BACKGROUND:L-3-n-butylphthalide(L-NBP) can inhibit phosphorylation of tau protein and reduce the neurotoxicity of beta-amyloid peptide 1-42(Aβ_(1-42)). OBJECTIVE:To observe the neuroprotective effects of L-NBP on cas...BACKGROUND:L-3-n-butylphthalide(L-NBP) can inhibit phosphorylation of tau protein and reduce the neurotoxicity of beta-amyloid peptide 1-42(Aβ_(1-42)). OBJECTIVE:To observe the neuroprotective effects of L-NBP on caspase-3 and nuclear factor kappa-B(NF-κB) expression in a rat model of Alzheimer's disease. DESIGN,TIME AND SETTING:A cell experiment was performed at the Central Laboratory of Provincial Hospital affiliated to Shandong University between January 2008 and August 2008. MATERIALS:L-NBP(purity>98%) was provided by Shijiazhuang Pharma Group NBP Pharmaceutical Company Limited.Aβ_(1-42),3-[4,5-dimethylthiazolo-2]-2,5 iphenyltetrazolium bromide(MTT),and rabbit anti-Caspase-3 polyclonal antibody were provided by Cell Signaling, USA;goat anti-choactase and rabbit anti-NF-κB antibodies were provided by Santa Cruz,USA. METHODS:Primary cultures were generated from rat basal forebrain and hippocampal neurons at 17 or 19 days of gestation.The cells were assigned into five groups:the control group,the Aβ_(1-42) group(2μmol/ L),the Aβ_(1-42) + 0.1μmol/L L-NBP group,the Aβ_(1-42)+ 1μmol/L L-NBP group,and the Aβ_(1-42)+ 10μmol/L L-NBP group.The neurons were treated with Aβ_(1-42)(2μmol/L) alone or in combination with L-NBP(0.1,1,10μmol/L) for 48 hours.Cells in the control group were incubated in PBS. MAIN OUTCOME MEASURES:Morphologic changes were evaluated using inverted microscopy, viability using the MTT method,and the changes in caspase-3 and NF-κB expression using Western blot. RESULTS:Induction with Aβ_(1-42) for 48 hours caused cell death and soma atrophy,and increased caspase-3 and NF-κB expression(P<0.05).L-NBP blocked these changes in cell morphology, decreased caspase-3 and NF-κB expression(P<0.05),and improved cell viability,especially at the high dose(P<0.05). CONCLUSION:Aβ_(1-42) is toxic to basal forebrain and hippocampal primary neurons;L-NBP protects against this toxicity and inhibits the induction of caspase-3 and NF-κB expression.展开更多
The relation between the expression and activity of MMP-9 in C-reactive protein (CRP)-induced human THP-1 mononuclear cells and the activation of nuclear factor kappa-B (NF-кB) was studied to investigate the possible...The relation between the expression and activity of MMP-9 in C-reactive protein (CRP)-induced human THP-1 mononuclear cells and the activation of nuclear factor kappa-B (NF-кB) was studied to investigate the possible role of CRP in plaque destabilization. Human THP-1 cells were incubated in the presence of CRP at 0 (control group), 25, 50 and 100 μg/mL (CRP groups) for 24 h. In PDTC (a specific NF-кB inhibitor) group, the cells were pre-treated with PDTC at 10 μmol/L and then with 100 μg/mL CRP. The conditioned media (CM) and human THP-1 cells in different groups were harvested. MMP-9 expression in CM and human THP-1 cells was measured by ELISA and Western blotting. MMP-9 activity was assessed by fluorogenic substrates. The expression of NF-кB inhibitor α (IкB-α) and NF-кB P65 was detected by Western blotting and ELISA respectively. The results showed that CRP increased the expression and activity of MMP-9 in a dose-dependent manner in the human THP-1 cells. Western blotting revealed that IкB-α expression was decreased in the cells with the concentrations of CRP and ELISA demonstrated that NF-кB P65 expression in the CRP-induced cells was increased. After pre-treatment of the cells with PDTC at 10 μmol/L, the decrease in IкB-α expression and the increase in NF-кB P65 expression in the CRP-induced cells were inhibited, and the expression and activity of MMP-9 were lowered too. It is concluded that increased expression and activity of MMP-9 in CRP-induced human THP-1 cells may be associated with acti- vation of NF-кB. Down-regulation of the expression and activity of MMP-9 may be a new treatment alternative for plaque stabilization by inhibiting the NF-кB activation.展开更多
Medium-chain fatty acids and their derivatives are natural ingredients that support immunological functions in animals.The effects of glycerol monolaurate(GML)on intestinal innate immunity and associated molecular mec...Medium-chain fatty acids and their derivatives are natural ingredients that support immunological functions in animals.The effects of glycerol monolaurate(GML)on intestinal innate immunity and associated molecular mechanisms were investigated using a chicken embryo model.Sixty-four Arbor Acres broiler embryos were randomly allocated into four groups.On embryonic day 17.5,the broiler embryos were administered with 9 mg of GML,which was followed by a 12-h incubation period and a12-h challenge with 32μg of lipopolysaccharide(LPS).On embryonic day 18.5,the jejunum and ileum were harvested.Results indicated that GML reversed the LPS-induced decline in villus height and upregulated the expression of mucin 2(P<0.05).GML decreased LPS-induced malondialdehyde production and boosted antioxidant enzyme activity(P<0.05).GML alleviated LPS-stimulated intestinal secretion of interleukin(IL)-1β,IL-6,and tumor necrosis factor-a(TNF-a)(P<0.05).GML also normalized LPS-induced changes in the gene expression of Toll-like receptor 4,nuclear factor kappa-B p65(NF-κB p65),cyclooxygenase-2,NOD-like receptor protein 3,IL-18,zonula occludens 1,and occludin(P<0.05).GML enhanced as well the expression of AMP-activated protein kinase a1 and claudin 1(P<0.05).In conclusion,GML improved intestinal morphology and antioxidant status by alleviating inflammatory responses and modulating NF-κB signaling in LPS-challenged broiler embryos.展开更多
Background:Inflammation is an important factor in pathological scarring.The role of neutrophils,one of the most important inflammatory cells,in scar hyperplasia remains unclear.The purpose of this article is to study ...Background:Inflammation is an important factor in pathological scarring.The role of neutrophils,one of the most important inflammatory cells,in scar hyperplasia remains unclear.The purpose of this article is to study the correlation between neutrophil extracellular traps(NETs)and scar hyperplasia and identify a new target for inhibiting scar hyperplasia.Methods:Neutrophils were isolated from human peripheral blood by magnetic-bead sorting.NETs in plasma and scars were detected by enzyme-linked immunosorbent assays(ELISAs),immunofluorescence and flow cytometry.Immunohistochemistry was used to assess neutrophil(CD66B)infiltration in hypertrophic scars.To observe the entry of NETs into fibroblasts we used immunofluorescence and flow cytometry.Results:We found that peripheral blood neutrophils in patients with hypertrophic scars were more likely to form NETs(p<0.05).Hypertrophic scars showed greater infiltration with neutrophils and NETs(p<0.05).NETs activate fibroblasts in vitro to promote their differentiation and migration.Inhibition of NETs with cytochalasin in wounds reduced the hyperplasia of scars in mice.We induced neutrophils to generate NETs with different stimuli in vitro and detected the proteins carried by NETs.We did not find an increase in the expression of common scarring factors[interleukin(IL)-17 and transforming growth factor-β(TGF-β),p>0.05].However,inhibiting the production of NETs or degrading DNA reduced the differentiation of fibroblasts intomyofibroblasts.In vitro,NETs were found to be mediated by Toll-like receptor 9(TLR-9)in fibroblasts and further phosphorylated nuclear factor Kappa-B(NF-κB).We found that IL-6,which is downstream of NF-κB,was increased in fibroblasts.Additionally,IL-6 uses autocrine and paracrine signaling to promote differentiation and secretion.Conclusions:Our experiments found that NETs activate fibroblasts through the TLR-9/NF-κB/IL-6 pathway,thereby providing a new target for regulating hypertrophic scars.展开更多
This study aims to analyze the clinical significance and mechanism of nuclear factor erythroid 2-related factor 2(NRF2)and glutathione peroxidase 4(GPX4)in primary hepatic carcinoma(PHC).Methods:The expression of NRF2...This study aims to analyze the clinical significance and mechanism of nuclear factor erythroid 2-related factor 2(NRF2)and glutathione peroxidase 4(GPX4)in primary hepatic carcinoma(PHC).Methods:The expression of NRF2 and GPX4 in peripheral blood of patients with PHC was determined to analyze the diagnostic value of the two combined for PHC.The prognostic significance of NRF2 and GPX4 was evaluated by 3-year followup.Human liver epithelial cells THLE-2 and human hepatocellular carcinoma cells HepG2 were purchased,and the expression of NRF2 and GPX4 in the cells was determined.NRF2 and GPX4 aberrant expression vectors were constructed and transfected into HepG2,and changes in cell proliferation and invasion capabilities were observed.Results:The expression of NRF2 and GPX4 in patients with PHC was higher than that in patients with LC or VH(p<0.05),and the two indicators combined was excellent in diagnosing PHC.Moreover,patients with high expression of NRF2 and GPX4 had a higher risk of death(p<0.05).In in vitro experiments,both NRF2 and GPX4 expression was elevated in HepG2(p<0.05).HepG2 activity was enhanced by increasing the expression of the two,vice versa(p<0.05).Conclusion:NRF2 and GPX4 combined is excellent in diagnosing PHC,and promotes the malignant development of PHC.展开更多
BACKGROUND The Nuclear factor erythroid 2-related factor 2(NRF2)transcription factor has attracted much attention in the context of neurological diseases.However,none of the studies have systematically clarified this ...BACKGROUND The Nuclear factor erythroid 2-related factor 2(NRF2)transcription factor has attracted much attention in the context of neurological diseases.However,none of the studies have systematically clarified this field's research hotspots and evolution rules.AIM To investigate the research hotspots,evolution patterns,and future research trends in this field in recent years.METHODS We conducted a comprehensive literature search in the Web of Science Core Collection database using the following methods:(((((TS=(NFE2 L2))OR TS=(Nfe2 L2 protein,mouse))OR TS=(NF-E2-Related Factor 2))OR TS=(NRF2))OR TS=(NFE2L2))OR TS=(Nuclear factor erythroid2-related factor 2)AND(((((((TS=(neurological diseases))OR TS=(neurological disorder))OR TS=(brain disorder))OR TS=(brain injury))OR TS=(central nervous system disease))OR TS=(CNS disease))OR TS=(central nervous system disorder))OR TS=(CNS disorder)AND Language=English from 2010 to 2022.There are just two forms of literature available:Articles and reviews.Data were processed with the software Cite-Space(version 6.1.R6).RESULTS We analyzed 1884 articles from 200 schools in 72 countries/regions.Since 2015,the number of publications in this field has increased rapidly.China has the largest number of publications,but the articles published in the United States have better centrality and H-index.Among the top ten authors with the most published papers,five of them are from China,and the author with the most published papers is Wang Handong.The institution with the most articles was Nanjing University.To their credit,three of the top 10 most cited articles were written by Chinese scholars.The keyword co-occurrence map showed that"oxidative stress","NRF2","activation","expression"and"brain"were the five most frequently used keywords.CONCLUSION Research on the role of NRF2 in neurological diseases continues unabated.Researchers in developed countries published more influential papers,while Chinese scholars provided the largest number of articles.There have been numerous studies on the mechanism of NRF2 transcription factor in neurological diseases.NRF2 is also emerging as a potentially effective target for the treatment of neurological diseases.However,despite decades of research,our knowledge of NRF2 transcription factor in nervous system diseases is still limited.Further studies are needed in the future.展开更多
Previous studies have found that deficiency in nuclear receptor-related factor 1(Nurr1),which participates in the development,differentiation,survival,and degeneration of dopaminergic neurons,is associated with Parkin...Previous studies have found that deficiency in nuclear receptor-related factor 1(Nurr1),which participates in the development,differentiation,survival,and degeneration of dopaminergic neurons,is associated with Parkinson s disease,but the mechanism of action is perplexing.Here,we first asce rtained the repercussion of knocking down Nurr1 by pe rforming liquid chromatography coupled with tandem mass spectrometry.We found that 231 genes were highly expressed in dopaminergic neurons with Nurr1 deficiency,14 of which were linked to the Parkinson’s disease pathway based on Kyoto Encyclopedia of Genes and Genomes analysis.To better understand how Nurr1 deficiency autonomously invokes the decline of dopaminergic neurons and elicits Parkinson’s disease symptoms,we performed single-nuclei RNA sequencing in a Nurr1 LV-shRNA mouse model.The results revealed cellular heterogeneity in the substantia nigra and a number of activated genes,the preponderance of which encode components of the major histocompatibility Ⅱ complex.Cd74,H2-Ab1,H2-Aα,H2-Eb1,Lyz2,Mrc1,Slc6α3,Slc47α1,Ms4α4b,and Ptprc2 were the top 10 diffe rentially expressed genes.Immunofluorescence staining showed that,after Nurr1knockdown,the number of CD74-immunoreactive cells in mouse brain tissue was markedly increased.In addition,Cd74 expression was increased in a mouse model of Parkinson’s disease induced by treatment with 6-hydroxydopamine.Ta ken togethe r,our res ults suggest that Nurr1 deficiency results in an increase in Cd74 expression,thereby leading to the destruction of dopaminergic neuro ns.These findings provide a potential therapeutic target for the treatment of Parkinson’s disease.展开更多
This study aims to thoroughly investigate the axial power peaking factors (PPF) within the low-enriched uranium (LEU) core of the Ghana Research Reactor-1 (GHARR-1). This study uses advanced simulation tools, like the...This study aims to thoroughly investigate the axial power peaking factors (PPF) within the low-enriched uranium (LEU) core of the Ghana Research Reactor-1 (GHARR-1). This study uses advanced simulation tools, like the MCNPX code for analysing neutron behavior and the PARET/ANL code for understanding power variations, to get a clearer picture of the reactor’s performance. The analysis covers the initial six years of GHARR-1’s operation and includes projections for its whole 60-year lifespan. We closely observed the patterns of both the highest and average PPFs at 21 axial nodes, with measurements taken every ten years. The findings of this study reveal important patterns in power distribution within the core, which are essential for improving the safety regulations and fuel management techniques of the reactor. We provide a meticulous approach, extensive data, and an analysis of the findings, highlighting the significance of continuous monitoring and analysis for proactive management of nuclear reactors. The findings of this study not only enhance our comprehension of nuclear reactor safety but also carry significant ramifications for sustainable energy progress in Ghana and the wider global context. Nuclear engineering is essential in tackling global concerns, such as the demand for clean and dependable energy sources. Research on optimising nuclear reactors, particularly in terms of safety and efficiency, is crucial for the ongoing advancement and acceptance of nuclear energy.展开更多
Heavy infection of the virus leads to overproduction of cytokines. The overproduction of cytokine (cytokines storms) is responsible for the critical cases and deaths of COVID-19. The nuclear factor kappa-B stimulates ...Heavy infection of the virus leads to overproduction of cytokines. The overproduction of cytokine (cytokines storms) is responsible for the critical cases and deaths of COVID-19. The nuclear factor kappa-B stimulates the expression of the genes, which is responsible for cytokines storm and RNA transcription. The COVID-19 virus can be controlled by inhibition of nuclear factor kappa-B. Nuclear factor kappa-B is controlled by inhibition of hydrogen peroxide and inhibitor kappa-B kinase enzyme.展开更多
BACKGROUND:The active form of nuclear factor-kappa B(NF- κB)is involved in the initiation,generation,and development of hepatocellular carcinoma(HCC),and is up-regulated in inflammation-associated malignancies.We inv...BACKGROUND:The active form of nuclear factor-kappa B(NF- κB)is involved in the initiation,generation,and development of hepatocellular carcinoma(HCC),and is up-regulated in inflammation-associated malignancies.We investigated the dynamic expression of NF-κB and its influences on the occurrence of HCC through antiangiogenic(thalidomide) intervention in NF-κB activation. METHODS:Hepatoma models were induced with 2-fluorenyl- acetamide(2-FAA,0.05%)in male Sprague-Dawley rats,and thalidomide(100 mg/kg body weight)was administered intragastrically to intervene in NF-κB activation.The pathological changes in the liver of sacrificed rats were assessed after hematoxylin and eosin staining.NF-κB mRNA was amplified by RT-nested PCR.The alterations of NF-κB and vascular endothelial growth factor(VEGF)expression were analyzed by enzyme-linked immunosorbent assay,immunohistochemistry,and Western blotting. RESULTS:Rat hepatocytes showed denatured,precancerous,and cancerous stages in hepatocarcinogenesis,with an increasing tendency of hepatic NF-κB,NF-κB mRNA,and VEGF expression,and their values in the HCC group were higher than those in controls(P<0.001).In the thalidomide- treated group,the morphologic changes generated only punctiform denaturation and necrosis at the early or middle stages,and nodular hyperplasia or a little atypical hyperplasia at the final stages,with the expression of NF-κB (χ2=9.93,P<0.001)and VEGF(χ2=8.024,P<0.001)lower than that in the 2-FAA group. CONCLUSION:NF-κB is overexpressed in hepatocarcinogenesis and antiangiogenic treatment down-regulates the expression of NF-κB and VEGF,and delays the occurrence of HCC.展开更多
BACKGROUND:Urinary trypsin inhibitor(UTI)inhibits the inflammatory response and protects against ischemia- reperfusion(I/R)injury.The inflammatory response is mediated by nuclear factor-kappa B(NF-κB)and its related ...BACKGROUND:Urinary trypsin inhibitor(UTI)inhibits the inflammatory response and protects against ischemia- reperfusion(I/R)injury.The inflammatory response is mediated by nuclear factor-kappa B(NF-κB)and its related target genes and products such as vascular endothelial cell adhesion molecule and CXC chemokines.We aimed to assess the roles of those mediators in a UTI-treated mouse model of hepatic I/R injury. METHODS:Treatment group 1(UTI given 5 minutes prior to liver ischemia),treatment group 2(UTI given 5 minutes after the anhepatic phase)and a control group were investigated.Blood and liver samples were obtained and compared at 1,3,6 and 24 hours after reperfusion. RESULTS:Attenuation of pathological hepatocellular damage was greater in the treatment groups than in the control group(P<0.05).Compared with the control group, the UTI treatment groups showed significantly lower serum alanine aminotransferase and aspartate aminotransferase levels,decreased myeloperoxidase activity,and reduced NF- κB activation.Also downregulated was the expression of tumor necrosis factor-alpha,cytokine-induced neutrophil chemoattractant,and macrophage inflammatory protein-2 at the mRNA level.P-selectin protein and intercellular adhesion molecule-1 protein expression were also downregulated.In addition,the treatment group 1 showed a better protective effect against I/R injury than the treatment group 2.CONCLUSIONS:UTI reduces NF-κB activation and downregulates the expression of its related mediators, followed by the inhibition of neutrophil aggregation and infiltration in hepatic I/R injury.The protective role of UTI is more effective in prevention than in treatment.展开更多
AIM: To investigate whether NF-κB is activated in human gastric carcinoma tissues and, if so, to study whether there is any correlation between NF-κB activity and heparanase expression in gastric carcinoma.METHODS: ...AIM: To investigate whether NF-κB is activated in human gastric carcinoma tissues and, if so, to study whether there is any correlation between NF-κB activity and heparanase expression in gastric carcinoma.METHODS: NF-κB activation was assayed by immunohistochemical staining in formalin-fixed, paraffin-embedded specimens from 45 gastric carcinoma patients. Electrophoretic mobility shift assay (EMSA) method was used for nuclear protein from these fresh tissue specimens. Heparanase gene expression was quantified using quantitative RT-PCR.RESULTS: The nuclear translocation of RelA (marker of NF-κB activation) was significantly higher in tumor cells compared to adjacent and normal epithelial cells [(41.3±3.52)% vs (0.38±0.22) %, t= 10.993, P= 0.000＜0.05; (41.3±3.52)%vs (0±0.31)%, t = 11.484, P = 0.000＜0.05]. NF-κB activation was correlated with tumor invasion-related clinicopathological features such as lymphatic invasion,pathological stage, and depth of invasion (Z = 2.148,P= 0.032＜0.05; χ2 = 8.758, P= 0.033＜0.05; χ2 = 18.531,P = 0.006＜0.05). NF-κB activation was significantly correlated with expression of heparanase gene (r= 0.194,P= 0.046＜0.05).CONCLUSION: NF-κB RelA (p65) activation was related with increased heparanase gene expression and correlated with poor clinicopathological characteristics in gastric cancers. This suggests NF-κB as a major controller of the metastatic phenotype through its reciprocal regulation of some metastasis-related genes.展开更多
Concomitantly with the increase in the prevalences of overweight/obesity, nonalcoholic fatty liver disease(NAFLD) has worldwide become the main cause of chronic liver disease in both adults and children. Patients with...Concomitantly with the increase in the prevalences of overweight/obesity, nonalcoholic fatty liver disease(NAFLD) has worldwide become the main cause of chronic liver disease in both adults and children. Patients with fatty liver display features of metabolic syndrome(Met S), like insulin resistance(IR), glucose intolerance, hypertension and dyslipidemia. Recently, epidemiological studies have linked obesity, Met S, and NAFLD to decreased bone mineral density and osteoporosis, highlighting an intricate interplay among bone, adipose tissue, and liver. Osteoprotegerin(OPG), an important symbol of the receptor activator of nuclear factor-B ligand/receptor activator of nuclear factor kappa B/OPG system activation, typically considered for its role in bone metabolism, may also play critical roles in the initiation and perpetuation of obesityrelated comorbidities. Clinical data have indicated that OPG concentrations are associated with hypertension, left ventricular hypertrophy, vascular calcification, endothelial dysfunction, and severity of liver damage in chronic hepatitis C. Nonetheless, the relationship between circulating OPG and IR as a key feature of Met S as well as between OPG and NAFLD remains uncertain. Thus, the aims of the present review are to provide the existent knowledge on these associations and to discuss briefly the underlying mechanisms linking OPG and NAFLD.展开更多
AIM: To detect the nuclear factor kappa B (NF-κB) condition in human stage Ⅳ gastric carcinoma patients and to explore the correlation between NF- κB activation and survival of these patients after chemotherapy. ME...AIM: To detect the nuclear factor kappa B (NF-κB) condition in human stage Ⅳ gastric carcinoma patients and to explore the correlation between NF- κB activation and survival of these patients after chemotherapy. METHODS: Expression of NF-κB-p65 was determined by immunohistochemical analysis. Activity of NF- κB DNA-binding in carcinoma tissue was detected by electrophoretic mobility shift assay. Kaplan-Meier survival analysis was performed to show the relation between NF-κB and progression-free survival (PFS) or overall survival (OS) of the patients. RESULTS: The positive expression rate of NF-κB-p65 in 60 gastric cancer tissue samples was 76.7% (46/60). The expression of NF-κB-p65 was reduced in adjacent carcinoma and normal tissue samples. Electrophoretic mobility shift assay (EMSA) analysis showed a strong activation of NF-κB in cancer tissue samples. A survival difference was found in NF- κB-p65 positive and negative patients. NF-κB-p65 expression was negative in cancer tissue samples (n = 14). PFS was 191.40 ± 59.88 d and 152.93 ± 16.99 d, respectively, in patients with positive NF- κB-p65 expression (n = 46) (P = 0.4028). Thesurvival time of patients with negative and positive NF-κB-p65 expression was 425.16 ± 61.61 d and 418.85 ± 42.98 d, respectively (P = 0.7303). Kaplan-Meier analysis showed no significant difference in PFS or OS. The 46 patient tissue which positive NF- κB-p65 expression was found in the tissue samples from the 46 patients whose PFS and OS were 564.89 ± 75.94 d and s 352.37 ± 41.32 d, respectively (P = 0.0165). CONCLUSION: NF-κB is activated in gastric carcinoma tissue, which is related to the OS after chemotherapy.展开更多
AIM: Nuclear factor kappa B (NF-κB) regulates a large number of genes involved in the inflammatory response to critical illnesses, but it is not known if and how NF-κB is activated and intercellular adhesion molecul...AIM: Nuclear factor kappa B (NF-κB) regulates a large number of genes involved in the inflammatory response to critical illnesses, but it is not known if and how NF-κB is activated and intercellular adhesion molecule-1 (ICAM-1)expressed in the gut following traumatic brain injury (TBI).The aim of current study was to investigate the temporal pattern of intestinal NF-κB activation and ICAM-1expression following TBI.METHODS: Male Wistar rats were randomly divided into six groups (6 rats in each group) including controls with sham operation and TBI groups at hours 3, 12, 24, and 72, and on d 7. Parietal brain contusion was adopted using weight-dropping method. All rats were decapitated at corresponding time point and mid-jejunum samples were taken. NF-κB binding activity in jejunal tissue was measured using EMSA. Immunohistochemistry was used for detection of ICAM-1 expression in jejunal samples.RESULTS: There was a very low NF-κB binding activity and little ICAM-1 expression in the gut of control rats after sham surgery. NF-κB binding activity in jejunum significantly increased by 160% at 3 h following TBI (P＜0.05 vs control), peaked at 72 h (500% increase)and remained elevated on d 7 post-injury by 390% increase. Compared to controls, ICAM-1 was significantly up-regulated on the endothelia of microvessels in villous interstitium and lamina propria by 24 h following TBI and maximally expressed at 72 h post-injury (P＜0.001). The endothelial ICAM-1 immunoreactivity in jejunal mucosa still remained strong on d 7 post-injury. The peak of NF-κB activation and endothelial ICAM-1 expression coincided in time with the period during which secondary mucosal injury of the gut was also at their culmination following TBI.CONCLUSION: TBI could induce an immediate and persistent up-regulation of NF-κB activity and subsequent up-regulation of ICAM-1 expression in the intestine.Inflammatory response mediated by increased NF-κB activation and ICAM-1 expression may play an important role in the pathogenesis of acute gut mucosal injury following TBI.展开更多
BACKGROUND:Hepatocellular carcinoma(HCC)is one of the most common malignant tumors.We analyzed the expression of nuclear-transcription factor-kappa B(NF-κB) during hepatocarcinogenesis in order to evaluate its dynami...BACKGROUND:Hepatocellular carcinoma(HCC)is one of the most common malignant tumors.We analyzed the expression of nuclear-transcription factor-kappa B(NF-κB) during hepatocarcinogenesis in order to evaluate its dynamic expression and its clinical value in the development and diagnosis of HCC. METHODS:Hepatoma models were induced by oral administration of 2-acetamidoflurene(2-FAA)to male Sprague-Dawley rats.Morphological changes were observed after hematoxylin and eosin staining.The cellular distribution of NF-κB expression during different stages of cancer development was investigated by immunohistochemistry, and the level of NF-κB expression in liver tissues was quantitatively analyzed by ELISA.The gene fragments of hepatic NF-κB were amplified by nested-polymerase chain reaction assay. RESULTS:Hepatocytes showed vacuole-like degeneration during the early stages,then had a hyperplastic nodal appearance during the middle stages,and finally progressed to tubercles of cancerous nests with high differentiation. The NF-κB-positive material was buff-colored,fine particles localized in the nucleus,and the incidence of NF-κB-positive cells was 81.8%in degeneration,83.3%in precancerous lesions,and 100%in cancerous tissues.All of these values were higher than those in controls(P<0.01). Hepatic NF-κB expression and hepatic NF-κB-mRNA were also higher during the course of HCC development(P<0.01).CONCLUSION:The NF-κB signal transduction pathway is activated during the early stages of HCC development, and its abnormal expression may be associated with the occurrence of HCC.展开更多
Activation of nuclear factor kappa B(NF-κB) is a hallmark of various central nervous system(CNS) pathologies. Neuron-specific inhibition of its transcriptional activator subunit RelA, also referred to as p65, promote...Activation of nuclear factor kappa B(NF-κB) is a hallmark of various central nervous system(CNS) pathologies. Neuron-specific inhibition of its transcriptional activator subunit RelA, also referred to as p65, promotes neuronal survival under a range of conditions, i.e., for ischemic or excitotoxic insults. In macro- and microglial cells, post-lesional activation of NF-κB triggers a growth-permissive program which contributes to neural tissue inflammation, scar formation, and the expression of axonal growth inhibitors. Intriguingly, inhibition of such inducible NF-κB in the neuro-glial compartment, i.e., by genetic ablation of RelA or overexpression of a transdominant negative mutant of its upstream regulator IκBα, significantly enhances functional recovery and promotes axonal regeneration in the mature CNS. By contrast, depletion of the NF-κB subunit p50, which lacks transcriptional activator function and acts as a transcriptional repressor on its own, causes precocious neuronal loss and exacerbates axonal degeneration in the lesioned brain. Collectively, the data imply that NF-κB orchestrates a multicellular program in which κB-dependent gene expression establishes a growth-repulsive terrain within the post-lesioned brain that limits structural regeneration of neuronal circuits. Considering these subunit-specific functions, interference with the NF-κB pathway might hold clinical potentials to improve functional restoration following traumatic CNS injury.展开更多
AIM: To investigate the effect of different dietary fatty acids on hepatic inflammasome activation.METHODS: Wild-type C57BL/6 mice were fed either a high-fat diet or polyunsaturated fatty acid(PUFA)-enriched diet. Pri...AIM: To investigate the effect of different dietary fatty acids on hepatic inflammasome activation.METHODS: Wild-type C57BL/6 mice were fed either a high-fat diet or polyunsaturated fatty acid(PUFA)-enriched diet. Primary hepatocytes were treated with either saturated fatty acids(SFAs) or PUFAs as well as combined with lipopolysaccharide(LPS). The expression of NOD-like receptor protein 3(NLRP3) inflammasome, peroxisome proliferator-activated receptor-γ and nuclear factor-kappa B(NF-κB) was determined by real-time PCR and Western blot. The activity of Caspase-1 and interleukine-1β production were measured.RESULTS: high-fat diet-induced hepatic steatosis was sufficient to induce and activate hepatic NLRP3 inflammasome. SFA palmitic acid(PA) directly activated NLRP3 inflammasome and increased sensitization to LPS-induced inflammasome activation in hepatocytes. In contrast, PUFA docosahexaenoic acid(Dh A) had thepotential to inhibit NLRP3 inflammasome expression in hepatocytes and partly abolished LPS-induced NLRP3 inflammasome activation. Furthermore, a highfat diet increased but PUFA-enriched diet decreased sensitization to LPS-induced hepatic NLRP3 inflammasome activation in vivo. Moreover, PA increased but Dh A decreased phosphorylated NF-κB p65 protein expression in hepatocytes.CONCLUSION:Hepatic NLRP 3 inflammasome activation played an important role in the development of non-alcoholic fatty liver disease. Dietary SFAs and PUFAs oppositely regulated the activity of NLRP3 inflammasome through direct activation or inhibition of NF-κB.展开更多
A mouse model of viral encephalitis was induced by intracranial injection of a Coxsackie virus B3 suspension. Quantitative real-time reverse transcription-PCR and western blot assay were applied to detect mRNA and pro...A mouse model of viral encephalitis was induced by intracranial injection of a Coxsackie virus B3 suspension. Quantitative real-time reverse transcription-PCR and western blot assay were applied to detect mRNA and protein expression of intelectin-2 and nuclear factor-kappa B in the viral encephalitis and control groups. Nuclear factor-kappa B and intelectin-2 mRNA and protein expression were significantly increased in mice with viral encephalitis. After intraperitoneal injection of Shuanghuanglian at a dose of 1.5 mg/kg for 5 successive days, intelectin-2 and nuclear factor-kappa B protein and mRNA expression were significantly decreased. To elucidate the relationship between intelectin-2 and nuclear factor-kappa B, mice with viral encephalitis were administered an intracerebral injection of 107 pfu recombinant lentivirus expressing intelectin shRNA. Both protein and mRNA levels of intelectin and nuclear factor-kappa B in brain tissue of mice were significantly decreased. Experimental findings suggest that Shuanghuanglian injection may downregulate nuclear factor-kappa B production via suppression of intelectin production, thus inhibiting inflammation associated with viral encephalitis.展开更多
AIM: To investigate the role of p38 mitogen-activated protein kinase (p38MAPK) in murine experimental autoimmune hepatitis (EAH). METHODS: To induce EAH, the syngeneic S-100 antigen emulsified in complete Freud's ...AIM: To investigate the role of p38 mitogen-activated protein kinase (p38MAPK) in murine experimental autoimmune hepatitis (EAH). METHODS: To induce EAH, the syngeneic S-100 antigen emulsified in complete Freud's adjuvant was injected intraperitoneally into adult male C57Bl/6 mice. Liver injury was assessed by serum ALT and liver histology. The expression and activity of p38 MAPK were measured by Western blot and kinase activity assays. In addition, DNA binding activities of nuclear factor kappa B (NF-κB) were analyzed by electrophoretic mobility shift assay. The effects of SB203580, a specifi c p38 MAPK inhibitor, on liver injuries and expression of proin? ammatory cytokines (interferon-γ, IL-12, IL-1β and TNF-α) were observed. RESULTS: The activity of p38 MAPK and NF-κB was increased and reached its peak 14 or 21 d after the fi rst syngeneic S-100 administration. Inhibition of p38 MAPK activation by SB203580 decreased the activation of NF-κB and the expression of proin? ammatory cytokines. Moreover, hepatic injuries were improved significantly after SB203580 administration. CONCLUSION: p38 MAPK and NF-κB play an important role in an animal model of autoimmune hepatitis (AIH) induced by autoantigens.展开更多
基金Supported by:the Medicine and Health Scientific Research Projects of Shandong Province,No. 2007HZ065
文摘BACKGROUND:L-3-n-butylphthalide(L-NBP) can inhibit phosphorylation of tau protein and reduce the neurotoxicity of beta-amyloid peptide 1-42(Aβ_(1-42)). OBJECTIVE:To observe the neuroprotective effects of L-NBP on caspase-3 and nuclear factor kappa-B(NF-κB) expression in a rat model of Alzheimer's disease. DESIGN,TIME AND SETTING:A cell experiment was performed at the Central Laboratory of Provincial Hospital affiliated to Shandong University between January 2008 and August 2008. MATERIALS:L-NBP(purity>98%) was provided by Shijiazhuang Pharma Group NBP Pharmaceutical Company Limited.Aβ_(1-42),3-[4,5-dimethylthiazolo-2]-2,5 iphenyltetrazolium bromide(MTT),and rabbit anti-Caspase-3 polyclonal antibody were provided by Cell Signaling, USA;goat anti-choactase and rabbit anti-NF-κB antibodies were provided by Santa Cruz,USA. METHODS:Primary cultures were generated from rat basal forebrain and hippocampal neurons at 17 or 19 days of gestation.The cells were assigned into five groups:the control group,the Aβ_(1-42) group(2μmol/ L),the Aβ_(1-42) + 0.1μmol/L L-NBP group,the Aβ_(1-42)+ 1μmol/L L-NBP group,and the Aβ_(1-42)+ 10μmol/L L-NBP group.The neurons were treated with Aβ_(1-42)(2μmol/L) alone or in combination with L-NBP(0.1,1,10μmol/L) for 48 hours.Cells in the control group were incubated in PBS. MAIN OUTCOME MEASURES:Morphologic changes were evaluated using inverted microscopy, viability using the MTT method,and the changes in caspase-3 and NF-κB expression using Western blot. RESULTS:Induction with Aβ_(1-42) for 48 hours caused cell death and soma atrophy,and increased caspase-3 and NF-κB expression(P<0.05).L-NBP blocked these changes in cell morphology, decreased caspase-3 and NF-κB expression(P<0.05),and improved cell viability,especially at the high dose(P<0.05). CONCLUSION:Aβ_(1-42) is toxic to basal forebrain and hippocampal primary neurons;L-NBP protects against this toxicity and inhibits the induction of caspase-3 and NF-κB expression.
文摘The relation between the expression and activity of MMP-9 in C-reactive protein (CRP)-induced human THP-1 mononuclear cells and the activation of nuclear factor kappa-B (NF-кB) was studied to investigate the possible role of CRP in plaque destabilization. Human THP-1 cells were incubated in the presence of CRP at 0 (control group), 25, 50 and 100 μg/mL (CRP groups) for 24 h. In PDTC (a specific NF-кB inhibitor) group, the cells were pre-treated with PDTC at 10 μmol/L and then with 100 μg/mL CRP. The conditioned media (CM) and human THP-1 cells in different groups were harvested. MMP-9 expression in CM and human THP-1 cells was measured by ELISA and Western blotting. MMP-9 activity was assessed by fluorogenic substrates. The expression of NF-кB inhibitor α (IкB-α) and NF-кB P65 was detected by Western blotting and ELISA respectively. The results showed that CRP increased the expression and activity of MMP-9 in a dose-dependent manner in the human THP-1 cells. Western blotting revealed that IкB-α expression was decreased in the cells with the concentrations of CRP and ELISA demonstrated that NF-кB P65 expression in the CRP-induced cells was increased. After pre-treatment of the cells with PDTC at 10 μmol/L, the decrease in IкB-α expression and the increase in NF-кB P65 expression in the CRP-induced cells were inhibited, and the expression and activity of MMP-9 were lowered too. It is concluded that increased expression and activity of MMP-9 in CRP-induced human THP-1 cells may be associated with acti- vation of NF-кB. Down-regulation of the expression and activity of MMP-9 may be a new treatment alternative for plaque stabilization by inhibiting the NF-кB activation.
基金supported by the National Natural Science Foundation of China(32272910)the Natural Science Foundation of Shandong Province(ZR2020MC170).
文摘Medium-chain fatty acids and their derivatives are natural ingredients that support immunological functions in animals.The effects of glycerol monolaurate(GML)on intestinal innate immunity and associated molecular mechanisms were investigated using a chicken embryo model.Sixty-four Arbor Acres broiler embryos were randomly allocated into four groups.On embryonic day 17.5,the broiler embryos were administered with 9 mg of GML,which was followed by a 12-h incubation period and a12-h challenge with 32μg of lipopolysaccharide(LPS).On embryonic day 18.5,the jejunum and ileum were harvested.Results indicated that GML reversed the LPS-induced decline in villus height and upregulated the expression of mucin 2(P<0.05).GML decreased LPS-induced malondialdehyde production and boosted antioxidant enzyme activity(P<0.05).GML alleviated LPS-stimulated intestinal secretion of interleukin(IL)-1β,IL-6,and tumor necrosis factor-a(TNF-a)(P<0.05).GML also normalized LPS-induced changes in the gene expression of Toll-like receptor 4,nuclear factor kappa-B p65(NF-κB p65),cyclooxygenase-2,NOD-like receptor protein 3,IL-18,zonula occludens 1,and occludin(P<0.05).GML enhanced as well the expression of AMP-activated protein kinase a1 and claudin 1(P<0.05).In conclusion,GML improved intestinal morphology and antioxidant status by alleviating inflammatory responses and modulating NF-κB signaling in LPS-challenged broiler embryos.
基金supported by the National Natural Science Foundation of China,(No.82072217,81772135 and U21A20370)by the Jiangsu Natural Science Foundation(No.BK20201178).
文摘Background:Inflammation is an important factor in pathological scarring.The role of neutrophils,one of the most important inflammatory cells,in scar hyperplasia remains unclear.The purpose of this article is to study the correlation between neutrophil extracellular traps(NETs)and scar hyperplasia and identify a new target for inhibiting scar hyperplasia.Methods:Neutrophils were isolated from human peripheral blood by magnetic-bead sorting.NETs in plasma and scars were detected by enzyme-linked immunosorbent assays(ELISAs),immunofluorescence and flow cytometry.Immunohistochemistry was used to assess neutrophil(CD66B)infiltration in hypertrophic scars.To observe the entry of NETs into fibroblasts we used immunofluorescence and flow cytometry.Results:We found that peripheral blood neutrophils in patients with hypertrophic scars were more likely to form NETs(p<0.05).Hypertrophic scars showed greater infiltration with neutrophils and NETs(p<0.05).NETs activate fibroblasts in vitro to promote their differentiation and migration.Inhibition of NETs with cytochalasin in wounds reduced the hyperplasia of scars in mice.We induced neutrophils to generate NETs with different stimuli in vitro and detected the proteins carried by NETs.We did not find an increase in the expression of common scarring factors[interleukin(IL)-17 and transforming growth factor-β(TGF-β),p>0.05].However,inhibiting the production of NETs or degrading DNA reduced the differentiation of fibroblasts intomyofibroblasts.In vitro,NETs were found to be mediated by Toll-like receptor 9(TLR-9)in fibroblasts and further phosphorylated nuclear factor Kappa-B(NF-κB).We found that IL-6,which is downstream of NF-κB,was increased in fibroblasts.Additionally,IL-6 uses autocrine and paracrine signaling to promote differentiation and secretion.Conclusions:Our experiments found that NETs activate fibroblasts through the TLR-9/NF-κB/IL-6 pathway,thereby providing a new target for regulating hypertrophic scars.
文摘This study aims to analyze the clinical significance and mechanism of nuclear factor erythroid 2-related factor 2(NRF2)and glutathione peroxidase 4(GPX4)in primary hepatic carcinoma(PHC).Methods:The expression of NRF2 and GPX4 in peripheral blood of patients with PHC was determined to analyze the diagnostic value of the two combined for PHC.The prognostic significance of NRF2 and GPX4 was evaluated by 3-year followup.Human liver epithelial cells THLE-2 and human hepatocellular carcinoma cells HepG2 were purchased,and the expression of NRF2 and GPX4 in the cells was determined.NRF2 and GPX4 aberrant expression vectors were constructed and transfected into HepG2,and changes in cell proliferation and invasion capabilities were observed.Results:The expression of NRF2 and GPX4 in patients with PHC was higher than that in patients with LC or VH(p<0.05),and the two indicators combined was excellent in diagnosing PHC.Moreover,patients with high expression of NRF2 and GPX4 had a higher risk of death(p<0.05).In in vitro experiments,both NRF2 and GPX4 expression was elevated in HepG2(p<0.05).HepG2 activity was enhanced by increasing the expression of the two,vice versa(p<0.05).Conclusion:NRF2 and GPX4 combined is excellent in diagnosing PHC,and promotes the malignant development of PHC.
文摘BACKGROUND The Nuclear factor erythroid 2-related factor 2(NRF2)transcription factor has attracted much attention in the context of neurological diseases.However,none of the studies have systematically clarified this field's research hotspots and evolution rules.AIM To investigate the research hotspots,evolution patterns,and future research trends in this field in recent years.METHODS We conducted a comprehensive literature search in the Web of Science Core Collection database using the following methods:(((((TS=(NFE2 L2))OR TS=(Nfe2 L2 protein,mouse))OR TS=(NF-E2-Related Factor 2))OR TS=(NRF2))OR TS=(NFE2L2))OR TS=(Nuclear factor erythroid2-related factor 2)AND(((((((TS=(neurological diseases))OR TS=(neurological disorder))OR TS=(brain disorder))OR TS=(brain injury))OR TS=(central nervous system disease))OR TS=(CNS disease))OR TS=(central nervous system disorder))OR TS=(CNS disorder)AND Language=English from 2010 to 2022.There are just two forms of literature available:Articles and reviews.Data were processed with the software Cite-Space(version 6.1.R6).RESULTS We analyzed 1884 articles from 200 schools in 72 countries/regions.Since 2015,the number of publications in this field has increased rapidly.China has the largest number of publications,but the articles published in the United States have better centrality and H-index.Among the top ten authors with the most published papers,five of them are from China,and the author with the most published papers is Wang Handong.The institution with the most articles was Nanjing University.To their credit,three of the top 10 most cited articles were written by Chinese scholars.The keyword co-occurrence map showed that"oxidative stress","NRF2","activation","expression"and"brain"were the five most frequently used keywords.CONCLUSION Research on the role of NRF2 in neurological diseases continues unabated.Researchers in developed countries published more influential papers,while Chinese scholars provided the largest number of articles.There have been numerous studies on the mechanism of NRF2 transcription factor in neurological diseases.NRF2 is also emerging as a potentially effective target for the treatment of neurological diseases.However,despite decades of research,our knowledge of NRF2 transcription factor in nervous system diseases is still limited.Further studies are needed in the future.
基金supported by the National Natural Science Foundation of China,No. 81971006 (to DSG)。
文摘Previous studies have found that deficiency in nuclear receptor-related factor 1(Nurr1),which participates in the development,differentiation,survival,and degeneration of dopaminergic neurons,is associated with Parkinson s disease,but the mechanism of action is perplexing.Here,we first asce rtained the repercussion of knocking down Nurr1 by pe rforming liquid chromatography coupled with tandem mass spectrometry.We found that 231 genes were highly expressed in dopaminergic neurons with Nurr1 deficiency,14 of which were linked to the Parkinson’s disease pathway based on Kyoto Encyclopedia of Genes and Genomes analysis.To better understand how Nurr1 deficiency autonomously invokes the decline of dopaminergic neurons and elicits Parkinson’s disease symptoms,we performed single-nuclei RNA sequencing in a Nurr1 LV-shRNA mouse model.The results revealed cellular heterogeneity in the substantia nigra and a number of activated genes,the preponderance of which encode components of the major histocompatibility Ⅱ complex.Cd74,H2-Ab1,H2-Aα,H2-Eb1,Lyz2,Mrc1,Slc6α3,Slc47α1,Ms4α4b,and Ptprc2 were the top 10 diffe rentially expressed genes.Immunofluorescence staining showed that,after Nurr1knockdown,the number of CD74-immunoreactive cells in mouse brain tissue was markedly increased.In addition,Cd74 expression was increased in a mouse model of Parkinson’s disease induced by treatment with 6-hydroxydopamine.Ta ken togethe r,our res ults suggest that Nurr1 deficiency results in an increase in Cd74 expression,thereby leading to the destruction of dopaminergic neuro ns.These findings provide a potential therapeutic target for the treatment of Parkinson’s disease.
文摘This study aims to thoroughly investigate the axial power peaking factors (PPF) within the low-enriched uranium (LEU) core of the Ghana Research Reactor-1 (GHARR-1). This study uses advanced simulation tools, like the MCNPX code for analysing neutron behavior and the PARET/ANL code for understanding power variations, to get a clearer picture of the reactor’s performance. The analysis covers the initial six years of GHARR-1’s operation and includes projections for its whole 60-year lifespan. We closely observed the patterns of both the highest and average PPFs at 21 axial nodes, with measurements taken every ten years. The findings of this study reveal important patterns in power distribution within the core, which are essential for improving the safety regulations and fuel management techniques of the reactor. We provide a meticulous approach, extensive data, and an analysis of the findings, highlighting the significance of continuous monitoring and analysis for proactive management of nuclear reactors. The findings of this study not only enhance our comprehension of nuclear reactor safety but also carry significant ramifications for sustainable energy progress in Ghana and the wider global context. Nuclear engineering is essential in tackling global concerns, such as the demand for clean and dependable energy sources. Research on optimising nuclear reactors, particularly in terms of safety and efficiency, is crucial for the ongoing advancement and acceptance of nuclear energy.
文摘Heavy infection of the virus leads to overproduction of cytokines. The overproduction of cytokine (cytokines storms) is responsible for the critical cases and deaths of COVID-19. The nuclear factor kappa-B stimulates the expression of the genes, which is responsible for cytokines storm and RNA transcription. The COVID-19 virus can be controlled by inhibition of nuclear factor kappa-B. Nuclear factor kappa-B is controlled by inhibition of hydrogen peroxide and inhibitor kappa-B kinase enzyme.
基金supported by grants from the Project of Elitist Peak in Six Fields(No.2006-B-063)the Project of Medical Sciences(H200727),the Bureau of Health,Jiangsu Province,China
文摘BACKGROUND:The active form of nuclear factor-kappa B(NF- κB)is involved in the initiation,generation,and development of hepatocellular carcinoma(HCC),and is up-regulated in inflammation-associated malignancies.We investigated the dynamic expression of NF-κB and its influences on the occurrence of HCC through antiangiogenic(thalidomide) intervention in NF-κB activation. METHODS:Hepatoma models were induced with 2-fluorenyl- acetamide(2-FAA,0.05%)in male Sprague-Dawley rats,and thalidomide(100 mg/kg body weight)was administered intragastrically to intervene in NF-κB activation.The pathological changes in the liver of sacrificed rats were assessed after hematoxylin and eosin staining.NF-κB mRNA was amplified by RT-nested PCR.The alterations of NF-κB and vascular endothelial growth factor(VEGF)expression were analyzed by enzyme-linked immunosorbent assay,immunohistochemistry,and Western blotting. RESULTS:Rat hepatocytes showed denatured,precancerous,and cancerous stages in hepatocarcinogenesis,with an increasing tendency of hepatic NF-κB,NF-κB mRNA,and VEGF expression,and their values in the HCC group were higher than those in controls(P<0.001).In the thalidomide- treated group,the morphologic changes generated only punctiform denaturation and necrosis at the early or middle stages,and nodular hyperplasia or a little atypical hyperplasia at the final stages,with the expression of NF-κB (χ2=9.93,P<0.001)and VEGF(χ2=8.024,P<0.001)lower than that in the 2-FAA group. CONCLUSION:NF-κB is overexpressed in hepatocarcinogenesis and antiangiogenic treatment down-regulates the expression of NF-κB and VEGF,and delays the occurrence of HCC.
文摘BACKGROUND:Urinary trypsin inhibitor(UTI)inhibits the inflammatory response and protects against ischemia- reperfusion(I/R)injury.The inflammatory response is mediated by nuclear factor-kappa B(NF-κB)and its related target genes and products such as vascular endothelial cell adhesion molecule and CXC chemokines.We aimed to assess the roles of those mediators in a UTI-treated mouse model of hepatic I/R injury. METHODS:Treatment group 1(UTI given 5 minutes prior to liver ischemia),treatment group 2(UTI given 5 minutes after the anhepatic phase)and a control group were investigated.Blood and liver samples were obtained and compared at 1,3,6 and 24 hours after reperfusion. RESULTS:Attenuation of pathological hepatocellular damage was greater in the treatment groups than in the control group(P<0.05).Compared with the control group, the UTI treatment groups showed significantly lower serum alanine aminotransferase and aspartate aminotransferase levels,decreased myeloperoxidase activity,and reduced NF- κB activation.Also downregulated was the expression of tumor necrosis factor-alpha,cytokine-induced neutrophil chemoattractant,and macrophage inflammatory protein-2 at the mRNA level.P-selectin protein and intercellular adhesion molecule-1 protein expression were also downregulated.In addition,the treatment group 1 showed a better protective effect against I/R injury than the treatment group 2.CONCLUSIONS:UTI reduces NF-κB activation and downregulates the expression of its related mediators, followed by the inhibition of neutrophil aggregation and infiltration in hepatic I/R injury.The protective role of UTI is more effective in prevention than in treatment.
文摘AIM: To investigate whether NF-κB is activated in human gastric carcinoma tissues and, if so, to study whether there is any correlation between NF-κB activity and heparanase expression in gastric carcinoma.METHODS: NF-κB activation was assayed by immunohistochemical staining in formalin-fixed, paraffin-embedded specimens from 45 gastric carcinoma patients. Electrophoretic mobility shift assay (EMSA) method was used for nuclear protein from these fresh tissue specimens. Heparanase gene expression was quantified using quantitative RT-PCR.RESULTS: The nuclear translocation of RelA (marker of NF-κB activation) was significantly higher in tumor cells compared to adjacent and normal epithelial cells [(41.3±3.52)% vs (0.38±0.22) %, t= 10.993, P= 0.000＜0.05; (41.3±3.52)%vs (0±0.31)%, t = 11.484, P = 0.000＜0.05]. NF-κB activation was correlated with tumor invasion-related clinicopathological features such as lymphatic invasion,pathological stage, and depth of invasion (Z = 2.148,P= 0.032＜0.05; χ2 = 8.758, P= 0.033＜0.05; χ2 = 18.531,P = 0.006＜0.05). NF-κB activation was significantly correlated with expression of heparanase gene (r= 0.194,P= 0.046＜0.05).CONCLUSION: NF-κB RelA (p65) activation was related with increased heparanase gene expression and correlated with poor clinicopathological characteristics in gastric cancers. This suggests NF-κB as a major controller of the metastatic phenotype through its reciprocal regulation of some metastasis-related genes.
文摘Concomitantly with the increase in the prevalences of overweight/obesity, nonalcoholic fatty liver disease(NAFLD) has worldwide become the main cause of chronic liver disease in both adults and children. Patients with fatty liver display features of metabolic syndrome(Met S), like insulin resistance(IR), glucose intolerance, hypertension and dyslipidemia. Recently, epidemiological studies have linked obesity, Met S, and NAFLD to decreased bone mineral density and osteoporosis, highlighting an intricate interplay among bone, adipose tissue, and liver. Osteoprotegerin(OPG), an important symbol of the receptor activator of nuclear factor-B ligand/receptor activator of nuclear factor kappa B/OPG system activation, typically considered for its role in bone metabolism, may also play critical roles in the initiation and perpetuation of obesityrelated comorbidities. Clinical data have indicated that OPG concentrations are associated with hypertension, left ventricular hypertrophy, vascular calcification, endothelial dysfunction, and severity of liver damage in chronic hepatitis C. Nonetheless, the relationship between circulating OPG and IR as a key feature of Met S as well as between OPG and NAFLD remains uncertain. Thus, the aims of the present review are to provide the existent knowledge on these associations and to discuss briefly the underlying mechanisms linking OPG and NAFLD.
文摘AIM: To detect the nuclear factor kappa B (NF-κB) condition in human stage Ⅳ gastric carcinoma patients and to explore the correlation between NF- κB activation and survival of these patients after chemotherapy. METHODS: Expression of NF-κB-p65 was determined by immunohistochemical analysis. Activity of NF- κB DNA-binding in carcinoma tissue was detected by electrophoretic mobility shift assay. Kaplan-Meier survival analysis was performed to show the relation between NF-κB and progression-free survival (PFS) or overall survival (OS) of the patients. RESULTS: The positive expression rate of NF-κB-p65 in 60 gastric cancer tissue samples was 76.7% (46/60). The expression of NF-κB-p65 was reduced in adjacent carcinoma and normal tissue samples. Electrophoretic mobility shift assay (EMSA) analysis showed a strong activation of NF-κB in cancer tissue samples. A survival difference was found in NF- κB-p65 positive and negative patients. NF-κB-p65 expression was negative in cancer tissue samples (n = 14). PFS was 191.40 ± 59.88 d and 152.93 ± 16.99 d, respectively, in patients with positive NF- κB-p65 expression (n = 46) (P = 0.4028). Thesurvival time of patients with negative and positive NF-κB-p65 expression was 425.16 ± 61.61 d and 418.85 ± 42.98 d, respectively (P = 0.7303). Kaplan-Meier analysis showed no significant difference in PFS or OS. The 46 patient tissue which positive NF- κB-p65 expression was found in the tissue samples from the 46 patients whose PFS and OS were 564.89 ± 75.94 d and s 352.37 ± 41.32 d, respectively (P = 0.0165). CONCLUSION: NF-κB is activated in gastric carcinoma tissue, which is related to the OS after chemotherapy.
基金Supported by Scientific Research Foundation of the Chinese PLA Key Medical Programs During the 10th Five-Year Plan Period, No. 01Z011
文摘AIM: Nuclear factor kappa B (NF-κB) regulates a large number of genes involved in the inflammatory response to critical illnesses, but it is not known if and how NF-κB is activated and intercellular adhesion molecule-1 (ICAM-1)expressed in the gut following traumatic brain injury (TBI).The aim of current study was to investigate the temporal pattern of intestinal NF-κB activation and ICAM-1expression following TBI.METHODS: Male Wistar rats were randomly divided into six groups (6 rats in each group) including controls with sham operation and TBI groups at hours 3, 12, 24, and 72, and on d 7. Parietal brain contusion was adopted using weight-dropping method. All rats were decapitated at corresponding time point and mid-jejunum samples were taken. NF-κB binding activity in jejunal tissue was measured using EMSA. Immunohistochemistry was used for detection of ICAM-1 expression in jejunal samples.RESULTS: There was a very low NF-κB binding activity and little ICAM-1 expression in the gut of control rats after sham surgery. NF-κB binding activity in jejunum significantly increased by 160% at 3 h following TBI (P＜0.05 vs control), peaked at 72 h (500% increase)and remained elevated on d 7 post-injury by 390% increase. Compared to controls, ICAM-1 was significantly up-regulated on the endothelia of microvessels in villous interstitium and lamina propria by 24 h following TBI and maximally expressed at 72 h post-injury (P＜0.001). The endothelial ICAM-1 immunoreactivity in jejunal mucosa still remained strong on d 7 post-injury. The peak of NF-κB activation and endothelial ICAM-1 expression coincided in time with the period during which secondary mucosal injury of the gut was also at their culmination following TBI.CONCLUSION: TBI could induce an immediate and persistent up-regulation of NF-κB activity and subsequent up-regulation of ICAM-1 expression in the intestine.Inflammatory response mediated by increased NF-κB activation and ICAM-1 expression may play an important role in the pathogenesis of acute gut mucosal injury following TBI.
基金supported by grants from the Project of Elitist Peak in Six Fields(No.2006-B-063)the Projectof Medical Sciences(H200727),the Bureau of Health,Jiangsu Province,China
文摘BACKGROUND:Hepatocellular carcinoma(HCC)is one of the most common malignant tumors.We analyzed the expression of nuclear-transcription factor-kappa B(NF-κB) during hepatocarcinogenesis in order to evaluate its dynamic expression and its clinical value in the development and diagnosis of HCC. METHODS:Hepatoma models were induced by oral administration of 2-acetamidoflurene(2-FAA)to male Sprague-Dawley rats.Morphological changes were observed after hematoxylin and eosin staining.The cellular distribution of NF-κB expression during different stages of cancer development was investigated by immunohistochemistry, and the level of NF-κB expression in liver tissues was quantitatively analyzed by ELISA.The gene fragments of hepatic NF-κB were amplified by nested-polymerase chain reaction assay. RESULTS:Hepatocytes showed vacuole-like degeneration during the early stages,then had a hyperplastic nodal appearance during the middle stages,and finally progressed to tubercles of cancerous nests with high differentiation. The NF-κB-positive material was buff-colored,fine particles localized in the nucleus,and the incidence of NF-κB-positive cells was 81.8%in degeneration,83.3%in precancerous lesions,and 100%in cancerous tissues.All of these values were higher than those in controls(P<0.01). Hepatic NF-κB expression and hepatic NF-κB-mRNA were also higher during the course of HCC development(P<0.01).CONCLUSION:The NF-κB signal transduction pathway is activated during the early stages of HCC development, and its abnormal expression may be associated with the occurrence of HCC.
基金supported by the Leibniz Association,Germany,and the VELUX Foundation,Switzerland
文摘Activation of nuclear factor kappa B(NF-κB) is a hallmark of various central nervous system(CNS) pathologies. Neuron-specific inhibition of its transcriptional activator subunit RelA, also referred to as p65, promotes neuronal survival under a range of conditions, i.e., for ischemic or excitotoxic insults. In macro- and microglial cells, post-lesional activation of NF-κB triggers a growth-permissive program which contributes to neural tissue inflammation, scar formation, and the expression of axonal growth inhibitors. Intriguingly, inhibition of such inducible NF-κB in the neuro-glial compartment, i.e., by genetic ablation of RelA or overexpression of a transdominant negative mutant of its upstream regulator IκBα, significantly enhances functional recovery and promotes axonal regeneration in the mature CNS. By contrast, depletion of the NF-κB subunit p50, which lacks transcriptional activator function and acts as a transcriptional repressor on its own, causes precocious neuronal loss and exacerbates axonal degeneration in the lesioned brain. Collectively, the data imply that NF-κB orchestrates a multicellular program in which κB-dependent gene expression establishes a growth-repulsive terrain within the post-lesioned brain that limits structural regeneration of neuronal circuits. Considering these subunit-specific functions, interference with the NF-κB pathway might hold clinical potentials to improve functional restoration following traumatic CNS injury.
基金Supported by The National Natural Science Foundation of ChinaNO.81170374 and NO.81470842 to Hua J
文摘AIM: To investigate the effect of different dietary fatty acids on hepatic inflammasome activation.METHODS: Wild-type C57BL/6 mice were fed either a high-fat diet or polyunsaturated fatty acid(PUFA)-enriched diet. Primary hepatocytes were treated with either saturated fatty acids(SFAs) or PUFAs as well as combined with lipopolysaccharide(LPS). The expression of NOD-like receptor protein 3(NLRP3) inflammasome, peroxisome proliferator-activated receptor-γ and nuclear factor-kappa B(NF-κB) was determined by real-time PCR and Western blot. The activity of Caspase-1 and interleukine-1β production were measured.RESULTS: high-fat diet-induced hepatic steatosis was sufficient to induce and activate hepatic NLRP3 inflammasome. SFA palmitic acid(PA) directly activated NLRP3 inflammasome and increased sensitization to LPS-induced inflammasome activation in hepatocytes. In contrast, PUFA docosahexaenoic acid(Dh A) had thepotential to inhibit NLRP3 inflammasome expression in hepatocytes and partly abolished LPS-induced NLRP3 inflammasome activation. Furthermore, a highfat diet increased but PUFA-enriched diet decreased sensitization to LPS-induced hepatic NLRP3 inflammasome activation in vivo. Moreover, PA increased but Dh A decreased phosphorylated NF-κB p65 protein expression in hepatocytes.CONCLUSION:Hepatic NLRP 3 inflammasome activation played an important role in the development of non-alcoholic fatty liver disease. Dietary SFAs and PUFAs oppositely regulated the activity of NLRP3 inflammasome through direct activation or inhibition of NF-κB.
基金funded by the Health Research Fund from the Health Department of Shanxi Province, China, No.04015
文摘A mouse model of viral encephalitis was induced by intracranial injection of a Coxsackie virus B3 suspension. Quantitative real-time reverse transcription-PCR and western blot assay were applied to detect mRNA and protein expression of intelectin-2 and nuclear factor-kappa B in the viral encephalitis and control groups. Nuclear factor-kappa B and intelectin-2 mRNA and protein expression were significantly increased in mice with viral encephalitis. After intraperitoneal injection of Shuanghuanglian at a dose of 1.5 mg/kg for 5 successive days, intelectin-2 and nuclear factor-kappa B protein and mRNA expression were significantly decreased. To elucidate the relationship between intelectin-2 and nuclear factor-kappa B, mice with viral encephalitis were administered an intracerebral injection of 107 pfu recombinant lentivirus expressing intelectin shRNA. Both protein and mRNA levels of intelectin and nuclear factor-kappa B in brain tissue of mice were significantly decreased. Experimental findings suggest that Shuanghuanglian injection may downregulate nuclear factor-kappa B production via suppression of intelectin production, thus inhibiting inflammation associated with viral encephalitis.
基金Supported by grants from National Natural Science Foundation of China, No. 30471614 (to DK Qiu) and No.30571730 (to X Ma)Shanghai Leading Academic Discipline Project, No.Y0205 (to X Ma)
文摘AIM: To investigate the role of p38 mitogen-activated protein kinase (p38MAPK) in murine experimental autoimmune hepatitis (EAH). METHODS: To induce EAH, the syngeneic S-100 antigen emulsified in complete Freud's adjuvant was injected intraperitoneally into adult male C57Bl/6 mice. Liver injury was assessed by serum ALT and liver histology. The expression and activity of p38 MAPK were measured by Western blot and kinase activity assays. In addition, DNA binding activities of nuclear factor kappa B (NF-κB) were analyzed by electrophoretic mobility shift assay. The effects of SB203580, a specifi c p38 MAPK inhibitor, on liver injuries and expression of proin? ammatory cytokines (interferon-γ, IL-12, IL-1β and TNF-α) were observed. RESULTS: The activity of p38 MAPK and NF-κB was increased and reached its peak 14 or 21 d after the fi rst syngeneic S-100 administration. Inhibition of p38 MAPK activation by SB203580 decreased the activation of NF-κB and the expression of proin? ammatory cytokines. Moreover, hepatic injuries were improved significantly after SB203580 administration. CONCLUSION: p38 MAPK and NF-κB play an important role in an animal model of autoimmune hepatitis (AIH) induced by autoantigens.
