A trip through the signaling pathways of melanoma

Many cellular signaling pathways are involved in the development of cancer. Depending on the tumor entity, the nature as well as the mode of activation can differ. Some signaling pathways frequently show changes as all tumor cells have to fulfill some basic requirements such as independence from growth factors or insensitivity against apoptosis. In this review, the possibilities of a tumor to manipulate signaling pathways to reach these goals are exemplified based on an archetypical melanoma cell. In addition, new therapeutic options based on the knowledge of signaling pathways will be discussed.     

核因子kB在大鼠胃缺血再灌注损伤中的表达及意义

目的研究核因子kB（NF-kB）在大鼠胃缺血再灌注损伤中的表达及意义。方法采用大鼠胃缺血再灌注（gustric ischemia/reperfusion, CI／R）模型（夹闭腹腔动脉30min后再灌注），分别于再灌注0．5、1、3、24h取胃，计算胃黏膜损伤指数。应用免疫组化、Western blot方法检测胃黏膜NF-kB p65。结果大鼠GUR后引起胃黏膜损伤，再灌注1h时损伤最明显，随后降低，24h接近正常。GI／R后胃黏膜NF—kB阳性细胞数和蛋白表达量增多，与胃黏膜损伤变化规律一致。结论NF-kB在大鼠CI／R损伤过程中发挥着重要作用。     

低分子肝素对缺血再灌注大鼠肾组织核因子-κB表达的影响

探讨低分子肝素对缺血再灌注大鼠肾组织核因子-κB（NF-κB）表达的影响。建立大鼠IRI模型，健康WistaI大鼠80只随机分为正常对照组、假手术组、模型未治疗组、LMWH治疗组，后两组又分别分为术后1、3、6、24h组。检测各组血清肌酐（Scr）水平及中性粒细胞（PMNs）细胞间黏附分子-1（ICAM-1）表达；通过光镜和免疫组织化学方法观察各组大鼠肾组织形态学及趋化因子NF-κB表达变化。结果表明：（1）肾缺血再灌注未治疗组造模后1h，Scr水平虽然没有明显变化，但ICAM-1、NF-κB表达增多，肾小管坏死积分值亦较假手术组明显增加（P〈0．01）；（2）缺血再灌注6h以后，两组Scr浓度明显增高（P〈0．01），但LMWH治疗组SCr、ICAM-1、NF-κB表达水平及肾小管坏死积分值均明显低于模型未治疗组（P〈0．05）；（3）肾组织中NF-κB表达与肾小管损伤积分值呈现良好的相关性（r=0．71，P〈0、01）；而NF-κB与ICAM-1间则呈现显著正相关（r=0．62，P〈0．05）。由此说明：（1）ICAM-1、NF-κB在肾缺血再灌注早期的瞬时表达，可能参与了炎症早期的白细胞迁移与浸润，与肾损伤的发生密切相关；（2）LMWH可通过减少ICAM-1及NF-κB的表达，阻抑炎症反应过程，减轻肾组织损伤。     

小白菊内酯抑制紫杉醇诱导的肿瘤细胞凋亡

目的　探讨NF κB在紫杉醇诱导肿瘤细胞凋亡中的作用及小白菊内酯对紫杉醇诱导凋亡的影响。方法　以人乳癌BCap37细胞和人表皮KB细胞为研究对象 ,用 5,1 0和 2 0 μmol·L-1 小白菊内酯预处理细胞 ,以DNA凋亡梯状条带、DNA含量、MTT、细胞甩片及电泳迁移率变动分析 (EMSA)法检测它对紫杉醇诱导细胞凋亡的影响并探索其作用靶点。结果　通过检测DNA凋亡梯状条带、DNA含量和细胞生存率 ,2 0μmol·L-1 小白菊内酯能显著抑制紫杉醇所诱导的BCap37和KB细胞凋亡 ,但不影响紫杉醇诱导肿瘤细胞G2 /M期阻滞。EMSA实验表明小白菊内酯能抑制紫杉醇诱导激活NF κB。结论　小白菊内酯通过抑制NF κB的激活来抑制紫杉醇所诱导的肿瘤细胞凋亡 ,而紫杉醇诱导肿瘤细胞凋亡的过程可能与G2 /M期阻滞无关     

Effects of Simvastatin on NF-kB-DNA Binding Activity and Monocyte Chemoattractant Protein-1 Expression in a Rabbit Model of Atherosclerosis

To observe the effects of simvastatin on nuclear factor kappaB （NF-kB）-DNA binding activity and on the expression of monocyte chemoattractant protein-1 （MCP-1） in atherosclerotic plaque in rabbits and to explore the anti-atherosclerotic properties beyond its lipid-lowering effects. Thirty-six New Zealand male rabbits were randomly divided into low-cholesterol group （LC）, high- cholesterol group （HC）, high-cholesterol＋ simvastatin group （HC＋S） and then were fed for 12 weeks. At the end of the experiment, standard enzymatic assays, electrophoretic mobility shift as- say （EMSA）, immunohistochemical staining, and morphometry were performed to observe serum lipids, NF-kB-DNA binding activity, MCP-1 protein expression, intirna thickness and plaque area of aorta respectively in all three groups. Our results showed that the serum lipids, NF-kB-DNA binding activity, expression of MCP-1 protein, intima thickness, and plaque area of aorta in the LC and HC＋S groups were significantly lower than those in the HC group （P〈0.05）. There was no significant difference in the serum lipids between the LC and HC＋S groups （P〉0.05）, but the NF-kB-DNA binding activity, the expression of MCP-1 protein and the intirna thickness and plaque area of aorta in the HC＋S group were significantly decreased as compared to the LC group （P〈0. 05）. This study demonstrated that simvastatin could decrease atherosclerosis by inhibiting the NF-kB-DNA binding activity and by reducing the expression of MCP-1 protein.     

Attenuation of diabetic nephropathy by Chaihuang-Yishen granule through anti-inflammatory mechanism in streptozotocin-induced rat model of diabetics

Ethnopharmacological relevance

Traditional Chinese medical herbs have been used in China for a long time to treat different diseases. Based on traditional Chinese medicine (TCM) principle, Chaihuang-Yishen granule (CHYS) was developed and has been employed clinically to treat chronic kidney disease including diabetic nephropathy (DN). The present study was designed to investigate its mechanism of action in treatment of DN.

Materials and methods

Diabetic rats were established by having a right uninephrectomy plus a single intraperitoneal injection of STZ. Rats were divided into four groups of sham, diabetes, diabetes with CHYS and diabetes with fosinopril. CHYS and fosinopril were given to rats by gavage for 20 weeks. Samples from blood, urine and kidney were collected for biochemical, histological, immunohistochemical and molecular analyses.

Results

Rats treated with CHYS showed reduced 24 h urinary protein excretion, decreased serum TC and TG levels, but CHYS treatment did not affect blood glucose level. Glomerular mesangial expansion and tubulointerstitial fibrosis in diabetic rats were significantly alleviated by CHYS treatment. Moreover, CHYS administration markedly reduced mRNA levels of NF-κB p65 and TGF-β1, as well as decreased protein levels of NF-κB p65, MCP-1, TNF-α and TGF-β1 in the kidney of diabetic rats.

Conclusions

CHYS ameliorates renal injury in diabetic rats through reduction of inflammatory cytokines and their intracellular signaling.     

右旋美托咪啶对围术期炎症介质及外周血单核细胞NF-κB的影响

目的探讨右旋美托咪啶的抗炎作用及其对外周血单核细胞NF-κB活性的影响。方法选择20~70岁ASAⅠ~Ⅱ行择期腰椎手术病人60例,随机分为右旋美托咪啶对照组（Ⅰ组）、0.5 μg组（Ⅱ组）、1.0 μg组（Ⅲ组）。选择气管内插管全身麻醉,分别于麻醉诱导后手术开始前（T1）、手术结束前半小时（T2）、术后24 h（T3）抽取静脉血,用ELISA法测定血浆中的IL-6、TNF-α的浓度,用流式细胞仪测量外周血单核细胞NF-κB活性的表达。结果三组患者术中芬太尼用量Ⅰ组（0.90±0.72）mg,Ⅱ组（0.71±0.58）mg,Ⅲ组（0.65±0.05）mg,瑞芬太尼用量Ⅰ组（1.35±0.80）mg,Ⅱ组（1.15±0.74） mg,Ⅲ组（1.02±0.70） mg和术后镇痛芬太尼使用剂量Ⅰ组（0.98±0.37）mg,Ⅱ组（0.84±0.19）mg,Ⅲ组（0.55±0.16）mg的差异具有统计学意义（P〈0.05）,三组患者血浆IL-6、TNF-α以及外周血单核细胞NF-κB的活性组间差异无统计学意义（P〉0.05）。结论在行腰椎手术的麻醉中使用右旋美托咪啶可以减少阿片类药物用量。右旋美托咪啶定可以作为腰椎手术的麻醉的辅助药。右旋美托咪啶对IL-6、TNF-α以及外周血单核细胞NF-κB的表达没有明显影响。     

Effect of Qingre Quyu Granule (清热祛瘀颗粒) on stabilizing plaques in the brachiocephalic artery of apolipoprotein E deficient mice

Objective： To investigate the effect of Qingre Quyu Granule （清热祛瘀颗粒, QRQYG） on stabilizing vulnerable plaques in apolipoprotein E （ApoE） defficient mice. Methods： Seventy-two male ApoE defficient mice were given a high-fat diet from 6 weeks of age. At the 16th week, all the mice were randomized into 3 groups： the QRQYG group, the simvastatin group, and the control group. Sixteen weeks after administration of 0.9 g/kg QRQYG, 3 mg/kg simvastatin or 10 mg/kg sodium chloride per day to the respective groups, the animals were euthanized. The pathological morphologic changes in the vulnerable plaques were evaluated, the matrix metalloprotease-9 （MMP-9） expression was measured by immunohistofluorescence, the soluble intercellular adhesion molecule 1 （ICAM-1） was determined by ELISA, the nuclear factor kappaB （NF-κB） subunit p65 was measured by quantitative RT-PCR, and, finally, thrombospondin-1 （TSP-1） was determined by the immunohistochemical method. Results： The plaque cross-sectional area in the brachiocephalic artery （23.7%, P0.01）, the lipid core of the plaque （43.1%±3.1%）, and the number of buried ？brotic caps of the plaque were significantly decreased in the QRQYG group compared to the control group （both P0.01）; furthermore, the thickness of the ？brotic cap of the plaque increased and the intra-plaque hemorrhage of the plaque decreased. The serum soluble ICAM-1 （27.1±5.1 μg/mL）, the protein expression of MMP-9 and TSP-1 and the p65 mRNA expression increased in the QRQYG group in comparison with the control group （P0.05 or P0.01）. Conclusion： QRQYG could stabilize the vulnerable plaque through inhibition of the inflammatory response.     

NF-κB p50和VEGF在弥漫性大B细胞淋巴瘤组织中的表达及其临床意义

目的：探讨弥漫性大B细胞淋巴瘤（DLBCL）组织中NF-κB p50、VEGF和MVD的表达及其临床意义。方法：应用免疫组化SP法对62例DLBCL组织和10例反应增生淋巴结组织中NF-κB p50、VEGF及MVD进行检测。结果：62例DLBCL组织中NF-κBp50阳性表达率为63%（39/62）,VEGF阳性表达率为68%（42/62）,二者在反应增生淋巴结组织中都不表达。NF-κB p50的表达与病理类型和治疗反应有关（P〈0.05）。VEGF和MVD的表达与IPI、LDH值、肿瘤分期、病理类型和治疗反应有关（P〈0.05）。NF-κB p50,VEGF阳性表达组的MVD值明显高于阴性组。NF-κB p50的表达与VEGF的表达呈正相关（r=0.285,P=0.025）。结论：NF-κB p50对VEGF表达有正向调节作用,在DLBCL的发生和发展中起着重要的作用。