Keap1-Nrf2-ARE通路与脑缺血

Keap1 -Nrf2-ARE通路在抗肿瘤、抗应激、抗凋亡、抗炎症等方面具有广泛的细胞保护功能.其在神经系统疾病中的神经保护作用已成为目前的研究热点之一.文章综述了Keap1-Nrf2-ARE通路在脑缺血中的神经保护作用.     

The effect of RCTs on drug demand: Evidence from off-label cancer drugs

This paper investigates the effect of scientific information from randomized controlled clinical trials (RCTs) on the demand for off-label uses of cancer drugs. This is a unique setting where demand for a drug for a specific use is observable both before and after the first RCT results are released. Using variation in the timing of RCTs across off-label uses of drugs, I find that demand responds asymmetrically to the trial results based on the statistical significance of the clinically relevant endpoint. When this endpoint is statistically significant, there is a large and immediate increase in demand. When this end point is not statistically significant, physicians are relatively slow to abandon use of the drug.     

MicroRNA在胃癌中的调控机制及预后价值

作为非编码RNA (ncRNAs)的一种,微小RNA(microRNA,miRNA)在基因表达调控方面受到广泛关注.MiRNA参与细胞周期、细胞凋亡、细胞迁移等进程,在肿瘤发生发展过程中也发挥重要作用.中国胃癌发病率较高,但对胃癌的治疗未能取得突破性进展,进展期胃癌患者往往预后不佳.目前尚缺乏可对胃癌患者预后进行判断的有效生物学标志,胃癌耐药也是临床的棘手问题.如何根据有效的生物学标志来判断预后,并针对这些靶点展开治疗,如何改善胃癌化疗耐药问题.miRNA在基因调控方面的作用给攻破这些难题带来了可能.该文是近年来关于miRNA与胃癌患者预后关系,改善患者预后,化疗耐药调控等方面的最新研究的综合论述.     

The lipid connection–regulation of voltage-gated Ca2+ channels by phosphoinositides

Recent findings have revealed a pivotal role for phospholipids phosphatidylinositol -4,5-biphosphate (PIP₂) and phosphatidylinositol -3,4,5-trisphosphate (PIP₃) in the regulation of high voltage-activated (HVA) Ca²⁺ channels. PIP₂ exerts two opposing actions on HVA Ca²⁺ channels: It stabilizes their activity but also produces a voltage-dependent inhibition that can be antagonized by protein kinase A (PKA) phosphorylation. PIP₂ depletion and arachidonic acid together mediate the slow, voltage-independent inhibition of HVA Ca²⁺ channels by G _q/11 -coupled receptors in neurons. A sufficient level of plasma membrane PIP₂ also appears to be necessary for G _βγ -mediated inhibition. On the other hand, increased production of PIP₃ by PI-3 kinases promotes trafficking of HVA Ca²⁺ channels to the plasma membrane. This review discusses these findings and their implications.     

An examination of the incremental contribution of emotion regulation difficulties to health anxiety beyond specific emotion regulation strategies

Given the potential transdiagnostic importance of emotion dysregulation, as well as a lack of research examining emotion dysregulation in relation to health anxiety, the present study sought to examine associations among specific emotion regulation strategies (cognitive reappraisal and expressive suppression), emotion regulation difficulties, and health anxiety in a physically healthy sample of adults (N = 482). As hypothesized, results of a series of hierarchical multiple regression analyses showed that emotion regulation difficulties provided a significant incremental contribution, beyond the specific emotion regulation strategies, in predicting each of the three health anxiety variables. Among the six dimensions of emotion regulation difficulties, the dimension representing perceived access to effective emotion regulation strategies was the only emotion regulation difficulty dimension that predicted all three health anxiety variables beyond the effects of the specific emotion regulation strategies. Results indicate that emotion regulation difficulties, and particularly one's subjective appraisal of his/her ability to effectively regulate emotions, may be of importance to health anxiety. Clinical implications are discussed.     

健康大鼠血管衰老性重塑与血管衰老相关基因的关系

目的通过研究健康大鼠血管衰老性重塑形态学变化及衰老相关基因表达,探讨血管衰老性重塑可能的分子调控机制,为临床有效干预血管衰老提供分子靶点。方法观察主动脉组织形态及内皮细胞显微结构变化,应用Western blotting分析4、10、16月和24月龄大鼠血管重塑p16INK4a和p21cip1蛋白表达变化。结果随增龄,大鼠主动脉管壁增厚,纤维化程度增高,内皮细胞形态呈现衰老改变,p16INK4a和p21cip1蛋白表达呈时间依赖性上调。结论血管衰老性重塑的分子机制之一可能与上调细胞周期蛋白p16INK4a和p21cip1的表达有关。进一步阐明其调控机制可为延缓血管衰老,防治动脉粥样硬化提供理论依据。     

Intracellular energetic units in healthy and diseased hearts

BACKGROUND:

The present review examines the role of intra-cellular compartmentation of energy metabolism in vivo.

OBJECTIVE:

To compare the kinetics of the activation of mitochondrial respiration in skinned cardiac fibres by exogenous and endogenous adenine nucleotides in dependence of the modulation of cellular structure and contraction.

METHODS:

Saponin-permeabilized cardiac fibres or cells were analyzed using oxygraphy and confocal microscopy.

RESULTS:

Mitochondria respiration in fibres or cells was upregulated by cumulative additions of ADP to the medium with an apparent K_m of 200 μM to 300 μM. When respiration was stimulated by endogenous ADP produced by intracellular ATPases, a near maximum respiration rate was achieved at an ADP concentration of less than 20 μM in the medium. A powerful ADP-consuming system, consisting of pyruvate kinase and phosphoenolpyruvate, that totally suppressed the activation of respiration by exogenous ADP, failed to abolish the stimulation of respiration by endogenous ADP, but did inhibit respiration after the cells were treated with trypsin. The addition of up to 4 μM of free Ca²⁺ to the actively respiring fibres resulted in reversible hypercontraction associated with a decreased apparent K_m for exogenous ADP. These changes were fully abolished in fibres after the removal of myosin by KCl treatment.

CONCLUSIONS:

Mitochondria and ATPases, together with cytoskeletal proteins that establish the structural links between mitochondria and sarcomeres, form complexes – intracellular energetic units (ICEUs) – in cardiac cells. Within the ICEUs, the mitochondria and ATPases interact via specialized energy transfer systems, such as the creatine kinase- and adenylate kinase-phosphotransfer networks, and direct ATP channelling. Disintegration of the structure and function of ICEUs results in dyscompartmentation of adenine nucleotides and may represent a basis for cardiac diseases.