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目的:研究Toll样受体4(TLR4) mRNA及其下游炎性因子肿瘤坏死因子-α(TNF-α)与肝衰竭肠源性内毒素血症(IETM)大鼠肝细胞凋亡的关系,并探索温阳解毒化瘀颗粒对内毒素介导的肝细胞凋亡的调控机制。方法:SPF级雄性SD大鼠85只,随机分为正常组,模型组,TLR4单克隆抗体组和温阳解毒化瘀颗粒组(8.925 g·kg^-1)。采用D-半乳糖胺(D-Gal)腹腔注射建立肝衰竭IETM模型,TLR4单克隆抗体组和温阳解毒化瘀颗粒组在造模前5 d给予温阳解毒化瘀颗粒溶液灌胃,正常组、模型组以等容积蒸馏水代替,直至处死。各组分别在24,48,72 h随机处死大鼠并采集标本。检测24,48,72 h各组时间点血清丙氨酸氨基转移酶(ALT),天门冬氨酸氨基转移酶(AST)水平,苏木素-伊红(HE)染色观察肝组织病理变化,实时荧光定量聚合酶链式反应(Real-time PCR)检测肝组织TLR4 mRNA表达,酶联免疫吸附测定法(ELISA)检测肝组织TNF-α表达,流式细胞仪检测肝细胞凋亡率。结果:与正常组比较,模型组ALT,AST升高,肝组织病理损伤程度明显加重,TLR4mRNA,TNF-α表达均增高(P<0.05,P<0.01),肝细胞凋亡率明显上升(P<0.05,P<0.01);与模型组比较,温阳解毒化瘀颗粒组ALT,AST显著降低(P<0.01),肝组织病理损伤程度明显减轻(P<0.05),TLR4 mRNA,TNF-α表达显著下降(P<0.01),肝细胞凋亡率亦显著降低(P<0.01)。结论:TLR4 mRNA,TNF-α在肝衰竭时与肝细胞凋亡呈正相关,温阳解毒化瘀颗粒能够改善肝衰竭IETM大鼠肝功能,减轻肝细胞损伤,减少肝细胞凋亡,其机制可能与其下调肝脏TLR4 mRNA表达,抑制TNF-α释放,降低肝细胞凋亡率有关。  相似文献   
3.
肠道微生态系统由定植于肠道的固有菌群、肠上皮细胞、肠黏膜免疫系统组成。非酒精性脂肪性肝病(NAFLD)是一种与胰岛素抵抗和遗传易感性相关的代谢应激性肝损伤。近年来关于肠道微生态与NAFLD发病机制关系的研究越来越多。肠道微生态失衡导致的肠道菌群过度生长、肠黏膜通透性增加、肠源性内毒素血症、炎症因子产生等在NAFLD的发生发展过程中扮演着重要的角色。深入研究肠道微生态失衡与NAFLD的关系将有助于为NAFLD的治疗及预防提供新方向。  相似文献   
4.
Similar to IL-1α and IL-33, IL-1 family member IL-37b translocates to the nucleus and is associated with suppression of innate and adaptive immunity. Here we demonstrate an extracellular function of the IL-37 precursor and a processed form. Recombinant IL-37 precursor reduced LPS-induced IL-6 by 50% (P < 0.001) in highly inflammatory human blood-derived M1 differentiated macrophages derived from selective subjects but not M2 macrophages. In contrast, a neutralizing monoclonal anti–IL-37 increased LPS-induced IL-6, TNFα and IL-1β (P < 0.01). The suppression by IL-37 was consistently observed at low picomolar but not nanomolar concentrations. Whereas LPS induced a 12-fold increase in TNFα mRNA, IL-37 pretreatment decreased the expression to only 3-fold over background (P < 0.01). Mechanistically, LPS-induced p38 and pERK were reduced by IL-37. Recombinant IL-37 bound to the immobilized ligand binding α-chain of the IL-18 receptor as well as to the decoy receptor IL-1R8. In M1 macrophages, LPS increased the surface expression of IL-1R8. Compared with human blood monocytes, resting M1 cells express more surface IL-1R8 as well as total IL-1R8; there was a 16-fold increase in IL-1R8 mRNA levels when pretreated with IL-37. IL-37 reduced LPS-induced TNFα and IL-6 by 50–55% in mouse bone marrow-derived dendritic cells, but not in dendritic cells derived from IL-1R8–deficient mice. In mice subjected to systemic LPS-induced inflammation, pretreatment with IL-37 reduced circulating and organ cytokine levels. Thus, in addition to a nuclear function, IL-37 acts as an extracellular cytokine by binding to the IL-18 receptor but using the IL-1R8 for its anti-inflammatory properties.IL-37, previously known as IL-1 family member 7, broadly reduces innate inflammation as well as acquired immune responses (1). In human peripheral blood mononuclear cells (PBMCs), a knockdown of endogenous IL-37 results in increased production of LPS- as well as IL-1β–induced cytokines (2). Mice transgenic for full-length human IL-37 (IL-37tg) are protected against LPS-induced systemic inflammation (2), chemical colitis (3), metabolic syndrome (4), and acute myocardial infarction (5). IL-37tg mice also have suppressed immune responses following challenge by specific antigen (6). We believe that full-length IL-37 expressed in the transgenic mice is processed extracellularly.In mouse macrophages stably transfected with human IL-37, ∼20% of IL-37 translocates to the nucleus (7), which is associated with decreased cytokine production (2, 7). However, in the presence of a caspase-1 inhibitor, there is no translocation to the nucleus and no reduction in LPS-induced cytokines (7). Mutation of aspartic acid at the caspase-1 cleavage position 20 to alanine also results in failure to translocate to the nucleus and loss of the suppression of cytokine production (8). Thus, as with IL-1α and IL-33, IL-37 is the third member of the IL-1 family that translocates to the nucleus and affects cellular responses. Nevertheless, it remains unclear whether the reduction in cytokines in vitro or in vivo is due solely to nuclear translocation of IL-37.Support for an extracellular function for IL-37 comes from early studies reported over 10 y ago that demonstrated binding of IL-37 to the α-chain of IL-18 receptor (IL-18Rα). We therefore hypothesized that extracellular IL-37 can function through the IL-18Rα surface receptor to mediate its anti-inflammatory effects but that a negative or decoy receptor would be required. The candidate decoy receptor would likely be IL-1R8 [formerly, single IgG IL-1–related receptor (SIGIRR)] because, similar to IL-18BP, IL-1R8 has only a single Ig domain and is known for providing a brake on inflammation (9). In the present study, we have characterized the function of full-length recombinant IL-37b in inhibiting inflammation in vitro and in vivo and the role of IL-1R8.  相似文献   
5.
目的:通过观察阳明病(阳明腑实证)模型大鼠"欲解时"血常规及肠黏膜上有关炎症因子的变化,初步探讨阳明病"欲解时"的病理生理学基础。方法:实验大鼠随机分为欲解时对照组、欲解时模型组、非欲解时对照组、非欲解时模型组,建立阳明腑实证大鼠模型后,分别于阳明病"欲解时"及"非欲解时"每天取血及肠组织,连续5d,血细胞分析仪检测血常规,免疫组化法测Toll样受体4(TLR4)蛋白含量,荧光实时定量聚合酶链反应(PCR)检测肠组织TLR4 mRNA水平。结果:欲解时模型组大鼠白细胞、中性粒细胞、单核细胞数较非欲解时模型组升高,其中单核细胞数上升差异有统计学意义(P<0.05);模型组淋巴细胞显著低于对照组(P<0.05)。欲解时模型组TLR4 mRNA及蛋白较非欲解时模型组显著降低,第1天TLR4 mRNA相对表达量差异有统计学意义(P<0.05)。结论:阳明腑实证病程中,欲解时模型组大鼠中性粒及淋巴细胞较对照组体现出较早较长时间的差异性,意味着欲解时的免疫反应更为明显。通过TLR4检测表明欲解时阳明腑实证的炎症反应较非欲解时轻,可能与其表达下调相关炎性介质的释放减少有关。  相似文献   
6.
Background and aimsFollowing an infection, cytokines not only regulate the acute immune response, but also contribute to symptoms such as inflammatory hyperalgesia. We aimed to characterize the acute inflammatory response induced by a human endotoxemia model, and its effect on pain perception using evoked pain tests in two different dose levels. We also attempted to determine whether combining a human endotoxemia challenge with measurement of pain thresholds in healthy subjects could serve as a model to study drug effects on inflammatory pain.Methods and resultsThis was a placebo-controlled, randomized, cross-over study in 24 healthy males. Twelve subjects were administered a bolus of 1 ng/kg LPS intravenously, and twelve 2 ng/kg LPS. Before days of placebo/LPS administration, subjects completed a full study day without study drug administration, but with identical pain threshold testing. Blood sampling and evoked pain tests (electrical burst and -stair, heat, pressure, and cold pressor test) were performed pre-dose and at frequent intervals up to 10hr post-dose. Data were analysed with a repeated-measures ANCOVA. For both dose levels, LPS induced an evident acute inflammatory response, but did not significantly affect any of the pain modalities. In a post-hoc analysis, lowering of pain thresholds was observed in the first 3 h after dosing, corresponding with the peak of the acute inflammatory response around 1–3 h post-dose.ConclusionMild acute systemic inflammation, as induced by 1 ng/kg and 2 ng/kg LPS intravenous administration, did not significantly change pain thresholds in this study. The endotoxemia model in combination with evoked pain tests is not suitable to study acute inflammatory hyperalgesia in healthy males.  相似文献   
7.
目的:分析内毒素又称脂多糖(lipopolysaccharide, LPS)血症大鼠心肌组织miRNA表达谱变化,探讨miRNA在内毒素血症心肌损伤中的作用。方法20只雄性SD大鼠随机分为对照组(n=10)和LPS组(n=10)。LPS组腹腔注射LPS 10 mg/kg,对照组腹腔注射等量生理盐水。24 h后颈脱臼处死大鼠,取心肌组织。Real-time PCR检测TLR4、TNF-α、IL-1β表达水平,透射电镜观察其超微结构变化。miRNA芯片筛选心肌组织中差异表达的miRNA,Real-time PCR验证候选miRNA实际表达水平。结果 LPS组大鼠心肌组织TLR4、TNF-α、IL-1β表达明显升高,心肌细胞发生胞质空泡,线粒体水肿、结构破坏等超微结构改变。芯片技术及Real-time PCR证实LPS组大鼠心肌组织中miR-194-3p,miR-344a-3p,miR-465-3p,miR-501-5p,miR-3596c,miR-185-3p,miR-877显著上调,miR-208b-3p,miR-547-3p,miR-141-3p,miR-28-5p,miR-3585-5p显著下调。结论内毒素血症大鼠心肌组织中发现的这些差异表达miRNA可能与其心肌损伤发生有关。  相似文献   
8.
摘要:目的探究水飞蓟宾(SIL)对小鼠内毒素血症心肌损伤的保护作用和分子机制。方法24只C57BL/6小鼠分为对照(Control)组、SIL组、LPS组、LPS+SIL组,每组6只。通过腹腔注射脂多糖(LPS,10 mg/kg)制备内毒素血症心肌损伤小鼠模型。LPS注射前3 d,SIL组和LPS+SIL组每日通过灌胃方式给予SIL(100 mg/kg),共给药3次;Control组和LPS组每日通过灌胃方式给予等量(0.2 mL)生理盐水,共灌胃3次。LPS注射6 h后超声检测各组小鼠心脏收缩功能;ELISA检测血清IL-1β和TNF-α表达水平;DHE染色观察各组小鼠心肌组织内活性氧(ROS)产量;TUNEL染色检测心肌凋亡率;Western blot检测凋亡相关蛋白Bax、Bcl-2、Caspase 3和NOX2表达。结果与Control组相比,LPS组小鼠左心室射血分数、左心室短轴缩短率和Bcl-2表达量明显降低,而ROS产量、NOX2、Bax、Caspase 3、IL-1β与TNF-α表达量以及心肌凋亡率明显增加(P<0.05)。与LPS组相比,LPS+SIL组经水飞蓟宾预处理后可明显改善LPS引起的上述改变(P<0.05)。与Control组相比,单纯给予SIL干预对上述指标的变化无明显影响(P>0.05)。结论水飞蓟宾可有效缓解内毒素血症心肌损伤,其作用可能与抑制氧化应激、炎症反应和抗凋亡有关。  相似文献   
9.
Dietary fat strongly affects human health by modulating gut microbiota composition and low-grade systemic inflammation. High-fat diets have been implicated in reduced gut microbiota richness, increased Firmicutes to Bacteroidetes ratio, and several changes at family, genus and species levels. Saturated (SFA), monounsaturated (MUFA), polyunsaturated (PUFA) and conjugated linolenic fatty acids share important pathways of immune system activation/inhibition with gut microbes, modulating obesogenic and proinflammatory profiles. Mechanisms that link dietary fat, gut microbiota and obesity are mediated by increased intestinal permeability, systemic endotoxemia, and the activity of the endocannabinoid system. Although the probiotic therapy could be a complementary strategy to improve gut microbiota composition, it did not show permanent effects to treat fat-induced dysbiosis. Based upon evidence to date, we believe that high-fat diets and SFA consumption should be avoided, and MUFA and omega-3 PUFA intake should be encouraged in order to regulate gut microbiota and inflammation, promoting body weight/fat control.  相似文献   
10.
目的:研究温阳解毒化瘀颗粒对肠源性内毒素血症( IETM )模型大鼠结肠黏膜上皮紧密连接的影响,探索其抗肝衰竭的作用机制。方法:将大鼠随机分为正常组、模型组、温阳解毒化瘀颗粒(实验组)和对照组4组,采用D-半乳糖胺(D-gal)腹腔注射致肝衰竭ITEM大鼠模型。正常组在腹腔注射生理盐水24h后处死,模型组、实验组、对照组分别于造模后24h、48h、72h各取6只、7只、7只大鼠处死,检测各组肝功能、内毒素、结肠黏膜上皮咬合蛋白(occludin)及肌球蛋白轻链激酶(MLCK)。结果:模型组血清ALT/AST、内毒素、 MLCK表达水平均高于正常组, occludin表达低于模型组( P<0.01);实验组血清ALT/AST、内毒素、 MLCK表达水平均低于模型组, occlu-din表达高于模型组( P<0.05)。结论:增强结肠粘膜上皮紧密连接功能,降低内毒素的吸收是温阳解毒化瘀颗粒抗肝衰竭的作用机制之一。  相似文献   
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