The Role of Cell Cycle Regulators in Cell Survival—Dual Functions of Cyclin-Dependent Kinase 20 and p21Cip1/Waf1

The mammalian cell cycle is important in controlling normal cell proliferation and the development of various diseases. Cell cycle checkpoints are well regulated by both activators and inhibitors to avoid cell growth disorder and cancerogenesis. Cyclin dependent kinase 20 (CDK20) and p21^Cip1/Waf1 are widely recognized as key regulators of cell cycle checkpoints controlling cell proliferation/growth and involving in developing multiple cancers. Emerging evidence demonstrates that these two cell cycle regulators also play an essential role in promoting cell survival independent of the cell cycle, particularly in those cells with a limited capability of proliferation, such as cardiomyocytes. These findings bring new insights into understanding cytoprotection in these tissues. Here, we summarize the new progress of the studies on these two molecules in regulating cell cycle/growth, and their new roles in cell survival by inhibiting various cell death mechanisms. We also outline their potential implications in cancerogenesis and protection in heart diseases. This information renews the knowledge in molecular natures and cellular functions of these regulators, leading to a better understanding of the pathogenesis of the associated diseases and the discovery of new therapeutic strategies.     

Sensitization of MCF7 Cells with High Notch1 Activity by Cisplatin and Histone Deacetylase Inhibitors Applied Together

Histone deacetylase inhibitors (HDIs) are promising anti-cancer agents that inhibit proliferation of many types of cancer cells including breast carcinoma (BC) cells. In the present study, we investigated the influence of the Notch1 activity level on the pharmacological interaction between cisplatin (CDDP) and two HDIs, valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA, vorinostat), in luminal-like BC cells. The type of drug–drug interaction between CDDP and HDIs was determined by isobolographic analysis. MCF7 cells were genetically modified to express differential levels of Notch1 activity. The cytotoxic effect of SAHA or VPA was higher on cells with decreased Notch1 activity and lower for cells with increased Notch1 activity than native BC cells. The isobolographic analysis demonstrated that combinations of CDDP with SAHA or VPA at a fixed ratio of 1:1 exerted additive or additive with tendency toward synergism interactions. Therefore, treatment of CDDP with HDIs could be used to optimize a combined therapy based on CDDP against Notch1-altered luminal BC. In conclusion, the combined therapy of HDIs and CDDP may be a promising therapeutic tool in the treatment of luminal-type BC with altered Notch1 activity.     

Migraine: Calcium Channels and Glia

Migraine is a common neurological disease that affects about 11% of the adult population. The disease is divided into two main clinical subtypes: migraine with aura and migraine without aura. According to the neurovascular theory of migraine, the activation of the trigeminovascular system (TGVS) and the release of numerous neuropeptides, including calcitonin gene-related peptide (CGRP) are involved in headache pathogenesis. TGVS can be activated by cortical spreading depression (CSD), a phenomenon responsible for the aura. The mechanism of CSD, stemming in part from aberrant interactions between neurons and glia have been studied in models of familial hemiplegic migraine (FHM), a rare monogenic form of migraine with aura. The present review focuses on those interactions, especially as seen in FHM type 1, a variant of the disease caused by a mutation in CACNA1A, which encodes the α1A subunit of the P/Q-type voltage-gated calcium channel.     

Salivary Proteome Changes in Response to Acute Psychological Stress Due to an Oral Exam Simulation in University Students: Effect of an Olfactory Stimulus

The autonomic nervous system (ANS) plays a crucial role both in acute and chronic psychological stress eliciting changes in many local and systemic physiological and biochemical processes. Salivary secretion is also regulated by ANS. In this study, we explored salivary proteome changes produced in thirty-eight University students by a test stress, which simulated an oral exam. Students underwent a relaxation phase followed by the stress test during which an electrocardiogram was recorded. To evaluate the effect of an olfactory stimulus, half of the students were exposed to a pleasant odor diffused in the room throughout the whole session. Saliva samples were collected after the relaxation phase (T0) and the stress test (T1). State anxiety was also evaluated at T0 and T1. Salivary proteins were separated by two-dimensional electrophoresis, and patterns at different times were compared. Spots differentially expressed were trypsin digested and identified by mass spectrometry. Western blot analysis was used to validate proteomic results. Anxiety scores and heart rate changes indicated that the fake exam induced anxiety. Significant changes of α-amylase, polymeric immunoglobulin receptor (PIGR), and immunoglobulin α chain (IGHA) secretion were observed after the stress test was performed in the two conditions. Moreover, the presence of pleasant odor reduced the acute social stress affecting salivary proteome changes. Therefore, saliva proteomic analysis was a useful approach to evaluate the rapid responses associated to an acute stress test also highlighting known biomarkers.     

Boosting the activity of FeOOH via integration of ZIF-12 and graphene to efficiently catalyze the oxygen evolution reaction

Transition metal oxyhydroxides have been used as promising electrocatalysts for water splitting however, their catalytic activity is restricted due to low surface area and poor conductivity. Herein, we report novel composite FeOOH@ZIF-12/graphene composite as electrocatalyst for water oxidation, whereby ZIF-12 provide extra surface for the FeOOH dispersion whilst graphene act as excellent electron mediator. The composite shows a low overpotential value of 291 mV to attain a current density of 10 mA cm^?2 and a low Tafel slope value of 78 mV dec^?1. The catalyst offers a maximum current density of 101 mA cm^?2, while it gives a turnover frequency (TOF) value of 0.031 s^?1 at an overpotential of 291 mV only. The excellent activity and remarkable stability of composite is attributed to highly conductive and porous support.     

Seismic behavior of geosynthetic-reinforced retaining walls backfilled with cohesive soil

This study investigates the seismic performance of geosynthetic-reinforced modular block retaining walls backfilled with cohesive, fine grained clay-sand soil mixture. Shaking table tests were performed for three ½ scaled (wall height 190 cm) and ¼ scaled model walls to investigate the effects of backfill type, the influence of reinforcement length and reinforcement stiffness effects. The El Centro and Kobe earthquake records of varying amplitudes were used as base acceleration. Displacement of the front wall, accelerations at different locations, strains on the reinforcements, and the visual observations of the facing and the backfill surface were used to evaluate the seismic performance of model walls. The model walls were subjected to rigorous shaking and the walls did not exhibit any stability problems or signs of impending failure. The maximum deformations observed on the models with cohesive backfill was less than half of the deformation of the sand model. The load transfers between the geogrid and cohesive soil was comparable to that of sand and hence the needed reinforcement length was similar as well. As a result; the model walls with cohesive backfills performed within acceptable limits under seismic loading conditions when compared with granular backfilled counterparts.     

樟芝多糖通过降低NLRP3 Caspase1炎性小体表达改善帕金森小鼠神经行为学的机制研究

目的:研究樟芝多糖通过降低NLRP3-Caspase1炎性小体表达改善6-OHDA构建的帕金森小鼠模型的行为学机制。方法:利用6-OHDA脑内注射构建帕金森小鼠模型，通过酪氨酸羟化酶（TH）免疫组化染色和行为学判定小鼠模型的构建成功。利用樟芝多糖进行干预，分别在干预前、干预后的第1、3、7天4个时间点进行神经行为学实验，分别采用转棒实验、爬杆实验检测小鼠自主行为能力以及协调能力，4个时间点取小鼠尾静脉外周血采用ELISA法检测外周血中Caspase1和IL-1β的表达，樟芝多糖干预第7天时待进行完行为学实验后小鼠断颈处死，取小鼠脑组织-纹状体，Western blot法检测纹状体中Caspase1、proCaspase1、NLRP3的表达，高效液相色谱检测纹状体中单胺类神经递质的表达，RT-QPCR检测Caspase1、NLRP3、IL-1β、IL-4、IL-6的mRNA表达。NISSl染色检测小鼠脑组织神经细胞凋亡情况。 结果:6-OHDA脑内注射可以造成小鼠帕金森样病变，且TH蛋白表达显著下调，樟芝多糖干预后小鼠的行为学得到显著改善（P<0.05），纹状体中Caspase1、proCaspase1、NLRP3的表达显著下调，与模型小鼠相比具有统计学差异（P<0.05），且相关炎症因子Caspase1、NLRP3、IL-1β、IL-4、IL-6的mRNA表达下调（P<0.05），纹状体中单胺类神经递质表达上升（P<0.05）。结论:樟芝多糖可以通过下调NLRP3-Caspase1炎性小体表达来改善6-OHDA构建的帕金森小鼠模型行为改善，这可能是樟芝多糖治疗帕金森的机制之一。