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311.
Burcu Çalışkan Esra Sinoplu Kübra İbiş Ece Akhan Güzelcan Rengül Çetin Atalay 《Journal of enzyme inhibition and medicinal chemistry》2018,33(1):1352-1361
In our endeavour towards the development of effective anticancer therapeutics, a novel series of isoxazole-piperazine hybrids were synthesized and evaluated for their cytotoxic activities against human liver (Huh7 and Mahlavu) and breast (MCF-7) cancer cell lines. Within series, compounds 5l-o showed the most potent cytotoxicity on all cell lines with IC50 values in the range of 0.3–3.7?μM. To explore the mechanistic aspects fundamental to the observed activity, further biological studies with 5m and 5o in liver cancer cells were carried out. We have demonstrated that 5m and 5o induce oxidative stress in PTEN adequate Huh7 and PTEN deficient Mahlavu human liver cancer cells leading to apoptosis and cell cycle arrest at different phases. Further analysis of the proteins involved in apoptosis and cell cycle revealed that 5m and 5o caused an inhibition of cell survival pathway through Akt hyperphosphorylation and apoptosis and cell cycle arrest through p53 protein activation. 相似文献
312.
Mitofusin gain and loss of function drive pathogenesis in Drosophila models of CMT2A neuropathy 下载免费PDF全文
Najla El Fissi Manuel Rojo Aїcha Aouane Esra Karatas Gabriela Poliacikova Claudine David Julien Royet Thomas Rival 《EMBO reports》2018,19(8)
Charcot–Marie–Tooth disease type 2A (CMT2A) is caused by dominant alleles of the mitochondrial pro‐fusion factor Mitofusin 2 (MFN2). To address the consequences of these mutations on mitofusin activity and neuronal function, we generate Drosophila models expressing in neurons the two most frequent substitutions (R94Q and R364W, the latter never studied before) and two others localizing to similar domains (T105M and L76P). All alleles trigger locomotor deficits associated with mitochondrial depletion at neuromuscular junctions, decreased oxidative metabolism and increased mtDNA mutations, but they differently alter mitochondrial morphology and organization. Substitutions near or within the GTPase domain (R94Q, T105M) result in loss of function and provoke aggregation of unfused mitochondria. In contrast, mutations within helix bundle 1 (R364W, L76P) enhance mitochondrial fusion, as demonstrated by the rescue of mitochondrial alterations and locomotor deficits by over‐expression of the fission factor DRP1. In conclusion, we show that both dominant negative and dominant active forms of mitofusin can cause CMT2A‐associated defects and propose for the first time that excessive mitochondrial fusion drives CMT2A pathogenesis in a large number of patients. 相似文献
313.
Chad McKee Junpei Soeda Esra Asilmaz Barbara Sigalla Maelle Morgan Nicoletta Sinelli Tania Roskams Jude A. Oben 《Biochemical and biophysical research communications》2013
Prazosin an α1-adrenoceptor (AR) antagonist has been shown to reduce liver injury in a mouse model of non-alcoholic steatohepatitis (NASH) and is suggested as a potential treatment of NASH especially given its concomitant anti-fibrotic properties. The effect however, of β-AR blockade in non-cirrhotic NASH is unknown and is as such investigated here. In the presence of the β-blocker propranolol (PRL), mice fed normal chow or a half methionine and choline deficient diet, supplemented with ethionine (HMCDE), to induce NASH, showed significantly enhanced liver injury, as evidenced by higher hepatic necrosis scores and elevated serum aminotransferases (ALT). Mechanistically, we showed that murine hepatocytes express α and β adrenoceptors; that PRL directly induces hepatocyte injury and death as evidenced by increased release of lactate dehydrogenase, FASL and TNF-α from hepatocytes in the presence of PRL; and that PRL activated the apoptotic pathway in primary hepatocyte cultures, as indicated by upregulation of Fas receptor and caspase-8 proteins. The β-AR antagonist PRL therefore appears to enhance liver injury through induction of hepatocyte death via the death pathway. Further studies are now required to extrapolate these findings to humans but meanwhile, β-AR antagonists should be avoided or used with caution in patients with non-cirrhotic NASH as they may worsen liver injury. 相似文献
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This study was designed to define the most suitable anthropometric technique among body mass index (BMI), waist circumference (WC) and waist-hip ratio (WHR) as indices of obesity in adult people living in Adana, a Southern province of Turkey. A random sample design was used. A total of 900 individuals (men and non-pregnant women aged 25-65 years) were enrolled in the study. Of subjects, 50.9% were females. Anthropometric measurements were performed. Data were analysed using statistical package program. The prevalence of obesity among adults living in Adana was 20.8% 28.4% when defined using BMI, 30.5% by WC and 15.8% 42.0% by WHR. Truncal obesity and gynoid obesity showed similar prevalence with 26.6%, in the same age group. Waist circumference, BMI and WHR identified different proportions of the population, as measured for obesity prevalence. The most common methods for diagnosing overweight and obesity are based on BMI (kg/m2). However, BMI is suboptimal marker for total body fat percentage and even less suitable to assess body fat distribution. WHR is the most useful measure of obesity and the best simple anthropometric index in predicting a wide range of risk factors and related health conditions. 相似文献
316.
Fluoxetine, as a serotonin re-uptake inhibitor augments serotonin concentration within the synapse by inhibiting the serotonin
transporter. The contribution of amino acids has also been shown in depression. We hypothesized that fluoxetine exerts its
actions at least in part by intervening brain signaling operated by amino acid transmitters. Therefore the aim of this study
is to supply neurochemical evidence that fluoxetine produces changes in amino acids in cerebrospinal fluid of rats. Sprague-Dawley
rats were anesthetized and concentric microdialysis probes were implanted stereotaxically into the right lateral ventricle.
Intraperitoneal fluoxetine (2.5 or 5 mg/kg) or physiological saline was administered and the probes were perfused with artificial
cerebrospinal fluid at a rate of 1 μl/min. In the chronic fluoxetine group, the rats were treated daily with oral fluoxetine
solution or inert syrup for 3 weeks. The microdialysis probes were placed on the 21st day and perfused the next day. Fluoxetine
was ineffective in changing the cerebrospinal fluid GABA levels at the dose of 2.5 mg/kg but produced a significant increase
in the perfusates following injection of 5 mg/kg of fluoxetine (P < 0.05). Oral fluoxetine administration (5 mg/kg) for 21 days also elevated the CSF GABA levels by approximately 2-fold (P < 0.05). l-glutamic acid levels were not affected in all groups. These neurochemical findings show that fluoxetine, a selective serotonin
re-uptake inhibitor affects brain GABA levels indirectly, and our results suggest that acute or chronic effects may be involved
in beneficial and/or adverse effects of the drug. 相似文献
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319.
Molecular Biology Reports - Colorectal cancer (CRC) is one of the most common cancers worldwide. Natural Killer Group 2D Receptor (NKG2D) and their ligands (NKG2DLs) play crucial roles in natural... 相似文献
320.
Esra Betül Kalaz Jale Çoban A. Fatih Aydın Işın Doğan-Ekici Semra Doğru-Abbasoğlu Serdar Öztezcan Müjdat Uysal 《Journal of physiology and biochemistry》2014,70(1):15-25
d-galactose (GAL) causes aging-related changes and oxidative stress in the organism. We investigated the effect of carnosine (CAR) or taurine (TAU), having antioxidant effects, on hepatic injury and oxidative stress in GAL-treated rats. Rats received GAL (300 mg/kg; s.c.; 5 days/week) alone or together with CAR (250 mg/kg/daily; i.p.; 5 days/week) or TAU (2.5 % w/w; in rat chow) for 2 months. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and hepatic malondialdehyde (MDA), protein carbonyl (PC) and glutathione (GSH) levels and superoxide dismutase (SOD), glutathione peroxidase (GSH-0050x), and glutathione transferase (GST) activities were determined. Hepatic expressions of B cell lymphoma-2 (Bcl-2), Bax and Ki-67 were evaluated. Serum ALT, AST, hepatic MDA, and PC levels were observed to increase in GAL-treated rats. Hepatic Bax expression, but not Bcl-2, increased, Ki-67 expression decreased. GAL treatment caused decreases in GSH levels, SOD and GSH-Px activities in the liver. Hepatic mRNA expressions of SOD, but not GSH-Px, also diminished. CAR or TAU treatments caused significant decreases in serum ALT and AST activities. These treatments decreased apoptosis and increased proliferation and ameliorated histopathological findings in the livers of GAL-treated rats. Both CAR and TAU reduced MDA and PC levels and elevated GSH levels, SOD and GSH-Px (non significant in TAU?+?GAL group) activities. These treatments did not alter hepatic mRNA expressions of SOD and GSH-Px enzymes. Our results indicate that CAR and TAU restored liver prooxidant status together with histopathological amelioration in GAL-induced liver damage. 相似文献