全文获取类型
收费全文 | 1497篇 |
免费 | 108篇 |
国内免费 | 67篇 |
专业分类
耳鼻咽喉 | 5篇 |
儿科学 | 4篇 |
妇产科学 | 14篇 |
基础医学 | 199篇 |
口腔科学 | 20篇 |
临床医学 | 148篇 |
内科学 | 231篇 |
皮肤病学 | 5篇 |
神经病学 | 199篇 |
特种医学 | 69篇 |
外科学 | 185篇 |
综合类 | 175篇 |
预防医学 | 62篇 |
眼科学 | 30篇 |
药学 | 139篇 |
1篇 | |
中国医学 | 25篇 |
肿瘤学 | 161篇 |
出版年
2024年 | 6篇 |
2023年 | 132篇 |
2022年 | 156篇 |
2021年 | 118篇 |
2020年 | 167篇 |
2019年 | 80篇 |
2018年 | 53篇 |
2017年 | 81篇 |
2016年 | 54篇 |
2015年 | 56篇 |
2014年 | 184篇 |
2013年 | 98篇 |
2012年 | 61篇 |
2011年 | 80篇 |
2010年 | 56篇 |
2009年 | 79篇 |
2008年 | 42篇 |
2007年 | 27篇 |
2006年 | 27篇 |
2005年 | 13篇 |
2003年 | 5篇 |
2002年 | 1篇 |
2001年 | 5篇 |
2000年 | 3篇 |
1999年 | 6篇 |
1998年 | 7篇 |
1997年 | 6篇 |
1996年 | 12篇 |
1995年 | 15篇 |
1994年 | 3篇 |
1993年 | 4篇 |
1992年 | 1篇 |
1991年 | 2篇 |
1990年 | 3篇 |
1989年 | 5篇 |
1987年 | 3篇 |
1986年 | 8篇 |
1984年 | 6篇 |
1983年 | 1篇 |
1982年 | 1篇 |
1981年 | 3篇 |
1978年 | 2篇 |
排序方式: 共有1672条查询结果,搜索用时 15 毫秒
91.
《International immunopharmacology》2009,9(6):781-791
The response of the immune system during injury of the central nervous system may play a role in protecting neurons. We have previously reported that immunization with MOG 35–55 prior to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced injury of the dopaminergic system promotes less dopamine depletion and less dopaminergic damage of neurons in mice. In this study, we evaluate the influence of MOG immunization on the inflammatory reaction that occurs at the place of injury. C57Bl male mice, 2 and 12 months old, received i.p. injections of MPTP (40 mg/kg) and some groups animals also received an additional injection with myelin oligodendrocyte glycoprotein (MOG) 35–55 in CFA 6 days before MPTP administration. MPTP caused a common inflammatory reaction characterized by microglial activation, infiltration of T cells into the substantia nigra and striatum and increased expression of mRNA encoding pro-inflammatory cytokines (IL-1β, TNFα, INFγ) and trophic factors (TGFβ, GDNF). MOG immunization prior to MPTP administration significantly diminished the microglial reaction and reduced the levels of infiltrating CD8+ lymphocytes. The number of CD4+ T cells remained at the same level as in the MPTP group. Expression of pro-inflammatory cytokines was diminished. The mRNA expression of GDNF was significantly higher in the MOG pretreated mice relative to the MPTP group, both in the 2 month old and 12 month old groups. Since MOG immunization prior to MPTP intoxication appears to prevent nigrostriatal injury, the observed decrease of inflammation and increase of GDNF mRNA expression in the injured areas might represent one of the mechanisms of observed neuroprotection. 相似文献
92.
《International immunopharmacology》2013,15(4):620-628
Increased reactive oxygen species (ROS) such as superoxide have been implicated as causal elements of oncogenesis. A variety of cancers have displayed changes in steady-state levels of key antioxidant enzymes, with the mitochondrial form of superoxide dismutase (MnSOD) being commonly implicated. Increasing MnSOD expression suppresses the malignant phenotype in various cancer cell lines and suppresses tumor formation in xenograft and transgenic mouse models. In this study, we examined the anti-proliferation effect of mimic of manganese superoxide dismutase (MnSODm) on human non-Hodgkin lymphoma Raji cells. The results showed that MnSODm significantly reduced the proliferation of Raji cells in a concentration and a time-dependent manner. By flow cytometric analysis, we found that MnSODm treatment resulted in an increased apoptosis in Raji cells. MnSODm also increased the production of ROS and the expression levels of cleaved caspase-9, caspase-3, poly (ADP-ribose) polymerase (PARP) and Bax in Raji cells. Moreover, the expression of Bcl-2 protein showed down-regulation in the MnSODm treatment group. In addition, MnSODm significantly elevated the level of cytochrome c in cytosol. These findings suggest that the activation of the mitochondrial pathway is involved in MnSODm-induced apoptosis in Raji cells. 相似文献
93.
Aiguo Shen Shangfeng Gao Zhiyun Ben Haibo Wang Junxia Jia Tao Tao Shugiong Niu Xin Li Chun Cheng 《Neurological sciences》2008,29(5):321-330
Postsynaptic density-95 (PSD-95) is one of neuronal nitric oxide synthase (nNOS)-anchoring proteins and plays an important
role in specifying the sites of reaction of nitric oxide (NO) in the nervous system. The present study aims to investigate
the presence of PSD-95 in rat Schwann cells (SCs) and the association of PSD-95 and nNOS with serum-induced SCs proliferation.
The expression of both molecules downregulated significantly after 48 h of serum deprivation, and increased gradually to the
peak at 12 h, ultimately returned to the control level at 48 h after serum stimulation. The association of PSD-95 with nNOS
was observed in Ki67 and BrdU-positive SCs. The selective nNOS inhibitor arrested the cell cycle progress and decreased the
proliferating cell nuclear antigen (PCNA) levels. These findings suggested that PSD-95 and nNOS may collectively participate
in the proliferation of SCs, providing further evidence for the role of NO during peripheral nerve regeneration. 相似文献
94.
《European Journal of Cancer Supplements》2008,6(1):1-14
Imatinib mesylate is considered the standard first-line systemic treatment for patients with advanced gastrointestinal stromal tumor (GIST). Results from recent research have expanded the knowledge of tyrosine kinase inhibitors in management of GIST. In the setting of unresectable and metastatic GIST, long-term follow-up of the B2222 study showed that imatinib 400 and 600 mg/d produced objective responses in 68% of patients and clinical benefit in 84%; it also extended median survival from 19 months in historical controls to 57 months. The MetaGIST analysis in two large phase 3 trials consisting of more than 1600 patients with metastatic and/or unresectable GIST showed that imatinib 800 mg/d compared with the standard 400-mg/d dose conferred a progression-free survival advantage in patients with KIT exon 9 mutations but not in other subpopulations. The higher starting dose does not significantly improve overall survival. The BFR14 trial demonstrated that interrupting imatinib is associated with a high risk of rapid disease progression. For patients with imatinib-intolerant or imatinib-resistant GIST, sunitinib or a variety of investigational agents, including the next-generation kinase inhibitor nilotinib, may be viable options for achieving disease control. In the setting of primary localized GIST, function- sparing surgical resection is the standard treatment approach, but some patients may be at substantial risk of disease recurrence and metastasis depending on tumor size, mitotic count, and possibly other factors. Initial results from ACOSOG Z9001 indicate that adjuvant imatinib for 1 year prolongs recurrence-free survival following surgical resection of larger (at least 3 cm) KIT-expressing GIST. Other ongoing studies are further exploring the role of imatinib in both adjuvant and neoadjuvant therapy. Recent updates to clinical practice guidelines and recommendations now incorporate some of these new findings. 相似文献
95.
Sexual function which comprises of desire, arousal, orgasm and satisfaction and pain, involves coordinated physiologic responses from multiple different pathways. Sexual dysfunction (SD) occurs when these domains of the sexual response cycle are affected. SD is a common but under-recognized non-motor feature in Parkinson’s disease (PD), a common age-related neurodegenerative disorder. SD significantly affects the quality of life of PD patients and their partners. Advanced age, gender, hormone deficiency, neuropsychiatric and medical comorbidities contribute to SD in PD. Possible potential pathological mechanisms include vasculogenic, endocrinologic, neurogenic and psychogenic factors. Various therapeutic interventions, both pharmacological and non-pharmacological modalities have been suggested to improve SD in PD. However, erectile dysfunction (ED) is the only SD with evidence-based treatment available. Non-pharmacological therapies are also offering promising evidence in the improvement of SD. A multidisciplinary approach in the assessment, investigation, and treatment is needed to address the real life complex issues (gender and comorbidities, neurobiological, vasoactive, hormonal as well as psychosocial aspects). Future clinical studies with validated and standardized methods in assessing SD as well as experimental models will be necessary for better insight into the pathophysiology. This would facilitate appropriate therapy and improve sexual rehabilitation in PD patients. 相似文献
96.
Jinfei Yang Xiaolong Wu Banghua Yang Yirong Liu Rui Cheng Zijun Gong Fei Sun 《RSC advances》2020,11(1):164
A Mn(ii)-catalysed ortho-alkenylation of aromatic amines and its application in reproductive diseases were developed. The use of MnCl2 was critical for the ortho-alkenylation of aromatic amines. The general applicability of this procedure was highlighted by the synthesis of 27 vinylanilines, with good regioselectivities. The value of our approach in practical applications was investigated by studying the effects of one of the compounds 3m on 8 week-old adult male rats with azoospermia as a mammalian model. The results show that a small amount of sperm will gradually be produced in the epididymis and testes by treatment of 8 week-old adult male rats with azoospermia with 1 mg kg−13m after two weeks, while treatment with 10 mg kg−13m led to obvious sperm production. Notably, if we increase the dose to 100 mg kg−1, there will be a lot of sperm production in the epididymis and testes after two weeks of treatment. The results of this study will be of great significance in research on drugs for treating azoospermia and oligospermia diseases.A Mn(ii)-catalysed ortho-alkenylation of aromatic amines and its application in reproductive diseases were developed.Alkenyl arylamines are very important intermediates for the synthesis of drug molecules, such as carbamazepine,1 opipramol,2 and indopan3 (Scheme 1). O-Alkenyl arylamines have attracted much attention because of their widespread presence in a variety of heterocycles including indoles, quinolines and cinnolines, which are key structural units for many biologically important compounds.4 Moreover, they have also been used as synthetic intermediates in several total synthetic methods.5 Therefore, it is of great significance to carry out the ortho-alkenylation reaction of aromatic amines. But it is not an easily accessible process under normal Friedel–Crafts conditions due to the coordination of the Lewis acid with the nitrogen atom of amino group, which leads to the deactivation of the aromatic ring.6 To overcome this challenge, chemists began to try other methods to achieve ortho-alkenylation of aromatic amines. Subsequently, several related ortho-alkenylation of aromatic amines with phenylacetylene was reported in the literature.4a,7 However, the ortho-alkenylation of aromatic amines catalyzed by base metals has not yet been developed, especially manganese. Therefore, it is still very important to develop a Mn-catalyzed ortho-alkenylation reaction of aromatic amines. Notably, there have been more C–H bond functionalization reactions catalyzed by monovalent manganese in recent years, but few of them were catalyzed by divalent manganese.8 Ackermann''s research group reported several Mn(ii)-catalyzed ortho-functionalization reactions of arylamides.9 In addition, a Mn(ii)-catalysed dehydrogenative annulation of N-aryl anilines with alkenes or alkynes was reported by our group last year.10Open in a separate windowScheme 1Drug molecules containing alkenyl arylamine skeleton.Herein, we report an example of Mn(ii)-catalysed ortho-alkenylation of aromatic amines and its application in reproductive diseases (Scheme 2). In our previous work, divalent manganese is easily oxidized to tetravalent manganese by K2S2O8.10 This work, we hypothesis the ortho-alkenylation product of aromatic amine will be generated after the oxidant was removed in the system. Based on this hypothesis, we tried a series of manganese catalysts.Open in a separate windowScheme 2Proposed strategy.We began by treating N-benzylaniline and phenylacetylene with toluene as a solvent. Initially, we attempted using various Mn(ii) catalysts to catalyse the ortho-alkenylation of aromatic amines at 120 °C, i.e., MnO, MnSO4, Mn(OAc)2, and Mn(acac)2, as detected by GC analysis, while 73% and 61% yields were observed when MnBr2 and MnI2 were used as catalysts (Table 1, entries 1–7). Fortunately, a 80% yield of N-benzyl-2-(1-phenylvinyl)aniline was obtained when using MnCl2. To improve the reaction efficiency, different solvents, including N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile (CH3CN), 1,4-dioxane, tetrahydrofuran (THF), 1,2-dichloroethane (DCE), p-xylene, mesitylene and n-hexane were tested (Table 1, entries 8–16). The optimal reaction solvent was found to be toluene. To increase conversion to the N-benzyl-2-(1-phenylvinyl) aniline, we examined a wide range of reaction temperatures (Table 1, entries 17–22). The results show that 120 °C was the optimum temperature, and the corresponding N-benzyl-2-(1-phenylvinyl)aniline was obtained the best yield. It is worth noting that more cyclization products were formed when the temperature is raised to 130 °C. Therefore, temperature is another key factor that drives the reaction forward. Notably, the addition of oxidant will terminate this reaction (see the ESI Table 1† for details). These results therefore support our initial hypothesis that the ortho-alkenylation product of aromatic amine will be generated after the oxidant was removed.Effects of catalyst, temperature, and solvent. N-Benzylaniline (0.2 mmol), phenylacetylene (0.4 mmol), catalyst (0.04 mmol), solvent (2.0 mL), at 120 °C for 24 h
Open in a separate windowaThe reactions were carried out in sealed tubes.bYields were determined by GC analysis.cWithout MnCl2.With the optimum reaction conditions in hand, a series of aromatic amine were investigated for extending the substrate scope (Scheme 3). This Mn(ii)-catalysed ortho-alkenylation of aromatic amines shows good functional group tolerance. Aromatic amine with electron-neutral or electron-donating groups such as alkyl, phenyl, and methoxy on the aryl rings all gave the corresponding ortho-olefination products with high selectivities and in good yields. Aryls containing an electron-withdrawing group such as chloro, and bromo were also tolerated and afforded the corresponding ortho-olefination products 3v–3ab in moderate yields with highly ortho-selectivities. Moreover, the reaction of aromatic amine containing naphthyl of the aromatic rings also gave the corresponding ortho-olefination products 3k and 3l in good yields. Unfortunately, it does not give good yields for meta-substituted aromatic amines.Open in a separate windowScheme 3Reaction conditions: substrate 1 (0.2 mmol), aryl acetylene (0.4 mmol), MnCl2 (0.04 mmol), toluene (2.0 mL), at 120 °C for 24 h, and isolated yields for products.In addition, aryl acetylene with electron-neutral or electron donating groups such as alkyl and anthryl on the aryl rings all gave the corresponding ortho-olefination products with high selectivities and in good yields. Aryls containing an electron-withdrawing group such as fluoro, chloro, bromo and trifluoromethyl were also tolerated and afforded the corresponding ortho olefination products 3b–3e, 3i, 3j, 3l, 3m, 3s–3u, 3w and 3z in moderate to good yields. More importantly, retention of the fluorine, chlorine, and bromine atoms in the products makes the products of considerable use in organic transformations.The synthetic utility of the current method was tested by performing a gram-scale ortho-alkenylation of aromatic amines under the optimum conditions. The target N-benzyl-4-methoxy-2-(1-(4-(trifluoromethyl)phenyl)vinyl)aniline 3m was obtained in 73% yield (Scheme 4).Open in a separate windowScheme 4Gram-scale synthesis.Azoospermia is the medical condition of a man whose semen contains no sperm.11 Pre- and post-testicular azoospermia are frequently correctible, while testicular azoospermia is usually permanent.12 In humans, azoospermia affects about 1% of the male population and may be seen in up to 20% of male infertility situations in Canada.13 However, there is no specific drugs for azoospermia currently on the market. The empirical drug commonly used in clinical practice is clomiphene.14 Clomiphene is a non-steroidal drug with a chemical structure similar to diethylstilbestrol. Its mechanism of action may be that the molecule competitively occupies the ER, thereby blocking the negative feedback effect of circulating endogenous estradiol, leading to increased secretion of GnRH released by the hypothalamus, stimulating the secretion of FSH and LH, and promoting spermatogenesis. Although it has been widely used by clinicians, clinical studies show that long-term use of clomiphene may increase the risk of cancer. Therefore, it is necessary to develop a safer drug that can replace clomiphene. Given that the structure of the 3m is similar to clomiphene, we envision that 3m may also have the effect of promoting spermatogenesis.To verify the potential of 3m in promoting spermatogenesis, we study the effects of 3m, with 8 week-old adult male rats with azoospermia as a mammalian model (Scheme 5). The test results show that a small amount of sperm will gradually be produced in the epididymis and testis by treatment of 8 week-old adult male rats with azoospermia with 1 mg kg−13m after two weeks later, and treatment with 10 mg kg−13m led to obvious sperm production. To our delight, a lot of sperm will be produced in the epididymis and testis after four weeks. Notably, if we increase its dose to 100 mg kg−1, there will be a lot of sperm production in the epididymis and testis after two weeks of treatment. In addition, to exclude the influence of DMSO, we made a group of control test, and the test results showed that the sperm number has no change in epididymis and testis. So DMSO has no effect on spermatogenesis. Accordingly, we have discovered a drug molecule that can effectively promote spermatogenesis. The results of this study will be of great significance in research on drugs for treating azoospermia and oligospermia diseases.Open in a separate windowScheme 5Biological activity evaluation test in spermatogenesis.Additional experiments were performed to gain a better understanding of the roles of MnCl2 in the ortho-alkenylation of aromatic amines. Control experiments showed that the absence of MnCl2 shut down the reaction (Table 1, entry 23). These results imply that MnCl2 is essential to this reaction. We propose the catalytic cycle shown in the ESI.† Phenylacetylene and aromatic amine first undergoes ligand coordination with the metal center, and subsequent electrophilic addition with aromatic amine provides an intermediate A. and then the target product is obtained through proton migration, with regeneration of the catalytic Mn(ii) (see the ESI Fig. 1† for details). 相似文献
Entry | Catalyst | Solvent | T (°C) | Yield 3ab (%) |
---|---|---|---|---|
1 | Mn(OAc)2 | Toluene | 120 | 20 |
2 | MnO | Toluene | 120 | 0 |
3 | MnSO4 | Toluene | 120 | 0 |
4 | Mn(acac)2 | Toluene | 120 | 50 |
5 | MnBr2 | Toluene | 120 | 73 |
6 | MnI2 | Toluene | 120 | 61 |
7 | MnCl 2 | Toluene | 120 | 80 |
8 | MnCl2 | DMF | 120 | 0 |
9 | MnCl2 | DMSO | 120 | 0 |
10 | MnCl2 | CH3CN | 120 | 3 |
11 | MnCl2 | Dioxane | 120 | 28 |
12 | MnCl2 | THF | 120 | 14 |
13 | MnCl2 | DCE | 120 | 26 |
14 | MnCl2 | p-Xylene | 120 | 50 |
15 | MnCl2 | Mesitylene | 120 | 52 |
16 | MnCl2 | n-Hexane | 120 | 10 |
17 | MnCl2 | Toluene | 80 | 12 |
18 | MnCl2 | Toluene | 90 | 29 |
19 | MnCl2 | Toluene | 100 | 51 |
20 | MnCl2 | Toluene | 110 | 63 |
21 | MnCl2 | Toluene | 130 | 70 |
22 | MnCl2 | Toluene | 140 | 63 |
23c | None | Toluene | 120 | 0 |
97.
98.
99.
Cognitive deficiency and oxidative stress have been well documented in aging disorders including Alzheimer’s disease. The aim of this study was to investigate the therapeutic efficacy of Caralluma tuberculata methanolic extract (CTME) on cognitive impairment in mice induced with d-galactose. In this study we assessed the therapeutic efficacy of CTME on cognitive impairment in mice induced with d-galactose by conduction of behavioral and cognitive performance tests. In order to explore the possible role of CTME against d-galactose-induced oxidative damages, various biochemical indicators were assessed. Chronic administration of d-galactose (150 mg/kg d, s.c.) for 7 weeks significantly impaired cognitive performance (in step-through passive, active avoidance test, Hole-Board test, Novel object recognition task and Morris water maze) and oxidative defense as compared to the control group. The results revealed that CTME treatment for two weeks (100, 200 and 300 mg/kg p.o) significantly ameliorated cognitive performance and oxidative defense. All groups of CTME enhanced the learning and memory ability in step-through passive, active avoidance test, Hole-Board test Novel object recognition task and Morris water maze. Furthermore, high and middle level of CTME (300 and 200 mg/kg p.o) significantly increased Total antioxidative capacity (T-AOC), Glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) activity, neprilysin (NEP), and β-site AβPP cleaving enzyme 1 (BACE1) expression while Nitric Oxide (NO), Nitric Oxide Synthase (NOS) activity and Malondialdehyde (MDA) concentration, and the level of Aβ1-42 and presenilin 1 (PS1) were decreased. The present study showed that CTME have a significant relieving effect on learning, memory and spontaneous activities in d-galactose-induced mice model, and ameliorates cognitive impairment and biochemical dysfunction in mice. 相似文献
100.
目的观察高脂饲料喂养的大鼠心脏组织中src抑制的C激酶底物(SSeCKS)的表达变化,探讨高脂血症对SSeCKS表达的影响。方法高脂饮食组(n=8)和正常饮食组(n=8)SD大鼠分别经高脂饲料和普通饲料喂养16周后,测血清总胆固醇及甘油三酯;用HE染色观察心脏病理学改变;用免疫组织化学法检测SSeCKS在心脏的表达;用免疫荧光双标法观察SSeCKS在心脏中的细胞定位。结果高脂饮食组总胆固醇和甘油三酯较正常饮食组明显升高(P〈0.05);病理学观察发现高脂饮食组形成高脂性心脏病变;免疫组织化学检测发现高脂饮食组中SSeCKS表达主要分布在心内膜、心间质;免疫荧光双标发现SSeCKS与心脏组织内皮细胞和α-平滑肌肌动蛋白阳性细胞部分共定位。结论高脂饲料喂养能使大鼠形成高脂血症,并引起心脏SSeCKS表达升高,SSeCKS可能参与了心脏结构重塑及细胞凋亡,从而促进动脉粥样硬化心脏病的发展。 相似文献