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1.
Major depressive disorder and other neuropsychiatric disorders are often managed with long-term use of antidepressant medication. Fluoxetine, an SSRI antidepressant, is widely used as a first-line treatment for neuropsychiatric disorders. However, fluoxetine has also been shown to increase the risk of metabolic diseases such as non-alcoholic fatty liver disease. Fluoxetine has been shown to increase hepatic lipid accumulation in vivo and in vitro. In addition, fluoxetine has been shown to alter the production of prostaglandins which have also been implicated in the development of non-alcoholic fatty liver disease. The goal of this study was to assess the effect of fluoxetine exposure on the prostaglandin biosynthetic pathway and lipid accumulation in a hepatic cell line (H4-II-E-C3 cells). Fluoxetine treatment increased mRNA expression of prostaglandin biosynthetic enzymes (Ptgs1, Ptgs2, and Ptgds), PPAR gamma (Pparg), and PPAR gamma downstream targets involved in fatty acid uptake (Cd36, Fatp2, and Fatp5) as well as production of 15-deoxy-Δ12,14PGJ2 a PPAR gamma ligand. The effects of fluoxetine to induce lipid accumulation were attenuated with a PTGS1 specific inhibitor (SC-560), whereas inhibition of PTGS2 had no effect. Moreover, SC-560 attenuated 15-deoxy-Δ12,14PGJ2 production and expression of PPAR gamma downstream target genes. Taken together these results suggest that fluoxetine-induced lipid abnormalities appear to be mediated via PTGS1 and its downstream product 15d-PGJ2 and suggest a novel therapeutic target to prevent some of the adverse effects of fluoxetine treatment.  相似文献   
2.
ObjectiveTo investigate the relationship between peroxisome proliferator-activated receptor gamma (PPARγ) mRNA, serum adiponectin (ADP) and lipids in paediatric patients with Kawasaki disease (KD).MethodsThis prospective study enrolled paediatric patients with KD and grouped them according to the presence or absence of coronary artery lesions (CAL). A group of healthy age-matched children were recruited as the control group. The levels of PPARγ mRNA, serum ADP and lipids were compared between the groups. Receiver operating characteristic (ROC) curve analysis was undertaken to determine if the PPARγ mRNA level could be used as a predictive biomarker of CAL prognosis.ResultsThe study enrolled 42 patients with KD (18 with CAL [CAL group] and 24 without CAL [NCAL group]) and 20 age-matched controls. PPARγ mRNA levels in patients with KD were significantly higher than those in the controls; but significantly lower in the CAL group than the NCAL group. ROC curve analysis demonstrated that the PPARγ mRNA level provided good predictive accuracy for the prognosis of CAL. There was no association between PPARγ, ADP and lipid levels.ConclusionThere was dyslipidaemia in children with KD, but there was no correlation with PPARγ and ADP. PPARγ may be a predictor of CAL in patients with KD with good predictive accuracy.  相似文献   
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Frontal fibrosing alopecia (FFA) is a primary patterned cicatricial alopecia with a complicated pathogenesis yet to be fully understood. FFA appears to be increasing in incidence worldwide, especially in the last decade. In order to consider current treatment options, we reviewed current evidence for its pathogenesis comprising immune-mediated, genetic, hormonal and environmental factors. Th1-mediated inflammation with collapse of hair follicle immune privilege and bulge epithelial stem cell destruction, peroxisome proliferator-activated receptor gamma (PPAR-γ) depletion and epithelial–mesenchymal transition are key events leading to permanent hair follicle destruction in FFA. Although the vast majority of cases are sporadic, familial reports of FFA implicate genetic or epigenetic mechanisms in its pathogenesis. The frequent onset of FFA in post-menopausal women, similar patterning and co-existence with female pattern hair loss, together with a reportedly good response to 5α-reductase inhibitors suggest a role for sex steroid hormones. The reported increasing incidence invites speculation for, yet unproven, environmental triggers such as sun exposure and topical allergens. More robust research into this unique entity is required to help understand the complexity of the pathogenesis of FFA in order to find satisfactory therapeutic targets for this often distressing condition.  相似文献   
5.
Atherosclerosis (AS) is a chronic inflammatory disease of the arterial wall. Macrophages are considered to be closely associated with the development and progression of AS. However, the precise mechanism of miR-17-5p in the macrophages under AS remains incompletely clarified. This study investigated the regulatory effect of miR-17-5p on the inflammation and lipid accumulation in mouse macrophages both in vivo and in vitro. It was found that miR-17-5p was highly expressed with lowered ATP-binding cassette transporterA1 (ABCA1) level in the peripheral blood leucocytes (PBLs) of AS patients. Moreover, the level of miR-17-5p was up-regulated in the macrophages of ApoE?/? mice fed with a high-cholesterol diet. Furthermore, we injected miR-17-5p antagomir into AS mice or transfected miR-17-5p inhibitors into mouse macrophage RAW264.7 cells. Results showed that downregulation of miR-17-5p significantly reduced the production of inflammatory cytokines, inhibited the lipid accumulation and up-regulated ABCA1, and activated peroxisome proliferator-activated receptor (PPAR) γ/Liver X receptor (LXR) α signaling pathway. Additionally, ABCA1 was found to be a target of miR-17-5p by directly binding to 3′-untranslated region (3′-UTR) of its mRNA. Our study indicates a novel regulatory mechanism for miR-17-5p by interacting with ABCA1, which could be a therapy-target for the treatment of AS.  相似文献   
6.
ObjectiveTo evaluate the association between bezafibrate, a drug used to treat hypertriglyceridemia, and long-term cancer incidence in patients with coronary artery disease (CAD).Patients and MethodsThe study comprised 2980 patients with CAD (mean age, 60 years; 2729 [91.6%] men) who were free of cancer and were enrolled in the Bezafibrate Infarction Prevention study, a double-blind trial conducted between May 1, 1990, and January 31, 1993, in 18 cardiology departments in Israel. Patients randomized to receive 400 mg of bezafibrate (n=1486) or placebo (n=1494) daily for a median of 6.2 years (range, 4.7-7.6 years) were followed up for incidence of cancer through the Israeli National Cancer Registry and all-cause death through the Population Registry of the State of Israel until December 31, 2013. Cox proportional hazards and Fine and Gray survival models were used to assess the bezafibrate-cancer association.ResultsClinical characteristics and laboratory values were well balanced between the 2 groups at the study entry. Over a median follow-up of 22.5 years (range, 21.2-23.9 years), cancer developed in 753 patients. With death considered a competing event, the cumulative incidence of cancer at the end of the follow-up was lower in the bezafibrate vs the placebo group (23.9%; 95 CI, 21.9%-26.1% vs 27.2%; 95 CI, 25.1%-29.4%; P=.04). The hazard ratio for cancer in the bezafibrate vs placebo groups was 0.86 (95% CI, 0.74-0.99). In mediation analysis, the association between bezafibrate treatment and cancer incidence was not sensitive to adjustment for on-trial lipid levels but was attenuated on adjustment for on-trial fibrinogen levels.ConclusionBezafibrate treatment is associated with reduced risk of cancer among patients with CAD. Fibrinogen, but not lipid lowering, is linked to this association.  相似文献   
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过氧化物酶体增殖物受体(PPARs)是细胞能量代谢的主要调节因子,PPARs的3种亚型在多种肿瘤细胞中具有不同的转录活性与效应,能量代谢稳态对细胞的命运至关重要,关于肿瘤的能量代谢一直是热点问题。所有细胞活动都强烈依赖于分解代谢和合成代谢途径之间的平衡,破坏能量平衡和微环境,将表现出一系列的代谢改变包括葡萄糖消耗增加,线粒体呼吸的减少,细胞死亡抗性增强,所有这些都是癌症进展的原因。了解癌症中的代谢过程和阐明PPARs的调控机制会产生新的治疗策略。  相似文献   
9.
Early stage localized prostate cancer (PCa) has an excellent prognosis; however, patient survival drops dramatically when PCa metastasizes. The molecular mechanisms underlying PCa metastasis are complex and remain unclear. Here, we examine the role of a new member of the fatty acid‐binding protein (FABP) family, FABP12, in PCa progression. FABP12 is preferentially amplified and/or overexpressed in metastatic compared to primary tumors from both PCa patients and xenograft animal models. We show that FABP12 concurrently triggers metastatic phenotypes (induced epithelial‐to‐mesenchymal transition (EMT) leading to increased cell motility and invasion) and lipid bioenergetics (increased fatty acid uptake and accumulation, increased ATP production from fatty acid β‐oxidation) in PCa cells, supporting increased reliance on fatty acids for energy production. Mechanistically, we show that FABP12 is a driver of PPARγ activation which, in turn, regulates FABP12''s role in lipid metabolism and PCa progression. Our results point to a novel role for a FABP‐PPAR pathway in promoting PCa metastasis through induction of EMT and lipid bioenergetics.

Abbreviations

AR
androgen receptor
ATP
adenosine triphosphate
CN
copy number
CPT1
carnitine palmitoyltransferase I
CS
citrate synthase
EMT
epithelial–mesenchymal transition
ET
electron transfer‐state
FABP
fatty acid‐binding protein
LD
lipid droplet
OA
oleic acid
PCa
prostate cancer
PPAR
peroxisome proliferator‐activated receptor
PPRE
peroxisome proliferator‐activated receptor response element
TZD
thiazolidinediones
  相似文献   
10.
BACKGROUND Aloe vera exerts several biological activities, such as, anti-inflammatory, antioxidant, and antimicrobial effects. It was recently shown to reduce insulin resistance and triglyceride level. We hypothesized that aloe vera would have beneficial effects in alleviating non-alcoholic steatohepatitis(NASH) in rats.AIM To examine the therapeutic effects of aloe vera in NASH rats.METHODS All rats were randomly divided into 3 groups(n = 6 in each group). Rats in the control group were fed ad libitum with a standard diet for 8 wk. Rats in the NASH group were fed ad libitum with a high-fat high-fructose diet(HFHFD) for 8 wk. Rats in the aloe vera group were fed ad libitum with a HFHFD and aloe vera in dimethylsulfoxide(50 mg/kg) by gavage daily for 8 wk. Liver samples were collected at the end of the treatment period.RESULTS Hepatic malondialdehyde(MDA) levels increased significantly in the NASH group as compared with the control group(377 ± 77 nmol/mg vs 129 ± 51 nmol/mg protein, respectively, P 0.001). Glutathione(GSH) levels were significantly lower in the NASH group than the control group(9 ± 2 nmol/mg vs 24 ± 8 nmol/mg protein, respectively, P = 0.001). The expression of interleukin-18(IL-18), nuclear factor-kappa β, and caspase-3 increased, while peroxisome proliferator-activated receptor gamma decreased in the NASH group compared with the controls. Following aloe vera administration, MDA levels decreased(199 ± 35 nmol/mg protein) and GSH increased(18 ± 4 nmol/mg protein) markedly. Steatosis, hepatocyte ballooning, lobular inflammation and increased hepatocyte apoptosis were observed in the NASH group. Aloe vera treatment attenuated these changes in liver histology.CONCLUSION Aloe vera attenuated oxidative stress, hepatic inflammation and hepatocyte apoptosis, thus improving liver pathology in rats with NASH.  相似文献   
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