We established a rat model of cardiac arrest by clamping the endotracheal tube of adult rats at expiration. Twenty-four hours after cardiopulmonary resuscitation, nerve cell injury and expression of tumor necrosis fac...We established a rat model of cardiac arrest by clamping the endotracheal tube of adult rats at expiration. Twenty-four hours after cardiopulmonary resuscitation, nerve cell injury and expression of tumor necrosis factor-α, interleukin-1β, and p38 mitogen activated protein kinase content were increased. Rats injected with Xuebijing, a Chinese herb compound preparation, exhibited normal cellular structure and morphology, dense neuronal cytoplasm, and decreased tumor necrosis factor-α, interleukin-1β, and p38 mitogen activated protein kinase expression at 24 hours following cardiopulmonary resuscitation. These data suggest that Xuebijing can attenuate neuronal injury induced by hypoxia and reperfusion during cardiopulmonary resuscitation.展开更多
Objectives:Vascular endothelial growth factor(VEGF)regulates tumor vascularization in response to hypoxia and inflammatory signals.The polyphenol curcumin is supposed to interfere with inflammation-induced VEGF secret...Objectives:Vascular endothelial growth factor(VEGF)regulates tumor vascularization in response to hypoxia and inflammatory signals.The polyphenol curcumin is supposed to interfere with inflammation-induced VEGF secretion and might therefore support anti-VEGF-based treatments.We aimed to investigate the interaction between curcumin and the inflammatory cytokine Interleukin-1β(IL-1β)for VEGF secretion in breast cancer cell lines representing major breast cancer subtypes.Methods:VEGF in cell cultures was detected by Western blot and enzyme-linked immunosorbent assay(ELISA).Kinase phosphorylation was investigated by Western blotting.Gene expressions were analyzed by correlation tests.VEGF was evaluated in a retrospective breast cancer cohort by immunohistochemistry.Survival analysis was performed by the Kaplan-Meier algorithm.Results:VEGF secretion and kinase signaling in response to IL-1βand curcumin varied significantly for the cell lines MCF-7(Luminal A),SK-BR-3(HER2/neu+),MDA-MB-231,and UACC-3199(triple negative breast cancer).All cell lines increased VEGF secretion under hypoxia,but IL-1βincreased VEGF secretion only in MCF-7 cells.Curcumin inhibited VEGF secretion in MDA-MB-231,but increased it in MCF-7 and UACC-3199 cells.Curcumin induced phosphorylation of extracellular signal-regulated kinase(ERK)and p38-mitogen-activated protein kinase(p38-MAPK).However,inhibitor experiments demonstrated that ERK was more important for VEGF secretion.In gene expression data from the METABRIC study,no clear correlation of hypoxia-induced factor(HIF1A),IL-1β,and VEGF mRNA expression was observed;however,a suggested crosstalk of hypoxia and inflammatory pathways was observed.Conclusion:These dissimilar responses of breast cancer cell lines suggest that therapy efficiency with anti-VEGF,anti-IL-1β,or curcumin will also vary within breast cancers.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is an inflammation-associated tumor with a dismal prognosis.Immunotherapy has become an important treatment strategy for HCC,as immunity is closely related to inflammation in th...BACKGROUND Hepatocellular carcinoma(HCC)is an inflammation-associated tumor with a dismal prognosis.Immunotherapy has become an important treatment strategy for HCC,as immunity is closely related to inflammation in the tumor microenvir-onment.Inflammation regulates the expression of programmed death ligand-1(PD-L1)in the immunosuppressive tumor microenvironment and affects im-munotherapy efficacy.Interleukin-17A(IL-17A)is involved in the remodeling of the tumor microenvironment and plays a protumor or antitumor role in different tumors.We hypothesized that IL-17A participates in tumor progression by affe-cting the level of immune checkpoint molecules in HCC.The upregulation of PD-L1 expression in HCC cells by IL-17A was assessed by reverse transcription PCR,western blotting,and flow cytometry.Mechanistic studies were conducted with gene knockout models and pathway inhibitors.The function of IL-17A in immune evasion was explored through coculture of T cells and HCC cells.The effects of IL-17A on the malignant biological behaviors of HCC cells were evaluated in vitro,and the antitumor effects of an IL-17A inhibitor and its synergistic effects with a PD-L1 inhibitor were studied in vivo.RESULTS IL-17A upregulated PD-L1 expression in HCC cells in a dose-dependent manner,whereas IL-17A receptor knockout or treatment with a small mothers against decapentaplegic 2 inhibitor diminished the PD-L1 expression induced by IL-17A.IL-17A enhanced the survival of HCC cells in the coculture system.IL-17A increased the viability,G2/M ratio,and migration of HCC cells and decreased the apoptotic index.Cyclin D1,VEGF,MMP9,and Bcl-1 expression increased after IL-17A treatment,whereas BAX expression decreased.The combination of IL-17A and PD-L1 inhibitors showed synergistic antitumor efficacy and increased cluster of differentiation 8+T lymphocyte infiltration in an HCC mouse model.CONCLUSION IL-17A upregulates PD-L1 expression via the IL-17A receptor/phosphorylation-small mothers against decapenta-plegic 2 signaling pathway in HCC cells.Blocking IL-17A enhances the therapeutic efficacy of PD-L1 antibodies in HCC in vivo.展开更多
AIM： To study the relationship between interleukin-lbeta （IL-1β） up-regulating tissue inhibitor of matrix metalloproteinase-1 （TIMMP-1） mRNA expression and phosphorylation of both c-jun N-terminal kinase （INK）...AIM： To study the relationship between interleukin-lbeta （IL-1β） up-regulating tissue inhibitor of matrix metalloproteinase-1 （TIMMP-1） mRNA expression and phosphorylation of both c-jun N-terminal kinase （INK） and p38 in rat heffatic stellate cells （HSC）. METHODS： RT-PCR was performed to measure the expression of TIMMP-1 mRNA in rat HSC. Western blot was performed to measure IL-1β-induced JNK and p38 activities in rat HSC. RESULTS： TIMMP-1 mRNA expression （1.191± 0.079） was much higher after treatment with IL-1β （10 ng/mL） for 24 h than in control group （0.545±0.091） （P〈0.01）. IL-1β activated INK and p38 in a time-dependent manner. After stimulation with IL-1β for 0, 5, 15, 30, 60 and 120 min, the INK activity was 0.982±0.299, 1.501±0.720, 2.133±0.882, 3.360±0.452, 2.181±0.789, and 1.385 ± 0.368, respectively. There was a significant difference in JNK activity at 15 min （P〈 0.01）, 30 min （P〈 0.01） and 60 min （P〈0.01） in comparison to that at 0 min. The p38 activity was 1.061±0.310, 2.050±0.863, 2.380±0.573, 2.973±0.953, 2.421±0.793, and 1.755 ± 0.433 at the 6 time points （0, 5, 15, 30, 60 and 120 min） respectively. There was a significant difference in p38 activity at 5 min （P〈0.05）, 15 min （P〈0.01）, 30 min （P〈0.01） and 60 min （P〈0.01） compared to that at 0 min. TIMMP-1 mRNA expression trended to decrease in 3 groups pretreated with different concentrations of SP600125 （10 μmol/L, 1.022±0.113; 20 μmol/L, 0.869±0.070; 40 μmol/L, 0.666±0.123）. Their decreases were all significant （P〈0.05, P〈0.01, P〈0.01） in comparison to control group （without SP600125 treatment, 1.163±0.107）. In the other 3 groups pretreated with different concentrations of SB203580 （10 μmol/L, 1.507±0.099; 20 μmol/L, 1.698±0.107; 40 μmol/L, 1.857±0.054）, the expression of TIMMP-1 mRNA increased. Their levels were higher than those in the control group （without SB203580 treatment, 1.027 ± 0.061） with a significant statistical significance （P〈 0.01）. CONCLUSION： IL-1β has a direct action on hepatic fibrosis by up-regulating TIMMP-1 mRNA expression in ratessionin in rate HSC.JNK and p38 mitogen-activated protein kinases （MAPKs） are involved in IL-1β-induced TIMMP-1 gene expression, and play a distinct role in this process, indicating that p38 and .INK pathways cooperatively mediate TIMP-1 mRNA expression in rat HSC.展开更多
Objective:Pain from herniated disc is a common type of neuropathic pain.This study investigated whether electroacupuncture (EA) stimulation at distal-proximal combinations of acupoints in the rat model of neuropathic ...Objective:Pain from herniated disc is a common type of neuropathic pain.This study investigated whether electroacupuncture (EA) stimulation at distal-proximal combinations of acupoints in the rat model of neuropathic pain modulates spinal interleukin-1 beta (IL-1β) to induce acupuncture analgesia and possibly serve as a pain-relief modality for herniated disc.Methods:A rat model of neuropathic pain was established.Rats were randomly divided into normal,model,sham,EA 1,EA 2,and EA 3 groups.EA 1 rats were needled at bilateral ExB2,BL25,BL40,and BL60 acupoints.EA 2 rats Were needled at bilateral BL40 and BL60.EA 3 rats were needled at bilateral L5 Ex-B2 and BL25.EA stimulation was administered once daily over 7 days.Mechanical withdrawal threshold from noxious mechanical stimulation was measured 1 day preoperatively and at 3,5,and7 days postoperatively.After 7 days of intervention,enzyme-linked immunosorbent assay (ELISA) was used to quantify IL-1β in the spinal cord.Results:Mechanical withdrawal threshold of rats in the model group decreased at 3 days postoperatively when compared with the normal group (P < 0.01),lasting 7 days postoperatively.Mechanical withdrawal thresholds in the EA 1,EA 2,and EA 3 groups were elevated over the model group (P < 0.05;P < 0.01).No obvious differences were found between EA 1,EA 2,and EA 3 groups.ELISA demonstrated an increase in IL-1β in the spinal cord of rats in the model group compared with the normal group (P < 0.01).EA treatment attenuated the increase in spinal IL-1β in the model group.Expression of spinal IL-1β was significantly lower in EA 1,EA 2,and EA 3 groups.Conclusion:EA at distal + proximal acupoints,distal points,as well as proximal points attenuated upregulation of spinal IL-1β,alleviated the extent of neuropathic pain hypersensitivity,and promoted mechanical withdrawal threshold,resulting in EA analgesia.展开更多
BACKGROUND Hypertension is a chronic cardiovascular disease characterized by persistently elevated arterial blood pressure.It is not only a significant risk factor for cardio-vascular and cerebrovascular diseases(such...BACKGROUND Hypertension is a chronic cardiovascular disease characterized by persistently elevated arterial blood pressure.It is not only a significant risk factor for cardio-vascular and cerebrovascular diseases(such as myocardial infarction and stroke)but also closely related to multiple organ damages(such as kidney disease and retinopathy),imposing a heavy health and economic burden on individuals and society.AIM To investigate the expression differences and relationships of endothelin-1(ET-1),interleukin-6(IL-6),stem cell factor(SCF),and its receptor(c-kit)in hypertensive patients with or without depression.METHODS A retrospective analysis was conducted on the clinical data of 163 hypertensive patients admitted to our hospital from March 2022 to January 2024.Based on the presence of depression,patients were divided into Group A(n=77,with depre-ssion)and Group B(n=86,without depression).Serum levels of ET-1 and IL-6 were measured using radioimmunoassay,while serum levels of SCF and c-kit were measured using ELISA.The differences in ET-1,IL-6,SCF,and c-kit levels between Groups A and B were compared.Additionally,the differences in these biomarkers among patients with varying degrees of depression in Group A were analyzed.Pearson correlation analysis was used to examine the relationship between ET-1,IL-6,SCF,c-kit levels,and Hamilton depression rating scale(HAMD)scores.Multivariate logistic regression analysis was performed to identify factors influencing hypertension with depression.The diagnostic efficacy of individual and combined biomarkers was analyzed using receiver operating characteristic(ROC)curves.Comparative statistical analysis of the area under the curve(AUC)values was performed using DeLong’s test to assess the superiority of combined biomarker detection.RESULTS The levels of ET-1 and IL-6 in Group A were significantly higher than those in Group B,while the levels of SCF and c-kit were significantly lower in Group A compared to Group B(P<0.05).In the severe depression subgroup,ET-1 and IL-6 levels were higher than those in the mild-to-moderate depression subgroup,while SCF and c-kit levels were lower(P<0.05).Pearson correlation analysis showed that ET-1 and IL-6 levels were positively correlated with HAMD scores(r=0.442,0.463,P<0.05),while SCF and c-kit levels were negatively correlated with HAMD scores(r=-0.429,-0.394,P<0.05).Multivariate logistic regression analysis revealed that high ET-1,high IL-6,low SCF,and low c-kit were independent influencing factors for hypertension with depression(P<0.05).ROC analysis revealed AUCs of 0.746(ET-1),0.801(IL-6),0.732(SCF),0.779(c-kit),and 0.884(combination).The combined diagnosis demonstrated significantly higher AUC than individual markers(DeLong's test,P<0.01),with superior sensitivity(90.24%)and specificity(85.37%).CONCLUSION Compared to patients with hypertension alone,patients with hypertension and depression exhibited higher serum levels of ET-1 and IL-6 and lower levels of SCF and c-kit.High ET-1,high IL-6,low SCF,and low c-kit were inde-pendent influencing factors for hypertension with depression.The combination of ET-1,IL-6,SCF,and c-kit demonstrated significant diagnostic value for hypertension with depression.展开更多
Interleukin-1 receptor-associated kinase 4(IRAK4)is a key kinase downstream of the interleukin-1 receptor(IL-1R)and Toll-like receptors(TLRs)signaling pathway,whose overexpression and hyperactivation have been associa...Interleukin-1 receptor-associated kinase 4(IRAK4)is a key kinase downstream of the interleukin-1 receptor(IL-1R)and Toll-like receptors(TLRs)signaling pathway,whose overexpression and hyperactivation have been associated with several inflammatory diseases or cancer.Therefore,targeting IRAK4 has emerged as a promising therapeutic strategy.A range of potent and selective IRAK4 inhibitors and degraders based on draggability have been designed and developed.This article provides a comprehensive summary of the IRAK4 inhibitors and degraders that have been developed and discusses the challenges and opportunities for research in this area.展开更多
Type 1 diabetes(T1D)is a chronic organ-specific autoimmune disorder characterized by a progressive loss of the insulin-secreting pancreatic beta cells,which ultimately results in insulinopenia,hyperglycemia and lifelo...Type 1 diabetes(T1D)is a chronic organ-specific autoimmune disorder characterized by a progressive loss of the insulin-secreting pancreatic beta cells,which ultimately results in insulinopenia,hyperglycemia and lifelong need for exogenous insulin therapy.In the pathophysiological landscape of T1D,T helper 17 cells(Th17 cells)and their hallmark cytokine,interleukin(IL)-17,play pivotal roles from disease onset to disease progression.In this narrative mini-review,we discuss the dynamic interplay between Th17 cells and IL-17 in the context of T1D,providing insights into the underlying immunologic mechanisms contributing to the IL-17-immunity-mediated pancreatic beta-cell destruction.Furthermore,we summarized the main animal and clinical studies that investigated Th17-and IL-17-targeted interventions as promising immunotherapies able to alter the natural history of T1D.展开更多
Background: Cytokines are mediators of disease. Expression levels in the blood could be of clinical relevance. Objective: Aim of this study was to show if serum levels of IL-1β could be of any clinical relevance conc...Background: Cytokines are mediators of disease. Expression levels in the blood could be of clinical relevance. Objective: Aim of this study was to show if serum levels of IL-1β could be of any clinical relevance concerning dogs. IL-1β was measured in serum samples of healthy dogs to find a reference range for healthy individuals. Measurements of IL-1β should show if this substance was a possible marker for early stages of inflammation. Therefore, a possible relation between serum levels and grades of leukocytosis was analyzed. Methods: IL-1β concentrations in the blood were assessed by the use of a human enzyme linked immunosorbent assay (ELISA). 39 dogs with different inflammatory diseases were analyzed to figure out if there was a correlation between IL-1β serum levels and the number of leukocytes in peripheral blood. The control group consisted of 16 healthy dogs. Results: about half of the samples IL-1β were detected. Most of the patients showed no detectable amounts of IL-1β. The IL-1β levels measured in the serum were stable for at least nine weeks when stored at ?20?C. The patients tested positively on IL-1β had mostly lower-grade leukocytosis compared to those who had no IL-1β in serum. All the dogs which were suffering from disease but still had no traceable IL-1β, showed a leukocytosis as a common symptom. Conclusion: This study showed that IL-1β could become an interesting marker for the detection of early stages of inflammation when leukocytosis does not yet appear in peripheral blood. Nonetheless, the possible use in diagnosis is restricted. This is due to the fact that there are only low amounts of IL-1β to be detected in the serum, even concerning patients are suffering from disease.展开更多
High mobility group box 1(HMGB1),when released extracellularly,plays a pivotal role in the development of spinal cord synapses and exacerbates autoimmune diseases within the central nervous system.In experimental auto...High mobility group box 1(HMGB1),when released extracellularly,plays a pivotal role in the development of spinal cord synapses and exacerbates autoimmune diseases within the central nervous system.In experimental autoimmune encephalomyelitis(EAE),a condition that models multiple sclerosis,the levels of extracellular HMGB1 and interleukin-33(IL-33)have been found to be inversely correlated.However,the mechanism by which IL-33 deficiency enhances HMGB1 release during EAE remains elusive.Our study elucidates a potential signaling pathway whereby the absence of IL-33 leads to increased binding of P300/CBP-associated factor with HMGB1 in the nuclei of astrocytes,upregulating HMGB1 acetylation and promoting its release from astrocyte nuclei in the spinal cord of EAE mice.Conversely,the addition of IL-33 counteracts the TNF-α-induced increase in HMGB1 and acetylated HMGB1 levels in primary astrocytes.These findings underscore the potential of IL-33-associated signaling pathways as a therapeutic target for EAE treatment.展开更多
BACKGROUND： It has been shown that interleukin-1β（IL-1β） can induce fever by activating vascular endothelial cells and macrophages of the supraoptic crest to generate prostaglandin E2, which binds with receptors ...BACKGROUND： It has been shown that interleukin-1β（IL-1β） can induce fever by activating vascular endothelial cells and macrophages of the supraoptic crest to generate prostaglandin E2, which binds with receptors of the thermo-sensitive hypothalamic neurons. Lonicera japonica is one of the medicinal plants used widely in Asia for its antipyretic properties. However, these mechanisms have not yet been intensively studied. OBJECTIVE： To investigate the antipyretic effect and mechanisms of Lonicera japonica on IL-1β- induced febrile New Zealand rabbits by observing expression changes of E-type prostaglandin receptor-3 （EP3） mRNA in the preoptic anterior hypothalamus （POAH）. DESIGN： A randomized controlled study. SETTING： Electrophysiological Laboratory at the Department of Pathophysiology, Medical College of Jinan University; Department of Orthopaedics, First Hospital Affiliated to Medical College of Jinan University. MATERIALS： The experiment was performed from April to December 2005, using a total of 32 New Zealand white rabbits of both sexes, weighing 1.5 2.0 kg. All the animal experiments were performed according to the internationally accepted ethical guidelines. Lonicera japonica injection was purchased from Huanghe pharmaceutical factory of Xi＇an, China. IL-1βwas purchased from Sigma, USA. METHODS： A total of 32 rabbits were divided randomly into four groups： ① Normal saline （NS） control group;② Lonicerajaponica treatment group; ③ IL-1βtreatment group; and ④Lonicerajaponica plus IL-1βtreatment group. In the first 3 groups, the rabbits were given separate intravenous （i.v.） injections of l mL NS, l mL Lonicera japonica, and 100 ng IL-l β （dissolved in 0.9% NS without pyrogen）. In the Lonicerajaponica plus IL-1βgroup each rabbit was given i.v. injections of l mL NS and, 30 minutes later, 100 ng IL-1 β. MAIN OUTCOME MEASURES： Colonic temperature of each rabbit was measured at 0, 10, 20, 30, 40, 50, 60, and 70 minutes after injection and the maximum temperature rise （ A T） and the temperature response index after l hour （TRII） was calculated. Subsequently, in situ hybridization （ISH） was done with an ISH kit, EP3 mRNA expression in the POAH of all groups was measured （number of positive cells and average gray scale value）. RESULTS： A total of 32 rabbits were included in the result analysis, without any loss, （i） A T and TRII： there was no significant difference between the Lonicera japonica group and NS group （P 〉 0.05）. The IL-1β group was significantly greater compared to NS group （P 〈 0.01）. The Lonicera japonica plus IL-1β group was significantly less than the IL-1β group （P 〈 0.05）. ② In the NS and Lonicera japonica groups, the EP3 mRNA expression was negative （no coloration） or only weakly positive （only a few brown yellow particles in the cytoplasm cells could not be identified）. The number of positive cells and the average gray scale value were not significantly different between the two groups （P 〉 0.05）. In the IL-1β group, the number of positive cells was remarkably higher and the average gray scale value was lower than the NS group （P 〈 0.0 l）. In the Lonicera japonica plus IL-1β group, the number of positive cells was significantly less than the IL-1β group （P 〈 0.05）. However, the average gray scale value was greater than the IL-1β group （P 〈 0.05）. CONCLUSION： Lonicera japonica has obvious antipyretic effects on IL-1β-induced febrile rabbits and acts by inhibiting expression of EP3 mRNA in the POAH.展开更多
A previous study by our research group showed that nerve growth factor is involved in the onset of asthma through regulating SH2-Bβ expression in the lung and visceral primary afferent neurons of asthmatic mice. This...A previous study by our research group showed that nerve growth factor is involved in the onset of asthma through regulating SH2-Bβ expression in the lung and visceral primary afferent neurons of asthmatic mice. This study sought to assess the expression level of interleukin-1β in primary afferent neurons in C7-T5 spinal ganglia, spinal cord and lung in asthmatic mice after blockage of SH2-Bβ. The levels of interleukin-1β protein in primary afferent neurons in the C7-T5 spinal ganglia and lung were decreased, and interleukin-1β mRNA expression also down-regulated in the spinal cord, medulla oblongata and lung tissue after blockage of SH2-Bβ. Our findings indicate that SH2-Bβ can upregulate the expression of interleukin-1β in C7-T5 spinal ganglia, spinal cord and lung of asthmatic mice.展开更多
基金a grant from the Science and Technology Department of Jilin Province,No. 200705172
文摘We established a rat model of cardiac arrest by clamping the endotracheal tube of adult rats at expiration. Twenty-four hours after cardiopulmonary resuscitation, nerve cell injury and expression of tumor necrosis factor-α, interleukin-1β, and p38 mitogen activated protein kinase content were increased. Rats injected with Xuebijing, a Chinese herb compound preparation, exhibited normal cellular structure and morphology, dense neuronal cytoplasm, and decreased tumor necrosis factor-α, interleukin-1β, and p38 mitogen activated protein kinase expression at 24 hours following cardiopulmonary resuscitation. These data suggest that Xuebijing can attenuate neuronal injury induced by hypoxia and reperfusion during cardiopulmonary resuscitation.
基金funded by the Deutsche Forschungsgemeinschaft(DFG)grant number(KA2663/3-1)supported by the Ministry of Science,Research and Cultural Affairs of the State of Brandenburg.
文摘Objectives:Vascular endothelial growth factor(VEGF)regulates tumor vascularization in response to hypoxia and inflammatory signals.The polyphenol curcumin is supposed to interfere with inflammation-induced VEGF secretion and might therefore support anti-VEGF-based treatments.We aimed to investigate the interaction between curcumin and the inflammatory cytokine Interleukin-1β(IL-1β)for VEGF secretion in breast cancer cell lines representing major breast cancer subtypes.Methods:VEGF in cell cultures was detected by Western blot and enzyme-linked immunosorbent assay(ELISA).Kinase phosphorylation was investigated by Western blotting.Gene expressions were analyzed by correlation tests.VEGF was evaluated in a retrospective breast cancer cohort by immunohistochemistry.Survival analysis was performed by the Kaplan-Meier algorithm.Results:VEGF secretion and kinase signaling in response to IL-1βand curcumin varied significantly for the cell lines MCF-7(Luminal A),SK-BR-3(HER2/neu+),MDA-MB-231,and UACC-3199(triple negative breast cancer).All cell lines increased VEGF secretion under hypoxia,but IL-1βincreased VEGF secretion only in MCF-7 cells.Curcumin inhibited VEGF secretion in MDA-MB-231,but increased it in MCF-7 and UACC-3199 cells.Curcumin induced phosphorylation of extracellular signal-regulated kinase(ERK)and p38-mitogen-activated protein kinase(p38-MAPK).However,inhibitor experiments demonstrated that ERK was more important for VEGF secretion.In gene expression data from the METABRIC study,no clear correlation of hypoxia-induced factor(HIF1A),IL-1β,and VEGF mRNA expression was observed;however,a suggested crosstalk of hypoxia and inflammatory pathways was observed.Conclusion:These dissimilar responses of breast cancer cell lines suggest that therapy efficiency with anti-VEGF,anti-IL-1β,or curcumin will also vary within breast cancers.
基金Supported by the Natural Science Foundation of Gansu Province,No.21JR7RA373 and No.24JRRA295.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is an inflammation-associated tumor with a dismal prognosis.Immunotherapy has become an important treatment strategy for HCC,as immunity is closely related to inflammation in the tumor microenvir-onment.Inflammation regulates the expression of programmed death ligand-1(PD-L1)in the immunosuppressive tumor microenvironment and affects im-munotherapy efficacy.Interleukin-17A(IL-17A)is involved in the remodeling of the tumor microenvironment and plays a protumor or antitumor role in different tumors.We hypothesized that IL-17A participates in tumor progression by affe-cting the level of immune checkpoint molecules in HCC.The upregulation of PD-L1 expression in HCC cells by IL-17A was assessed by reverse transcription PCR,western blotting,and flow cytometry.Mechanistic studies were conducted with gene knockout models and pathway inhibitors.The function of IL-17A in immune evasion was explored through coculture of T cells and HCC cells.The effects of IL-17A on the malignant biological behaviors of HCC cells were evaluated in vitro,and the antitumor effects of an IL-17A inhibitor and its synergistic effects with a PD-L1 inhibitor were studied in vivo.RESULTS IL-17A upregulated PD-L1 expression in HCC cells in a dose-dependent manner,whereas IL-17A receptor knockout or treatment with a small mothers against decapentaplegic 2 inhibitor diminished the PD-L1 expression induced by IL-17A.IL-17A enhanced the survival of HCC cells in the coculture system.IL-17A increased the viability,G2/M ratio,and migration of HCC cells and decreased the apoptotic index.Cyclin D1,VEGF,MMP9,and Bcl-1 expression increased after IL-17A treatment,whereas BAX expression decreased.The combination of IL-17A and PD-L1 inhibitors showed synergistic antitumor efficacy and increased cluster of differentiation 8+T lymphocyte infiltration in an HCC mouse model.CONCLUSION IL-17A upregulates PD-L1 expression via the IL-17A receptor/phosphorylation-small mothers against decapenta-plegic 2 signaling pathway in HCC cells.Blocking IL-17A enhances the therapeutic efficacy of PD-L1 antibodies in HCC in vivo.
文摘AIM： To study the relationship between interleukin-lbeta （IL-1β） up-regulating tissue inhibitor of matrix metalloproteinase-1 （TIMMP-1） mRNA expression and phosphorylation of both c-jun N-terminal kinase （INK） and p38 in rat heffatic stellate cells （HSC）. METHODS： RT-PCR was performed to measure the expression of TIMMP-1 mRNA in rat HSC. Western blot was performed to measure IL-1β-induced JNK and p38 activities in rat HSC. RESULTS： TIMMP-1 mRNA expression （1.191± 0.079） was much higher after treatment with IL-1β （10 ng/mL） for 24 h than in control group （0.545±0.091） （P〈0.01）. IL-1β activated INK and p38 in a time-dependent manner. After stimulation with IL-1β for 0, 5, 15, 30, 60 and 120 min, the INK activity was 0.982±0.299, 1.501±0.720, 2.133±0.882, 3.360±0.452, 2.181±0.789, and 1.385 ± 0.368, respectively. There was a significant difference in JNK activity at 15 min （P〈 0.01）, 30 min （P〈 0.01） and 60 min （P〈0.01） in comparison to that at 0 min. The p38 activity was 1.061±0.310, 2.050±0.863, 2.380±0.573, 2.973±0.953, 2.421±0.793, and 1.755 ± 0.433 at the 6 time points （0, 5, 15, 30, 60 and 120 min） respectively. There was a significant difference in p38 activity at 5 min （P〈0.05）, 15 min （P〈0.01）, 30 min （P〈0.01） and 60 min （P〈0.01） compared to that at 0 min. TIMMP-1 mRNA expression trended to decrease in 3 groups pretreated with different concentrations of SP600125 （10 μmol/L, 1.022±0.113; 20 μmol/L, 0.869±0.070; 40 μmol/L, 0.666±0.123）. Their decreases were all significant （P〈0.05, P〈0.01, P〈0.01） in comparison to control group （without SP600125 treatment, 1.163±0.107）. In the other 3 groups pretreated with different concentrations of SB203580 （10 μmol/L, 1.507±0.099; 20 μmol/L, 1.698±0.107; 40 μmol/L, 1.857±0.054）, the expression of TIMMP-1 mRNA increased. Their levels were higher than those in the control group （without SB203580 treatment, 1.027 ± 0.061） with a significant statistical significance （P〈 0.01）. CONCLUSION： IL-1β has a direct action on hepatic fibrosis by up-regulating TIMMP-1 mRNA expression in ratessionin in rate HSC.JNK and p38 mitogen-activated protein kinases （MAPKs） are involved in IL-1β-induced TIMMP-1 gene expression, and play a distinct role in this process, indicating that p38 and .INK pathways cooperatively mediate TIMP-1 mRNA expression in rat HSC.
基金This study was supported by grants from the Project of Beijing University of Chinese Medicine in China(No.JYB22 e JS022).
文摘Objective:Pain from herniated disc is a common type of neuropathic pain.This study investigated whether electroacupuncture (EA) stimulation at distal-proximal combinations of acupoints in the rat model of neuropathic pain modulates spinal interleukin-1 beta (IL-1β) to induce acupuncture analgesia and possibly serve as a pain-relief modality for herniated disc.Methods:A rat model of neuropathic pain was established.Rats were randomly divided into normal,model,sham,EA 1,EA 2,and EA 3 groups.EA 1 rats were needled at bilateral ExB2,BL25,BL40,and BL60 acupoints.EA 2 rats Were needled at bilateral BL40 and BL60.EA 3 rats were needled at bilateral L5 Ex-B2 and BL25.EA stimulation was administered once daily over 7 days.Mechanical withdrawal threshold from noxious mechanical stimulation was measured 1 day preoperatively and at 3,5,and7 days postoperatively.After 7 days of intervention,enzyme-linked immunosorbent assay (ELISA) was used to quantify IL-1β in the spinal cord.Results:Mechanical withdrawal threshold of rats in the model group decreased at 3 days postoperatively when compared with the normal group (P < 0.01),lasting 7 days postoperatively.Mechanical withdrawal thresholds in the EA 1,EA 2,and EA 3 groups were elevated over the model group (P < 0.05;P < 0.01).No obvious differences were found between EA 1,EA 2,and EA 3 groups.ELISA demonstrated an increase in IL-1β in the spinal cord of rats in the model group compared with the normal group (P < 0.01).EA treatment attenuated the increase in spinal IL-1β in the model group.Expression of spinal IL-1β was significantly lower in EA 1,EA 2,and EA 3 groups.Conclusion:EA at distal + proximal acupoints,distal points,as well as proximal points attenuated upregulation of spinal IL-1β,alleviated the extent of neuropathic pain hypersensitivity,and promoted mechanical withdrawal threshold,resulting in EA analgesia.
文摘BACKGROUND Hypertension is a chronic cardiovascular disease characterized by persistently elevated arterial blood pressure.It is not only a significant risk factor for cardio-vascular and cerebrovascular diseases(such as myocardial infarction and stroke)but also closely related to multiple organ damages(such as kidney disease and retinopathy),imposing a heavy health and economic burden on individuals and society.AIM To investigate the expression differences and relationships of endothelin-1(ET-1),interleukin-6(IL-6),stem cell factor(SCF),and its receptor(c-kit)in hypertensive patients with or without depression.METHODS A retrospective analysis was conducted on the clinical data of 163 hypertensive patients admitted to our hospital from March 2022 to January 2024.Based on the presence of depression,patients were divided into Group A(n=77,with depre-ssion)and Group B(n=86,without depression).Serum levels of ET-1 and IL-6 were measured using radioimmunoassay,while serum levels of SCF and c-kit were measured using ELISA.The differences in ET-1,IL-6,SCF,and c-kit levels between Groups A and B were compared.Additionally,the differences in these biomarkers among patients with varying degrees of depression in Group A were analyzed.Pearson correlation analysis was used to examine the relationship between ET-1,IL-6,SCF,c-kit levels,and Hamilton depression rating scale(HAMD)scores.Multivariate logistic regression analysis was performed to identify factors influencing hypertension with depression.The diagnostic efficacy of individual and combined biomarkers was analyzed using receiver operating characteristic(ROC)curves.Comparative statistical analysis of the area under the curve(AUC)values was performed using DeLong’s test to assess the superiority of combined biomarker detection.RESULTS The levels of ET-1 and IL-6 in Group A were significantly higher than those in Group B,while the levels of SCF and c-kit were significantly lower in Group A compared to Group B(P<0.05).In the severe depression subgroup,ET-1 and IL-6 levels were higher than those in the mild-to-moderate depression subgroup,while SCF and c-kit levels were lower(P<0.05).Pearson correlation analysis showed that ET-1 and IL-6 levels were positively correlated with HAMD scores(r=0.442,0.463,P<0.05),while SCF and c-kit levels were negatively correlated with HAMD scores(r=-0.429,-0.394,P<0.05).Multivariate logistic regression analysis revealed that high ET-1,high IL-6,low SCF,and low c-kit were independent influencing factors for hypertension with depression(P<0.05).ROC analysis revealed AUCs of 0.746(ET-1),0.801(IL-6),0.732(SCF),0.779(c-kit),and 0.884(combination).The combined diagnosis demonstrated significantly higher AUC than individual markers(DeLong's test,P<0.01),with superior sensitivity(90.24%)and specificity(85.37%).CONCLUSION Compared to patients with hypertension alone,patients with hypertension and depression exhibited higher serum levels of ET-1 and IL-6 and lower levels of SCF and c-kit.High ET-1,high IL-6,low SCF,and low c-kit were inde-pendent influencing factors for hypertension with depression.The combination of ET-1,IL-6,SCF,and c-kit demonstrated significant diagnostic value for hypertension with depression.
基金supported by the National Natural Science Foundation of China(Nos.82293684,82293680)the National Key R&D Program of China(No.2020YFA0908004)CAMS Innovation Fund for Medical Science of China(No.2022-I2M-1-014)。
文摘Interleukin-1 receptor-associated kinase 4(IRAK4)is a key kinase downstream of the interleukin-1 receptor(IL-1R)and Toll-like receptors(TLRs)signaling pathway,whose overexpression and hyperactivation have been associated with several inflammatory diseases or cancer.Therefore,targeting IRAK4 has emerged as a promising therapeutic strategy.A range of potent and selective IRAK4 inhibitors and degraders based on draggability have been designed and developed.This article provides a comprehensive summary of the IRAK4 inhibitors and degraders that have been developed and discusses the challenges and opportunities for research in this area.
基金Supported by the European Union-NextGenerationEU,through the National Recovery and Resilience Plan of the Republic of Bulgaria,No.BG-RRP-2.004-0008.
文摘Type 1 diabetes(T1D)is a chronic organ-specific autoimmune disorder characterized by a progressive loss of the insulin-secreting pancreatic beta cells,which ultimately results in insulinopenia,hyperglycemia and lifelong need for exogenous insulin therapy.In the pathophysiological landscape of T1D,T helper 17 cells(Th17 cells)and their hallmark cytokine,interleukin(IL)-17,play pivotal roles from disease onset to disease progression.In this narrative mini-review,we discuss the dynamic interplay between Th17 cells and IL-17 in the context of T1D,providing insights into the underlying immunologic mechanisms contributing to the IL-17-immunity-mediated pancreatic beta-cell destruction.Furthermore,we summarized the main animal and clinical studies that investigated Th17-and IL-17-targeted interventions as promising immunotherapies able to alter the natural history of T1D.
文摘Background: Cytokines are mediators of disease. Expression levels in the blood could be of clinical relevance. Objective: Aim of this study was to show if serum levels of IL-1β could be of any clinical relevance concerning dogs. IL-1β was measured in serum samples of healthy dogs to find a reference range for healthy individuals. Measurements of IL-1β should show if this substance was a possible marker for early stages of inflammation. Therefore, a possible relation between serum levels and grades of leukocytosis was analyzed. Methods: IL-1β concentrations in the blood were assessed by the use of a human enzyme linked immunosorbent assay (ELISA). 39 dogs with different inflammatory diseases were analyzed to figure out if there was a correlation between IL-1β serum levels and the number of leukocytes in peripheral blood. The control group consisted of 16 healthy dogs. Results: about half of the samples IL-1β were detected. Most of the patients showed no detectable amounts of IL-1β. The IL-1β levels measured in the serum were stable for at least nine weeks when stored at ?20?C. The patients tested positively on IL-1β had mostly lower-grade leukocytosis compared to those who had no IL-1β in serum. All the dogs which were suffering from disease but still had no traceable IL-1β, showed a leukocytosis as a common symptom. Conclusion: This study showed that IL-1β could become an interesting marker for the detection of early stages of inflammation when leukocytosis does not yet appear in peripheral blood. Nonetheless, the possible use in diagnosis is restricted. This is due to the fact that there are only low amounts of IL-1β to be detected in the serum, even concerning patients are suffering from disease.
基金supported by the National Natural Science Foundation of China(82001281 and 82371195)Hubei Provincial Natural Science Foundation of China for Distinguished Young Scholars(2022CFA104)the Research Fund of Jianghan University(2022XKZX28).
文摘High mobility group box 1(HMGB1),when released extracellularly,plays a pivotal role in the development of spinal cord synapses and exacerbates autoimmune diseases within the central nervous system.In experimental autoimmune encephalomyelitis(EAE),a condition that models multiple sclerosis,the levels of extracellular HMGB1 and interleukin-33(IL-33)have been found to be inversely correlated.However,the mechanism by which IL-33 deficiency enhances HMGB1 release during EAE remains elusive.Our study elucidates a potential signaling pathway whereby the absence of IL-33 leads to increased binding of P300/CBP-associated factor with HMGB1 in the nuclei of astrocytes,upregulating HMGB1 acetylation and promoting its release from astrocyte nuclei in the spinal cord of EAE mice.Conversely,the addition of IL-33 counteracts the TNF-α-induced increase in HMGB1 and acetylated HMGB1 levels in primary astrocytes.These findings underscore the potential of IL-33-associated signaling pathways as a therapeutic target for EAE treatment.
基金Grants from the National Natural Science Foundation of China, No. 39600061National Administration of Traditional Chinese Medicine, No.2003LHR13+3 种基金Medical Science Foundation of Guangdong Province, No. A2004327, A2006334the Natural Science Foundation of Guangdong, No. 04010443, 06105246 Administration Bureau of Traditional Chinese Medicine of Guangdong Province, No.1040074Technology Bureau of Guangzhou, No. 2007J1-C0041
文摘BACKGROUND： It has been shown that interleukin-1β（IL-1β） can induce fever by activating vascular endothelial cells and macrophages of the supraoptic crest to generate prostaglandin E2, which binds with receptors of the thermo-sensitive hypothalamic neurons. Lonicera japonica is one of the medicinal plants used widely in Asia for its antipyretic properties. However, these mechanisms have not yet been intensively studied. OBJECTIVE： To investigate the antipyretic effect and mechanisms of Lonicera japonica on IL-1β- induced febrile New Zealand rabbits by observing expression changes of E-type prostaglandin receptor-3 （EP3） mRNA in the preoptic anterior hypothalamus （POAH）. DESIGN： A randomized controlled study. SETTING： Electrophysiological Laboratory at the Department of Pathophysiology, Medical College of Jinan University; Department of Orthopaedics, First Hospital Affiliated to Medical College of Jinan University. MATERIALS： The experiment was performed from April to December 2005, using a total of 32 New Zealand white rabbits of both sexes, weighing 1.5 2.0 kg. All the animal experiments were performed according to the internationally accepted ethical guidelines. Lonicera japonica injection was purchased from Huanghe pharmaceutical factory of Xi＇an, China. IL-1βwas purchased from Sigma, USA. METHODS： A total of 32 rabbits were divided randomly into four groups： ① Normal saline （NS） control group;② Lonicerajaponica treatment group; ③ IL-1βtreatment group; and ④Lonicerajaponica plus IL-1βtreatment group. In the first 3 groups, the rabbits were given separate intravenous （i.v.） injections of l mL NS, l mL Lonicera japonica, and 100 ng IL-l β （dissolved in 0.9% NS without pyrogen）. In the Lonicerajaponica plus IL-1βgroup each rabbit was given i.v. injections of l mL NS and, 30 minutes later, 100 ng IL-1 β. MAIN OUTCOME MEASURES： Colonic temperature of each rabbit was measured at 0, 10, 20, 30, 40, 50, 60, and 70 minutes after injection and the maximum temperature rise （ A T） and the temperature response index after l hour （TRII） was calculated. Subsequently, in situ hybridization （ISH） was done with an ISH kit, EP3 mRNA expression in the POAH of all groups was measured （number of positive cells and average gray scale value）. RESULTS： A total of 32 rabbits were included in the result analysis, without any loss, （i） A T and TRII： there was no significant difference between the Lonicera japonica group and NS group （P 〉 0.05）. The IL-1β group was significantly greater compared to NS group （P 〈 0.01）. The Lonicera japonica plus IL-1β group was significantly less than the IL-1β group （P 〈 0.05）. ② In the NS and Lonicera japonica groups, the EP3 mRNA expression was negative （no coloration） or only weakly positive （only a few brown yellow particles in the cytoplasm cells could not be identified）. The number of positive cells and the average gray scale value were not significantly different between the two groups （P 〉 0.05）. In the IL-1β group, the number of positive cells was remarkably higher and the average gray scale value was lower than the NS group （P 〈 0.0 l）. In the Lonicera japonica plus IL-1β group, the number of positive cells was significantly less than the IL-1β group （P 〈 0.05）. However, the average gray scale value was greater than the IL-1β group （P 〈 0.05）. CONCLUSION： Lonicera japonica has obvious antipyretic effects on IL-1β-induced febrile rabbits and acts by inhibiting expression of EP3 mRNA in the POAH.
基金grant from the Liaoning Provincial Education Bureau, No. 20060890
文摘A previous study by our research group showed that nerve growth factor is involved in the onset of asthma through regulating SH2-Bβ expression in the lung and visceral primary afferent neurons of asthmatic mice. This study sought to assess the expression level of interleukin-1β in primary afferent neurons in C7-T5 spinal ganglia, spinal cord and lung in asthmatic mice after blockage of SH2-Bβ. The levels of interleukin-1β protein in primary afferent neurons in the C7-T5 spinal ganglia and lung were decreased, and interleukin-1β mRNA expression also down-regulated in the spinal cord, medulla oblongata and lung tissue after blockage of SH2-Bβ. Our findings indicate that SH2-Bβ can upregulate the expression of interleukin-1β in C7-T5 spinal ganglia, spinal cord and lung of asthmatic mice.
