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951.
Alexander So 《Arthritis research & therapy》2013,15(5):118
Most research in gout has concentrated on the proinflammatory mechanisms to
explain the inflammation that is generated when leucocytes are in contact with
monosodium urate crystals. However, the episodic nature of gout and the absence
of inflammation even when crystals are present suggest that there are natural
counter-regulatory mechanisms to limit the inflammatory response. Gagné and
colleagues showed that myeloid inhibitory C-type lectin, a C-type lectin
inhibitory receptor expressed on neutrophils, modulates monosodium urate-induced
neutrophil responses in vitro.Neutrophil recruitment and activation play a key role in the acute inflammatory
response to monosodium urate (MSU) crystals. In acute gout, our current treatments
such as nonsteroidal anti-inflammatory drugs, colchicine or corticosteroids all act
on different steps of neutrophil activation. These drugs form part of the first
treatment objective in gout – to relieve the painful symptoms of the acute
attack – but do not address the second objective, which is to treat the
underlying metabolic disorder hyperuricemia. Can neutrophil activation be
manipulated or regulated? Are there signals that can be modulated and can this be of
clinical relevance?The article by Gagné and colleagues provides evidence for an inhibitory pathway
of neutrophil activation that acts through a recently described C-type lectin
receptor called the myeloid inhibitory C-type lectin (MICL) [1]. This membrane receptor, also known as CLEC12A, inhibits neutrophil
activation when it is engaged. C-type lectin receptors form a large family of
proteins that have a common type of carbohydrate-binding domain that mediate cell
adhesion and ligand binding in a calcium-dependent manner. Members of the C-type
lectin receptors are known to participate in immune regulation, with well-known
examples including Dectin-1 (CLE7A), DC-sign (CD209 or CLEC4L) and natural killer
cell receptors (Ly49 or KLRA1). The MICL protein is encoded on chromosome 12p13,
closely linked to the natural killer gene complex. MICL contains a cytoplasmic
immunoreceptor tyrosine-based inhibitory motif and is expressed mainly on
neutrophils and monocytes. Previous work has shown that the receptor could inhibit
cellular activation [2]. The ligands that lead to MICL activation are currently unknown, as there
is only a small body of data to show that the receptor interacts with ligands
expressed in the bone marrow, thymus and kidney [3].In their studies, Gagné and colleagues showed that MSU crystals as well as a
MICL-specific antibody downmodulated MICL expression on neutrophils. Reducing the
expression of MICL by transfecting small interfering RNA or by antibody modulation
of the receptor led to enhanced production of IL-8 when MSU was added to
neutrophils, but no changes in IL-1β secretion were observed. The mechanisms of
MICL signaling probably involve tyrosine phosphorylation as well as calcium flux,
differing from previous results that showed MICL associated with the phosphatases
SHP-1 and SHP-2 [2]. Finally, the addition of colchicine to neutrophils abrogated the
negative effect of MSU on MICL expression.These results showed that reduced MICL expression is associated with augmented
inflammatory responses from neutrophils, and a higher level of neutrophil MICL
expression is associated with a reduced IL-8 production in vitro. As IL-8
is a major neutrophil chemoattractant, this can have important effects on neutrophil
recruitment to an inflammatory site in gout. By extrapolation, if MICL expression or
signaling could be enhanced or maintained during inflammation, the inhibitory signal
may be reinforced and thereby downregulate inflammation. The effect of colchicine in
this system is to elevate the expression of MICL, thereby increasing the inhibitory
signaling mechanisms that counteract the inflammatory process.A number of caveats need to be mentioned in the interpretation of these results. The
data presented were based on in vitro models of inflammation using MSU, and
we need to see how this works in vivo before coming to any conclusions, as
we have had examples where the in vivo results did not recapitulate the
in vitro findings. They convincingly showed that reducing MICL
expression on the surface of neutrophils enhanced the proinflammatory signature, but
they did not show the converse – that enhanced MICL signaling can further
downmodulate inflammation. Furthermore, the ligands that bind and activate MICL are
unknown, so we have no idea what is the signal or how to reinforce or manipulate
this signaling system. The results presented show that MSU had dual effects on
neutrophils – the first is to downregulate MICL expression, and the second is
to activate IL-8 production. How are these two mechanisms linked? If MSU acts mainly
on the cell membrane internalization of MICL, what is the trigger for the IL-8
secretion? Notwithstanding these uncertainties, the finding that MICL modulates
neutrophil activation in gout suggests that there are a number of counter-regulatory
mechanisms in operation during an inflammatory process. Identifying these mechanisms
may help us to understand the nature of gout as well as open up new therapeutic
perspectives. 相似文献
952.
So Nishimura Naoyoshi Nagata Takuro Shimbo Naoki Asayama Junichi Akiyama Norio Ohmagari Hirohisa Yazaki Shinichi Oka Naomi Uemura 《PloS one》2013,8(3)
Background
Candidia esophagitis (CE) is an AIDS-defining condition, usually occurring in individuals with low CD4 counts of <200 cells/µL. Endoscopy is a valuable definitive diagnostic method for CE but may not be indicated for asymptomatic patients or for those with high CD4 counts or without oral candidiasis. This study assessed such patients to clarify the factors associated with CE and its severity on endoscopy in the highly active antiretroviral therapy (HAART) era.Methodology/ Principal Findings
A total of 733 HIV-infected patients who underwent upper gastrointestinal (GI) endoscopy were analyzed. Sexual behavior, CD4+ count, HIV-RNA viral load (VL), history of HAART, GI symptoms, GI diseases, and oral candidiasis were assessed. Endoscopic severity of CE was classified as mild (Kodsi''s grade I/II) or severe (grade III/IV). Of the 733 subjects, 62 (8.46%) were diagnosed with CE (mild, n = 33; severe, n = 29). Of them, 56.5% (35/62) had no GI symptoms, 30.6% (19/62) had CD4 + ≥200 cells/μL, and 55.3% (21/38) had no oral candidiasis. Univariate analysis found lower CD4+ counts, higher HIV VL, and no history of HAART to be significantly associated with CE. With lower CD4+ counts and higher HIV VL, CE occurrence increased significantly (P<0.01 for trend in odds). Multivariate analysis showed low CD4+ counts and high HIV VL to be independently associated with CE. Of the severe CE patients, 55.2% (16/29) had no GI symptoms and 44.4% (8/18) had no oral candidiasis. Median CD4+ counts in severe cases were significantly lower than in mild cases (27 vs. 80; P = 0.04).Conclusions
Low CD4+ counts and high HIV VL were found to be factors associated with CE, and advanced immunosuppression was associated with the development of severity. Endoscopy is useful as it can detect CE, even severe CE, in patients without GI symptoms, those with high CD4 counts, and those without oral candidiasis. 相似文献953.
954.
Eun Sung Kim Yoon Kyung Jo So Jung Park Huikyoung Chang Ji Hyun Shin Eun Sun Choi Jun Bum Kim Su Hyeon Seok Jae-Sung Kim Jeong Su Oh Myoung-Hwan Kim Eunjoo H. Lee Dong-Hyung Cho 《FEBS letters》2013
Autophagy is a cooperative process between autophagosomes and lysosomes that degrades cellular organelles. Although autophagy regulates the turnover of cellular components, its role in melanogenesis is not clearly established. Previously, we reported that ARP101 induces autophagy in various cancer cells. Here, we show that ARP101 inhibits melanogenesis by regulation of autophagy. ARP101 inhibited α-MSH-stimulated melanin synthesis and suppressed the expression of tyrosinase and TRP1 in immortalized mouse melanocytes. ARP101 also induced autophagy in melanocytes. Knockdown of ATG5 reduced both anti-melanogenic activity and autophagy mediated by ARP101 in α-MSH treated melanocytes. Electron microscopy analysis further revealed that autophagosomes engulf melanin or melanosome in α-MSH and ARP101-treated cells. Collectively, our results suggest that ARP101 inhibits α-MSH-stimulated melanogenesis through the activation of autophagy in melanocytes. 相似文献
955.
Michael L. Ko Liheng Shi Cathy C.‐Y. Huang Kirill Grushin So‐Young Park Gladys Y.‐P. Ko 《Journal of neurochemistry》2013,127(3):314-328
Nitric oxide (NO) plays an important role in phase‐shifting of circadian neuronal activities in the suprachiasmatic nucleus and circadian behavior activity rhythms. In the retina, NO production is increased in a light‐dependent manner. While endogenous circadian oscillators in retinal photoreceptors regulate their physiological states, it is not clear whether NO also participates in the circadian regulation of photoreceptors. In this study, we demonstrate that NO is involved in the circadian phase‐dependent regulation of L‐type voltage‐gated calcium channels (L‐VGCCs). In chick cone photoreceptors, the L‐VGCCα1 subunit expression and the maximal L‐VGCC currents are higher at night, and both Ras‐mitogen‐activated protein kinase (MAPK)‐extracellular signal‐regulated kinase (Erk) and Ras‐phosphatidylinositol 3 kinase (PI3K)‐protein kinase B (Akt) are part of the circadian output pathways regulating L‐VGCCs. The NO‐cGMP‐protein kinase G (PKG) pathway decreases L‐VGCCα1 subunit expression and L‐VGCC currents at night, but not during the day, and exogenous NO donor or cGMP decreases the phosphorylation of Erk and Akt at night. The protein expression of neural NO synthase (nNOS) is also under circadian control, with both nNOS and NO production being higher during the day. Taken together, NO/cGMP/PKG signaling is involved as part of the circadian output pathway to regulate L‐VGCCs in cone photoreceptors.
956.
957.
Ki Wung Chung Hyoung Oh Jeong Eun Ji Jang Yeon Ja Choi Dae Hyun Kim So Ra Kim Kyung Jin Lee Hye Jin Lee Pusoon Chun Youngjoo Byun Hyung Ryong Moon Hae Young Chung 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
Excessive melanin production and accumulation are characteristics of a large number of skin diseases, including melasma, and post-inflammatory hyperpigmentation. During our on-going search for new agents with an inhibitory effect on tyrosinase, we synthesized a new type of tyrosinase inhibitor, 4-(thiazolidin-2-yl)benzene-1,2-diol (MHY-794), which directly inhibits mushroom tyrosinase.Methods
The inhibitory effect of MHY-794 on tyrosinase activity and nitric oxide (NO) scavenging activity was evaluated in cell free system. Additional experiments were performed using B16F10 melanoma cells to demonstrate the effects of MHY-794 in vitro. HRM2 hairless mice were used to evaluate anti-melanogenic effects of MHY-794 in vivo.Results
MHY-794 effectively inhibited mushroom tyrosinase activity in cell free system. In silico docking simulation also supported the inhibitory effects of MHY-794 on mushroom tyrosinase. MHY-794 also proved to be effective at scavenging nitric oxide (NO), which serves as an important modulator in the melanogenesis signaling pathway. In addition, MHY-794 effectively inhibited SNP (NO donor)-induced melanogenesis by directly inhibiting tyrosinase and diminishing NO-mediated melanogenesis signaling in B16 melanoma cells. The anti-melanogenic effects of MHY-794 were further confirmed in HRM2 hairless mice. Ultraviolet light (UV) significantly up-regulated NO-mediated melanogenesis signaling in HRM2 hairless mice, but MHY-794 effectively inhibited both melanogenesis and diminished UV-induced NO-signaling.Conclusions
Our results indicate that MHY-794 is highly effective at inhibiting NO-mediated melanogenesis in vitro and in vivo by direct NO scavenging and directly inhibiting tyrosinase activity, and suggest that MHY-794 be considered a new developmental candidate for the treatment of hyper-pigmentation disorders.General significance
MHY-794, which showed great efficacy on NO-mediated melanogenesis by direct NO scavenging as well as direct inhibition of tyrosinase catalytic activity, might be utilized for the development of a new candidate for treatment of the hyper-pigmentation disorders. 相似文献958.
Ginnae Ahn So Jin Bing Sung-Myung Kang Won-Woo Lee Seung-Hong Lee Hiroshi Matsuda Akane Tanaka Ik-Hyun Cho You-Jin Jeon Youngheun Jee 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
The proven immunomodulatory and immune system activating properties of Ecklonia cava (E. cava) have been attributed to its plentiful polysaccharide content. Therefore, we investigated whether the sulfated polysaccharide (SP) of E. cava specifically activates the protein kinases (MAPKs) and nuclear factor-κB (NFκB) to incite immune responses.Methods
To assess immune responsiveness, lymphocytes were isolated from spleens of ICR mice and cultured with SP and its inhibitors. Assays included 3H-thymidine incorporation, flow cytometry, real time polymerase chain reaction (rtPCR), enzyme linked immunosorbent assay (ELISA), intracellular cytokine assay, Western blot, and electrophoretic mobility shift assay (EMSA).Results
SP dose-dependently increased the proliferation of lymphocytes without cytotoxicity. In particular, SP markedly enhanced the proliferation and differentiation of CD3+ mature T cells and CD45R/B220+ pan B cells. Additionally, SP increased the expression and/or production of IL-2, IgG1a, and IgG2b compared to that in untreated cells. The subsequent application of JNK (SP600125), NFκB (PDTC), and serine protease (TPCK) inhibitors significantly inhibited the proliferation and IL-2 production of SP-treated lymphocytes as well as the phosphorylation of JNK and IκB, the activation of nuclear NFκB p65, and binding of NFκB p65 DNA. Moreover, co-application of both JNK and NFκB inhibitors completely blocked the proliferation of lymphocytes even in the presence of SP.Conclusion
These results suggest that SP induced T and B cell responses via both JNK and NFκB pathways.General significance
The effect of SP on splenic lymphocyte activation was assayed here for the first time and indicated the underlying functional mechanism. 相似文献959.
Jae Hoon Lee Hui Song Cui Seo Kyung Shin Jeong Min Kim So Yeon Kim Jong Eun Lee Bon-Nyeo Koo 《Neurochemical research》2013,38(11):2276-2286
Although propofol has been reported to offer neuroprotection against cerebral ischemia injury, its impact on cerebral edema following ischemia is not clear. The objective of this investigation is to evaluate the effects of propofol post-treatment on blood–brain barrier (BBB) integrity and cerebral edema after transient cerebral ischemia and its mechanism of action, focusing on modulation of aquaporins (AQPs), matrix metalloproteinases (MMPs), and hypoxia inducible factor (HIF)-1α. Cerebral ischemia was induced in male Sprague–Dawley rats (n = 78) by occlusion of the right middle cerebral artery for 1 h. For post-treatment with propofol, 1 mg kg?1 min?1 of propofol was administered for 1 h from the start of reperfusion. Nineteen rats undergoing sham surgery were also included in the investigation. Edema and BBB integrity were assessed by quantification of cerebral water content and extravasation of Evans blue, respectively, following 24 h of reperfusion. In addition, the expression of AQP-1, AQP-4, MMP-2, and MMP-9 was determined 24 h after reperfusion and the expression of HIF-1α was determined 8 h after reperfusion. Propofol post-treatment significantly reduced cerebral edema (P < 0.05) and BBB disruption (P < 0.05) compared with the saline-treated control. The expression of AQP-1, AQP-4, MMP-2, and MMP-9 at 24 h and of HIF-1α at 8 h following ischemia/reperfusion was significantly suppressed in the propofol post-treatment group (P < 0.05). Propofol post-treatment attenuated cerebral edema after transient cerebral ischemia, in association with reduced expression of AQP-1, AQP-4, MMP-2, and MMP-9. The decreased expression of AQPs and MMPs after propofol post-treatment might result from suppression of HIF-1α expression. 相似文献
960.
Kwang‐Youn Kim Hyo‐Jin Cho Sun‐Nyoung Yu Sang‐Hun Kim Hak‐Sun Yu Yeong‐Min Park Nooshin Mirkheshti So Young Kim Chung Seog Song Bandana Chatterjee Soon‐Cheol Ahn 《Journal of cellular biochemistry》2013,114(5):1124-1134
The limited treatment option for recurrent prostate cancer and the eventual resistance to conventional chemotherapy drugs has fueled continued interest in finding new anti‐neoplastic agents of natural product origin. We previously reported anti‐proliferative activity of deoxypodophyllotoxin (DPT) on human prostate cancer cells. Using the PC‐3 cell model of human prostate cancer, the present study reveals that DPT induced apoptosis via a caspase‐3‐dependent pathway that is activated due to dysregulated mitochondrial function. DPT‐treated cells showed accumulation of the reactive oxygen species (ROS), intracellular Ca surge, increased mitochondrial membrane potential (MMP, ΔΨm), Bax protein translocation to mitochondria and cytochrome c release to the cytoplasm. This resulted in caspase‐3 activation, which in turn induced apoptosis. The antioxidant N‐acetylcysteine (NAC) reduced ROS accumulation, MMP and Ca surge, on the other hand the Ca2+ chelator BAPTA inhibited the Ca overload and MMP without affecting the increase of ROS, indicating that the generation of ROS occurred prior to Ca2+ flux. This suggested that both ROS and Ca signaling play roles in the increased MMP via Ca‐dependent and/or ‐independent mechanisms, since ΔΨm elevation was reversed by NAC and BAPTA. This study provides the first evidence for the involvement of both ROS‐ and Ca‐activated signals in the disruption of mitochondrial homeostasis and the precedence of ROS production over the failure of Ca2+ flux homeostasis. J. Cell. Biochem. 114: 1124–1134, 2013. © 2012 Wiley Periodicals, Inc. 相似文献