外周血高迁移率族蛋白-1和NF-κB在肾病综合征中的作用

目的分析原发性肾病综合征患者血清中HMGB-1、NF-κB的关系,探讨其在原发性肾病综合征中的作用。方法2014年1月至2015年7月我院40例原发性肾病综合征患者为观察组,同时纳入40例健康体检者为对照组。采用ELISA法测定外周血清中HMGB-1、NF-κB的浓度,同时收集受试者尿蛋白、血脂等相关临床资料。评价尿蛋白定量、TG、TC、HDL-C、LDL-C水平、血清白蛋白水平、C-反应蛋白水平及血清HMGB-1、NF-κB水平。采用Pearson相关性分析进行变量之间的统计学分析。结果观察组HMGB-1和NF-κB的浓度均高于对照组,差异有统计学意义(P<0.01)。Pearson相关分析结果显示,HMGB-1与尿蛋白定量(r=0.74,P<0.01)、TG(r=0.33,P<0.01)、TC(r=0.52,P<0.01)、LDL-C(r=0.26,P<0.01)、CRP(r=0.41,P<0.01)呈正相关,与白蛋白(r=-0.56,P<0.01)呈负相关。NF-κB与尿蛋白定量(r=0.62,P<0.01)、TG(r=0.28,P<0.01)、TC(r=0.43,P<0.01)、LDL-C(r=0.29,P<0.01)呈正相关,与白蛋白(r=-0.45,P<0.01)呈负相关。HMGB-1与NF-κB呈正相关,相关系数为0.84,差异有统计学意义(P<0.01)。结论原发性肾病综合征患者血清中HMGB-1、NF-κB水平均升高,两者呈正相关。HMGB-1在肾病综合征的发病中可能通过NF-κB起作用。     

The role of inflammation in the pathogenesis of lung cancer

Introduction: It is reported that cancer may arise in chronically inflamed tissue. There is mounting evidence suggesting that the connection between inflammation and lung cancer is not coincidental but may indeed be causal. The inflammatory molecules may be responsible for augmented macrophage recruitment, delayed neutrophil clearance and an increase in reactive oxygen species. The cytokines and growth factors unusually produced in chronic pulmonary disorders have been found to have harmful properties that pave the way for epithelial-to-mesenchymal transition and tumor microenvironment. However, the role of inflammation in lung cancer is not yet fully understood.

Areas covered: The role of chronic inflammation in the pathogenesis of lung cancer and some of the possible mechanisms involved, with particular focus on inflammatory mediators, genetic and epigenetic alterations, inflammatory markers, tumor microenvironment and anti-inflammatory drugs are discussed. A framework for understanding the connection between inflammation and lung cancer is provided, which may afford the opportunity to intercede in specific inflammatory damage mediating lung carcinogenesis and therapeutic resistance.

Expert opinion: Advances in tumor immunology support the clinical implementation of immunotherapies for lung cancer. Along with therapeutic benefits, immunotherapy presents the challenges of drug-related toxicities. Gene modification of immunocytokine may lower the associated toxic effects.     

抑制NF-κB活性对糖尿病大鼠肾脏TGF-β1 mRNA表达影响

目的　研究抑制核因子 κB(NF κB)活性对糖尿病大鼠肾脏TGF β1mRNA表达影响。 方法　纯种♂Wistar大鼠分为 3组 :A组为正常对照组 (11只 ) ,B组为糖尿病大鼠未干预组 (11只 ) ,C组为糖尿病大鼠PDTC(NF κB活性抑制剂 )干预组 (9只 )。饲养 18wk后取出肾脏 :以电泳迁移率变动分析技术检测肾组织NF κB活性 ,透射电镜检测肾小球基底膜厚度及系膜基质密度 (系膜基质面积 /系膜面积 ) ,RT PCR检测TGF β1mRNA表达。酶免疫分析法检测 2 4h尿白蛋白排泄 (UAE)。结果　肾组织NF κB活性在B组大鼠肾组织 (1 85± 0 5 4× 10 6)显著高于A组 (0 0 7± 0 11×10 6,P <0 0 1) ,C组 (0 2 5± 0 2 5× 10 6)显著低于B组 (P <0 0 1)。B组与A组比较 ,UAE (2 18± 1 98mgvs 0 4 1± 0 4 7mg,P <0 0 1)、肾小球基底膜厚度 (5 31 6± 10 7 6nmvs 312 4±2 5 4nm ,P <0 0 1)及系膜基质密度 (5 6 4 1± 6 78vs 33 95±5 2 2 ,P <0 0 1)均显著增高 ;C组大鼠UAE(0 5 6± 0 72 )mg、肾小球基底膜厚度 (315 8± 2 1 4 )nm及系膜基质密度 (37 97±7 37)均显著低于B组 (均P <0 0 1)。肾组织TGF β1mR NA表达在B组大鼠 (0 5 3± 0 2 0 )显著高于A组 (0 2 6±0 13,P <0 0 1) ,C组 (0 2 9± 0 10 )显?     

Suppression of NF-kappaB activation by curcumin leads to inhibition of expression of cyclo-oxygenase-2 and matrix metalloproteinase-9 in human articular chondrocytes: Implications for the treatment of osteoarthritis

Pro-inflammatory cytokines such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) play a key role in the pathogenesis of osteoarthritis (OA). Anti-inflammatory agents capable of suppressing the production and catabolic actions of these cytokines may have therapeutic potential in the treatment of OA and a range of other osteoarticular disorders. The purpose of this study was to examine the effects of curcumin (diferuloylmethane), a pharmacologically safe phytochemical agent with potent anti-inflammatory properties on IL-1beta and TNF-alpha signalling pathways in human articular chondrocytes maintained in vitro. The effects of curcumin were studied in cultures of human articular chondrocytes treated with IL-1beta and TNF-alpha for up to 72h. Expression of collagen type II, integrin beta1, cyclo-oxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9) was monitored by western blotting. The effects of curcumin on the expression, phosphorylation and nuclear translocation of protein components of the NF-kappaB system were studied by western blotting and immunofluorescence, respectively. Treatment of chondrocytes with curcumin suppressed IL-1beta-induced NF-kappaB activation via inhibition of IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation and p65 nuclear translocation. Curcumin inhibited the IL-1beta-induced stimulation of up-stream protein kinase B Akt. These events correlated with down-regulation of NF-kappaB targets including COX-2 and MMP-9. Similar results were obtained in chondrocytes stimulated with TNF-alpha. Curcumin also reversed the IL-1beta-induced down-regulation of collagen type II and beta1-integrin receptor expression. These results indicate that curcumin has nutritional potential as a naturally occurring anti-inflammatory agent for treating OA through suppression of NF-kappaB mediated IL-1beta/TNF-alpha catabolic signalling pathways in chondrocytes.     

S-allylmercaptocysteine ameliorates lipopolysaccharide-induced acute lung injury in mice by inhibiting inflammation and oxidative stress via nuclear factor kappa B and Keap1/Nrf2 pathways

The garlic-derived organosulfur compound S-allylmercaptocysteine (SAMC) has been reported to exhibit anti-inflammatory and anti-oxidative activities, whereas its potential therapeutic effect on lipopolysaccharide (LPS)-induced acute lung injury (ALI) is unknown. In this study, we focused on exploring the therapeutic effects of SAMC on LPS-induced ALI mice and the involvement of underlying molecular mechanisms. BalB/c mice were treated with SAMC (10, 30 and 60 mg/kg) or positive control N-acetylcysteine (NAC, 500 mg/kg) by gavage after intratracheal instillation of LPS for 30 min and were sacrificed 24 h after LPS administration. Our results indicate that the treatment with SAMC not only ameliorated the histological changes but also decreased LPS-triggered lung edema. Moreover, SAMC displayed an anti-inflammatory effect through reducing inflammatory cells infiltration, myeloperoxidase (MPO) formation and inhibiting pro-inflammatory cytokines/mediator production including tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2) via suppressing the activation of nuclear factor-kappaB (NF-κB) signaling pathway. Furthermore, SAMC attenuated oxidative stress evoked by LPS via diminishing malondialdehyde (MDA) formation and reversing glutathione (GSH) and superoxide dismutase (SOD) depletion. Meanwhile, SAMC up-regulated expressions of endogenous antioxidant/detoxifying proteins including heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1(NQO1) through reversing the suppression of Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid-2 related factor 2 (Nrf2) signaling pathway. Our results demonstrate that SAMC effectively attenuated LPS-induced ALI which was largely dependent upon inhibition of inflammation and oxidative stress via NF-κB and Keap1/Nrf2 signaling pathways.     

EGCG downregulates IL-1RI expression and suppresses IL-1-induced tumorigenic factors in human pancreatic adenocarcinoma cells

Human pancreatic cancer is currently one of the fifth-leading causes of cancer-related mortality with a 5-year survival rate of less than 5%. Since pancreatic carcinoma is largely refractory to conventional therapies, there is a strong medical need for the development of novel and innovative therapeutic strategies. Increasing evidence suggests an association of carcinogenesis and chronic inflammation. Because IL-1 plays a crucial role in inflammation-associated carcinogenesis, we analyzed the biological effects of IL-1 and its modulation by the chemopreventive green tea polyphenol (−)-epigallocatechin-3-gallate (EGCG) in the human pancreatic adenocarcinoma cell line Colo357. Proinflammatory IL-6 and PGHS-2 as well as proangiogenic IL-8 and VEGF were induced by IL-1, whereas the secretion of invasion-promoting MMP-2 remained unaffected. IL-1 responsiveness and constitutive MMP-2 release in Colo357 were downregulated by EGCG in a dose- and time-dependent manner. Moreover, EGCG reduced cell viability via induction of apoptosis in Colo357. Since EGCG effects on cytokine production precede reduction in cell viability, we hypothesize that these findings are not only a result of cell death but also depend on alterations in the IL-1 signaling cascade. In this context, we found for the first time an EGCG-induced downregulation of the IL-1RI expression possibly being caused by NF-κB inhibition and causative for its inhibitory action on the production of tumorigenic factors. Thus, our data might have future clinical implications with respect to the development of novel approaches as an adjuvant therapy in high-risk patients with human pancreatic carcinoma.     

白芍总苷对免疫性肝纤维化大鼠肝组织NF-κB和TGF-β1蛋白表达的影响

目的研究免疫性肝纤维化大鼠肝组织中核转录因子-κB(nuclear factor-κB,NF-κB)和转化生长因子β1(trans-forming growth factor beta1,TGF-β1)的变化以及白芍总苷(TGP)对两者蛋白表达的影响。方法采用猪血清诱导建立大鼠肝纤维化模型,肝组织HE染色和V-G染色观察肝组织损伤及胶原表达变化;免疫组化S-P法观察NF-κB p65和TGF-β1蛋白表达;显微摄像及图像分析检测胶原、NF-κBp65和TGF-β1蛋白的表达量。结果与正常组比较,模型组大鼠肝组织明显破坏,胶原合成增加,NF-κB p65和TGF-β1表达增强(P<0.01);与模型组比较,TGP治疗组肝组织破坏减轻,纤维化程度也明显改善,胶原面积、NF-κB p65和TGF-β1表达均明显减少(P<0.01),三者呈相关性。结论NF-κB介导TGF-β1产生或活化在免疫性肝纤维化过程中可能发挥着重要作用,而TGP抑制纤维化大鼠肝组织NF-κB和TGF-β1的表达可能是TGP的抗肝纤维化主要作用机制之一。     

前列腺素E1对阻塞性黄疸大鼠肝细胞凋亡及凋亡相关蛋白表达的影响

目的探讨前列腺素E1(prostaglandin E1,PGE1)对阻塞性黄疸大鼠肝细胞凋亡的影响及其可能机制。方法选择雄性健康Wistar大鼠72只,建立阻塞性黄疸大鼠模型,随机分为三组:假手术组(SH组)、胆总管结扎组(OJ组)、胆总管结扎+前列腺素E1给药组(PGE1组),分别于手术后3、7、10 d各组测定胆红素(TBil,DBil)和转氨酶(ALT,AST),同时取肝组织在显微镜下观察病理变化。肝细胞凋亡采用TUNEL法检测,并计算凋亡指数(AI)。采用免疫组化法检测NF-κB和iNOS蛋白在各组肝脏中的表达。结果与OJ组比较,PGE1组大鼠血清转氨酶和胆红素水平下降(P0.05)。TUNEL结果显示,与OJ组相比,PGE1组细胞凋亡有所减轻(P0.01)。免疫组化结果显示,与OJ组相比,PGE1组的大鼠肝细胞iNOS蛋白表达降低,NF-κB表达升高,差异均有显著性(P0.05)。结论前列腺素E1可以减轻阻塞性黄疸大鼠的肝细胞凋亡,其机制可能通过直接或间接下调促凋亡蛋白iNOS、上调抗凋亡蛋白NF-κB的表达有关。     

The effect of resveratrol and its methylthio-derivatives on NF-κB and AP-1 signaling pathways in HaCaT keratinocytes

BackgroundResveratrol is a natural stilbene derivative whose chemopreventive activity has been well established. Our previous studies have shown that modification of the stilbene backbone with the methylthio group may influence selectivity and inhibitory potency toward P450 isozymes. The aim of this study was to further investigate the mechanism of their potential chemopreventive activity by evaluating the effect of two 4′-methylthio-trans-stilbene derivatives possessing one (3-M-4′-MTS; S2) and two (3,5-DM-4′-MTS; S5) additional methoxy groups on constitutive nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) activation in immortalized human HaCaT keratinocytes.MethodsThe synthesis of MTS was performed as described earlier. Translocation of NF-κB and AP-1 was evaluated by Western blot analysis. Binding of p65 (NF-κB) and c-Jun and c-Fos subunits (AP-1) to consensus oligonucleotide was assessed by ELISA. Real-time PCR and Western blot were used to evaluate COX-2 and iNOS expression.ResultsWe found differential modulation of signaling pathways depending on the stilbene structure after 24 h of cells treatment. The S2 compound, in contrast to S5 and resveratrol, significantly reduced NF-κB activation by blocking the translocation of the p65 subunit to the nucleus, and decreasing IκB kinase activity. All compounds, but particularly S5, increased c-Jun binding to the AP-1 consensus sequence, while c-Fos binding was not affected.ConclusionsWe conclude that methylthiostilbenes differently modulate constitutive signal transduction pathways in HaCaT cells. These observations should be taken into account in designing new stilbene derivatives with potential chemopreventive activity.     

肾脏组织中TGF-β1和CTGF对NF-κB基因调控的影响

目的 研究阿霉素肾病大鼠模型中核因子-κB(NF-κB)、转化生长因子β1(TGF-β 1)和结缔组织生长因子(CTGF)的浓度与病理变化的意义,探讨其参与肾病综合征的发病机制.方法 36只大鼠随机分成两组:对照组、模型组,每组各18只.模型组采用尾静脉注射阿霉素方法建立阿霉素肾病模型.检测各组大鼠24 h尿蛋白定量及血清肾功能指标,研究各组大鼠肾组织病理学改变,采用免疫学方法(ELISA)检测NF-κB、TGF-β1及CTGF浓度的变化.结果 ①模型组于第2、4、6周尿蛋白定量均高于同期对照组,差异有统计学意义(P＜ 0.01).第2、4、6周时模型组血尿素氮(BUN)及肌酐(Scr)、胆固醇(TC)水平均高于同期对照组(P＜0.01).②肾组织病理学提示随时间延长,肾病病理进展.③模型组第2、4、6周NF-κB、TGF-β1和CTGF浓度结果均高于同期对照组(P＜0.01).结论 NF-κB、TGF-β1和CTGF浓度增高是肾小球硬化发生发展的重要因素,三者共同促进细胞外基质(ECM)的积聚,造成肾小球硬化.阻断NF-κB、TGF-β1和CTGF可能成为延缓肾小球硬化的治疗手段.     

Triptolide inhibits murine-inducible nitric oxide synthase expression by down-regulating lipopolysaccharide-induced activity of nuclear factor-kappa B and c-Jun NH2-terminal kinase

Triptolide (PG490) is a natural, biologically active compound extracted from the Chinese herb Tripterygium wilfordii. It has been shown to possess potent anti-inflammatory and immunosuppressive properties. In Raw 264.7 cells stimulated with lipopolysaccharide (LPS) to mimic inflammation, triptolide inhibits nitric oxide (NO) production in a dose-dependent manner and abrogates inducible nitric oxide synthase (iNOS) gene expression. To investigate the mechanism by which triptolide inhibits murine iNOS gene expression, we examined activation of mitogen-activated protein kinases (MAP kinases) and nuclear factor-kappa B (NF-kappa B) in these cells. Addition of triptolide inhibited phosphorylation of c-Jun NH(2)-terminal kinase (JNK) but not that of extracellular signal-regulated kinase (ERK) or p38 mitogen-activated protein kinase. In addition, triptolide significantly inhibited the DNA binding activity of NF-kappa B. Taken together, these results suggest that triptolide acts to inhibit inflammation through inhibition of NO production and iNOS expression through blockade of NF-kappa B and JNK activation.     

卡维地洛改善心梗大鼠心肌氧化应激状态

目的探讨核转录因子κB(NFκB)活化和超氧阴离子(O-2)、羟自由基(·OH)与心梗后大鼠左室重构及心衰的关系,及药物卡维地洛(Carvedilol)的作用机制。方法将大鼠分为假手术组、心肌梗死(AMI)组和卡维地洛治疗组,在梗后3d进行治疗。治疗组给予卡维地洛1mg·kg-1·d-1灌胃,每日2次;假手术组及心肌梗死组给予等量生理盐水灌胃。治疗4wk后观察各组超声心动图、NFκB活性及氧自由基O-2、·OH的变化。结果心肌梗死4wk后,超声心动图结果显示心梗组大鼠心功能降低,LVEDD、LVESD均增大,EF降低;心肌NFκB活性增高,O-2、·OH水平升高。经卡维地洛干预后,大鼠心功能改善,NFκB活性及O-2、·OH水平降低。结论心肌梗死后,NFκB活性升高,O-2、·OH生成增多,而卡维地洛可以抑制NFκB及O-2、·OH,改善预后。     

与 P－糖蛋白及 MDR1基因关联的药物转运研究现状

P－糖蛋白（P－gp）由MDR1基因编码,腺苷三磷酸依赖的药物外向转运蛋白,是介导药物吸收与转运动力学的关键转运体。不少药物通过核因子κB（ NF－κB）和孕烷X受体（ PXR）信号通路直接影响MDR1基因和P－gp的表达,导致P－gp的功能发生改变,从而影响药物的吸收转运。因此,本文对P－gp介导的药物转运相互作用、药物对P－gp和MDR1基因表达的影响,以及与P－gp／MDR1基因表达相关的NF－κB和PXR信号通路的研究概况进行收集与探讨,以期从基因和蛋白水平上,为研究药物吸收转运特征的变化提供一定依据。