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
Diabetic cardiomyopathy is a disorder of the cardiac muscle that affects patients with diabetes.The exact mechanisms underlying diabetic cardiomyopathy are mostly unknown,but several factors have been implicated in th...Diabetic cardiomyopathy is a disorder of the cardiac muscle that affects patients with diabetes.The exact mechanisms underlying diabetic cardiomyopathy are mostly unknown,but several factors have been implicated in the pathogenesis of the disease and its progression towards heart failure,including endothelial dysfunction,autonomic neuropathy,metabolic alterations,oxidative stress,and alterations in ion homeostasis,especially calcium transients[1].In Military Medical Research,Jiang et al.[2]sought to determine the functional role of complement factor D(Adipsin)in the pathophysiology of diabetic cardiomyopathy.展开更多
Gastrointestinal(GI)cancer is a malignancy arising in the digestive system and accounts for approximately a third of increasing global cancer-related mortality,especially in the colorectum,esophagus,stomach,and liver....Gastrointestinal(GI)cancer is a malignancy arising in the digestive system and accounts for approximately a third of increasing global cancer-related mortality,especially in the colorectum,esophagus,stomach,and liver.Interleukin-1β(IL-1β)is a leukocytic pyrogen recognized as a tumor progression-related cytokine.IL-1βsecretion and maturation in inflammatory responses could be regulated by nuclear factor-kappaB-dependent expression of NLR family pyrin domain containing 3,inflammasome formation,and activation of IL-1 converting enzyme.Several studies have documented the pro-tumorigenic effects of IL-1β in tumor microenvironments,promoting proliferation and metastatic potential of cancer cells in vitro and tumorigenesis in vivo.The application of IL-1β inhibitors is also promising for targeted therapy development in some cancer types.However,as a leukocytic pro-inflammatory cytokine,IL-1β may also possess anti-tumorigenic effects and be type-specific in different cancers.This editorial discusses the up-to-date roles of IL-1β in GI cancers,including underlying mechanisms and down-stream signaling pathways.Understanding and clarifying the roles of IL-1β would significantly benefit future therapeutic targeting and help improve therapeutic outcomes in patients suffering from GI cancer.展开更多
BACKGROUND Dry eye is a common eye disease.Artificial tears supplements are widely used for the treatment of dry eyes.However,multiple adverse effects have been observed in patients receiving long-term treatment with ...BACKGROUND Dry eye is a common eye disease.Artificial tears supplements are widely used for the treatment of dry eyes.However,multiple adverse effects have been observed in patients receiving long-term treatment with artificial tears,which may affect the therapeutic effect.AIM To analyze the characteristics of interleukin-1β(IL-1β),interleukin-6(IL-6),and tumor necrosis factor-alpha(TNF-α)levels in patients with dry eye and the therapeutic effect of artificial tears combined with cyclosporine A.METHODS A total of 124 dry eye patients treated at The First People’s Hospital of Xining from April 2020 to April 2022 were selected as the observation group,while 20 healthy individuals served as the control group during the same period.Levels of inflammatory markers,including IL-1β,IL-6,and TNF-α,were analyzed.The observation group was further divided into a study group and a control group,each consisting of 62 patients.The control group received artificial tears,whereas the study group received a combination of artificial tears and cyclosporine A.Inflammatory markers,Schirmer’s test(SIT),tear break-up time(TBUT),corneal fluorescein staining(CFS),National Eye Institute Visual Function Questionnaire-25(NEI-VFQ-25)scores,and adverse events(AEs)were compared between the two groups.RESULTS The observation group exhibited significantly elevated serum levels of IL-1β,IL-6,and TNF-αin comparison to the healthy group.Following treatment,the study group demonstrated substantial reductions in IL-1β,IL-6,and TNF-αlevels relative to the control group.Moreover,after treatment,the study group experienced a marked decrease in CFS scores and significant increases in both SIT and BUT levels when compared to the control group.Additionally,significant improvements were observed in the primary symptom of dry eye and secondary symptoms such as photophobia,foreign body sensation,fatigue,red eye,and burning sensation within the study group.Furthermore,post-treatment NEI-VFQ-25 scores across all dimensions exhibited significant enhancements in the study group compared to the control group(P<0.05).It is noteworthy that significant AEs were reported in both groups throughout the treatment period.CONCLUSION Cyclosporine A combined with artificial tears is effective in treating dry eye,yielding enhanced outcomes by improving SIT and TBUT levels,reducing CFS scores,and ameliorating vision-related quality of life.展开更多
[Objective] The research aimed to carry out the cloning,identification and differential expression analysis of carp interleukin-1β （IL-1β） cDNA. [Method] By using DD-RTPCR method,the differential expression cDNA f...[Objective] The research aimed to carry out the cloning,identification and differential expression analysis of carp interleukin-1β （IL-1β） cDNA. [Method] By using DD-RTPCR method,the differential expression cDNA fragments were gained. The cDNA library of carp peripheral blood leucocytes which was stimulated by the mitogen was screened,and the full length cDNA of carp IL-1β was cloned. Moreover,the sequence analysis and differential expression analysis were carried out. [Result] The positive clone which had a whole ORF that encoded 276 amino acids was obtained. The cluster analysis showed that the amino acid sequence of carp IL-1β and Japanese carp closely gathered as a branch,and the homoeology of amino acid sequence reached 95%. The clustering order was the carassius,zebra fish,pig,cattle,horse,human and mouse in turn. The differential expression analysis showed that the expression of IL-1β in the leucocytes significantly increased in the prior period （4 h） after the mitogen stimulated. But as the time went by （12 and 24 h）,it didn＇t increase in the same period. The total trend of expression amount presented the peak type. [Conclusion] The research laid the foundation for further studying the expression manner,function characteristic,regulation mechanism of IL-1β in vivo and its action mechanisms in the inflammatory reaction,emergency reaction and immune response.展开更多
Elevated intraocular pressure(IOP)is one of the causes of retinal ischemia/reperfusion injury,which results in NRP3 inflammasome activation and leads to visual damage.Homerla is repo rted to play a protective role in ...Elevated intraocular pressure(IOP)is one of the causes of retinal ischemia/reperfusion injury,which results in NRP3 inflammasome activation and leads to visual damage.Homerla is repo rted to play a protective role in neuroinflammation in the cerebrum.However,the effects of Homerla on NLRP3inflammasomes in retinal ischemia/reperfusion injury caused by elevated IOP remain unknown.In our study,animal models we re constructed using C57BL/6J and Homer1^(flox/-)/Homerla^(+/-)/Nestin-Cre^(+/-)mice with elevated IOP-induced retinal ischemia/repe rfusion injury.For in vitro expe riments,the oxygen-glucose deprivation/repe rfusion injury model was constructed with M uller cells.We found that Homerla ove rexpression amelio rated the decreases in retinal thickness and Muller cell viability after ischemia/reperfusion injury.Furthermore,Homerla knockdown promoted NF-κB P65^(Ser536)activation via caspase-8,NF-κB P65 nuclear translocation,NLRP3 inflammasome formation,and the production and processing of interleukin-1βand inte rleukin-18.The opposite results we re observed with Homerla ove rexpression.Finally,the combined administration of Homerla protein and JSH-23 significantly inhibited the reduction in retinal thickness in Homer1^(flox/-)Homer1a^(+/-)/Nestin-Cre^(+/-)mice and apoptosis in M uller cells after ischemia/reperfusion injury.Taken together,these studies demonstrate that Homer1a exerts protective effects on retinal tissue and M uller cells via the caspase-8/NF-KB P65/NLRP3 pathway after I/R injury.展开更多
Spinal cord injury is a disabling condition with limited treatment options.Multiple studies have provided evidence suggesting that small extracellular vesicles(SEVs)secreted by bone marrow mesenchymal stem cells(MSCs)...Spinal cord injury is a disabling condition with limited treatment options.Multiple studies have provided evidence suggesting that small extracellular vesicles(SEVs)secreted by bone marrow mesenchymal stem cells(MSCs)help mediate the beneficial effects conferred by MSC transplantation following spinal cord injury.Strikingly,hypoxia-preconditioned bone marrow mesenchymal stem cell-derived SEVs(HSEVs)exhibit increased therapeutic potency.We thus explored the role of HSEVs in macrophage immune regulation after spinal cord injury in rats and their significance in spinal cord repair.SEVs or HSEVs were isolated from bone marrow MSC supernatants by density gradient ultracentrifugation.HSEV administration to rats via tail vein injection after spinal cord injury reduced the lesion area and attenuated spinal cord inflammation.HSEVs regulate macrophage polarization towards the M2 phenotype in vivo and in vitro.Micro RNA sequencing and bioinformatics analyses of SEVs and HSEVs revealed that mi R-146a-5p is a potent mediator of macrophage polarization that targets interleukin-1 receptor-associated kinase 1.Reducing mi R-146a-5p expression in HSEVs partially attenuated macrophage polarization.Our data suggest that HSEVs attenuate spinal cord inflammation and injury in rats by transporting mi R-146a-5p,which alters macrophage polarization.This study provides new insights into the application of HSEVs as a therapeutic tool for spinal cord injury.展开更多
AIM:To explore the relationship between gastric and intestinal microcirculatory impairment and inflammatory mediators released in rats with acute necrotizing pancreatitis (ANP). METHODS: A total of 64 rats were random...AIM:To explore the relationship between gastric and intestinal microcirculatory impairment and inflammatory mediators released in rats with acute necrotizing pancreatitis (ANP). METHODS: A total of 64 rats were randomized into control group and ANP group. ANP model was induced by injection of 5% sodium taurocholate under the pancreatic membrane. Radioactive biomicrosphere technique was used to measure the gastric and intestinal tissue blood flow at 2 and 12 h after the induction of ANP, meanwhile serum phospholipase A2 (PLA2) activities and interleukin-1β levels were determined. Pathologic changes in pancreas, gastric and intestinal mucosae were studied. RESULTS: The gastric blood flow in ANP group (0.62±0.06 and 0.35±0.05) mL/(min·g) was significantly lower than that in control group (0.86±0.11 and 0.85±0.06) mL/(min·g) (P<0.01) at 2 and 12 h after induction of ANP. The intestinal blood flow in ANP group (0.80±0.07 and 0.50±0.06) mlV(min·g) was significantly lower than that in control group (1.56±0.18 and 1.61±0.11) mL/(min·g) (P<0.01). Serum PLA2 activities (94.29±9.96 and 103.71± 14.40) U/L and IL-1β levels (0.78±0.13 and 0.83±0.20)μg/L in ANP group were higher than those in control group (65.27±10.52 and 66.63±9.81) U/L, (0.32±0.06 and 0.33±0.07)μg/L (P<0.01). At 2 and 12 h after introduction of the model, typical pathologic changes were found in ANP. Compared with control group, the gastric and intestinal mucosal pathologic changes were aggravated significantly (P<0.01) at 12 h after induction of ANP. Gastric and intestinal mucosal necrosis, multiple ulcer and hemorrhage occurred. CONCLUSION: Decrease of gastric and intestinal blood flow and increase of inflammatory mediators occur simultaneously early in ANP, both of them are important pathogenic factors for gastric and intestinal mucosal injury in ANP.展开更多
AIM： To study the association between Interleukin-1 （IL-1） and tumor necrosis factor （TNF）-α polymorphisms, infection by Helicobacter pylori （H pylori） and the development of gastrointestinal diseases.METHODS...AIM： To study the association between Interleukin-1 （IL-1） and tumor necrosis factor （TNF）-α polymorphisms, infection by Helicobacter pylori （H pylori） and the development of gastrointestinal diseases.METHODS： Genomic DNA was extracted from the peripheral blood of 177 patients with various gastrointestinal diseases and from 100 healthy volunteers. The polymorphisms in IL-1β and TNF-α genes were analyzed using the polymerase chain reactionrestriction fragment length polymorphism method （PCRRFLP） and those from IL-1RN with PCR. The presence of infection due to H pylori and the presence of the CagA toxin were detected by serology. The histopathological parameters in the gastric biopsies of the patients were according to the Sydney classification.RESULTS： A comparison of the frequencies of the different polymorphisms studied among the patients and the control group demonstrated that the allele IL- 1RN＊2 was more frequent among patients with gastric ulcers and adenocarcinoma. Carriers of the allele IL- RN＊2 and those with reactive serology for anti-CagA IgG had a greater risk of developing peptic ulcer and gastric adenocarcinoma, as well as a higher degree of inflammation and neutrophilic activity in the gastricCONCLUSION： Our results indicate a positive association between IL-1RN gene polymorphism and infection by positive H pylori CagA strains and the development of gastric ulcers and adenocarcinoma.展开更多
Autophagy acts as an important homoeostatic mechanism by degradation of cytosolic con- stituents and plays roles in many physiological processes. Recent studies demonstrated that autophagy can also regulate the produc...Autophagy acts as an important homoeostatic mechanism by degradation of cytosolic con- stituents and plays roles in many physiological processes. Recent studies demonstrated that autophagy can also regulate the production and secretion of the proinflammatory cytokine interleukin-1β （IL-1β）, which plays a critical role in the development and maintenance ofneuropathic pain. In the present study, the paw withdrawal threshold （PWT） and paw withdrawal latency （PWL） were significantly decreased after spinal nerve ligation （SNL）, and the changes were accompanied by inhibited autophagy in the spi- nal microglia and increased mR.NA and protein levels of IL-1β in the ipsilateral spinal cord. We then investigated the antinociceptive effect of rapamycin, a widely used autopahgy inducer, on SNL-induced neuropathic pain in rats and found that treatment with intrathecal rapamycin significantly attenuated the mechanical allodynia and thermal hyperalgesia. Moreover, rapamycin significantly enhanced autophagy in the spinal microglia, whereas it reduced the mRNA and protein levels of IL-1β in the ipsilateral spinal cord. Our results showed that rapamycin could ameliorate neuropathic pain by activating autophagy and inhibiting IL-1β in the spinal cord.展开更多
AIM： To examine the effect of interleukin-l-beta （IL-113） promoter region C-511T and IL-1 receptor antagonist （IL-1RN） polymorphism among the patients with chronic hepatitis B virus （HBV） infection （HCC and no...AIM： To examine the effect of interleukin-l-beta （IL-113） promoter region C-511T and IL-1 receptor antagonist （IL-1RN） polymorphism among the patients with chronic hepatitis B virus （HBV） infection （HCC and non-HCC）. METHODS： Genomic DNA from 136 Thai patients with chronic HBV infection （HCC =46 and non-HCC= 90） and 152 healthy individuals was genotyped for IL-113 gene polymorphism （-511） using polymerase chain reaction with sequence specific primers （PCR-SSP）. The variable number of tandem repeats （VNTR） of IL-1RN gene was assessed by a PCR-based assay. The association between these genes and status of the disease was evaluated by X^2 test. RESULTS： IL-1B-511 genotype c/c was found to be significantly different in patients with HCC when compared with healthy individuals （P = 0.036, OR = 2.29, 95%CI = 1.05-4.97） and patients without HCC （P=0.036, OR= 2.52, 95%CI=1.05-6.04）. Analysis of allele frequencies of IL-1B-511 showed that IL-1B-511 C allele was also significantly increased in patients with HCC, compared to that in healthy control （P=0.033, OR= 1.72, 95%CI=1.04-2.84）. However, no significant association in IL-1RN gene was found between the two groups. CONCLUSION： IL-1B-511C allele, which may be associated with high IL-1B production in the liver, is a genetic marker for the development of HCC in chronic hepatitis B patients in Thai population.展开更多
Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastrointestinal tract that share clinical and pathological characteristics. The most accredited hypothesis is that both CD a...Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastrointestinal tract that share clinical and pathological characteristics. The most accredited hypothesis is that both CD and UC result from a deregulated mucosal immune response to normal constituents of the gut microflora. Evidence, however, indicates that the main pathological processes in these two diseases are distinct. In CD, the tissue- damaging inflammatory reaction is driven by activated type 1 helper T-cell (Th1), whereas a humoral response predominates in UC. Consistently, a marked accumulation of macrophages making interleukin (IL)-12, the major Th1-inducing factor, is seen in CD but not in UC mucosa. Preliminary studies also indicate that administration of a monoclonal antibody blocking the IL-12/p40 subunit can be useful to induce and maintain clinical remission in CD patients. Notably, the recently described IL-23 shares the p40 subunit with IL-12, raising the possibility that the clinical benefit of the anti-IL-12/p40 antibody in CD may also be due to the neutralization of IL-23 activity. This review summarizes the current information on the expression and functional role of IL-12 and IL- 12-associated signaling pathways both in patients with CD and experimental models of colitis, thus emphasizing major differences between IL-12 and IL-23 activity on the development of intestinal inflammation.展开更多
AIM： To study the effect of interleukin-10 （IL-10） on the expression of transforming growth factor β1 （TGF-β1） in hepatic fibrosis rats and the anti-fibrotic role of exogenous IL-10. METHODS： Hepatic fibrosis ...AIM： To study the effect of interleukin-10 （IL-10） on the expression of transforming growth factor β1 （TGF-β1） in hepatic fibrosis rats and the anti-fibrotic role of exogenous IL-10. METHODS： Hepatic fibrosis was induced by carbon tetrachloride administered （CCh） intraperitoneally. The experiment was performed in two stages. In the first stage, 60 SD rats were divided randomly into normal control group I（GNI, n = 8）, hepatic fibrosis group（GC, n = 28）and IL-10 intervened group（GI, n = 24）. At the beginning of the 7^th and 11^th wk, hepatic stellate cells （HSCs） were isolated, reverse transcription-polymerase chain reation （RT-PCR） and immunocytochemistry were performed to detect the expression of TGF-β1 in HSCs. Histological examination was used to determine the degree of hepatic fibrosis. In the second stage, 47 SD rats were divided randomly into normal control group 2 （GN2, n = 6）and CCh group（GZ, n = 41）. At the end of the 9th week, rats in GZ group were allocated randomly into model group（GM, n = 9）, IL-10 treatment group（GT, n = 9） and recovered group （GR, n = 9）. At the end of the 12^th week, all rats were sacrificed. RT-PCR and immuno- histochemistry were performed to detect the expression of TGF-β1 in liver tissue. ELISA was used to assay serum TGF-β1 levels. RESULTS： Hepatic fibrosis developed in rats with the increase of the injection frequency of CCI4. In the first stage, hepatic fibrosis developed and HSCs were isolated successfully. At the 7^th and 11^th week, TGF-β1 mRNA in GC group increased significantly compared with that in GN1（P = 0.001/0.042） and GI groups（P = 0.001/0.007）, whereas there was no significant difference between the two groups. The levels of TGF-β1 at the beginning of the 7^th wk was higher than that of the 11^th wk （P = 0.049）.Immunocytochemistry results of TGF-β1 were consistent with the above findings. In the second stage, TGF-β1 increased significantly in GM group compared to GN2. Alter treatment with IL-10, TGF-β1 declined obviously. The expression of TGF-β1 decreased in GR group but was still higher than that in GT group. CONCLUSION： The levels of TGF-β1 are increased in hepatic fibrosis rats and decreased alter treatment with exogenous IL-10. IL-10 may play an anti-fibrotic role by suppressing TGF-β1 expression.展开更多
Objective To study the role of extracellular signal-regulated kinase (ERK) in cerebral ischemia and the mechanism of protective effects of U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio] butadiene) on ischem...Objective To study the role of extracellular signal-regulated kinase (ERK) in cerebral ischemia and the mechanism of protective effects of U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio] butadiene) on ischemic brain. Methods Mice underwent left middle cerebral artery occlusion (MCAO) by introducing a suture in the lumen. U0126 was injected intravenously through the internal jugular vein. The immuno-activity of phosphorylated ERK1/2 (pERK1/2), phos-phorylated mitogen activated protein kinase kinase (pMEK), and phosphorylated Elk-1 (pElk-1) was assessed by Western blot analysis and immunohistochemistry. Interleukin (IL)-1βmRNA level was measured by ribonuclease protection assay. Results Phosphorylated ERK1/2 in 2 hours MCAO mice was down-regulated after intravenous injection of U0126. The inhibition was dose dependent and treatment time related. pMEK and pElk-1 were also reduced in a similar fashion after U0126 treatment. IL-1βmRNA increased after 1 and 2 hours of MCAO. After injection of U0126, it was down-regulated during 1 to 4 hours after MCAO. Conclusion Intravenous administration of the MEK inhibitor U0126 inhibits pMEK, pERK1/2, and pElk-1 up-regulation induced by cerebral ischemia. The protective effect of U0126 against ischemic injury is probably resulted from the reduction of IL-1βmRNA via the inhibition of ERK pathway.展开更多
AIM:To investigate the associations between interleukin(IL)-1B and IL-1RN polymorphisms and gastric cancers among the Tibet,Hui and Han ethnicities.METHODS:Genomic DNA was extracted from peripheral blood of 210,205,an...AIM:To investigate the associations between interleukin(IL)-1B and IL-1RN polymorphisms and gastric cancers among the Tibet,Hui and Han ethnicities.METHODS:Genomic DNA was extracted from peripheral blood of 210,205,and 202 healthy volunteers and from 155,158,and 197 gastric cancer patients from the Tibet,Hui,and Han populations,respectively.Polymorphisms in IL-1B and IL-1RN were analyzed by denaturing high-performance liquid chromatography.RESULTS:Carriers of the IL-1B-31 CC genotype had an increased risk of intestinal type gastric cancer [odds ratio(OR) = 2.17,P = 0.037] in the Tibet ethnicity.Carriers of the IL-1B 2/L genotype had an increased risk of both intestinal and diffuse types of gastric cancer(OR = 2.08,2.31,P = 0.007,0.016,respectively) in the Hui ethnicity.In the Han population,carriers of the IL-1B-31 CC,IL-1B-511CT,TT genotypes had increased risk of intestinal type gastric cancer(OR = 2.51,2.74,5.66,P = 0.005,0.002,0.000,respectively).CONCLUSION:IL-1B and IL-RN genotypes may differentially contribute to gastric cancer among the Tibet,Hui,and Han ethnicities in the Qinghai area of China.展开更多
Vascular endothelial growth factor (VEGF, namely VEGF-A) is an angiogenic polypeptide and VEGF-C is a lymphangiogenic polypeptide that has been implicated in cancer growth, invasion and metastasis. Several cytokines a...Vascular endothelial growth factor (VEGF, namely VEGF-A) is an angiogenic polypeptide and VEGF-C is a lymphangiogenic polypeptide that has been implicated in cancer growth, invasion and metastasis. Several cytokines and growth factors play an important part in cancer progression. These cytokines and growth factors are the principal mediators of cancer cells-stromal cell interaction , which is critical for invasion of cancer cells to the surrounding tissues and metastatic dissemination to distant organs. In this study, we studied VEGF-A, C expression in cultured human pancreatic cancer cell lines and whether the presence of VEGF-A, C in the cell lines is regulated by cytokines interleukin-lct (EL-1α), and interleukin-6 (IL-6). METHODS: We used Northern blot and Western blot methods to analyze expression of the gene and protein of VEGF-A, C in all 6 tested cell lines (ASPC-1, CAPAN-1, MIA-PaCa-2, PANC-1, COLO-357 and T3M4) respectively. To analyze what is the regulator for this VEGF-A, C expression in pancreatic cancer,we used the reverse transcription -polymerase chain reaction (RT-PCR) method to analyze VEGF-A, C expression in cultured human pancreatic cancer cell lines (CAPAN-1 and COLO-357) under the stimulation with IL-1α (10μg/L) or IL-6 (100 μg/L). RESULTS:Northern blot analysis revealed the presence of the 4.1-kb VEGF-A mRNA transcript and 2.4-kb VEGF-C mRNA transcript in all 6 tested cell lines. Immunoblotting with highly specific anti-VEGF-A, anti-VEGF-C antibody revealed the presence of a molecular weight of 43-kDa VEGF-A protein and 55-kDa VEGF-C protein in all the cell lines. RT-PCR analysis revealed the levels of the VEGF-A and VEGF-C gene were 1-2 fold and a 1-fold increase in the COLO-357 cell line by stimulation with IL-la, however, no effect was found in the CAPAN-1 cell line. The levels of the VEGF-A and VEGF-C gene were 2-5 fold and a 1-fold increase in the CAPAN-1 cell line by stimulation with IL-6, but, no effect was found in the COLO-357 cell line. CONCLUSION:These findings suggested that the expression of VEGF-A, C and their regulation by IL-1α, IL-6 in pancreatic cancer contributes to the lymphatic and distant metastasis and the disease progression.展开更多
BACKGROUND It is challenging to distinguish intestinal tuberculosis from Crohn’s disease due to dynamic changes in epidemiology and similar clinical characteristics. Recent studies have shown that polymorphisms in ge...BACKGROUND It is challenging to distinguish intestinal tuberculosis from Crohn’s disease due to dynamic changes in epidemiology and similar clinical characteristics. Recent studies have shown that polymorphisms in genes involved in the interleukin (IL)- 23/IL-17 axis may affect intestinal mucosal immunity by affecting the differentiation of Th17 cells. AIM To investigate the specific single-nucleotide polymorphisms (SNPs) in genes involved in the IL-23/IL-17 axis and possible pathways that affect susceptibility to intestinal tuberculosis and Crohn's disease. METHODS We analysed 133 patients with intestinal tuberculosis, 128 with Crohn’s disease, and 500 normal controls. DNA was extracted from paraffin-embedded specimens or whole blood. Four SNPs in the IL23/Th17 axis (IL22 rs2227473, IL1β rs1143627, TGFβ rs4803455, and IL17 rs8193036) were genotyped with TaqMan assays. The transcriptional activity levels of different genotypes of rs2227473 were detected by dual luciferase reporter gene assay. The expression of IL-22R1 in different intestinal diseases was detected by immunohistochemistry. RESULTS The A allele frequency of rs2227473 (P = 0.030, odds ratio = 0.60, 95% confidence interval: 0.37-0.95) showed an abnormal distribution between intestinal tuberculosis and healthy controls. The presence of the A allele was associated with a higher IL-22 transcriptional activity (P < 0.05). In addition, IL-22R1 was expressed in intestinal lymphoid tissues, especially under conditions of intestinal tuberculosis, and highly expressed in macrophage-derived Langhans giant cells. The results of immunohistochemistry showed that the expression of IL-22R1 in patients with Crohn's disease and intestinal tuberculosis was significantly higher than that in patients with intestinal polyps and colon cancer (P < 0.01). CONCLUSION High IL-22 expression seems to be a protective factor for intestinal tuberculosis. IL-22R1 is expressed in Langhans giant cells, suggesting that the IL-22/IL-22R1 system links adaptive and innate immunity.展开更多
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.
基金National Institutes of Health(NIH):National Heart,Lung,and Blood Institute(NHLBI:R01-HL164772,R01-HL159062,R01-HL146691,T32-HL144456)National Institute of Diabetes and Digestive and Kidney Diseases(NIDDK:R01-DK123259,R01-DK033823)+2 种基金National Center for Advancing Translational Sciences(NCATS:UL1-TR002556-06,UM1-TR004400)(to Gaetano Santulli)Diabetes Action Research and Education Foundation(to Gaetano Santulli)Monique Weill-Caulier and Irma T.Hirschl Trusts(to Gaetano Santulli).
文摘Diabetic cardiomyopathy is a disorder of the cardiac muscle that affects patients with diabetes.The exact mechanisms underlying diabetic cardiomyopathy are mostly unknown,but several factors have been implicated in the pathogenesis of the disease and its progression towards heart failure,including endothelial dysfunction,autonomic neuropathy,metabolic alterations,oxidative stress,and alterations in ion homeostasis,especially calcium transients[1].In Military Medical Research,Jiang et al.[2]sought to determine the functional role of complement factor D(Adipsin)in the pathophysiology of diabetic cardiomyopathy.
基金Supported by National Research Council of Thailand,No.N41A640108Mekong-Lancang Cooperation Special Fund+1 种基金The Development and Promotion of Science and Technology Talents ProjectMinistry of Education,Science,Sports,and Culture of Japan,No.22K16327 and No.22K08482.
文摘Gastrointestinal(GI)cancer is a malignancy arising in the digestive system and accounts for approximately a third of increasing global cancer-related mortality,especially in the colorectum,esophagus,stomach,and liver.Interleukin-1β(IL-1β)is a leukocytic pyrogen recognized as a tumor progression-related cytokine.IL-1βsecretion and maturation in inflammatory responses could be regulated by nuclear factor-kappaB-dependent expression of NLR family pyrin domain containing 3,inflammasome formation,and activation of IL-1 converting enzyme.Several studies have documented the pro-tumorigenic effects of IL-1β in tumor microenvironments,promoting proliferation and metastatic potential of cancer cells in vitro and tumorigenesis in vivo.The application of IL-1β inhibitors is also promising for targeted therapy development in some cancer types.However,as a leukocytic pro-inflammatory cytokine,IL-1β may also possess anti-tumorigenic effects and be type-specific in different cancers.This editorial discusses the up-to-date roles of IL-1β in GI cancers,including underlying mechanisms and down-stream signaling pathways.Understanding and clarifying the roles of IL-1β would significantly benefit future therapeutic targeting and help improve therapeutic outcomes in patients suffering from GI cancer.
文摘BACKGROUND Dry eye is a common eye disease.Artificial tears supplements are widely used for the treatment of dry eyes.However,multiple adverse effects have been observed in patients receiving long-term treatment with artificial tears,which may affect the therapeutic effect.AIM To analyze the characteristics of interleukin-1β(IL-1β),interleukin-6(IL-6),and tumor necrosis factor-alpha(TNF-α)levels in patients with dry eye and the therapeutic effect of artificial tears combined with cyclosporine A.METHODS A total of 124 dry eye patients treated at The First People’s Hospital of Xining from April 2020 to April 2022 were selected as the observation group,while 20 healthy individuals served as the control group during the same period.Levels of inflammatory markers,including IL-1β,IL-6,and TNF-α,were analyzed.The observation group was further divided into a study group and a control group,each consisting of 62 patients.The control group received artificial tears,whereas the study group received a combination of artificial tears and cyclosporine A.Inflammatory markers,Schirmer’s test(SIT),tear break-up time(TBUT),corneal fluorescein staining(CFS),National Eye Institute Visual Function Questionnaire-25(NEI-VFQ-25)scores,and adverse events(AEs)were compared between the two groups.RESULTS The observation group exhibited significantly elevated serum levels of IL-1β,IL-6,and TNF-αin comparison to the healthy group.Following treatment,the study group demonstrated substantial reductions in IL-1β,IL-6,and TNF-αlevels relative to the control group.Moreover,after treatment,the study group experienced a marked decrease in CFS scores and significant increases in both SIT and BUT levels when compared to the control group.Additionally,significant improvements were observed in the primary symptom of dry eye and secondary symptoms such as photophobia,foreign body sensation,fatigue,red eye,and burning sensation within the study group.Furthermore,post-treatment NEI-VFQ-25 scores across all dimensions exhibited significant enhancements in the study group compared to the control group(P<0.05).It is noteworthy that significant AEs were reported in both groups throughout the treatment period.CONCLUSION Cyclosporine A combined with artificial tears is effective in treating dry eye,yielding enhanced outcomes by improving SIT and TBUT levels,reducing CFS scores,and ameliorating vision-related quality of life.
基金Supported by the National Natural Science Foundation Item(30972277)~~
文摘[Objective] The research aimed to carry out the cloning,identification and differential expression analysis of carp interleukin-1β （IL-1β） cDNA. [Method] By using DD-RTPCR method,the differential expression cDNA fragments were gained. The cDNA library of carp peripheral blood leucocytes which was stimulated by the mitogen was screened,and the full length cDNA of carp IL-1β was cloned. Moreover,the sequence analysis and differential expression analysis were carried out. [Result] The positive clone which had a whole ORF that encoded 276 amino acids was obtained. The cluster analysis showed that the amino acid sequence of carp IL-1β and Japanese carp closely gathered as a branch,and the homoeology of amino acid sequence reached 95%. The clustering order was the carassius,zebra fish,pig,cattle,horse,human and mouse in turn. The differential expression analysis showed that the expression of IL-1β in the leucocytes significantly increased in the prior period （4 h） after the mitogen stimulated. But as the time went by （12 and 24 h）,it didn＇t increase in the same period. The total trend of expression amount presented the peak type. [Conclusion] The research laid the foundation for further studying the expression manner,function characteristic,regulation mechanism of IL-1β in vivo and its action mechanisms in the inflammatory reaction,emergency reaction and immune response.
基金supported by the Youth Development Project of Air Force Military Medical University,No.21 QNPY072Key Project of Shaanxi Provincial Natural Science Basic Research Program,No.2023-JC-ZD-48(both to FF)。
文摘Elevated intraocular pressure(IOP)is one of the causes of retinal ischemia/reperfusion injury,which results in NRP3 inflammasome activation and leads to visual damage.Homerla is repo rted to play a protective role in neuroinflammation in the cerebrum.However,the effects of Homerla on NLRP3inflammasomes in retinal ischemia/reperfusion injury caused by elevated IOP remain unknown.In our study,animal models we re constructed using C57BL/6J and Homer1^(flox/-)/Homerla^(+/-)/Nestin-Cre^(+/-)mice with elevated IOP-induced retinal ischemia/repe rfusion injury.For in vitro expe riments,the oxygen-glucose deprivation/repe rfusion injury model was constructed with M uller cells.We found that Homerla ove rexpression amelio rated the decreases in retinal thickness and Muller cell viability after ischemia/reperfusion injury.Furthermore,Homerla knockdown promoted NF-κB P65^(Ser536)activation via caspase-8,NF-κB P65 nuclear translocation,NLRP3 inflammasome formation,and the production and processing of interleukin-1βand inte rleukin-18.The opposite results we re observed with Homerla ove rexpression.Finally,the combined administration of Homerla protein and JSH-23 significantly inhibited the reduction in retinal thickness in Homer1^(flox/-)Homer1a^(+/-)/Nestin-Cre^(+/-)mice and apoptosis in M uller cells after ischemia/reperfusion injury.Taken together,these studies demonstrate that Homer1a exerts protective effects on retinal tissue and M uller cells via the caspase-8/NF-KB P65/NLRP3 pathway after I/R injury.
基金supported by the Fujian Minimally Invasive Medical Center Foundation,No.2128100514(to CC,CW,HX)the Natural Science Foundation of Fujian Province,No.2023J01640(to CC,CW,ZL,HX)。
文摘Spinal cord injury is a disabling condition with limited treatment options.Multiple studies have provided evidence suggesting that small extracellular vesicles(SEVs)secreted by bone marrow mesenchymal stem cells(MSCs)help mediate the beneficial effects conferred by MSC transplantation following spinal cord injury.Strikingly,hypoxia-preconditioned bone marrow mesenchymal stem cell-derived SEVs(HSEVs)exhibit increased therapeutic potency.We thus explored the role of HSEVs in macrophage immune regulation after spinal cord injury in rats and their significance in spinal cord repair.SEVs or HSEVs were isolated from bone marrow MSC supernatants by density gradient ultracentrifugation.HSEV administration to rats via tail vein injection after spinal cord injury reduced the lesion area and attenuated spinal cord inflammation.HSEVs regulate macrophage polarization towards the M2 phenotype in vivo and in vitro.Micro RNA sequencing and bioinformatics analyses of SEVs and HSEVs revealed that mi R-146a-5p is a potent mediator of macrophage polarization that targets interleukin-1 receptor-associated kinase 1.Reducing mi R-146a-5p expression in HSEVs partially attenuated macrophage polarization.Our data suggest that HSEVs attenuate spinal cord inflammation and injury in rats by transporting mi R-146a-5p,which alters macrophage polarization.This study provides new insights into the application of HSEVs as a therapeutic tool for spinal cord injury.
基金Supported by the Traditional Chinese Medicine Administration Bureau Foundation of Jiangsu Province,No.9965the Applied Basic Research Program of Science and Technology Commission Foundation of Jiangsu Province,No.BJ2000327
文摘AIM:To explore the relationship between gastric and intestinal microcirculatory impairment and inflammatory mediators released in rats with acute necrotizing pancreatitis (ANP). METHODS: A total of 64 rats were randomized into control group and ANP group. ANP model was induced by injection of 5% sodium taurocholate under the pancreatic membrane. Radioactive biomicrosphere technique was used to measure the gastric and intestinal tissue blood flow at 2 and 12 h after the induction of ANP, meanwhile serum phospholipase A2 (PLA2) activities and interleukin-1β levels were determined. Pathologic changes in pancreas, gastric and intestinal mucosae were studied. RESULTS: The gastric blood flow in ANP group (0.62±0.06 and 0.35±0.05) mL/(min·g) was significantly lower than that in control group (0.86±0.11 and 0.85±0.06) mL/(min·g) (P<0.01) at 2 and 12 h after induction of ANP. The intestinal blood flow in ANP group (0.80±0.07 and 0.50±0.06) mlV(min·g) was significantly lower than that in control group (1.56±0.18 and 1.61±0.11) mL/(min·g) (P<0.01). Serum PLA2 activities (94.29±9.96 and 103.71± 14.40) U/L and IL-1β levels (0.78±0.13 and 0.83±0.20)μg/L in ANP group were higher than those in control group (65.27±10.52 and 66.63±9.81) U/L, (0.32±0.06 and 0.33±0.07)μg/L (P<0.01). At 2 and 12 h after introduction of the model, typical pathologic changes were found in ANP. Compared with control group, the gastric and intestinal mucosal pathologic changes were aggravated significantly (P<0.01) at 12 h after induction of ANP. Gastric and intestinal mucosal necrosis, multiple ulcer and hemorrhage occurred. CONCLUSION: Decrease of gastric and intestinal blood flow and increase of inflammatory mediators occur simultaneously early in ANP, both of them are important pathogenic factors for gastric and intestinal mucosal injury in ANP.
基金Supported by Secretaria Executiva de Ciência,Tecnologiae Meio Ambiente-SECTAM and Coordenao de Aperfeioamento de Pessoal de Nível Superior-CAPES
文摘AIM： To study the association between Interleukin-1 （IL-1） and tumor necrosis factor （TNF）-α polymorphisms, infection by Helicobacter pylori （H pylori） and the development of gastrointestinal diseases.METHODS： Genomic DNA was extracted from the peripheral blood of 177 patients with various gastrointestinal diseases and from 100 healthy volunteers. The polymorphisms in IL-1β and TNF-α genes were analyzed using the polymerase chain reactionrestriction fragment length polymorphism method （PCRRFLP） and those from IL-1RN with PCR. The presence of infection due to H pylori and the presence of the CagA toxin were detected by serology. The histopathological parameters in the gastric biopsies of the patients were according to the Sydney classification.RESULTS： A comparison of the frequencies of the different polymorphisms studied among the patients and the control group demonstrated that the allele IL- 1RN＊2 was more frequent among patients with gastric ulcers and adenocarcinoma. Carriers of the allele IL- RN＊2 and those with reactive serology for anti-CagA IgG had a greater risk of developing peptic ulcer and gastric adenocarcinoma, as well as a higher degree of inflammation and neutrophilic activity in the gastricCONCLUSION： Our results indicate a positive association between IL-1RN gene polymorphism and infection by positive H pylori CagA strains and the development of gastric ulcers and adenocarcinoma.
基金supported by grants from the National Natural Science Foundation of China(Nos.31100801 and81200858)
文摘Autophagy acts as an important homoeostatic mechanism by degradation of cytosolic con- stituents and plays roles in many physiological processes. Recent studies demonstrated that autophagy can also regulate the production and secretion of the proinflammatory cytokine interleukin-1β （IL-1β）, which plays a critical role in the development and maintenance ofneuropathic pain. In the present study, the paw withdrawal threshold （PWT） and paw withdrawal latency （PWL） were significantly decreased after spinal nerve ligation （SNL）, and the changes were accompanied by inhibited autophagy in the spi- nal microglia and increased mR.NA and protein levels of IL-1β in the ipsilateral spinal cord. We then investigated the antinociceptive effect of rapamycin, a widely used autopahgy inducer, on SNL-induced neuropathic pain in rats and found that treatment with intrathecal rapamycin significantly attenuated the mechanical allodynia and thermal hyperalgesia. Moreover, rapamycin significantly enhanced autophagy in the spinal microglia, whereas it reduced the mRNA and protein levels of IL-1β in the ipsilateral spinal cord. Our results showed that rapamycin could ameliorate neuropathic pain by activating autophagy and inhibiting IL-1β in the spinal cord.
基金Supported by the Thailand Research Fund,RSA4680021
文摘AIM： To examine the effect of interleukin-l-beta （IL-113） promoter region C-511T and IL-1 receptor antagonist （IL-1RN） polymorphism among the patients with chronic hepatitis B virus （HBV） infection （HCC and non-HCC）. METHODS： Genomic DNA from 136 Thai patients with chronic HBV infection （HCC =46 and non-HCC= 90） and 152 healthy individuals was genotyped for IL-113 gene polymorphism （-511） using polymerase chain reaction with sequence specific primers （PCR-SSP）. The variable number of tandem repeats （VNTR） of IL-1RN gene was assessed by a PCR-based assay. The association between these genes and status of the disease was evaluated by X^2 test. RESULTS： IL-1B-511 genotype c/c was found to be significantly different in patients with HCC when compared with healthy individuals （P = 0.036, OR = 2.29, 95%CI = 1.05-4.97） and patients without HCC （P=0.036, OR= 2.52, 95%CI=1.05-6.04）. Analysis of allele frequencies of IL-1B-511 showed that IL-1B-511 C allele was also significantly increased in patients with HCC, compared to that in healthy control （P=0.033, OR= 1.72, 95%CI=1.04-2.84）. However, no significant association in IL-1RN gene was found between the two groups. CONCLUSION： IL-1B-511C allele, which may be associated with high IL-1B production in the liver, is a genetic marker for the development of HCC in chronic hepatitis B patients in Thai population.
文摘Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastrointestinal tract that share clinical and pathological characteristics. The most accredited hypothesis is that both CD and UC result from a deregulated mucosal immune response to normal constituents of the gut microflora. Evidence, however, indicates that the main pathological processes in these two diseases are distinct. In CD, the tissue- damaging inflammatory reaction is driven by activated type 1 helper T-cell (Th1), whereas a humoral response predominates in UC. Consistently, a marked accumulation of macrophages making interleukin (IL)-12, the major Th1-inducing factor, is seen in CD but not in UC mucosa. Preliminary studies also indicate that administration of a monoclonal antibody blocking the IL-12/p40 subunit can be useful to induce and maintain clinical remission in CD patients. Notably, the recently described IL-23 shares the p40 subunit with IL-12, raising the possibility that the clinical benefit of the anti-IL-12/p40 antibody in CD may also be due to the neutralization of IL-23 activity. This review summarizes the current information on the expression and functional role of IL-12 and IL- 12-associated signaling pathways both in patients with CD and experimental models of colitis, thus emphasizing major differences between IL-12 and IL-23 activity on the development of intestinal inflammation.
基金Supported by Natural Science Foundation of Fujian Province, No. 2005D094 and No. C0410025
文摘AIM： To study the effect of interleukin-10 （IL-10） on the expression of transforming growth factor β1 （TGF-β1） in hepatic fibrosis rats and the anti-fibrotic role of exogenous IL-10. METHODS： Hepatic fibrosis was induced by carbon tetrachloride administered （CCh） intraperitoneally. The experiment was performed in two stages. In the first stage, 60 SD rats were divided randomly into normal control group I（GNI, n = 8）, hepatic fibrosis group（GC, n = 28）and IL-10 intervened group（GI, n = 24）. At the beginning of the 7^th and 11^th wk, hepatic stellate cells （HSCs） were isolated, reverse transcription-polymerase chain reation （RT-PCR） and immunocytochemistry were performed to detect the expression of TGF-β1 in HSCs. Histological examination was used to determine the degree of hepatic fibrosis. In the second stage, 47 SD rats were divided randomly into normal control group 2 （GN2, n = 6）and CCh group（GZ, n = 41）. At the end of the 9th week, rats in GZ group were allocated randomly into model group（GM, n = 9）, IL-10 treatment group（GT, n = 9） and recovered group （GR, n = 9）. At the end of the 12^th week, all rats were sacrificed. RT-PCR and immuno- histochemistry were performed to detect the expression of TGF-β1 in liver tissue. ELISA was used to assay serum TGF-β1 levels. RESULTS： Hepatic fibrosis developed in rats with the increase of the injection frequency of CCI4. In the first stage, hepatic fibrosis developed and HSCs were isolated successfully. At the 7^th and 11^th week, TGF-β1 mRNA in GC group increased significantly compared with that in GN1（P = 0.001/0.042） and GI groups（P = 0.001/0.007）, whereas there was no significant difference between the two groups. The levels of TGF-β1 at the beginning of the 7^th wk was higher than that of the 11^th wk （P = 0.049）.Immunocytochemistry results of TGF-β1 were consistent with the above findings. In the second stage, TGF-β1 increased significantly in GM group compared to GN2. Alter treatment with IL-10, TGF-β1 declined obviously. The expression of TGF-β1 decreased in GR group but was still higher than that in GT group. CONCLUSION： The levels of TGF-β1 are increased in hepatic fibrosis rats and decreased alter treatment with exogenous IL-10. IL-10 may play an anti-fibrotic role by suppressing TGF-β1 expression.
文摘Objective To study the role of extracellular signal-regulated kinase (ERK) in cerebral ischemia and the mechanism of protective effects of U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio] butadiene) on ischemic brain. Methods Mice underwent left middle cerebral artery occlusion (MCAO) by introducing a suture in the lumen. U0126 was injected intravenously through the internal jugular vein. The immuno-activity of phosphorylated ERK1/2 (pERK1/2), phos-phorylated mitogen activated protein kinase kinase (pMEK), and phosphorylated Elk-1 (pElk-1) was assessed by Western blot analysis and immunohistochemistry. Interleukin (IL)-1βmRNA level was measured by ribonuclease protection assay. Results Phosphorylated ERK1/2 in 2 hours MCAO mice was down-regulated after intravenous injection of U0126. The inhibition was dose dependent and treatment time related. pMEK and pElk-1 were also reduced in a similar fashion after U0126 treatment. IL-1βmRNA increased after 1 and 2 hours of MCAO. After injection of U0126, it was down-regulated during 1 to 4 hours after MCAO. Conclusion Intravenous administration of the MEK inhibitor U0126 inhibits pMEK, pERK1/2, and pElk-1 up-regulation induced by cerebral ischemia. The protective effect of U0126 against ischemic injury is probably resulted from the reduction of IL-1βmRNA via the inhibition of ERK pathway.
基金Supported by Grants from the National Natural Science Foun dation of China,No.30860259the Youth Scientific Re search Foundation of Qinghai University,No.2008-QY-09
文摘AIM:To investigate the associations between interleukin(IL)-1B and IL-1RN polymorphisms and gastric cancers among the Tibet,Hui and Han ethnicities.METHODS:Genomic DNA was extracted from peripheral blood of 210,205,and 202 healthy volunteers and from 155,158,and 197 gastric cancer patients from the Tibet,Hui,and Han populations,respectively.Polymorphisms in IL-1B and IL-1RN were analyzed by denaturing high-performance liquid chromatography.RESULTS:Carriers of the IL-1B-31 CC genotype had an increased risk of intestinal type gastric cancer [odds ratio(OR) = 2.17,P = 0.037] in the Tibet ethnicity.Carriers of the IL-1B 2/L genotype had an increased risk of both intestinal and diffuse types of gastric cancer(OR = 2.08,2.31,P = 0.007,0.016,respectively) in the Hui ethnicity.In the Han population,carriers of the IL-1B-31 CC,IL-1B-511CT,TT genotypes had increased risk of intestinal type gastric cancer(OR = 2.51,2.74,5.66,P = 0.005,0.002,0.000,respectively).CONCLUSION:IL-1B and IL-RN genotypes may differentially contribute to gastric cancer among the Tibet,Hui,and Han ethnicities in the Qinghai area of China.
基金This work was supported by a grant from the Chinese Ministry of Education, China (JWSL 2002247).
文摘Vascular endothelial growth factor (VEGF, namely VEGF-A) is an angiogenic polypeptide and VEGF-C is a lymphangiogenic polypeptide that has been implicated in cancer growth, invasion and metastasis. Several cytokines and growth factors play an important part in cancer progression. These cytokines and growth factors are the principal mediators of cancer cells-stromal cell interaction , which is critical for invasion of cancer cells to the surrounding tissues and metastatic dissemination to distant organs. In this study, we studied VEGF-A, C expression in cultured human pancreatic cancer cell lines and whether the presence of VEGF-A, C in the cell lines is regulated by cytokines interleukin-lct (EL-1α), and interleukin-6 (IL-6). METHODS: We used Northern blot and Western blot methods to analyze expression of the gene and protein of VEGF-A, C in all 6 tested cell lines (ASPC-1, CAPAN-1, MIA-PaCa-2, PANC-1, COLO-357 and T3M4) respectively. To analyze what is the regulator for this VEGF-A, C expression in pancreatic cancer,we used the reverse transcription -polymerase chain reaction (RT-PCR) method to analyze VEGF-A, C expression in cultured human pancreatic cancer cell lines (CAPAN-1 and COLO-357) under the stimulation with IL-1α (10μg/L) or IL-6 (100 μg/L). RESULTS:Northern blot analysis revealed the presence of the 4.1-kb VEGF-A mRNA transcript and 2.4-kb VEGF-C mRNA transcript in all 6 tested cell lines. Immunoblotting with highly specific anti-VEGF-A, anti-VEGF-C antibody revealed the presence of a molecular weight of 43-kDa VEGF-A protein and 55-kDa VEGF-C protein in all the cell lines. RT-PCR analysis revealed the levels of the VEGF-A and VEGF-C gene were 1-2 fold and a 1-fold increase in the COLO-357 cell line by stimulation with IL-la, however, no effect was found in the CAPAN-1 cell line. The levels of the VEGF-A and VEGF-C gene were 2-5 fold and a 1-fold increase in the CAPAN-1 cell line by stimulation with IL-6, but, no effect was found in the COLO-357 cell line. CONCLUSION:These findings suggested that the expression of VEGF-A, C and their regulation by IL-1α, IL-6 in pancreatic cancer contributes to the lymphatic and distant metastasis and the disease progression.
基金Supported by Key R&D Plan of Science and Technology Department of Jiangxi Province,No.20171BBG70087
文摘BACKGROUND It is challenging to distinguish intestinal tuberculosis from Crohn’s disease due to dynamic changes in epidemiology and similar clinical characteristics. Recent studies have shown that polymorphisms in genes involved in the interleukin (IL)- 23/IL-17 axis may affect intestinal mucosal immunity by affecting the differentiation of Th17 cells. AIM To investigate the specific single-nucleotide polymorphisms (SNPs) in genes involved in the IL-23/IL-17 axis and possible pathways that affect susceptibility to intestinal tuberculosis and Crohn's disease. METHODS We analysed 133 patients with intestinal tuberculosis, 128 with Crohn’s disease, and 500 normal controls. DNA was extracted from paraffin-embedded specimens or whole blood. Four SNPs in the IL23/Th17 axis (IL22 rs2227473, IL1β rs1143627, TGFβ rs4803455, and IL17 rs8193036) were genotyped with TaqMan assays. The transcriptional activity levels of different genotypes of rs2227473 were detected by dual luciferase reporter gene assay. The expression of IL-22R1 in different intestinal diseases was detected by immunohistochemistry. RESULTS The A allele frequency of rs2227473 (P = 0.030, odds ratio = 0.60, 95% confidence interval: 0.37-0.95) showed an abnormal distribution between intestinal tuberculosis and healthy controls. The presence of the A allele was associated with a higher IL-22 transcriptional activity (P < 0.05). In addition, IL-22R1 was expressed in intestinal lymphoid tissues, especially under conditions of intestinal tuberculosis, and highly expressed in macrophage-derived Langhans giant cells. The results of immunohistochemistry showed that the expression of IL-22R1 in patients with Crohn's disease and intestinal tuberculosis was significantly higher than that in patients with intestinal polyps and colon cancer (P < 0.01). CONCLUSION High IL-22 expression seems to be a protective factor for intestinal tuberculosis. IL-22R1 is expressed in Langhans giant cells, suggesting that the IL-22/IL-22R1 system links adaptive and innate immunity.
