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41.
《Vaccine》2019,37(31):4382-4391
Cancer-associated fibroblasts (CAFs), major components of the tumor microenvironment (TME), promote tumor growth and metastasis and inhibit the anti-tumor immune response. We previously constructed a DNA vaccine expressing human FAPα, which is highly expressed by CAFs, to target these cells in the TME, and observed limited anti-tumor effects in the 4T1 breast cancer model. When the treatment time was delayed until tumor nodes formed, the anti-tumor effect of the vaccine completely disappeared. In this study, to improve the safety and efficacy, we constructed a new FAPα-targeted vaccine containing only the extracellular domain of human FAPα with a tissue plasminogen activator signal sequence for enhanced antigen secretion and immunogenicity. The number of CAFs was more effectively reduced by CD8+ T cells induced by the new vaccine. This resulted in decreases in CCL2 and CXCL12 expression, leading to a significant decrease in the ratio of myeloid-derived suppressor cells in the TME. Moreover, when mice were treated after the establishment of tumors, the vaccine could still delay tumor growth. To facilitate the future application of the vaccine in clinical trials, we further optimized the gene codons and reduced the homology between the vaccine and the original sequence, which may be convenient for evaluating the vaccine distribution in the human body. These results indicated that the new FAPα-targeted vaccine expressing an optimized secreted human FAPα induced enhanced anti-tumor activity by reducing the number of FAPα+ CAFs and enhancing the recruitment of effector T cells in the 4T1 tumor model mice. 相似文献
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43.
目的:探讨二补助育汤对胚胎着床障碍模型小鼠子宫内膜形态及血管生成素-1(Ang-1)mRNA、血管内皮生长因子(VEGF)mRNA的表达和定位的影响。方法:24只ICR雌性小鼠随机分为空白组、模型组、戊酸雌二醇组、二补助育汤组,每组6只,用米非司酮建立胚胎着床障碍动物模型,各组给予相应药物灌胃,妊娠第5天处死小鼠后,检测各组妊娠率、平均着床位点数、子宫内膜Ang-1和VEGF mRNA表达量及其蛋白定位。结果:模型组小鼠平均胚胎着床位点数、Ang-1 mRNA、VEGF mRNA表达量明显低于空白组(均P<0.05);与模型组比较,二补助育汤组平均胚胎着床位点数、Ang-1 mRNA、VEGF mRNA表达量显著提高(均P<0.05)。结论:二补助育汤可提高子宫内膜Ang-1和VEGF蛋白表达量,促进子宫内膜血管生成,从而提高子宫内膜容受性。 相似文献
44.
目的通过网络药理学的方法预测气滞胃痛颗粒抗炎镇痛主要活性成分的作用靶点,结合中医方解配伍理论对其多成分-多靶点-多通路的作用进行分析。方法基于TCMSP中药系统生物学分析数据库收集气滞胃痛颗粒中6味中药的主要化学成分,并借助LC-MS技术对所筛成分进行分析,通过TCMSP检索和Pharmmapper软件预测获取各成分主要的作用靶标,并通过DIP数据库,利用蛋白质相互作用信息建立药物靶标与炎症疼痛靶标的关联,构建药物-靶标-疾病网络,通过网络特征分析气滞胃痛颗粒抗炎镇痛的作用靶标,阐释其抗炎镇痛的主要作用机制。结果根据网络分析,共有44个炎症疼痛靶点与气滞胃痛颗粒密切相关,其中直接作用靶点有20个,主要是对环加氧酶-2(COX-2)和诱导型一氧化氮合酶(i NOS)等蛋白酶的作用,作用机制可能与调节肿瘤坏死因子(TNF)信号通路、NOD样受体(NLR)信号通路、血管内皮生长因子(VEGF)信号通路等与炎症疼痛密切相关的信号通路有关。结论气滞胃痛颗粒抗炎镇痛作用体现了中药多成分、多靶点、多途径的作用特点,该研究为深入阐释气滞胃痛颗粒抗炎镇痛作用机制提供科学依据,并且进一步说明了中医药古方配伍理论的科学性。 相似文献
45.
46.
Peng Cheng Linlin Yang Xiaodan Huang Xuejun Wang Maoqing Gong 《Archiv der Pharmazie》2020,353(4):1900350
Malaria, one of the most striking, re-emerging infectious diseases caused by the genus Plasmodium, places a huge burden on global healthcare systems. A major challenge in the control and eradication of malaria is the continuous emergence of increasingly widespread drug-resistant malaria, creating an urgent need to develop novel antimalarial agents. Chalcone derivatives are ubiquitous in nature and have become indispensable units in medicinal chemistry applications due to their diverse biological profiles. Many chalcone derivatives demonstrate potential in vitro and in vivo antimalarial activity, so chalcone could be a useful template for the development of novel antimalarial agents. This review covers the recent development of chalcone hybrids as antimalarial agents. The critical aspects of the design and structure–activity relationship of these compounds are also discussed. 相似文献
47.
尿毒清颗粒治疗慢性肾功能衰竭临床研究 总被引:1,自引:0,他引:1
目的:观察尿毒清颗粒治疗慢性肾功能衰竭(CRF)的临床疗效及其对钙磷代谢、结缔组织生长因子(CTGF)的影响。方法:选取120例CRF患者,按随机数字表法分为对照组和观察组各60例。对照组采用常规治疗,包括控制饮食、纠正酸碱、水电解质平衡;观察组在对照组的基础上加用尿毒清颗粒治疗。2组均连续治疗2个月,观察比较2组肾功能[肌酐(SCr)、血尿素氮(BUN)]、血磷(P3-)、血钙(Ca2+)、甲状旁腺激素(PTH)、CTGF指标水平变化,并评定2组临床疗效及不良反应情况。结果:观察组总有效率为80.00%,对照组为61.67%,2组比较,差异有统计学意义(P<0.05)。治疗后,2组SCr、BUN水平均较治疗前降低(P<0.05),且观察组SCr、BUN水平均低于对照组(P<0.05)。治疗后,2组PTH、CTGF、P3-水平较治疗前降低(P<0.05),Ca2+水平较治疗前升高(P<0.05);观察组PTH、P3-、CTGF水平均低于对照组(P<0.05),Ca2+水平高于对照组(P<0.05)。观察组不良反应发生率为3.33%,对照组为16.67%,2组比较,差异有统计学意义(P<0.05)。结论:尿毒清颗粒治疗CRF临床疗效显著,可有效调节钙磷代谢、CTGF平衡,改善肾功能,且安全性较高。 相似文献
48.
Extensive research has indicated that miRNAs are crucial for the occurrence and progression of cancers. miR-451a, involved in breast cancer (BC), is one of the miRNAs. This study focused on the mechanism by which miR-451a regulates BC. The levels of miR-451a in BC tissues and cell lines were examined using quantitative real-time polymerase chain reaction (qRT-PCR). Kaplan‒Meier analysis showed that this was intimately related to the patient's overall survival rate. Functional experiments revealed the negative effects of miR-451a on the abilities of BC cells to multiply (tested by Cell Counting Kit-8), migrate (tested by wound healing assay), and invade (tested by Transwell assay) and its positive effects on apoptosis (tested by flow cytometry). Western blotting indicated that the expression of tumor-related proteins was affected by miR-451a. Moreover, in vivo experiments suggested that tumor growth was clearly restrained by an miR-451a agonist in a xenograft tumor model. Bioinformatic analysis indicated that miR-451a directly targeted Cyclin D2 (CCND2), as demonstrated by the luciferase reporter assay. An opposite change in the level of CCND2 and miR-451a in BC was indicated by qRT-PCR, western blotting, and immunohistochemistry. Subsequently, functional experiments and western blotting analysis confirmed that CCND2 accelerated BC progression, which was regulated by miR-451a. Cumulatively, research on miR-451a may be valuable for BC treatment. 相似文献
49.
The baroreflex is a critical physiological mechanism controlling cardiovascular function by modulating both the sympathetic and parasympathetic activities. Here, we report that electrical activation of the baroreflex attenuates joint inflammation in experimental arthritis induced by the administration of zymosan into the femorotibial cavity. Baroreflex activation combined with lumbar sympathectomy, adrenalectomy, celiac subdiaphragmatic vagotomy or splenectomy dissected the mechanisms involved in the inflammatory modulation, highlighting the role played by sympathetic inhibition in the attenuation of joint inflammation. From the immunological standpoint, baroreflex activation attenuates neutrophil migration and the synovial levels of inflammatory cytokines including TNF, IL-1β and IL-6, but does not affect the levels of the anti-inflammatory cytokine IL-10. The anti-inflammatory effects of the baroreflex system are not mediated by IL-10, the vagus nerve, adrenal glands or the spleen, but by the inhibition of the sympathetic drive to the knee. These results reveal a novel physiological neuronal network controlling peripheral local inflammation. 相似文献
50.
《药学学报(英文版)》2020,10(7):1294-1308
A great challenge in multi-targeting drug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations. Inspired by our previous efforts in designing antitumor evodiamine derivatives, herein selective histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) dual inhibitors were successfully identified, which showed potent in vitro and in vivo antitumor potency. Particularly, compound 30a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model (TGI = 75.2%, 150 mg/kg, p.o.) without significant toxicity, which was more potent than HDAC inhibitor vorinostat, TOP inhibitor evodiamine and their combination. Taken together, this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents. 相似文献