linked immunosorbent assay was conducted to measure the expression levels of interleukin 6,interleukin 4,transforming growth factorβand iron-metabolism related proteins such as hepcidin,soluble transferrin receptor,and erythropoietin.Gene alignment was performed by using a CLUSTAL W program.Collected data were analyzed statistically by using parametric and nonparametric tests with Statistical Product and Service Solutions(SPSS)20.0 for Windows.Results:Three novel genetic variants from TFR2 exon 4(position 603,605 and 606)were associated with anemia status.Moreover,the expression levels of interleukin 6,interleukin 4,transforming growth factorβand erythropoietin were higher in anemic pregnant women than those of nonanemic pregnant women but only erythropoietin level reached statistical significance.These results were followed by decreases of hepcidin and soluble transferrin receptor levels.Conclusions:Various factors contribute to anemia prevalence among pregnant women in Boyoali Regency,Central Java,Indonesia.Our novel findings showed that TFR2 exon 4 has 3 mutational sites in position 603,605 and 606.These novel genetic variants may provide a new insight into the role of TFR2 in anemia.展开更多
Objective To investigate involvement of the aryl hydrocarbon receptor(Ah R)in the immunomodulatory effects of cadmium(Cd).Methods The effect of Cd on Ah R activation(CYP1 A1 and CYP1 B1 m RNA expression)was examined i...Objective To investigate involvement of the aryl hydrocarbon receptor(Ah R)in the immunomodulatory effects of cadmium(Cd).Methods The effect of Cd on Ah R activation(CYP1 A1 and CYP1 B1 m RNA expression)was examined in lung leukocytes of Cd-exposed rats(5 and 50 mg/L,30 d orally)and by in vitro leukocyte exposure.The involvement of Ah R signaling in the effects of Cd on the interleukin(IL)-1β,IL-6,and tumor necrosis factor(TNF)lung leukocyte response was investigated in vitro using the receptor antagonist CH-223191.Results Cd increased CYP1 B1(in vivo and in vitro)and CYP1 A1(in vitro)m RNA,indicating Ah R involvement in the action of Cd.In response to Cd,lung leukocytes increased IL-6 and decreased TNF at the gene expression and protein levels,but decreased IL-1βproduction due to reduced NLRP3.The Ah R antagonist CH-223191 abrogated the observed effects of Cd on the cytokine response.The absence of Ah R reactivity and cytokine response to Cd of leukocytes from the lungs of a rat strain that is less sensitive to Cd toxicity coincided with a high Ah R repressor m RNA level.Conclusion Ah R signaling is involved in the lung leukocyte proinflammatory cytokine response to Cd.The relevance of the Ah R to the cytokine response to Cd provides new insight into the mechanisms of Cd immunotoxicity.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
The significant function of Toll-like receptors (TLR) is the detection of microbes by host guard cells that guide to the innate immune responses and to the successive adaptive. The current study patterns of TLR2, TLR3...The significant function of Toll-like receptors (TLR) is the detection of microbes by host guard cells that guide to the innate immune responses and to the successive adaptive. The current study patterns of TLR2, TLR3 and TLR9 expressing antigen presenting cells (APCs) in blood of mice after colonization with L. plantarum NC8 strain were assessed. The power of L. plantarum on serum innate cytokine and TLR responses stimulated by recombinant NC8-pSIP409-pgsA-VP6-DCpep, NC8-pSIP409-pgsA-VP7-DCpep and NC8-pSIP409-pgsA were also assessed. We confirmed that L. plantarum NC8 stimulated powerful TLR2 expressing APC responses in blood Recombinant strain stimulated a TLR3 response in spleen, and TLR9 responses were stimulated in blood or in spleen. Recombinant NC8-pSIP409-pgsA-VP6-DCpep, NC8-pSIP409-pgsA-VP7-DCpep on TLR2 and TLR9 expressing APC responses has a preservative outcome, reliable with the DCpep adjuvant outcome. In serum the recombinant NC8-pSIP409-pgsA-VP6-DCpep, NC8-pSIP409-pgsA-VP7-DCpep has increased the IL-4 and IFN-γ responses, except that on the TLR3 and TLR9 expressing CD14 APC responses it had an oppressive consequence in spleen and the IFN-α response in serum-stimulated by PRV. Our results give details that following PRV infection after immunization with NC8-pSIP409-pgsA-VP6-DCpep, NC8-pSIP409-pgsA-VP7-DCpep, the systemic TLR2, TLR3, and TLR9 expressing cDC and macrophage/monocyte responses.展开更多
Objective: To analyze the effect of chemotherapy on peripheral blood NK cell receptor NKG2D and related immune cytokines (IL-12, IL-15, IL-18) in patients with non-small cell lung cancer (NSCLC). Methods: A total of 4...Objective: To analyze the effect of chemotherapy on peripheral blood NK cell receptor NKG2D and related immune cytokines (IL-12, IL-15, IL-18) in patients with non-small cell lung cancer (NSCLC). Methods: A total of 48 patients with NSCLC who visited the Oncology Department of the Affiliated Hospital of Chengde Medical College from September 2018 to September 2019 were selected as the study subjects. Changes in the expression levels of NKG2D, IL-12, IL-15 and IL-18 in peripheral blood of patients at different time points (before chemotherapy, after the first chemotherapy and after the second chemotherapy) were analyzed to investigate the correlation between NKG2D and IL-12, IL-15 and IL-18 in peripheral blood at each time point. Results: The expression levels of NKG2D, IL-15, and IL-18 in the peripheral blood of the patient before chemotherapy, after the first chemotherapy, and after the second chemotherapy gradually decreased. After the first chemotherapy and the second chemotherapy, the peripheral blood IL-12 was significantly lower than before chemotherapy, and IL-12 in peripheral blood after the second chemotherapy was slightly increased compared with that after the first chemotherapy. The comparison of each factor at different time points was statistically significant (all P<span style="font-family: ">0.05). Pearson correlation analysis showed that after the first chemotherapy, NKG2D in peripheral blood was positively correlated with IL-18 (r = 0.342, P = 0.031);after the second chemotherapy, NKG2D in peripheral blood was positively correlated with IL-18 (r = 0.411, P = 0.023), negatively correlated with IL-15 (r = -0.451, P = 0.001). Conclusion: There was no significant change in the number of NK cells in the peripheral blood of NSCLC patients after chemotherapy, while NKG2D and related immune cytokines decreased, which may be one of the mechanisms for the suppression of immune function in patients, and this provides a potential target for immunotherapy in patients.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
Background and Objective: It has been found that human periodontal ligament (hPDL) cells express cannabinoid receptor CB2. However, the functional importance of CB2 in hPDL cells exposed to bacterial endotoxins is not...Background and Objective: It has been found that human periodontal ligament (hPDL) cells express cannabinoid receptor CB2. However, the functional importance of CB2 in hPDL cells exposed to bacterial endotoxins is not known. Here we investigate if the inflammation promoter lipopolysaccharide (LPS) affects CB2 expression and if activation of CB2 regulates LPS-induced pro-inflammatory cytokine production and osteoclastogenic gene expression in hPDL cells. Methods: The hPDL cells were obtained from extracted teeth of periodontally healthy subjects. CB2 expression in hPDL cells exposed to LPS was deter- mined by quantitative real-time PCR analysis. Then, the cells were incubated with or without CB2-specific agonist HU-308 before further stimulation with LPS. In some experiments, the cells were pre-treated with CB2-specific antagonist SR144528. The production of pro-inflammatory cytokines interleukin-1 beta (IL- 1β), interleukin-6 (IL-6) and tumor necrosis factoralpha (TNF-α) was assessed by enzyme-linked immunosorbent assay (ELISA). The mRNA expression of osteoclastogenic genes osteoprotegerin (OPG) and receptor activator of NF-κB ligand (RANKL) was examined using quantitative real-time PCR analysis. Results: CB2 expression in hPDL cells was markedly enhanced by LPS. HU-308 significantly suppressed the production of IL-1β, IL-6 and TNF-α exposed to LPS, whereas SR144528 attenuated this effect. The OPG/RANKL ratio decreased when exposed to LPS, furthermore increased significantly with the addition of HU-308 and finally decreased markedly after pretreatment with SR144528. Conclusion: Our study demonstrated that activation of CB2 had anti-inflammatory and anti-resorptive effects on LPS-stimulated hPDL cells. These findings suggest that activation of CB2 might be an effective therapeutic strategy for the treatment of inflammation and alveolar bone resorption in periodontitis.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
Toll-like receptors are well-defined barriers in innate immunity. Among them hTLR4 on the surface of monocytes, plays a critical role in the formation of atherosclerotic plaques, plaque instability and arterial remode...Toll-like receptors are well-defined barriers in innate immunity. Among them hTLR4 on the surface of monocytes, plays a critical role in the formation of atherosclerotic plaques, plaque instability and arterial remodeling through production of inflammatory cytokines. This study was designed to examine the association of hTLR4 monocyte expression and response with the severity of coronary stenosis in patients with stable angina (SA). Blood samples were obtained from 39 patients with SA who were scheduled for a coronary angiography and from 28 healthy volunteers. The samples were collected before the procedure. Expression of hTLR4 on CD14+ monocytes and serum levels of TNF-α and IL-1β were measured using flowcytometry and ELISA techniques respectively. Percentage stenosis diameter was measured by comparing the area of coronary stenosis to an adjacent normal segment of the vessel. Compared with control group, patients showed upregulation of hTLR4+/CD14+ monocytes. Furthermore, patients with more severe coronary stenosis exhibited enhanced expression of hTLR4+/CD14+ monocytes (p α (p β. In addition, significant correlations were seen between percentage stenosis diameter and monocyte expression of hTLR4 as well as TNF-α. hTLR4 monocytic expression and related cytokines are positively associated percentage stenosis diameter. These results suggest that hTLR4 activity may be involved in progression of atherosclerosis.展开更多
Western equine encephalitis virus(WEEV)is an arbovirus that historically caused large outbreaks of encephalitis throughout the Americas.WEEV binds protocadherin 10(PCDH10)as a receptor,and highly virulent ancestral WE...Western equine encephalitis virus(WEEV)is an arbovirus that historically caused large outbreaks of encephalitis throughout the Americas.WEEV binds protocadherin 10(PCDH10)as a receptor,and highly virulent ancestral WEEV strains also bind low-density lipoprotein receptor(LDLR)-related proteins.As WEEV declined as a human pathogen in North America over the past century,isolates have lost the ability to bind mammalian receptors while still recognizing avian receptors.To explain shifts in receptor dependencies and assess the risk of WEEV re-emergence,we determined cryoelectron microscopy structures of WEEV bound to human PCDH10,avian PCDH10,and human very-low-density lipoprotein receptor(VLDLR).We show that one to three E2 glycoprotein substitutions are sufficient for a nonpathogenic strain to regain the ability to bind mammalian receptors.A soluble VLDLR fragment protects mice from lethal challenge by a virulent ancestral WEEV strain.Because WEEV recently re-emerged in South America after decades of inactivity,our findings have important implications for outbreak preparedness.展开更多
BACKGROUND Yinchenhao decoction(YCHD)is a traditional Chinese medicine widely used to treat liver damage caused by obstructive jaundice(OJ).Although YCHD has demonstrated protective effects against liver damage,reduce...BACKGROUND Yinchenhao decoction(YCHD)is a traditional Chinese medicine widely used to treat liver damage caused by obstructive jaundice(OJ).Although YCHD has demonstrated protective effects against liver damage,reduced apoptosis,and mitigated oxidative stress in OJ,the precise molecular mechanisms involved remain poorly understood.AIM To investigate the beneficial effects of YCHD on OJ and elucidate the underlying mechanisms.METHODS The active constituents of YCHD were identified using liquid chromatography tandem mass spectrometry,and their potential targets for OJ treatment were predicted through network pharmacology.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed.An OJ rat model was established by common bile duct ligation.Rats were divided into three groups:Sham surgery(S Group),model(O Group),and YCHD(Y Group).YCHD was administered to Group Y for one week.Bilirubin levels,liver function parameters,and bile acid concentrations in blood and urine were measured by enzyme-linked immunosorbent assay.The bile acid renal clearance rate(Clr)was calculated.Histopathological evaluation of liver and kidney tissues was performed using hematoxylin-eosin staining.Western blotting was utilized to assess the expression of key bile acid metabolism and transport proteins in both liver and kidney tissues.The expression of the constitutive androstane receptor(CAR)and its nuclear localization were evaluated by immunohistochemistry.Molecular docking studies identified the epidermal growth factor receptor(EGFR)as a potential target of YCHD's active components.An OJ cell model was created using human liver(L02)and renal tubular epithelial(HK-2)cells,which were treated with YCHD-containing serum.Western blotting and immunofluorescence assays were employed to evaluate CAR expression and its nuclear localization in relation to EGFR activation.RESULTS Network analysis identified the EGFR signaling pathway as a key mechanism through which YCHD exerts its effects on OJ.In vivo experiments showed that YCHD improved liver function,reduced OJ-induced pathology in liver and kidney tissues,and decreased serum bile acid content by enhancing bile acid Clr and urine output.YCHD also increased CAR expression and nuclear heterotopy,upregulating proteins involved in bile acid metabolism and transport,including CYP3A4,UGT1A1,MRP3,and MRP4 in the liver,and MRP2 and MRP4 in the kidneys.In vitro,YCHD increased CAR expression and nuclear heterotopy in L02 and HK-2 cells,an effect that was reversed by EGFR agonists.CONCLUSION YCHD enhances bile acid metabolism in the liver and promotes bile acid excretion in the kidneys,ameliorating liver damage caused by OJ.These effects are likely mediated by the upregulation of CAR and its nuclear translocation.展开更多
Different from reversible agonist-stimulated receptor activation,singlet oxygen oxidation activates permanently G protein-coupled receptor(GPCR)cholecystokinin 1(CCK1R)in type II photodynamic action,with soluble photo...Different from reversible agonist-stimulated receptor activation,singlet oxygen oxidation activates permanently G protein-coupled receptor(GPCR)cholecystokinin 1(CCK1R)in type II photodynamic action,with soluble photosensitizer dyes(sulphonated aluminum phthalocyanine,λmax 675 nm)or genetically encoded protein photosensitizers(KillerRedλmax 585 nm;mini singlet oxygen generatorλmax 450 nm),together with a pulse of light(37 mW/cm2,1-2 minutes).Three lines of evidence shed light on the mechanism of GPCR activated by singlet oxygen(GPCR-ABSO):(1)CCK1R is quantitatively converted from dimer to monomer;(2)Transmembrane domain 3,a pharmacophore for permanent photodynamic CCK1R activation,can be transplanted to non-susceptible M3 acetylcholine receptor;and(3)Larger size of disordered region in intracellular loop 3 correlates with higher sensitivity to photodynamic CCK1R activation.GPCR-ABSO will add to the arsenal of engineered designer GPCR such as receptors activated solely by synthetic ligands and designer receptors exclusively activated by designer drugs,but show some clear advantages:Enhanced selectivity(double selectivity of localized photosensitizer and light illumination),long-lasting activation with no need for repeated drug administration,antagonist-binding site remains intact when needed,ease to apply to multiple GPCR.This type of permanent photodynamic activation may be applied to functional proteins other than GPCR.展开更多
Objective:To explore the effect of tumor necrosis factor-α(TNF-α),interleukin(IL)-6,IL-18,IL-1β,and aging on the expression of P2X7receptor(P2X7R)m RNA in the brains of mice with lipopolysaccharide(LPS)treatment.Me...Objective:To explore the effect of tumor necrosis factor-α(TNF-α),interleukin(IL)-6,IL-18,IL-1β,and aging on the expression of P2X7receptor(P2X7R)m RNA in the brains of mice with lipopolysaccharide(LPS)treatment.Methods:Young(4 months old)and aged(18 months old)male C57BL/6 mice were randomly divided into 5 groups(n=7).All of the mice were injected intraperitoneally with LPS(0.5 mg/kg).After 0,3,24,48,and 72 h,the m RNA expressions of TNF-α,IL-6,IL-18,IL-1β,and P2X7R in mice's brains were determined by q PCR.Results:In brains of young mice,the highest expressions of IL-6,IL-18 and IL-1βwere found at3 h,but for TNF-αand P2X7R,the highest expressions were found at 24 h.For the aged mice,the expressions of TNF-α,IL-6,IL-1β,and P2X7R reached the highest level at 3 h,but IL-18reached the highest level at 24 h.Aged mice showed significantly higher level of TNF-αat 0,3,48,and 72 h than young mice.The similar results were observed for P2X7R at 0,3 and72 h in aged mice.Conclusion:The m RNA expression of inflammatory cytokines and P2X7R in the brains of mice were consistent with the same time points after LPS treatment.Furthermore,they were higher in aged mice compared with young mice.This result suggested that P2X7R may be involved in the development of brain aging and relevant diseases of mice by regulating the expression of inflammatory cytokines.展开更多
Recent studies have revealed that the γ-chain of theIL-2 receptor is shared by the receptors for IL-4, IL7, IL-9, IL-13, and IL-15, and it is therefore also referred toas the common γ-chain (γc). Mutations of γc r...Recent studies have revealed that the γ-chain of theIL-2 receptor is shared by the receptors for IL-4, IL7, IL-9, IL-13, and IL-15, and it is therefore also referred toas the common γ-chain (γc). Mutations of γc result inX-linked severe combined immunodeficiency syndrome inhumans, indicating that rye is essential for normal development and function of the immune system. We demonstratethat human hematopoietic cells express two γc transcriptsdiffering in their carboxyl terminal coding region. Onetranscript is the previously reported sequence (γc-long),whereas the newly identified sequence exhibits a deletion of72 nucleotides close to the 3’-end of the open reading frame(γc-short). This alteration predicts a loss of 24 amino acidsincluding a conserved tyrosine residue which is shared byseveral members of the cytokine receptor family. Thepresence of these two distinct forms of rye transcripts wasdemonstrated by sequencing of reversely transcribed andpolymerase chain reaction (RT-PCR) amplified mRNA, restriction digestion of the RT-PCR products, RNAse protection, and Northern blotting from human cell lines andhuman peripheral blood lymphocytes. Furthermore, thetwo variants were present in peripheral blood lymphocytesfrom both female and male donors, which rules out allelicvariants since rye is a single copy gene located on the Xchromosome. A truncation mutant at a site near the observed changes in γc-short has been reported by othersto alter biochemical events activated by cytokines. Thiscombined with the loss of a potential SH2 "docking" sitein γc-short suggests that γc-long and γc-short may link todifferent signaling pathways and may play an importantrole in determining the cellular response to IL-2, IL-4, IL-7, IL-9, IL-13, IL-15.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
基金We thank Drs Hongbing Shu （Wuhan University, China）, Jiandong Li （University of Rochester Medical Center, USA）, Andrew Thorbum （University of Colorado Comprehensive Cancer Center, USA） and Andreas Strasser （The Walter and Eliza Hall Institute of Medical Research, Australia） for the generous gifts of the constructs. This work was partially supported by the National Natural Science Foundation of China （Grants 30571687 and 30721063） and the State Key Basic Research Program of China （Grant 2007CB507404）.
文摘In the present article, we report that DR4 or DR5 overexpression dramatically activates the release of the inflammatory cytokines IL-8, TNF-α, CCL20, MIP-2 and MIP-1β in an NF-κB-dependent manner in 293T, MDA-MB-231 and HCT-116 cells. We showed that death receptor-mediated signals were extracellular domain-independent, whereas the effect of overexpression of the DR4 intracellular domain was much less potent. The TRADD-TRAF2-NIK- IKKα/β signaling cascade, which plays an essential role in TNF-induced NF-κB activation, was found to be involved in tumor necrosis factor-related apoptosis-inducing ligand （TRAIL） receptor-mediated signal transduction. The FADD-caspase signaling pathway, which has been reported to be mostly related to apoptosis, was identified as being essential for DR4 or DR5 overexpression-mediated NF-κB activation and cytokine secretion and crosstalks with the TRADD-TRAF2-NIK-IKKα/β signaling cascade. Furthermore, a DR5 agonistic antibody （AD5-10） triggered the inflammatory cytokine release. These data, together with previous reports, provide strong evidence that TRAIL and TRAIL receptors play an important role in inflammation.
文摘This present study was aimed to investigate the roles of the receptors of Thl/Th2 cytokines and chemokines in lhe pathogenesis of chronic idiopathic urticaria （CIU）. Thirty patients with CIU, 30 patients with dermographism and 30 healthy controls were randomly enrolled. Reverse transcription-PCR （RT-PCR） was used to analyze the mRNA of cytokine receptors in peripheral blood mononuclear cells （PBMCs）. The mRNA levels of tumor necro- sis factor receptor （TNFR）, interferon-7 receptor （IFN-yR）, and interleukin-10 receptor （IL-IOR） were statistically increased in the CIU group （P 〈 0.05）, while IL-2R, IL-4R, IL-6R, and IL-13R showed no significant differences between the CIU and other groups. The mRNA levels of CCR3 and CCR6 were statistically increased in the CIU group （P 〈 0.05）. The toll-like receptor 2 （TLR2） mRNA level was significantly lower in the CIU group than the healthy control group （P 〈 0.05）. These findings indicate that the regulation of mRNA of TNFR, IFN-γR, IL-IOR, CCR3, CCR6 and TLR2 may be involved in the pathogenesis of CIU.
基金supported by grants from the National Key Research and Development Program of China(Grant No.2020YFA0707704)the National Key Research and Development Program of China(Grant No.2016YFC1303800)+1 种基金the Jilin Scientific and Technological Development Program(CN)(Grant No.20190303146SF)the National Natural Science Foundation of China(Grant No.81874052).
文摘Cytokine release syndrome(CRS)is a major obstacle to the widespread clinical application of chimeric antigen receptor(CAR)T cell therapies.CRS can also be induced by infections(such as SARS-CoV-2),drugs(such as therapeutic antibodies),and some autoimmune diseases.Myeloid-derived macrophages play key roles in the pathogenesis of CRS,and participate in the production and release of the core CRS cytokines,including interleukin(IL)-1,IL-6,and interferon-γ.In this review,we summarize the roles of macrophages in CRS and discuss new developments in macrophage activation and the related mechanisms of cytokine regulation in CRS.
文摘Background: Chemokines are small proteins that activate immune system in normal and pathological conditions. The induction of chemotaxis is a well-established role of chemokines. Moreover chemokines are important mediators of angiogenesis, implantation of fetus, and maturation of immune cells. In human body many types of cells express chemokines and cytokines at level of gene and protein. In blood cells chemokine and chemokine receptors mRNA level is a one of crucial points of chemokine system condition. The aim of the study was to evaluate the relationship between plasma concentration of cyto- kines and chemokines/chemokine receptors mRNA level in blood of healthy volunteers. Results: Gene expression of eotaxin, eotaxin-2, IL-8, MIP-1α, MIP- 1β, RANTES, CCR1, CCR3, CCR5, CXCR1, and CXCR2 was measured in peripheral blood cells, as well as the concentration of IL-1β, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, eotaxin, FGF-2, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, and VEGF was evaluated in the plasma of 19 healthy individuals. We studied rela- tionship between mRNA levels of chemokines/recaptors and cytokine concentration in blood of healthy volunteers. Conclusion: These data are allowed to assess chemokines impact in the cytokine regulation of healthy subjects. These results indicate that chemokines and their receptors is diverse and redundant system of immune reactivity in response to internal and external challenges.
文摘Objective:To assess the association between genetic variants of transferrin receptor 2(TFR2)exon 4 and anemia status and to describe the expression levels of several cytokines,hepcidin,soluble transferrin receptor and erythropoietin.Methods:Institutional based comparative study was done randomly to recruit 106 pregnant women who attended antenatal care in three different health centers in Boyolali Regency,Central Java from May 2015 to September 2015.DNA was extracted from peripheral blood samples of selected pregnant women and sequencing was done for TFR2 exon 4.Furthermore,enzyme-linked immunosorbent assay was conducted to measure the expression levels of interleukin 6,interleukin 4,transforming growth factorβand iron-metabolism related proteins such as hepcidin,soluble transferrin receptor,and erythropoietin.Gene alignment was performed by using a CLUSTAL W program.Collected data were analyzed statistically by using parametric and nonparametric tests with Statistical Product and Service Solutions(SPSS)20.0 for Windows.Results:Three novel genetic variants from TFR2 exon 4(position 603,605 and 606)were associated with anemia status.Moreover,the expression levels of interleukin 6,interleukin 4,transforming growth factorβand erythropoietin were higher in anemic pregnant women than those of nonanemic pregnant women but only erythropoietin level reached statistical significance.These results were followed by decreases of hepcidin and soluble transferrin receptor levels.Conclusions:Various factors contribute to anemia prevalence among pregnant women in Boyoali Regency,Central Java,Indonesia.Our novel findings showed that TFR2 exon 4 has 3 mutational sites in position 603,605 and 606.These novel genetic variants may provide a new insight into the role of TFR2 in anemia.
基金supported by the Ministry of Education,Science,and Technological Development of the Republic of Serbia[451-03-68/2020-14/200007]。
文摘Objective To investigate involvement of the aryl hydrocarbon receptor(Ah R)in the immunomodulatory effects of cadmium(Cd).Methods The effect of Cd on Ah R activation(CYP1 A1 and CYP1 B1 m RNA expression)was examined in lung leukocytes of Cd-exposed rats(5 and 50 mg/L,30 d orally)and by in vitro leukocyte exposure.The involvement of Ah R signaling in the effects of Cd on the interleukin(IL)-1β,IL-6,and tumor necrosis factor(TNF)lung leukocyte response was investigated in vitro using the receptor antagonist CH-223191.Results Cd increased CYP1 B1(in vivo and in vitro)and CYP1 A1(in vitro)m RNA,indicating Ah R involvement in the action of Cd.In response to Cd,lung leukocytes increased IL-6 and decreased TNF at the gene expression and protein levels,but decreased IL-1βproduction due to reduced NLRP3.The Ah R antagonist CH-223191 abrogated the observed effects of Cd on the cytokine response.The absence of Ah R reactivity and cytokine response to Cd of leukocytes from the lungs of a rat strain that is less sensitive to Cd toxicity coincided with a high Ah R repressor m RNA level.Conclusion Ah R signaling is involved in the lung leukocyte proinflammatory cytokine response to Cd.The relevance of the Ah R to the cytokine response to Cd provides new insight into the mechanisms of Cd immunotoxicity.
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.
文摘The significant function of Toll-like receptors (TLR) is the detection of microbes by host guard cells that guide to the innate immune responses and to the successive adaptive. The current study patterns of TLR2, TLR3 and TLR9 expressing antigen presenting cells (APCs) in blood of mice after colonization with L. plantarum NC8 strain were assessed. The power of L. plantarum on serum innate cytokine and TLR responses stimulated by recombinant NC8-pSIP409-pgsA-VP6-DCpep, NC8-pSIP409-pgsA-VP7-DCpep and NC8-pSIP409-pgsA were also assessed. We confirmed that L. plantarum NC8 stimulated powerful TLR2 expressing APC responses in blood Recombinant strain stimulated a TLR3 response in spleen, and TLR9 responses were stimulated in blood or in spleen. Recombinant NC8-pSIP409-pgsA-VP6-DCpep, NC8-pSIP409-pgsA-VP7-DCpep on TLR2 and TLR9 expressing APC responses has a preservative outcome, reliable with the DCpep adjuvant outcome. In serum the recombinant NC8-pSIP409-pgsA-VP6-DCpep, NC8-pSIP409-pgsA-VP7-DCpep has increased the IL-4 and IFN-γ responses, except that on the TLR3 and TLR9 expressing CD14 APC responses it had an oppressive consequence in spleen and the IFN-α response in serum-stimulated by PRV. Our results give details that following PRV infection after immunization with NC8-pSIP409-pgsA-VP6-DCpep, NC8-pSIP409-pgsA-VP7-DCpep, the systemic TLR2, TLR3, and TLR9 expressing cDC and macrophage/monocyte responses.
文摘Objective: To analyze the effect of chemotherapy on peripheral blood NK cell receptor NKG2D and related immune cytokines (IL-12, IL-15, IL-18) in patients with non-small cell lung cancer (NSCLC). Methods: A total of 48 patients with NSCLC who visited the Oncology Department of the Affiliated Hospital of Chengde Medical College from September 2018 to September 2019 were selected as the study subjects. Changes in the expression levels of NKG2D, IL-12, IL-15 and IL-18 in peripheral blood of patients at different time points (before chemotherapy, after the first chemotherapy and after the second chemotherapy) were analyzed to investigate the correlation between NKG2D and IL-12, IL-15 and IL-18 in peripheral blood at each time point. Results: The expression levels of NKG2D, IL-15, and IL-18 in the peripheral blood of the patient before chemotherapy, after the first chemotherapy, and after the second chemotherapy gradually decreased. After the first chemotherapy and the second chemotherapy, the peripheral blood IL-12 was significantly lower than before chemotherapy, and IL-12 in peripheral blood after the second chemotherapy was slightly increased compared with that after the first chemotherapy. The comparison of each factor at different time points was statistically significant (all P<span style="font-family: ">0.05). Pearson correlation analysis showed that after the first chemotherapy, NKG2D in peripheral blood was positively correlated with IL-18 (r = 0.342, P = 0.031);after the second chemotherapy, NKG2D in peripheral blood was positively correlated with IL-18 (r = 0.411, P = 0.023), negatively correlated with IL-15 (r = -0.451, P = 0.001). Conclusion: There was no significant change in the number of NK cells in the peripheral blood of NSCLC patients after chemotherapy, while NKG2D and related immune cytokines decreased, which may be one of the mechanisms for the suppression of immune function in patients, and this provides a potential target for immunotherapy in patients.
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.
文摘Background and Objective: It has been found that human periodontal ligament (hPDL) cells express cannabinoid receptor CB2. However, the functional importance of CB2 in hPDL cells exposed to bacterial endotoxins is not known. Here we investigate if the inflammation promoter lipopolysaccharide (LPS) affects CB2 expression and if activation of CB2 regulates LPS-induced pro-inflammatory cytokine production and osteoclastogenic gene expression in hPDL cells. Methods: The hPDL cells were obtained from extracted teeth of periodontally healthy subjects. CB2 expression in hPDL cells exposed to LPS was deter- mined by quantitative real-time PCR analysis. Then, the cells were incubated with or without CB2-specific agonist HU-308 before further stimulation with LPS. In some experiments, the cells were pre-treated with CB2-specific antagonist SR144528. The production of pro-inflammatory cytokines interleukin-1 beta (IL- 1β), interleukin-6 (IL-6) and tumor necrosis factoralpha (TNF-α) was assessed by enzyme-linked immunosorbent assay (ELISA). The mRNA expression of osteoclastogenic genes osteoprotegerin (OPG) and receptor activator of NF-κB ligand (RANKL) was examined using quantitative real-time PCR analysis. Results: CB2 expression in hPDL cells was markedly enhanced by LPS. HU-308 significantly suppressed the production of IL-1β, IL-6 and TNF-α exposed to LPS, whereas SR144528 attenuated this effect. The OPG/RANKL ratio decreased when exposed to LPS, furthermore increased significantly with the addition of HU-308 and finally decreased markedly after pretreatment with SR144528. Conclusion: Our study demonstrated that activation of CB2 had anti-inflammatory and anti-resorptive effects on LPS-stimulated hPDL cells. These findings suggest that activation of CB2 might be an effective therapeutic strategy for the treatment of inflammation and alveolar bone resorption in periodontitis.
文摘Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer’s disease treatments in the last decades.However,existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic,necessitating the exploration of alternative therapeutic strategies.Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer’s disease patients,with dysregulated astrocytic purinergic receptors,particularly the P2Y1 receptor,all of which constitute the pathophysiology of Alzheimer’s disease.These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer’s disease.This review delves into recent insights into the association between P2Y1 receptor and Alzheimer’s disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer’s disease by mitigating neuroinflammation,thus offering promising avenues for developing drugs for Alzheimer’s disease and potentially contributing to the development of more effective treatments.
文摘Toll-like receptors are well-defined barriers in innate immunity. Among them hTLR4 on the surface of monocytes, plays a critical role in the formation of atherosclerotic plaques, plaque instability and arterial remodeling through production of inflammatory cytokines. This study was designed to examine the association of hTLR4 monocyte expression and response with the severity of coronary stenosis in patients with stable angina (SA). Blood samples were obtained from 39 patients with SA who were scheduled for a coronary angiography and from 28 healthy volunteers. The samples were collected before the procedure. Expression of hTLR4 on CD14+ monocytes and serum levels of TNF-α and IL-1β were measured using flowcytometry and ELISA techniques respectively. Percentage stenosis diameter was measured by comparing the area of coronary stenosis to an adjacent normal segment of the vessel. Compared with control group, patients showed upregulation of hTLR4+/CD14+ monocytes. Furthermore, patients with more severe coronary stenosis exhibited enhanced expression of hTLR4+/CD14+ monocytes (p α (p β. In addition, significant correlations were seen between percentage stenosis diameter and monocyte expression of hTLR4 as well as TNF-α. hTLR4 monocytic expression and related cytokines are positively associated percentage stenosis diameter. These results suggest that hTLR4 activity may be involved in progression of atherosclerosis.
文摘Western equine encephalitis virus(WEEV)is an arbovirus that historically caused large outbreaks of encephalitis throughout the Americas.WEEV binds protocadherin 10(PCDH10)as a receptor,and highly virulent ancestral WEEV strains also bind low-density lipoprotein receptor(LDLR)-related proteins.As WEEV declined as a human pathogen in North America over the past century,isolates have lost the ability to bind mammalian receptors while still recognizing avian receptors.To explain shifts in receptor dependencies and assess the risk of WEEV re-emergence,we determined cryoelectron microscopy structures of WEEV bound to human PCDH10,avian PCDH10,and human very-low-density lipoprotein receptor(VLDLR).We show that one to three E2 glycoprotein substitutions are sufficient for a nonpathogenic strain to regain the ability to bind mammalian receptors.A soluble VLDLR fragment protects mice from lethal challenge by a virulent ancestral WEEV strain.Because WEEV recently re-emerged in South America after decades of inactivity,our findings have important implications for outbreak preparedness.
基金Supported by Tianjin Municipal Education Commission Scientific Research Program,China,No.2022KJ271.
文摘BACKGROUND Yinchenhao decoction(YCHD)is a traditional Chinese medicine widely used to treat liver damage caused by obstructive jaundice(OJ).Although YCHD has demonstrated protective effects against liver damage,reduced apoptosis,and mitigated oxidative stress in OJ,the precise molecular mechanisms involved remain poorly understood.AIM To investigate the beneficial effects of YCHD on OJ and elucidate the underlying mechanisms.METHODS The active constituents of YCHD were identified using liquid chromatography tandem mass spectrometry,and their potential targets for OJ treatment were predicted through network pharmacology.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed.An OJ rat model was established by common bile duct ligation.Rats were divided into three groups:Sham surgery(S Group),model(O Group),and YCHD(Y Group).YCHD was administered to Group Y for one week.Bilirubin levels,liver function parameters,and bile acid concentrations in blood and urine were measured by enzyme-linked immunosorbent assay.The bile acid renal clearance rate(Clr)was calculated.Histopathological evaluation of liver and kidney tissues was performed using hematoxylin-eosin staining.Western blotting was utilized to assess the expression of key bile acid metabolism and transport proteins in both liver and kidney tissues.The expression of the constitutive androstane receptor(CAR)and its nuclear localization were evaluated by immunohistochemistry.Molecular docking studies identified the epidermal growth factor receptor(EGFR)as a potential target of YCHD's active components.An OJ cell model was created using human liver(L02)and renal tubular epithelial(HK-2)cells,which were treated with YCHD-containing serum.Western blotting and immunofluorescence assays were employed to evaluate CAR expression and its nuclear localization in relation to EGFR activation.RESULTS Network analysis identified the EGFR signaling pathway as a key mechanism through which YCHD exerts its effects on OJ.In vivo experiments showed that YCHD improved liver function,reduced OJ-induced pathology in liver and kidney tissues,and decreased serum bile acid content by enhancing bile acid Clr and urine output.YCHD also increased CAR expression and nuclear heterotopy,upregulating proteins involved in bile acid metabolism and transport,including CYP3A4,UGT1A1,MRP3,and MRP4 in the liver,and MRP2 and MRP4 in the kidneys.In vitro,YCHD increased CAR expression and nuclear heterotopy in L02 and HK-2 cells,an effect that was reversed by EGFR agonists.CONCLUSION YCHD enhances bile acid metabolism in the liver and promotes bile acid excretion in the kidneys,ameliorating liver damage caused by OJ.These effects are likely mediated by the upregulation of CAR and its nuclear translocation.
基金Supported by the National Natural Science Foundation of China,No.32271278 and No.31971170.
文摘Different from reversible agonist-stimulated receptor activation,singlet oxygen oxidation activates permanently G protein-coupled receptor(GPCR)cholecystokinin 1(CCK1R)in type II photodynamic action,with soluble photosensitizer dyes(sulphonated aluminum phthalocyanine,λmax 675 nm)or genetically encoded protein photosensitizers(KillerRedλmax 585 nm;mini singlet oxygen generatorλmax 450 nm),together with a pulse of light(37 mW/cm2,1-2 minutes).Three lines of evidence shed light on the mechanism of GPCR activated by singlet oxygen(GPCR-ABSO):(1)CCK1R is quantitatively converted from dimer to monomer;(2)Transmembrane domain 3,a pharmacophore for permanent photodynamic CCK1R activation,can be transplanted to non-susceptible M3 acetylcholine receptor;and(3)Larger size of disordered region in intracellular loop 3 correlates with higher sensitivity to photodynamic CCK1R activation.GPCR-ABSO will add to the arsenal of engineered designer GPCR such as receptors activated solely by synthetic ligands and designer receptors exclusively activated by designer drugs,but show some clear advantages:Enhanced selectivity(double selectivity of localized photosensitizer and light illumination),long-lasting activation with no need for repeated drug administration,antagonist-binding site remains intact when needed,ease to apply to multiple GPCR.This type of permanent photodynamic activation may be applied to functional proteins other than GPCR.
基金supported by grants from National Natural Science Foundation of China(No.81170314,No. 81360421,No. 81560524)China Postdoctoral Science Foundation (No.2013M540686,No.2014T70839)Guangxi Natural Science Foundation(No.2012GXNSFBA053109)
文摘Objective:To explore the effect of tumor necrosis factor-α(TNF-α),interleukin(IL)-6,IL-18,IL-1β,and aging on the expression of P2X7receptor(P2X7R)m RNA in the brains of mice with lipopolysaccharide(LPS)treatment.Methods:Young(4 months old)and aged(18 months old)male C57BL/6 mice were randomly divided into 5 groups(n=7).All of the mice were injected intraperitoneally with LPS(0.5 mg/kg).After 0,3,24,48,and 72 h,the m RNA expressions of TNF-α,IL-6,IL-18,IL-1β,and P2X7R in mice's brains were determined by q PCR.Results:In brains of young mice,the highest expressions of IL-6,IL-18 and IL-1βwere found at3 h,but for TNF-αand P2X7R,the highest expressions were found at 24 h.For the aged mice,the expressions of TNF-α,IL-6,IL-1β,and P2X7R reached the highest level at 3 h,but IL-18reached the highest level at 24 h.Aged mice showed significantly higher level of TNF-αat 0,3,48,and 72 h than young mice.The similar results were observed for P2X7R at 0,3 and72 h in aged mice.Conclusion:The m RNA expression of inflammatory cytokines and P2X7R in the brains of mice were consistent with the same time points after LPS treatment.Furthermore,they were higher in aged mice compared with young mice.This result suggested that P2X7R may be involved in the development of brain aging and relevant diseases of mice by regulating the expression of inflammatory cytokines.
文摘Recent studies have revealed that the γ-chain of theIL-2 receptor is shared by the receptors for IL-4, IL7, IL-9, IL-13, and IL-15, and it is therefore also referred toas the common γ-chain (γc). Mutations of γc result inX-linked severe combined immunodeficiency syndrome inhumans, indicating that rye is essential for normal development and function of the immune system. We demonstratethat human hematopoietic cells express two γc transcriptsdiffering in their carboxyl terminal coding region. Onetranscript is the previously reported sequence (γc-long),whereas the newly identified sequence exhibits a deletion of72 nucleotides close to the 3’-end of the open reading frame(γc-short). This alteration predicts a loss of 24 amino acidsincluding a conserved tyrosine residue which is shared byseveral members of the cytokine receptor family. Thepresence of these two distinct forms of rye transcripts wasdemonstrated by sequencing of reversely transcribed andpolymerase chain reaction (RT-PCR) amplified mRNA, restriction digestion of the RT-PCR products, RNAse protection, and Northern blotting from human cell lines andhuman peripheral blood lymphocytes. Furthermore, thetwo variants were present in peripheral blood lymphocytesfrom both female and male donors, which rules out allelicvariants since rye is a single copy gene located on the Xchromosome. A truncation mutant at a site near the observed changes in γc-short has been reported by othersto alter biochemical events activated by cytokines. Thiscombined with the loss of a potential SH2 "docking" sitein γc-short suggests that γc-long and γc-short may link todifferent signaling pathways and may play an importantrole in determining the cellular response to IL-2, IL-4, IL-7, IL-9, IL-13, IL-15.
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.
