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Diabetes mellitus (DM) is a major health problem with devastating effects on ocular health in both industrialized and developing countries. The control of hyperglycemia is critical to minimizing the impact of DM on ocular tissues because inadequate glycemic control leads to ocular tissue changes that range from a temporary blurring of vision to permanent vision loss. The biochemical mechanisms that promote the development of diabetic complications have been extensively studied. As a result, a number of prominent biochemical pathways have been identified. Among these, the two-step sorbitol pathway has been the most extensively investigated; nevertheless, it remains controversial. To date, long-term pharmacological studies in animal models of diabetes have demonstrated that the onset and development of ocular complications that include keratopathy, retinopathy and cataract can be ameliorated by the control of excess metabolic flux through aldose reductase (AR). Clinically the alleles of AR have been linked to the rapidity of onset and severity of diabetic ocular complications in diabetic patient populations around the globe. In spite of these promising preclinical and human genetic rationales, several clinical trials of varying durations with structurally diverse aldose reductase inhibitors (ARIs) have shown limited success or failure in preventing or arresting diabetic retinopathy. Despite these clinical setbacks, topical ARI Kinostat® promises to find a home in clinical veterinary ophthalmology where its anticipated approval by the FDA will present an alternative treatment paradigm to cataract surgery in diabetic dogs. Here, we critically review the role of AR in diabetes mellitus-linked ocular disease and highlight the development of Kinostat® for cataract prevention in diabetic dogs. In addition to the veterinary market, we speculate that with further safety and efficacy studies in humans, Kinostat® or a closely related product could have a future role in treating diabetic keratopathy. 相似文献
104.
The incidence of breast cancer in India is on the rise and is rapidly becoming the primary cancer in Indian women. The aldoketo reductase (AKR) family has more than 190 proteins including aldose reductase (AKR1B1) and aldose reductase like protein (AKR1B10). Apart from liver cancer, the status of AKR1B1 and AKR1B10 with respect to their expression and activity has not been reported in other human cancers. We studied the specific activity and expression of AKR1B1 and AKR1B10 in breast non tumor and tumor tissues and in the blood. Fresh post-surgical breast cancer and non-cancer tissues and blood were collected from the subjects who were admitted for surgical therapy. Malignant, benign and pre-surgical chemotherapy samples were evaluated by histopathology scoring. Expression of AKR1B1 and AKR1B10 was carried out by immunoblotting and immunohistochemistry (IHC) while specific activity was determined spectrophotometrically. The specific activity of AKR1B1 was significantly higher in red blood cells (RBC) in all three grades of primary surgical and post-chemotherapy samples. Specific activity of both AKR1B1 and AKR1B10 increased in tumor samples compared to their corresponding non tumor samples (primary surgical and post-chemotherapy). Immunoblotting and IHC data also indicated overexpression of AKR1B1 in all grades of tumors compared to their corresponding non tumor samples. There was no change in the specific activity of AKR1B1 in benign samples compared to all grades of tumor and non-tumors. 相似文献
105.
Aim
Diabetes mellitus (DM) is a risk factor for hepatocellular carcinoma (HCC). It directs glucose to sorbitol and fructose in polyol pathway (PP). To pursue contribution of PP in hepatocarcinogenesis.Methods
We utilized ascorbic acid (AA) and diallyl sulfide (DAS) in experimental DM and HCC against control. HCC was induced by diethyl nitrosamine (DENA, one intraperitoneal (IP) dose 125 mg/kg), DM, by streptozotocin (STZ, IP dose 65 mg/kg). AA was given as 7.4 g/kg/d, I.P., DAS 200 mg/kg/d, orally. All animals were killed after 10 weeks.Results
DENA elevated serum AFP, erythrocyte sorbitol (ES), neoplastic changes in liver, lowered blood glucose, increased hepatocyte aldose reductase (AR) and sorbitol dehydrogenase (SDH), significantly alleviated by DAS/AA combination. DM elevated ES activating AR, inhibiting SDH, improved by DAS and AA.Conclusion
Co-induction of DM and HCC increased liver tissue lesion, serum AFP, ES, liver AR and SDH. Co-administration of DAS/AA reduced ES, AR without changing SDH. DAS/AA co-therapy lowered ES by depressing AR without affecting SDH, meaning that AR is activated by cancer and DM in different ways. PP is early marker for HCC detection and response to chemoprevention. DAS/AA combination is promising cost effective chemopreventive and anti-diabetic combination. 相似文献106.
目的:观察白藜芦醇对糖尿病肾病大鼠醛糖还原酶的影响。方法:将48只雄性SD大鼠随机分为空白对照组、模型组、白藜芦醇低、中、高剂量组和依帕司他组(n=8)。除正常对照组外,其余各组大鼠腹腔注射STZ(55 mg.kg-1),成功造模后白藜芦醇组分别给予5、154、5 mg.kg-1白藜芦醇,依帕司他组给予10 mg.kg-1依帕司他,连续灌胃6 w后,检测大鼠血糖、体重,HE染色检测肾脏病理改变,ELISA法检测醛糖还原酶(AR)活性。结果:与正常对照组相比,糖尿病组血糖与AR活性明显升高(P<0.05),与模型组比较,白藜芦醇各组血糖与AR活性明显降低(P<0.05)。结论:白藜芦醇可降低糖尿病大鼠血糖,其降糖效应可能与抑制AR活性有关。 相似文献
107.
目的筛选海南五层龙根乙醇提取物中抗糖尿病的组份。方法采用萃取和色谱技术,对海南五层龙根乙醇提取物进行组份分离;然后对分离所得的各组份进行体外α-糖苷酶和醛糖还原酶抑制活性测定。结果海南五层龙根乙醇提取物用有机溶剂萃取后的水层上D101大孔吸附树脂吸附后5,0%乙醇洗脱物具有明显的α-糖苷酶和醛糖还原酶抑制活性,其浓度为100μg/ml时,对两种酶的抑制率分别为(74.1±1.8)%和(81.0±1.9)%,效果明显优于阳性对照药阿卡波糖和槲皮素。结论 50%乙醇洗脱物对α-糖苷酶和醛糖还原酶具有明显的抑制活性,为海南五层龙根乙醇提取物抗糖尿病活性成分集中的组份。 相似文献
108.
目的研究醛糖还原酶(AR)基因5’端(AC)n二核苷酸串联重复序列及启动子区C(-106)T多态性与山东地区糖尿病视网膜病变(DR)患者易感性之间的关系。方法应用多聚酶链反应(PCR)琼脂糖凝胶电泳技术和DNA测序技术检测322例糖尿病(DM)患者及98名对照者(CON)的基因型。结果(1)DR患者Z-2等位基因、含Z-2等位基因但不含Z+2等位基因的基因型、C等位基因及CC基因型频率显著高于无视网膜病变(NDR)患者,Z+2等位基因频率显著低于NDR者。(2)Z-2/C单倍型分布频率在DR组显著高于NDR组。结论山东地区DM患者AR基因5’端(AC)/1多态标记Z-2等位基因及C(-106)T多态标记C等位基因可能与糖尿病视网膜病变易感性相关,Z+2等位基因可能是DR保护性因素。 相似文献
109.
目的探讨石斛酚与丁香酸联用对醛糖还原酶(AR)活性的抑制作用。方法采用紫外分光光度法表征石斛酚和丁香酸联合对AR的抑制活性;采用分子对接软件Sybyl中的FlexX方法预测二者作用残基、结合方式及其药效团。结果石斛酚和丁香酸联用的抑制活性优于单一组分——石斛酚和丁香酸,表现良好的协同效果,二者协同抑制AR的氨基酸残基为Asn160,主要作用力为范德华力,形成共同药效团。结论石斛酚与丁香酸联合对AR活性表现为抑制作用,并呈现协同性。 相似文献
110.