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51.
目的 探讨不同时间、不同剂量N-亚硝基双-2-氧丙基(N-nitrosobis-2-oxopropylamin,BOP)诱导仓鼠胰腺癌的成模效果及仓鼠胰腺癌组织COX-2、5-LOX、GAL-1、GAL-3、MHC-Ⅰ、MHC-Ⅱ等基因表达的变化.方法 72只仓鼠按完全随机法分为3组,每组24只.A组采用小剂量BOP长周期皮下注射诱导造模(10 mg/kg体质量,每周1次,连续8周);B组采用大剂量BOP短周期皮下注射诱导造模(首次剂量70 mg/kg体质量,后3周每周20 mg/kg体质量);C组为未注射BOP的对照组.成模后取胰腺组织及肝脏组织行病理组织学检查.采用实时PCR法及蛋白质印迹法检测仓鼠胰腺癌组织COX-2、5-LOX、GAL-1、GAL-3、MHC-Ⅰ、MHC-Ⅱ等基因的表达.结果 A组仓鼠中19只成功诱导胰腺癌模型;B组均未见胰腺肿瘤形成,而18只仓鼠成功诱导肝内胆管细胞癌;C组胰腺及肝脏均未见异常.仓鼠胰腺癌组织COX-2、5-LOX、GAL-1、GAL-3、MHC-Ⅰ mRNA的表达量分别为对照组的1.93、2.03、1.57、5.55和3.54倍,差异有统计学意义(P值均<0.05);COX-2、5-LOX、GAL-1、GAL-3、MHC-Ⅰ蛋白的表达量分别为2.47 ±0.22、0.56 ±0.05、1.23 ±0.05、1.55 ±0.13、2.02 ±0.01,而对照组仓鼠正常胰腺组织的蛋白表达量分别为0.80±0.08、0.39 ±0.01、0.60 ±0.01、0.53 ±0.03、0.40 ±0.02,两组差异均有统计学意义(P值均<0.05).两组MHC-ⅡmRNA及蛋白表达的差异无统计学意义.结论 小剂量BOP长周期皮下注射能成功诱导仓鼠胰腺癌模型,胰腺癌组织的COX-2、5-LOX、GAL-1、GAL-3、MHC-Ⅰ基因表达上调,可能参与仓鼠胰腺癌的发生和发展. 相似文献
52.
Julie K. Klint Géza Berecki Thomas Durek Mehdi Mobli Oliver Knapp Glenn F. King David J. Adams Paul F. Alewood Lachlan D. Rash 《Biochemical pharmacology》2014
Spider venoms are replete with peptidic ion channel modulators, often with novel subtype selectivity, making them a rich source of pharmacological tools and drug leads. In a search for subtype-selective blockers of voltage-gated calcium (CaV) channels, we isolated and characterized a novel 39-residue peptide, ω-TRTX-Cc1a (Cc1a), from the venom of the tarantula Citharischius crawshayi (now Pelinobius muticus). Cc1a is 67% identical to the spider toxin ω-TRTX-Hg1a, an inhibitor of CaV2.3 channels. We assembled Cc1a using a combination of Boc solid-phase peptide synthesis and native chemical ligation. Oxidative folding yielded two stable, slowly interconverting isomers. Cc1a preferentially inhibited Ba2+ currents (IBa) mediated by L-type (CaV1.2 and CaV1.3) CaV channels heterologously expressed in Xenopus oocytes, with half-maximal inhibitory concentration (IC50) values of 825 nM and 2.24 μM, respectively. In rat dorsal root ganglion neurons, Cc1a inhibited IBa mediated by high voltage-activated CaV channels but did not affect low voltage-activated T-type CaV channels. Cc1a exhibited weak activity at NaV1.5 and NaV1.7 voltage-gated sodium (NaV) channels stably expressed in mammalian HEK or CHO cells, respectively. Experiments with modified Cc1a peptides, truncated at the N-terminus (ΔG1–E5) or C-terminus (ΔW35–V39), demonstrated that the N- and C-termini are important for voltage-gated ion channel modulation. We conclude that Cc1a represents a novel pharmacological tool for probing the structure and function of L-type CaV channels. 相似文献
53.
DPPE, a tamoxifen derivative with antihistamine activity, was previously shown to potentiate the toxicity of chemotherapeutic drugs. Recently, a Phase III clinical study using doxorubicin with DPPE demonstrated significant increase in the overall survival of breast cancer patients. In this study we examined the effects of DPPE alone on the growth of drug sensitive and P-gp positive CHO cell line. Our results demonstrate DPPE is selectively toxic to P-gp positive cells and the sensitivity to DPPE alone correlated with the levels of P-gp expression. Moreover, in MDR cells, DPPE-induced apoptosis was significantly reduced with Bcl2 overexpression and in the presence of P-gp ATPase inhibitor, PSC833. Furthermore, knockdown of P-gp expression in MDR cells with P-gp-siRNA reversed DPPE sensitivity and increased their sensitivity to doxorubicin and taxol but not to cisplatin. The addition of DPPE to membrane fractions led to dose-dependent increase in P-gp ATPase that was inhibited with PSC833. Moreover, incubation of P-gp positive cells with DPPE led to a significant increase in superoxide levels and a drop in cellular ATP and GSH pools that were reversible with inhibitors of P-gp ATPase. The combined presence of DPPE and the mitochondria electron transport complex III inhibitor, antimycin A, synergized in their effects on the growth of MDR cells but had no effect on the growth of parental drug sensitive cells. Collectively, the results of this study provide a possible mechanism that may be relevant to the clinical results of DPPE in breast cancer trial and demonstrates DPPE as P-gp collateral sensitivity drug. 相似文献
54.
Arturo Contis Montes de Oca Andrea Cruz Baquero Rafael Campos Rodríguez Luz María Cárdenas Jaramillo José Eduardo Aguayo Flores Saúl Rojas Hernández Alfonso Olivos García Judith Pacheco Yepez 《Parasite immunology》2020,42(6):e12714
The main effector mechanisms of neutrophils are the release of neutrophil extracellular traps (NETs) and myeloperoxidase (MPO). In this work, we evaluated the role of NETs and the activity of MPO in the interactions of rodent neutrophils with amoebae and in amoebic liver abscess (ALA)-resistant and ALA-susceptible models. We showed with in vitro assays that mice produced greater amounts of NETs and MPO than did hamsters, and the elastase activity was high in both models. However, the inhibition of NETs and MPO promoted an increase in amoeba viability in the mice. The mouse ALAs showed a more profound presence of NETs and MPO than did the hamster ALAs. We concluded that both effector mechanisms were essential for the amoebic damage and could prevent the formation of ALAs in the resistant model. 相似文献
55.
56.
Pharmacological activation of AMP activated kinase (AMPK) by metformin has proven to be a beneficial therapeutic approach for the treatment of type II diabetes. Despite improved glucose regulation achieved by administration of small molecule activators of AMPK, the potential negative impact of enhanced AMPK activity on insulin secretion by the pancreatic beta cell is an important consideration. In this review, we discuss our current understanding of the role of AMPK in central functions of the pancreatic beta cell, including glucose-stimulated insulin secretion (GSIS), proliferation, and survival. In addition we discuss the controversy surrounding the role of AMPK in insulin secretion, underscoring the merits and caveats of methods used to date. 相似文献
57.
58.
目的 探讨氯化汞(HgCl2)对金黄地鼠胚胎发育的影响.方法 实验组于妊娠第6天开始经口灌服不同浓度的氯化汞水溶液,连续灌服5d,对照组在同一时间经口灌服蒸馏水.于孕第14天处死取胎,计录活胎数、死胎数、吸收胎数、植入数、畸形数,对活胎逐个检查外观并称重,测量其顶臀长;用HE染色方法对第8,9,10天胎鼠神经管进行形态学观察.结果 与对照组比较,经口灌服2mg/kg体重的氯化汞水溶液,对金黄地鼠胚胎体重和顶臀长的影响无显著差异,3mg/kg体重和4mg/kg体重的氯化汞水溶液对金黄地鼠胚胎的发育有一定的抑制作用,随着氯化汞剂量的增加,体重相应降低,但各实验组均未发现胎鼠畸形,HE染色结果显示,神经管形态与对照组相比无显著差异.结论 氯化汞对金黄地鼠胚胎发育有一定抑制作用,未检测到各种畸形. 相似文献
59.
目的 研究硫芥对中国仓鼠肺成纤维细胞(Chinese hamster fibroblast cell line,CHL)DNA的损伤作用及还原型谷胱甘肽(reduced glutathione,GSH)的保护作用。方法 将CHL分为2组,均以10、100、1000μmol/L硫芥染毒,其中1组以10mmol/L的GSH加以保护,分别在不同时间点(即刻,6、24、48、72 h)收集细胞进行单细胞凝胶电泳(single cell gel electrophoresis assay,SCG)检测。结果 硫芥染毒组CHL的DNA迁移率和迁移度在染毒后6、24、48、72h均显著高于相应时刻的生理盐水组和溶剂对照组(P〈0.01)。GSH保护组DNA迁移率和迁移度亦显著增高(P〈0.01),但较之单纯硫芥染毒组DNA迁移率下降了13.0%-52.5%,迁移度亦显著下降。结论 硫芥对CHL的DNA有损伤作用,呈时间、剂量关系。GSH对DNA的损伤有一定保护作用。 相似文献
60.
Taiko Oda Weifang Wang Ayako Fujita Masataka Mochizuki Kazuyo Ukai Michio Namikoshi 《Journal of natural medicines》2007,61(4):434-437
An extract of a marine sponge, Hippospongia sp., collected in Palau has inhibitory activity against colony formation by Chinese hamster V79 cells. Bioassay-guided isolation
gave eleven sesquiterpene quinones. Compounds 1–8 inhibited colony formation by V79 cells with EC50 values between 0.6 and 2.8 μmol L−1. Their effects on the production of an inflammatory cytokine, IL-8, in tetradecanoyl phorbol acetate (PMA)-stimulated HL-60
cells were also investigated, because IL-8 production is sometimes correlated with inhibition of cell growth. Ilimaquinone
(1) and its 5 epimer (2) had similar activity against V79 cells (EC50 = 2.8 and 2.3 μmol L−1, respectively) but did not modulate IL-8 production even at 10 μmol L−1. Smenospongidine (3) and its 5 epimer (4), smenospongiarine (5) and its 5 epimer (6), and smenospongine (7) and its 5-epimer (8), at 10 μmol L−1, promoted IL-8 production. Compounds 3, 5, and 7 had slightly stronger activity against V79 cells (EC50 = 0.6, 1.7, and 0.8 μmol L−1, respectively) than the corresponding 5 epimers 4, 6, and 8 (EC50 = 0.8, 2.3, and 2.0 μmol L−1, respectively). A similar structure–activity relationship was observed for promotion of IL-8 production. This is the first
report of modulation of IL-8 production by these sesquiterpene quinones. 相似文献