全文获取类型
收费全文 | 137136篇 |
免费 | 8372篇 |
国内免费 | 8804篇 |
出版年
2023年 | 1717篇 |
2022年 | 1775篇 |
2021年 | 3364篇 |
2020年 | 3631篇 |
2019年 | 5493篇 |
2018年 | 4250篇 |
2017年 | 3303篇 |
2016年 | 3665篇 |
2015年 | 5093篇 |
2014年 | 7896篇 |
2013年 | 10375篇 |
2012年 | 6409篇 |
2011年 | 8557篇 |
2010年 | 6402篇 |
2009年 | 6782篇 |
2008年 | 7075篇 |
2007年 | 7310篇 |
2006年 | 6643篇 |
2005年 | 5787篇 |
2004年 | 4985篇 |
2003年 | 4181篇 |
2002年 | 3712篇 |
2001年 | 2714篇 |
2000年 | 2246篇 |
1999年 | 2185篇 |
1998年 | 2000篇 |
1997年 | 1647篇 |
1996年 | 1500篇 |
1995年 | 1796篇 |
1994年 | 1653篇 |
1993年 | 1466篇 |
1992年 | 1504篇 |
1991年 | 1245篇 |
1990年 | 1109篇 |
1989年 | 1020篇 |
1988年 | 1002篇 |
1987年 | 944篇 |
1986年 | 665篇 |
1985年 | 1114篇 |
1984年 | 1563篇 |
1983年 | 1130篇 |
1982年 | 1508篇 |
1981年 | 1089篇 |
1980年 | 1049篇 |
1979年 | 997篇 |
1978年 | 614篇 |
1977年 | 511篇 |
1976年 | 403篇 |
1975年 | 318篇 |
1973年 | 324篇 |
排序方式: 共有10000条查询结果,搜索用时 31 毫秒
11.
Neven Zarkovic Zoran Ilic Mislav Jurin R. Jrg Schaur Herbert Puhl Hermann Esterbauer 《Cell biochemistry and function》1993,11(4):279-286
The aim of this study was to analyze the growth response of HeLa cells over a prolonged period of time to a single exposure of physiological and supraphysiological concentrations of 4-hydroxynonenal (HNE), a peroxidation product of omega-6-polyunsaturated fatty acids. Furthermore, the growth modulating effect of serum factors, particularly albumin, on the growth pattern was examined. The effects of HNE on the growth rate and viability of the cells, as well as on the incorporation of labelled amino acids were monitored daily over a period of four days. Fetal calf serum not only had a growth stimualting effect but also modulated the action of HNE. In neither respect was albumin able to substitute for serum indicating that the influence of serum was not exerted via an albumin–HNE conjugate. HNE had a clear dose-dependent effect and a distinction could be made between a supraphysiological concentration (100 μM), which was primarily cytotoxic and a physiological range (below 10 μM) which showed growth modulatory effects. These effects consisted of a transient inhibition in the initial phase of the cell growth, which under optimal conditions (in presence of serum) was followed by a period of increased proliferation, compared to untreated control cultures, until confluence was attained. It is suggested that HNE is not only a toxic product of lipid peroxidation, but a physiological growth regulating factor as well. 相似文献
12.
ZhiMeng Xu ChengBin Li QingLing Liu Hua Yang Ping Li 《Journal of cellular biochemistry》2019,120(10):18388-18397
Insufficient nutrients supply will greatly affect the function of cardiac myocytes. The adaptive responses of cardiac myocytes to nutritional stress are not fully known. Ginsenoside Rg1 is one of the most pharmacologically active components in Panax Ginseng and possesses protective effects on cardiomyocyte. Here, we investigate the effects of ginsenoside Rg1 on H9c2 cells which were subjected to nutritional stress. Nutritional stress-induced by glucose deprivation strongly induced cell death and this response was inhibited by ginsenoside Rg1. Importantly, glucose deprivation decreased intracellular ATP levels and mitochondrial membrane potential. Ginsenoside Rg1 rescued ATP levels and mitochondrial membrane potential in nutrient-starved cells. For molecular mechanisms, ginsenoside Rg1 increased the expressions of PTEN-induced kinase 1 (PINK1) and p-AMPK in glucose deprivation treated H9c2 cells. Reducing the expression of aldolase in H9c2 cells inhibited ginsenoside Rg1′s actions on PINK1 and p-AMPK. Further, the nutritional stress mice were used to verify the mechanisms obtained in vitro. Ginsenoside Rg1 increased the expressions of aldolase, p-AMPK, and PINK1 in starved mice heart. Taken together, our results reveal that ginsenoside Rg1 limits nutritional stress-induced H9c2 cells injury by regulating the aldolase /AMP-activated protein kinase/PINK1 pathway. 相似文献
13.
《Bioorganic & medicinal chemistry》2019,27(15):3279-3284
Photodynamic therapy (PDT) is a treatment method using light and photosensitizers (PSs), which is categorized as a non-invasive surgery treatment for cancers. When the tumor is exposed to a specific light, the PSs become active and generate reactive oxygen species (ROS), mainly singlet oxygen which kills nearby cancer cells. PDT is becoming more widely recognized as a valuable treatment option for localized cancers and pre-cancers of skin as it has no long-term effects on the patient. But, due to the limited penetration rate of light into the skin and other organs, PDT can’t be used to treat large cancer cells or cancer cells that have grown deeply into the skin or other organs. Hence, in this study, our focus centers on synthesizing glucose-conjugated phthalocyanine (Pc) compatible with near-infrared (NIR) irradiation as second-generation photosensitizer, so that PDT can be used in a wider range to treat cancers without obstacles. 相似文献
14.
Rongsheng Chen Xiaobo Zhang Changsheng Wang 《Journal of cellular biochemistry》2020,121(10):4043-4051
Multiple myeloma (MM) is defined as the second most common hematological tumor in the globe. Long noncoding RNAs (lncRNAs) have been reported to play stimulative or suppressive role in the progression of different carcinomas. The investigation of lncRNAs in MM is still inadequate. LncRNA HOXB cluster antisense RNA 1 (HOXB-AS1) was once revealed to facilitate glioma progression by affecting cellular activities of glioma cells. However, whether HOXB-AS1 participates in the development of MM still remains an enigma. In this study, we unveiled that HOXB-AS1 was highly expressed in MM and loss-of-function assays certified that HOXB-AS1 obstruction suppressed MM cell proliferation, and stimulated cell apoptosis. In addition, HOXB-AS1 could modulate fucosyltransferase 4 (FUT4) and FUT4-mediated Wnt/β-catenin pathway. In subsequence, it was observed from mechanism assays that HOXB-AS1 enhanced the interaction between ELAVL1 and FUT4 so as to stabilize FUT4 messenger RNA. In the end, rescue experiments affirmed that HOXB-AS1 affected the cell growth through FUT4 in MM. In conclusion, the whole modulation mechanism of HOXB-AS1/ELAVL1/FUT4 axis in MM was validated in this study, which suggested that HOXB-AS1 might function as a powerful and promising therapeutic biomarker for the clinical treatment of patients with MM. 相似文献
15.
《Bioorganic & medicinal chemistry》2020,28(22):115739
N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC50 = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest. 相似文献
16.
17.
《Bioorganic & medicinal chemistry》2020,28(11):115492
Effective chemotherapy for solid cancers is challenging due to a limitation in permeation that prevents anticancer drugs from reaching the center of the tumor, therefore unable to limit cancer cell growth. To circumvent this issue, we planned to apply the drugs directly at the center by first collapsing the outer structure. For this, we focused on cell–cell communication (CCC) between N-glycans and proteins at the tumor cell surface. Mature N-glycans establish CCC; however, CCC is hindered when numerous immature N-glycans are present at the cell surface. Inhibition of Golgi mannosidases (GMs) results in the transport of immature N-glycans to the cell surface. This can be employed to disrupt CCC. Here, we describe the molecular design and synthesis of an improved GM inhibitor with a non-sugar mimic scaffold that was screened from a compound library. The synthesized compounds were tested for enzyme inhibition ability and inhibition of spheroid formation using cell-based methods. Most of the compounds designed and synthesized exhibited GM inhibition at the cellular level. Of those, AR524 had higher inhibitory activity than a known GM inhibitor, kifunensine. Moreover, AR524 inhibited spheroid formation of human malignant cells at low concentration (10 µM), based on the disruption of CCC by GM inhibition. 相似文献
18.
19.
《Molecular cell》2020,77(4):748-760.e9
20.