Anti-N-methyl-D-aspartate receptor-associated encephalitis: A review of clinicopathologic hallmarks and multimodal imaging manifestations

Anti-N-methyl-D-aspartate receptor-associated encephalitis(NMDARE)is a rare immune-mediated neuroinflammatory condition characterized by the rapid onset of neuropsychiatric symptoms and autonomic dysfunction.The mechanism of pathogenesis remains incompletely understood,but is thought to be related to antibodies targeting the GluN1 subunit of the NMDA receptor with resultant downstream dysregulation of dopaminergic pathways.Young adults are most frequently affected;the median age at diagnosis is 21 years.There is a strong female predilection with a female sex predominance of 4:1.NMDARE often develops as a paraneoplastic process and is most commonly associated with ovarian teratoma.However,NMDARE has also been described in patients with small cell lung cancer,clear cell renal carcinoma,and other benign and malignant neoplasms.Diagnosis is based on correlation of the clinical presentation,electro-encephalography,laboratory studies,and imaging.Computed tomography,positron emission tomography,and magnetic resonance imaging are essential to identify an underlying tumor,exclude clinicopathologic mimics,and predict the likelihood of long-term functional impairment.Nuclear imaging may be of value for prognostication and to assess the response to therapy.Treatment may involve high-dose corticosteroids,intravenous immunoglobulin,and plasma exchange.Herein,we review the hallmark clinicopathologic features and imaging findings of this rare but potentially devastating condition and summarize diagnostic criteria,treatment regimens,and proposed pathogenetic mechanisms.

Tumor necrosis family receptor superfamily member 9/tumor necrosis factor receptor-associated f

Hepatitis C virus(HCV)infection is an excellent immunological model for understanding the mechanisms developed by non-cytopathic viruses and tumors to evade the adaptative immune response.The antigen-specific cytotoxic T cell response is essential for keeping HCV under control,but during persistent infection,these cells become exhausted or even deleted.The exhaustion process is progressive and depends on the infection duration and level of antigenemia.During high antigenic load and long duration of infection,T cells become extremely exhausted and ultimately disappear due to apoptosis.The development of exhaustion involves the impairment of positive co-stimulation induced by regulatory cytokines,such as transforming growth factor beta 1.This cytokine downregulates tumor necrosis factor receptor(TNFR)-associated factor 1(TRAF1),the signal transducer of the T cell co-stimulatory molecule TNFR superfamily member 9(known as 4-1BB).This impairment correlates with the low reactivity of T cells and an exhaustion phenotype.Treatment with interleukin-7 in vitro restores TRAF1 expression and rescues T cell effector function.The process of TRAF1 loss and its in vitro recovery is hierarchical,and more affected by severe disease progression.In conclusion,TRAF1 dynamics on T cells define a new pathogenic model that describes some aspects of the natural history of HCV,and sheds light on novel immunotherapy strategies for chronic viral infections and cancer.

Interleukin-1 receptor-associated kinase-2 is involved in IL-18-induced NF-κB activation

objective: To investigate whether interleukin-1 receptor-associated kinase-2 (IRAK-2) is involved in interleukin-18 (IL-18)-induced nuclear factor- κ B (NF-κ B) activation. Methods: Phosphorothioate oligodeoxynucleotide (ODN) was designed antisense to sequences of IRAK-2. Antisense IRAK-2 ODN was delivered by lipofectin encapsulation into cultured HepG2 cells. IRAK-2 mRNA expression was assayed by semiquantitative reverse transcription-PCR. The levels of NF- K B were measured by sandwich ELISA. Results: Antisense IRAK-2 ODN blocked IRAK -2expression. IL-18 activated NT- K B and the A value increased from a basal level of 0.115±0.004 to 2.141 ±0.038. Antisense IRAK-2 ODN inhibited IL-18-induced NT- K B activation in a dose (1-8μg )-dependent fashion. When the cells were treated with 4μg antisense IRAK-2 ODN for 8 h, a maximum inhibition of 45.4% was induced as shown by the reduction of the OD value from a control level of 2.141±0.038 down to 1.168±0.026. Conclusion: IRAK-2 can regulate IL-18-stimulated NF- K B activation.

Diagnostic and Predictive Levels of Calcium-binding Protein A8 and Tumor Necrosis Factor Receptor-associated Factor 6 in Sepsis-associated Encephalopathy： A Prospective Observational Study

Background： Despite its high prevalence, morbidity, and mortality, sepsis-associated encephalopathy （SAE） is still poorly understood. The aim of this prospective and observational study was to investigate the clinical significance of calcium-binding protein A8 （S 100AS） in serum and tumor necrosis factor receptor-associated factor 6 （TRAF6） in peripheral blood mononuclear cells （PBMCs） in diagnosing SAE and predicting its prognosis. Methods： Data of septic patients were collected within 24 h after Intensive Care Unit admission fi-om July 2014 to March 2015. Healthy medical personnel served as the control group. SAE was defined as cerebral dysfhnction in the presence of sepsis that fulfilled the exclusion criteria. The biochemical indicators, Glasgow Coma Scale, Acute Physiology and Chronic Health Evaluation score II, TRAF6 in PBMC, serum S 100A8, S 10013, and neuron-specific enolase were evaluated in SAE patients afresh. TRAF6 and S 100A8 were also measured in the control group. Results： Of the 57 enrolled patients, 29 were diagnosed with SAE. The S 100A8 and TRAF6 concentrations in SAE patients were both significantly higher than that in no-encephalopathy （NE） patients, and higher in NE than that in controls （3.74 ± 3.13 vs. 1.08 ± 0.75 vs. 0.37 ± 0.14 ng/ml, P 〈 0.01 ; 3.18 ± 1.55 vs. 1.02 ± 0.63 vs. 0.47 ± 0.10, P 〈 0.01）. S 100A8 levels of 1.93 ng/ml were diagnostic of SAE with 92.90% specificity and 69.00% sensitivity in the receiver operating characteristic （ROC） curve, and the area under the curve was 0.86 （95% confidence interval [CI]： 0.76-0.95）. TRAF6-relative levels of 1.44 were diagnostic of SAE with 85.70% specificity and 86.20% sensitivity, and the area under the curve was 0.94 （95% CI： 0.88-0.99）. In addition, S 100A8 levels of 2.41 ng/ml predicted 28-day mortality of SAE with 90.00% specificity and 73.70% sensitivity in the ROC curve, and the area under the curve was 0.88. TRAF6 relative levels of 2.94 predicted 28-day mortality of SAE with 80.00% specificity and 68.40% sensitivity, and the area under the curve was 0.77. Compared with TRAF6, the specificity of serum S 100A8 in diagnosing SAE and predicting mortality was higher, although the sensitivity was low. In contrast, the TRAF6 had higher sensitivity for diagnosis. Conclusions： Peripheral blood levels of S 100A8 and TRAF6 in SAE patients were elevated and might be related to the severity of SAE and predict the outcome of SAE. The efficacy and specificity of S 100A8 for SAE diagnosis were superior, despite its weak sensitivity. S100A8 might be a better biomarker for diagnosis of SAE and predicting prognosis.

Efficacy of Sishen Wan(四神丸) on dinitrobenzene sulfonic acid-induced ulcerative colitis and its effect on toll-like receptor 2/interleukin-1 receptor-associated kinase-4/nuclear factor-κB signal pathway

OBJECTIVE:To investigate the therapeutic effect of Sishen Wan(四神丸,SSW)on ulcerative colitis(UC)induced by dinitrobenzene sulfonic acid and its effect on toll-like receptor 2/interleukin-1 receptor-associated kinase-4/nuclear factor-κB(TLR2/IRAK4/NF-κB)signaling pathway in colonic tissue.METHODS:In this study,120 Sprague–Dawley rats were randomly divided into blank and model groups.The experimental UC model in rats was established by subcutaneous injection of hydrocortisone+senna gavage for 21 d+dinitrobenzene sulfonic acid(DNBS)/ethanol solution enema.The successful model rats were randomly divided into the model group;mesalazine(0.36 g/kg)group;and high-,medium-,and low-dose SSW(24,12,and 6 g/kg)groups.The model and blank groups were gavaged with equal volumes of distilled water once a day for 21 d.The general condition of the rats was observed,and the body mass,fecal properties,and occult blood were recorded for calculating the disease activity index(DAI)score.The colonic tissue of the rats was collected,and its general morphology and pathological form were noted for obtaining the colonic mucosal injury index(CMDI)score.Hematoxylin-eosin staining was used to view the pathological changes of the colon tissue in each group,apoptosis of the cells was detected using terminal deoxynucleotidyl transferase-mediated d UTP nick-end labeling staining,and quantitative real-time polymerase chain reaction was used to measure the expressions of TLR2,myeloid differentiation primary response gene 88(My D88),IRAK4,and NF-κB p65 mRNA in the colon tissue.The expressions of TLR2,My D88,IRAK4,and NF-κB p65 protein were detected using western blotting and immunohistochemistry assay,and the levels of interleukin-1β(IL-1β)and tumor necrosis factor-α(TNF-α)in the colon tissue were determined using enzyme linked immunosorbent assay.RESULTS:Compared with the blank group,the general condition of the model group was relatively poor.The DAI and CMDI scores of the model group increased significantly(P<0.01),the glands and intestinal mucosa disappeared partially,and several inflammatory cells infiltrated and gathered in the mucosal layer and base layer of the rats in the model group.Furthermore,the cell apoptosis and expression levels of TLR2,My D88,IRAK4,and NF-κB p65 mRNA and protein in the colon tissue of rats in the model group increased significantly(P<0.01).The levels of IL-1βand TNF-αincreased significantly in the colon tissue of rats in the model group(P<0.01).After treatment with SSW,compared with the model group,the general condition of the UC rats improved.Moreover,the DAI and CMDI scores of the UC rats decreased significantly(P<0.05),and the pathological changes in the colon tissue of the UC rats tended to be normal.The cell apoptosis and expression levels of TLR2,My D88,IRAK4,and NF-κB p65 mRNA and protein in the colon tissue of the UC rats decreased gradually(P<0.01),and the levels of IL-1βand TNF-αdecreased significantly(P<0.01).CONCLUSION:SSW can improve the general condition and alleviate the intestinal mucosal injury of UC model rats.Additionally,SSW can inhibit the TLR2/IRAK4/NF-κB signaling pathway,but further studies are required to confirm it.

Total glucosides of paeony improve complete freund’s adjuvant-induced rheumatoid arthritis in rats by inhibiting toll-like receptor 2-mediated tumor necrosis factor receptor-associated factor 6/nuclear factor-kappa B pathway activation

OBJECTIVE: To investigate the mechanism underlying anti-inflammatory and immunoregulatory effect of total glucosides of paeony(TGP) based on toll-like receptor 2(TLR2) mediated tumor necrosis factor(TNF) receptor-associated factor 6(TRAF6)/nuclear factor-kappa B(NF-κB) pathway activation in rats with rheumatoid arthritis.METHODS: Adjuvant arthritis(AA) model was developed by complete freund’s adjuvant(CFA) immunization. TGP(100, 50, 25 mg/kg) and celecoxib(2.8 mg/kg) were administered by intragastric administration for 21 d. Right hind paw swelling was assessed every 2 d. After 21 d, synovial changes of the ankle were detected by histopathology. CD4+and CD8+ T cell amounts in peripheral blood were measured by flow-cytometrically. Gene and protein levels of toll-like receptor(TLR)2, TRAF6, tumor necrosis factor ligand superfamily member 6(FASLG)in the spleen were assessed by RT-qPCR and Western Bolt, respectively. Nuclear expression of NF-κB p65 was detected by NF-κB p65 Assay Kit.RESULTS: Paw swelling and synovium lesions were obviously aggravated in AA rats. These symptoms were significantly relieved by TGP.The ratio of CD4+/CD8+ T cell was increased in AA rats, while TGP reduced this increased ratio.Gene and protein levels of splenic TLR2, TFAR6 and FASLG, and nuclear NF-κB p65 in AA rats were significantly increased, but overtly inhibited by TGP.CONCLUSION: These findings suggest that TGP’s anti-inflammatory effect onRA in rats with CFA may be related to the downregulation of TLR2/TRAF6/NF-κB pathway and the regulation of T cell subsets.

Tumor necrosis factor receptor-associated protein 1 regulates hypoxia-induced apoptosis through a mitochondria-dependent pathway mediated by cytochrome c oxidase subunit Ⅱ

Background:Tumor necrosis factor receptor-associated protein 1(TRAP1)plays a protective effect in hypoxic cardiomyocytes,but the precise mechanisms are not well clarified.The study is aimed to identify the mechanism of TRAP1 on hypoxic damage in cardiomyocytes.Methods:In this study,the effects of TRAP1 and cytochrome c oxidase subunit Ⅱ(COXⅡ)on apoptosis in hypoxia-induced cardiomyocytes were explored using overexpression and knockdown methods separately.Results:Hypoxia induced cardiomyocyte apoptosis,and TRAP1 overexpression notably inhibited apoptosis induced by hypoxia.Conversely,TRAP1 silencing promoted apoptosis in hypoxic cardiomyocytes.Further investigation revealed that the proapoptotic effects caused by the silencing of TRAP1 were prevented by COXⅡ overexpression,whereas COXⅡ knockdown reduced the antiapoptotic function induced by TRAP1 overexpression.Additionally,changes in the release of cytochrome c from mitochondria into the cytosol and the caspase-3 activity in the cytoplasm,as well as reactive oxygen species production,were found to be correlated with the changes in apoptosis.Conclusions:The current study uncovered that TRAP1 regulates hypoxia-induced cardiomyocyte apoptosis through a mitochondria-dependent apoptotic pathway mediated by COXⅡ,in which reactive oxygen species presents as an important component.

Functional polymorphism in exon 5 and variant haplotype of the interleukin-1 receptor-associated kinase 1 gene are associated with susceptibility to and severity of sepsis in the Chinese population

Background The interleukin-1 （IL-1） receptor-associated kinase 1 （IRAK1） is believed to play an important role in the pathogenesis of sepsis. Recent studies have suggested that the I RAK1 functional genetic variant could affect the severity of sepsis in Caucasians. In this report, we have investigated whether polymorphisms at the IRAK1 gene are associated with the susceptibility to and severity of sepsis among the Chinese population. Methods Haplotype-tagging single nucleotide polymorphisms （htSNPs） were selected from the HapMap database. They.were genotyped in 255 patients with sepsis and 260 control subjects by PCR/restriction fragment length polymorphism （RFLP） analysis. The association between the selected htSNPs and the susceptibility to and severity of sepsis were estimated by Logistic regression with adjustments for age, sex, smoking, drinking, chronic disease status, Acute Physiology and Chronic Health Evaluation （APACHE） II score and primary diseases. Results rs1059702 was selected to represent the six linked htSNPs for IRAKI. Genotype frequencies of the htSNPs were in Hardy-Weinberg equilibrium for females, as were allele frequencies for both sex groups. Associations were observed in females between the htSNPs C/C genotype and increased susceptibility to sepsis （odds ratio （OR）, 5.46; 95% confidence interval （C/）, 1.12-26.67; P=0.018）, and such associations were also observed between the IRAK1 variant haplotype （CC/C-allele） and increased susceptibility to sepsis （OR, 1.68; 95% C/, 1.05-2.70; P=0.031） when compared with the T/T ＋ T/C genotype and the wild-type haplotype （TC ＋ TT/T-allele）. In the multiple organ dysfunction syndrome （MODS） subgroup, the variant haplotype was also associated with increased severity of sepsis （OR, 2.37; 95% Cl, 1.13-4.94; P=-0.02） when compared with the wild haplotype. This association was not significant in male patients. Conclusions The functional polymorphism in exon 5 and the variant haplotype of IRAK1 gene mediate susceptibility to and severity of sepsis. IRAK1 might be a genetic risk factor for the occurrence and development of sepsis in the Chinese population.

Small extracellular vesicles from hypoxia-preconditioned bone marrow mesenchymal stem cells attenuate spinal cord injury via miR-146a-5p-mediated regulation of macrophage polarization

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.

Interleukin-1 receptor associated kinase 2 is a functional downstream regulator of complement factor D that controls mitochondrial fitness in diabetic cardiomyopathy

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.

TRAF6在抗β_2GPI/β_2GPI复合物诱导THP-1细胞表达组织因子时的活化

目的:探讨肿瘤坏死因子受体相关因子6(TRAF6)在抗β2GPI/β2GPI复合物诱导单核细胞株THP-1表达组织因子(TF)中的作用。方法:采用一定剂量抗β2GPI/β2GPI复合物刺激THP-1细胞一定时间,收集细胞总RNA及总蛋白,实时定量PCR检测细胞TF mRNA水平,发色底物法检测细胞TF活性;RT-qPCR及Western blot分别检测细胞TRAF6mRNA和蛋白表达情况;进一步采用蛋白酶体抑制剂MG-132,观察是否能够干预抗β2GPI/β2GPI复合物对细胞的刺激效应。结果:抗β2GPI/β2GPI复合物(100 mg/L)能够刺激THP-1细胞表达TF mRNA及活性,与对照相比差异显著(P<0.05);使细胞TRAF6 mRNA和蛋白表达均增加,并显示时间相关性,分别在刺激15 min和30 min时表达至高峰;MG-132(5μmol/L)明显抑制抗β2GPI/β2GPI复合物(100 mg/L)对THP-1细胞TRAF6 mRNA和蛋白的刺激效应及TF的诱导表达。结论:抗β2GPI/β2GPI复合物诱导THP-1细胞表达TF过程中,TRAF6被激活并发挥重要作用。

Potential mechanisms of hepatitis B virus induced liver injury

Chronic active hepatitis(CAH) is acknowledged as an imperative risk factor for the development of liver injury and hepatocellular carcinoma.The histological end points of CAH are chronic inflammation,fibrosis and cirrhosis which are coupled with increased DNA synthesis in cirrhotic vs healthy normal livers.The potential mechanism involved in CAH includes a combination of processes leading to liver cell necrosis,inflammation and cytokine production and liver scaring(fibrosis).The severity of liver damage is regulated by Hepatitis B virus genotypes and viral components.The viral and cellular factors that contribute to liver injury are discussed in this article.Liver injury caused by the viral infection affects many cellular processes such as cell signaling,apoptosis,transcription,DNA repair which in turn induce radical effects on cell survival,growth,transformation and maintenance.The consequence of such perturbations is resulted in the alteration of bile secretion,gluconeogenesis,glycolysis,detoxification and metabolism of carbohydrates,proteins,fat and balance of nutrients.The identification and elucidation of the molecular pathways perturbed by the viral proteins are important in order to design effective strategy to minimize and/or restore the hepatocytes injury.

Competition between TRAF2 and TRAF6 Regulates NF-κB Activation in Human B Lymphocytes

Objective To investigate the role of TNF receptor-associated factor 2 (TRAF-2) and TRAF6 in CD40-induced nuclear factor-κB (NF-κB) signaling pathway and whether CD40 signaling requires TRAF2. Methods Human B cell lines were transfected with plasmids expressing wild type TRAF2 or dominant negative TRAF2,TRAF2-shRNA,or TRAF6-shRNA. The activation of NF-κB was detected by Western blot,kinase assay,transfactor enzyme-linked immunosorbent assay (ELISA),and fluorescence resonance energy transfer (FRET). Analysis of the role of TRAF-2 and TRAF-6 in CD40-mediated NF-κB activity was examined following stimulation with recombinant CD154. Results TRAF2 induced activity of IκB-kinases (IKKα,IKKi/ε),phosphorylation of IκBα,as well as nuclear translocation and phosphorylation of p65/RelA. In contrast,TRAF6 strongly induced NF-κB activation and nuclear translocation of p65 as well as p50 and c-Rel. Engagement of CD154-induced nuclear translocation of p65 was inhibited by a TRAF6-shRNA,but conversely was enhanced by a TRAF2-shRNA. Examination of direct interactions between CD40 and TRAFs by FRET documented that both TRAF2 and TRAF6 directly interacted with CD40. However,the two TRAFs competed for CD40 binding. Conclusions These results indicate that TRAF2 can signal in human B cells,but it is not essential for CD40-mediated NF-κB activation. Moreover,TRAF2 can compete with TRAF6 for CD40 binding,and thereby limit the capacity of CD40 engagement to induce NF-κB activation.

Correlation between mitochondrial TRAP-1 expression and lymph node metastasis in colorectal cancer

AIM： To evaluate the effect of mitochondrial tumor ne- crosis factor receptor-associated protein-1 （TRAP-l） on the lymph node metastasis （LNM） in Chinese colorectal cancer （CRC） patients, and develop potential LNM- associated biomarkers for CRC using quantitative real- time polymerase chain reaction （RT-PCR） analysis. METHODS： Differences in mitochondrial TRAP-1 gene expression between primary CRC with LNM （LNM CRC） and without LNM （non-LNM CRC） were assessed in 96 Chinese colorectal carcinoma samples using quantita- tive RT-PCR analysis, Western blotting, and confirmed with immunohistochemical assay. The relationship between clinicopathological parameters and potential diaclnostic biomarkers was also examined.RESULTS： TRAP-1 was significantly upregulated in LNM CRC compared with non-LNM CRC, which was confirmed by RT-PCR, Western blotting and immuno- histochemical assay. The expression of TRAP-1 in two different metastatic potential human colorectal cancer cell lines, LoVo and HT29, was analyzed with Western blotting. The expression level of TRAP-1 was dramati- cally higher in LoVo than in HT29. Overexpression of TRAP-1 was significantly associated with LNM （90.2% in LNM group vs 22% in non-LNM group, P 〈 0.001）, the advanced tumor node metastasis stage （89.1% in LNM group vs 26.9% in non-LNM group, P 〈 0.001）, the increased 5-year recurrence rate （82.7% in LNM group vs 22.6% in non-LNM group, P 〈 0.001） and the decreased 5-year overall survival rate （48.4% in LNM vs 83.2% in non-LNM group, P 〈 0.001）. Univariate and multivariate analyses indicated that TRAP-1 expression was an independent prognostic factor for recurrence and survival of CRC patients （Hazard ratio of 2.445 in recurrence, P = 0.017; 2.867 in survival, P = 0.028）. CONCLUSION： Mitochondria TRAP-1 affects the lymph node metastasis in CRC, and may be a potential bio- marker for LNM and a prognostic factor in CRC. Over- expression of TRAP-1 is a predictive factor for the poor outcome of colorectal cancer patients. 2012 Baishideng. All rights reserved

Expression of TRAP1 in gastric cancer tissue and its correlation with malignant biology

Objective:To study the expression of tumor necrosis factor receptor-associated protein 1(TRAP1)in gastric cancer tissue and its correlation with malignant biology.Methods:Gastric cancer tissue and adjacent normal tissue were collected,and mRNA content and protein content of TRAP1 were detected;gastric cancer cell lines SGC7901,BGC823,AGS and MGC803 were cultured,and mRNA contents and protein contents of TRAP1,CyclinB1,CyclinD1,CyclinE,MMP-2 and VEGF were detected.Results:mRNA and protein expression levels of TRAP1 in gastric cancer tissue were significantly higher than those in adjacent normal tissue,and mRNA and protein expression levels of TRAP1 in gastric cancer tissue with muscularis and serosa infiltration,lymph node metastasis,distant organ metastasis and TNM Ⅲ/Ⅳ stage were significantly higher than those in gastric cancer tissue with mucosa and submucosa infiltration,non-lymph node metastasis,non-distant organ metastasis and TNM Ⅰ/Ⅱ stage.mRNA and protein expression levels of TRAP1,CyclinB1,CyclinD1,CyclinE,MMP-2 and VEGF in MGC803 were the highest,and mRNA and protein expression levels of TRAP1,CyclinB1,CyclinD1,CyclinE,MMP-2 and VEGF in SGC7901 were the lowest.mRNA and protein expression levels of TRAP1 in gastric cancer cell lines were positively correlated with mRNA and protein expression of CyclinB1,CyclinD1.CyclinE,MMP-2 and VEGF.Conclusions:The expression of TRAP1 significantly increases in gastric cancer tissue;TRAP1 may regulate the malignant biology of cells by increasing the expression of CyclinB1,CyclinD1,CyclinE,MMP-2 and VEGF,thereby resulting in the occurrence and development of gastric cancer.

Up-regulation of mitochondrial chaperone TRAP1 in ulcerative colitis associated colorectal cancer

AIM: To characterize tumor necrosis factor receptor-associated protein 1 (TRAP1) expression in the progression of ulcerative colitis (UC)-associated colorectal cancer.

Molecular mechanisms of triggering,amplifying and targeting RANK signaling in osteoclasts

Osteoclast differentiation depends on receptor activator of nuclear factor-κB(RANK) signaling,which can be divided into triggering,amplifying and targeting phases based on how active the master regulator nuclear factor of activated T-cells cytoplasmic 1(NFATc1) is. The triggering phase is characterized by immediateearly RANK signaling induced by RANK ligand(RANKL) stimulation mediated by three adaptor proteins,tumor necrosis factor receptor-associated factor 6,Grb-2-associated binder-2 and phospholipase C(PLC)γ2,leading to activation of IκB kinase,mitogen-activated protein kinases and the transcription factors nuclear factor(NF)-κB and activator protein-1(AP-1). Mice lacking NF-κB p50/p52 or the AP-1 subunit c-Fos(encoded by Fos) exhibit severe osteopetrosis due to a differentiation block in the osteoclast lineage. The amplification phase occurs about 24 h later in a RANKLinduced osteoclastogenic culture when Ca2+ oscillation starts and the transcription factor NFATc1 is abundantly produced. In addition to Ca2+ oscillation-dependent nuclear translocation and transcriptional auto-induction of NFATc1,a Ca2+ oscillation-independent,osteoblastdependent mechanism stabilizes NFATc1 protein in dif-ferentiating osteoclasts. Osteoclast precursors lacking PLCγ2,inositol-1,4,5-trisphosphate receptors,regulator of G-protein signaling 10,or NFATc1 show an impaired transition from the triggering to amplifying phases. The final targeting phase is mediated by activation of numerous NFATc1 target genes responsible for cell-cell fusion and regulation of bone-resorptive function. This review focuses on molecular mechanisms for each of the three phases of RANK signaling during osteoclast differentiation.

Inhibitory Effects of Parthenolide on the Activity of NF-κB in Multiple Myeloma via Targeting TRAF6

This study examined the mechanism of the inhibitory effect of parthenolide（PTL） on the activity of NF-κB in multiple myeloma（MM）. Human multiple myeloma cell line RPMI 8226 cells were treated with or without different concentrations of PTL for various time periods, and then MTT assay was used to detect cell proliferation. Cell cycle and apoptosis were flow cytometrically detected. The level of protein ubiquitination was determined by using immunoprecipitation. Western blotting was employed to measure the level of total protein ubiquitination, the expression of IκB-α in cell plasma and the content of p65 in nucleus. The content of p65 in nucleus before and after PTL treatment was also examined with immunofluorescence. Exposure of RPMI 8226 cells to PTL attenuated the level of ubiquitinated Nemo, increased the expression of IκB-α and reduced the level of p65 in nucleus, finally leading to the decrease of the activity of NF-κB. PTL inhibited cell proliferation, induced apoptosis and blocked cell cycle. Furthermore, the levels of ubiquitinated tumor necrosis factor receptor-associated factor 6（TRAF6） and total proteins were decreased after PTL treatment. By using Autodock software package, we predicted that PTL could bind to TRAF6 directly and tightly. Taken together, our findings suggest that PTL inhibits the activation of NF-κB signaling pathway via directly binding with TRAF6, thereby suppressing MM cell proliferation and inducing apoptosis.

An enriched environment reduces hippocampal inflammatory response and improves cognitive function in a mouse model of stroke

An enriched environment is used as a behavio ral intervention therapy that applies sensory,motor,and social stimulation,and has been used in basic and clinical research of va rious neurological diseases.In this study,we established mouse models of photothrombotic stroke and,24 hours later,raised them in a standard,enriched,or isolated environment for 4 weeks.Compared with the mice raised in a standard environment,the cognitive function of mice raised in an enriched environment was better and the pathological damage in the hippocampal CA1 region was remarkably alleviated.Furthermore,protein expression levels of tumor necrosis factor receptor-associated factor 6,nuclear factorκB p65,interleukin-6,and tumor necrosis factorα,and the mRNA expression level of tumor necrosis factor receptor-associated factor 6 were greatly lower,while the expression level of miR-146a-5p was higher.Compared with the mice raised in a standard environment,changes in these indices in mice raised in an isolated environment were opposite to mice raised in an enriched environment.These findings suggest that different living environments affect the hippocampal inflammatory response and cognitive function in a mouse model of stro ke.An enriched environment can improve cognitive function following stroke through up-regulation of miR-146a-5p expression and a reduction in the inflammatory response.

Inhibitory Effects of Cypermethrin on Interactions of the Androgen Receptor with Coactivators ARA70 and ARA55

Objective The purpose of this study was to investigate the anti-androgenic mechanism of cypermethrin involving coactivators.Methods Mammalian two-hybrid assays were performed to study the effects of cypermethrin on interactions of the androgen receptor(AR)with the coactivators androgen receptor-associated protein70(ARA70)and androgen receptor-associated protein 55(ARA55).Results The results showed that AR–ARA70 and AR–ARA55 interactions were remarkably enhanced by dihydrotestosterone(DHT,P≤0.05).Cypermethrin inhibited DHT-induced AR–ARA70 and AR–ARA55 interactions significantly(P≤0.05).Conclusion The study indicates that cypermethrin exhibits inhibitory effects on AR transcription associated with repression of AR–ARA70 and AR–ARA55 interactions in a ligand-dependent manner.The data show novel anti-androgenic mechanisms of cypermethrin that contribute to male reproductive toxicology.