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71.
72.
目的探讨饥饿诱导损伤调节自噬调控基因(DRAM)介导的自噬在HepG2细胞和Hep3B细胞凋亡中的作用。方法 HepG2细胞和Hep3B细胞经饥饿处理后,观察DRAM的表达和自噬的发生;利用DRAM小干扰RNA(siRNA)阻断DRAM,观察饥饿诱导的自噬水平;采用Calcein AM/PI染色,观察DRAM siRNA对饥饿引起的细胞凋亡的影响。结果经饥饿处理后12、24、36h,HepG2细胞和Hep3B细胞内DRAMmRNA均显著高于处理前(P﹤0.001),细胞凋亡明显增加(P﹤0.01),但两种细胞系间细胞凋亡计数的差异无统计学意义。DRAM siRNA阻断DRAM的功能后,HepG2和Hep3B细胞自噬减少,但对饥饿引起的细胞凋亡没有明显影响。结论 DRAM参与了饥饿诱导的自噬,可能不是饥饿引起肝癌细胞凋亡的机制。 相似文献
73.
Y.-H. Lee A. Bhattacharyya X. Wen Tang E.-C. Seah K. Schmidt D. L. Deupree Jang-Yen Wu 《Journal of neuroscience research》1995,40(6):797-806
One of the endogenous substances which modulate glutamate receptor binding was isolated and highly purified from porcine brain. The purification involved extraction of brain tissue with doubled distilled water, followed by gel filtration, anion exchange, cation exchange, and several steps of C18 reverse-phase high performance liquid chromatography (HPLC). A low molecular weight glutamate binding inhibitor (LGBI) was purified to apparent homogeneity as judged from the elution profile of an HPLC column, in which a symmetrical peak was obtained when the eluate was monitored at 220 nm. The LGBI appears to be a small molecule (< 2 kD) that is heat-and acid/base-stable. The highly purified LGBI has no effect on GABAA and benzodiazepine receptor binding. The LGBI is not L-glutamate, L-aspartate or other negatively charged endogenous substances, since they are clearly separated from the LGBI in anion exchange chromatography. The inhibitory effect of the LGBI on [3H]L-glutamate binding is reversible, and it only changes the Bmax while the Kd remains the same. Since the membrane preparations used for [3H]L-glutamate binding assays for the detection of LGBI activity were enriched with quisqualate (QA)-sensitive subtypes, it was suggested that the LGBI could be a modulator of the QA receptor. Some amino acids which produce significant inhibition of glutamate binding activity were also compared with the LGBI, and they all showed no resemblance to the LGBI. The chemical structure of the LGBI remains to be determined. © 1995 Wiley-Liss, Inc. 相似文献
74.
Jochen Müller-Ehmsen Klara Brixius Costas Schulze R. H. G. Schwinger 《Naunyn-Schmiedeberg's archives of pharmacology》1997,355(6):727-732
The enhancement of force of contraction (FOC) following increasing frequencies of stimulation is an important mechanism of
positive inotropy in human myocardium. The present study aimed to investigate the influence of alterations in Na+ influx on FFR in human myocardium. Isometric FOC of electrically stimulated right auricular trabeculae (AUT, n=12) from human nonfailing hearts (n=8) was measured at different stimulation rates (0.5-3 Hz) under control conditions, after increasing Na+ influx by the addition of (±)BDF 9148 (BDF, 3 μmol l-1) and after decreasing Na+ influx by the addition of lidocaine (LIDO, 10 μmol l-1). Additionally, the rate dependent changes in diastolic tension (DT) were measured in all experiments. Under control conditions
FOC increased with increasing frequencies of stimulation. The rate at which maximal FOC was observed (SFmax) was 2.0±0.2 Hz
and maximal increase in FOC (PIEmax) by increasing frequency of stimulation was +1.5±0.5 mN. After increase of Na+ influx by BDF (3 μmol l-1) SFmax was decreased to 0.8±0.1 Hz (p<0.05 versus control) and PIEmax was +0.1±0.3 mN (p<0.05). When Na+ influx was diminished by LIDO (10 μmol l-1) SFmax and PIEmax were increased compared to control (2.4±0.1 Hz and +4.1±0.9 mN, p<0.05 versus control). The diastolic tension (DT) of AUT at 3 Hz was not changed at higher rates in the control group and
after application of LIDO (10 μmol l-1), whereas after enhancement of Na+ influx by BDF there was an increase in DT of +0.7±0.2 at 3Hz (p<0.05 versus control and LIDO). An enhanced Na+ influx leads to a decrease in the optimal frequency and to a smaller force potentiation by higher stimulation rates which
could be at least partly due to incomplete relaxation at higher frequencies, whereas a reduced Na+ influx is followed by opposite alterations. It is concluded that besides Ca2+ handling also Na+ influx and Na+ homeostasis might determine the frequency-induced force potentiation in human myocardium. Thus, the negative FFR in diseased
human myocardium might result from changes in cellular Ca2+ or Na+ regulatory sites.
Received: 20 November 1996 / Accepted: 21 February 1997 相似文献
75.
The modulatory effects of taurine on [35S]-t-Butylbicyclophosphorothionate (TBPS) binding to rat brain synaptic membranes were evaluated and compared with that of GABA. Taurine allosterically inhibited TBPS binding by interacting with a bicuculline-sensitive site, similar to GABA. Taurine was as effective as GABA but less potent. The potency of taurine inhibition of TBPS binding varied among brain regions with cerebellum > olfactory bulb > cortex, similar to that of GABA. Inhibition of TBPS binding to cortical membranes measured under nonequilibrium conditions yielded a dynamic biphasic inhibition curve that was similarly shaped for GABA and taurine. The effect of taurine on TBPS binding was pharmacologically specific in that β-alanine and guanadinoethanesulfonate were as effective as taurine, while hypotaurine and -aminoethylhydrogen sulfate were only partially effective at high concentrations, and isethionic acid was without effect. Taurine, similar to GABA enhanced the effects of pentobarbital on TBPS binding when present at concentrations that were otherwise ineffective on their own. The results of these studies support the notion that taurine interacts with the GABA recognition site of the GABAA receptor complex. 相似文献
76.
OBJECTIVE: Tamoxifen, which is widely used in the treatment of breast cancer, also has a beneficial effect on cisplatin-refractory ovarian cancer. In this study, we investigated the long-term effects of this drug on estrogen-receptor-positive ovarian cancer cells. METHODS: We performed an in vitro selection process by long-term treatment of BG-1 ovarian cancer cells with 4-hydroxy tamoxifen (4-OH TAM). Drug effects on cell growth were determined by measurement of relative cell numbers (MTS assay), the apoptotic effects of 4-OH TAM were determined by analysis of poly (ADP-ribose) polymerase (PARP) cleavage and by ELISA measurement of DNA-histone complexes in cytoplasm. RESULTS: Analysis of BG-1(LT) ovarian cancer cells isolated after 5 months of long-term treatment with 4-OH TAM revealed both a significantly reduced apoptotic and antiproliferative effect of this drug. Further experiments to examine expression changes of the receptor tyrosine kinases EGFR, HER2 and estrogen receptor alpha did not reveal any alterations in BG-1(LT) if compared to wild-type cells. In contrast, in this cell line, a significant alteration in the expression of estrogen receptor beta was observed. CONCLUSION: Our findings indicate that long-term treatment with 4-OH TAM is able to diminish both the antiproliferative and apoptotic action of this drug on BG-1 ovarian cancer cells. Our data suggest that the responsiveness of ovarian cancer cells to 4-OH TAM decreases after long-term treatment with this drug in vitro like previously observed after long-term treatment of breast cancer cells. 相似文献
77.
V. I. Medvedev V. D. Bakharev O. A. Kaurov 《Neuroscience and behavioral physiology》1985,15(3):240-246
Neuropeptides are shown to exert a powerful influence on mnestic processes. They actively eliminate phenomena of electric-shock amnesia, the strongest agent here being arginine vasopressin, while derivatives of oxytocin, enkephalin, and melano-statin are active to a lesser degree. The selective effect on primary learning (ACTH4–7 and Leu-enkephalin) and on the consolidation and restoration of memory (vasopressin and oxytocin), and the presence of only antiamnestic properties (analog of the melanocyte-inhibiting factor)-all this suggests different mechanisms of action of these agents. Memory modulators act more strongly upon activated systems that are already prepared to receive the signal. A promising object for future study as a therapeutic antiamnestic factor is the long-term memory modulator arginine vasopressin.Translated from Fiziologicheskii Zhurnal SSSR imeni I. M. Sechenova, Vol. 68, No. 10, pp. 1322–1329, October, 1982. 相似文献
78.
Yan J Li L Khatibi NH Yang L Wang K Zhang W Martin RD Han J Zhang J Zhou C 《Experimental neurology》2011,230(2):240-247
The blood–brain barrier (BBB) plays a vital role as both a physiologic and physical barrier in regulating the movement of water from the vasculature to the brain. During a subarachnoid hemorrhage (SAH), the BBB is disrupted by a variety of mediators, one of which can result in endothelial cell death. As a result, in the present study, we investigated the role of PUMA (p53 upregulated modulator of apoptosis) following SAH injury in rats. Specifically evaluating whether through the endoplasmic reticulum (ER), PUMA could orchestrate the induction of endothelial cell apoptosis and cause a disruption in the blood–brain barrier integrity. One hundred twelve male Sprague–Dawley rats were randomly divided into 4 groups: sham, SAH, SAH + control siRNA, SAH + PUMA siRNA. Outcomes measured include mortality rate, brain edema, BBB disruption, and neurobehavioral testing. We also used Western blotting techniques to measure the expression of key pro-apoptotic proteins such as BAX, BAK, and DRP1. PUMA siRNA treatment significantly reduced the mortality rate, cerebral edema, neurobehavioral deficits, and BBB disruption as measured by Evans blue assay following SAH injury. The T2WI images showed there was an increase in vasogenic edema in the brain following SAH, which could be alleviated by PUMA siRNA. Immunohistochemical staining and Western blot analysis demonstrated an increased expression of PUMA, BAX, BAK, GRP78 and DRP1 in the microvascular endothelial cells of the hippocampus, which was accompanied with endothelium apoptosis. This study showed that PUMA induced endothelial cell apoptosis may in fact play a significant role in BBB disruption following SAH and its mediation may be through the endoplasmic reticulum. By blocking the activity of PUMA using siRNA, we were able to prevent the accumulation of cerebral edema that occurs following BBB disruption. This translated into a preservation of functional integrity and an improvement in mortality. 相似文献
79.
This Review describes recent activity in the advancement of ligands for the metabotropic glutamate 4 receptor subtype and their potential utility as central nervous system (CNS) therapeutics. Until recently, there was a paucity of compounds with suitable selectivity and druglike properties to elucidate the value of this target. The search for selective entities has led several groups to the investigation of allosteric modulators as a path to optimization of potential ligands. Recent efforts, discussed here, have afforded a variety of derivatives with improvements in potency, solubility, and pharmacokinetic properties that garner support for continued investigation and optimization. 相似文献
80.
SR Stauffer 《ACS chemical neuroscience》2011,2(8):450-470
This Review describes recent trends in the development of small molecule mGlu(5) positive allosteric modulators (PAMs). A large body of pharmacological, genetic, electrophysiological, and in vivo behavioral evidence has accumulated over the past decade which continues to support the hypothesis and rationale for the activation of the metabotropic glutamate receptor subtype 5 (mGlu(5)) as a viable and promising target for the development of novel antipsychotics. Until recently, functionally efficacious and potent mGlu(5) PAMs have been somewhat structurally limited in scope and slow to emerge. This Review will discuss efforts since late 2008 which have provided novel mGlu(5) PAM chemotypes, offering ligands with a diverse range of pharmacological, physicochemical, and DMPK properties that were previously unavailable. In addition, significant biological studies of importance in the past few years using the well established PAMs known as DFB, CPPHA, CDPPB, and ADX-47273 will be discussed. 相似文献