Protein kinase C-related kinase targets nuclear localization signals in a subset of class IIa histone deacetylases

Class IIa histone deacetylases (HDACs) -4, -5, -7 and -9 undergo signal-dependent nuclear export upon phosphorylation of conserved serine residues that are targets for 14-3-3 binding. Little is known of other mechanisms for regulating the subcellular distribution of class IIa HDACs. Using a biochemical purification strategy, we identified protein kinase C-related kinase-2 (PRK2) as an HDAC5-interacting protein. PRK2 and the related kinase, PRK1, phosphorylate HDAC5 at a threonine residue (Thr-292) positioned within the nuclear localization signal (NLS) of the protein. HDAC7 and HDAC9 contain analogous sites that are phosphorylated by PRK, while HDAC4 harbors a non-phosphorylatable alanine residue at this position. We provide evidence to suggest that the unique phospho-acceptor cooperates with the 14-3-3 target sites to impair HDAC nuclear import.

Structured summary

MINT-7710106:HDAC5 (uniprotkb:Q9UQL6) physically interacts (MI:0915) with PRK2 (uniprotkb:Q16513) by pull down (MI:0096)     

Design,synthesis and biological evaluation of novel histone deacetylase inhibitors incorporating 4-aminoquinazolinyl systems as capping groups

A series of hydroxamic acid-based HDACIs with 4-aminoquinazolinyl moieties as capping groups was profiled. Most compounds showed more potent HDACs inhibition activity than clinically used drug SAHA. Among them, compounds 5f and 5h selectively inhibited HDAC 1,2 over HDAC8, and showed strong activity in several cellular assays, not possessing significant toxicity to primary human cells and hERG inhibition. Strikingly, 5f possessed acceptable pharmacokinetic characteristics and exhibited significant antitumor activity in an A549 xenograft model study at well tolerated doses.     

Role of class I and class II histone deacetylases in carcinoma cells using siRNA

The role of the individual histone deacetylases (HDACs) in the regulation of cancer cell proliferation was investigated using siRNA-mediated protein knockdown. The siRNA for HDAC3 and HDAC1 demonstrated significant morphological changes in HeLa S3 consistent with those observed with HDAC inhibitors. SiRNA for HDAC 4 or 7 produced no morphological changes in HeLa S3 cells. HDAC1 and 3 siRNA produced a concentration-dependent inhibition of HeLa cell proliferation; whereas, HDAC4 and 7 siRNA showed no effect. HDAC3 siRNA caused histone hyperacetylation and increased the percent of apoptotic cells. These results demonstrate that the Class I HDACs such as HDACs 1 and 3 are important in the regulation of proliferation and survival in cancer cells. These results and the positive preclinical results with non-specific inhibitors of the HDAC enzymes provide further support for the development of Class I selective HDAC inhibitors as cancer therapeutics.     

血小板生成素研究进展

血小板生成素(thrombopoietin,TPO)是近几年发现的一种造血生长因子,其功能是促进巨核细胞的发育成熟,调节血液中血小板的水平。由于它在临床上纠正较难对付的血小板减少症方面具有较好的应用前景,短短两年时间其开发研究已进入了Ⅰ/Ⅱ期临床试验,据称初步结果比较乐观;在理论研究方面,TPO基因的克隆大大丰富了人们对巨核细胞发育过程和调控机制的认识,出现了大量相关文献。本文根据最新文献,综述人们在有关TPO的表达调控、信号转导、生物活性、临床应用等方面的认识。     

Recent advances in ion channel research

The field of ion channels has entered into a rapid phase of development in the last few years, partly due to the breakthroughs in determination of the crystal structures of membrane proteins and advances in computer simulations of biomolecules. These advances have finally enabled the long-dreamed goal of relating function of a channel to its underlying molecular structure. Here we present simplified accounts of the competing permeation theories and then discuss their application to the potassium, gramicidin A and calcium channels.     

肩周炎活动受限的分子生物学研究新进展

肩周炎(FS)是一种常见疾病,分为急性期、慢性期和恢复期3个阶段,其特点是肩部疼痛和各个方向的运动受限。由于长期肩关节活动受限,一些患者生活质量明显下降。目前,关于肩周炎活动受限的分子生物学的文献很少,并且对关节周围炎引起的肩关节运动受限的分子生物学机制仍不清楚。有研究表明,肩周炎患者较正常人滑膜组织内某些炎症介质和纤维化相关细胞因子有所改变,这些细胞因子可能通过引起肩关节结构变化导致肩关节运动受限,从而参与肩周炎的发生。     

艾滋病患者肠道微生态与抗逆转录病毒治疗及耐药相关性研究新进展

艾滋病(AIDS)是一种由人类免疫缺陷病毒(HIV)引起的免疫缺陷性疾病,因其高传染性和不可治愈而备受关注。本文综述了HIV患者肠道菌群的变化与其发病机制、抗逆转录病毒耐药及肠道免疫激活的相关性。抗逆转录病毒治疗(ART)是降低肠道黏膜免疫和导致持续炎症的独立风险因素。肠道菌群参与或干扰抗病毒药物的代谢,造成肠道黏膜的通透性增加,微生物移位,激活不同的T细胞亚群的免疫活性,产生炎性因子导致CD4+细胞数量持续低下。某些特定的益生菌及粪菌移植(FMT)可调节HIV患者的肠道微生态的平衡,延缓AIDS的发病进程。     

Recent advances in polysaccharide bio-based flocculants

Natural polysaccharides, derived from biomass feedstocks, marine resources, and microorganisms, have been attracting considerable attention as benign and environmentally friendly substitutes for synthetic polymeric products. Besides many other applications, these biopolymers are rapidly emerging as viable alternatives to harmful synthetic flocculating agents for the removal of contaminants from water and wastewater. In recent years, a great deal of effort has been devoted to improve the production and performance of polysaccharide bio-based flocculants. In this review, current trends in preparation and chemical modification of polysaccharide bio-based flocculants and their flocculation performance are discussed. Aspects including mechanisms of flocculation, biosynthesis, classification, purification and characterization, chemical modification, the effect of physicochemical factors on flocculating activity, and recent applications of polysaccharide bio-based flocculants are summarized and presented.     

中药抗卵巢癌作用及机制研究新进展

卵巢癌是女性常见的生殖器官恶性肿瘤之一,严重威胁着女性的生殖健康.中药治疗卵巢癌具有多靶点、多途径、毒副作用小等特点,近年来已成为国内外学者的研究热点.本文系统总结了中药复方药、植物药(多糖、黄酮类、生物碱、酚类、萜类、醌类、皂苷、酯类、挥发油、醚类)、动物药及矿物药抗卵巢癌的活性及作用机制,并初步分析了中药有效成分抗...     

Mental health care for older adults: recent advances and new directions in clinical practice and research

The world''s population is aging, bringing about an ever‐greater burden of mental disorders in older adults. Given multimorbidities, the mental health care of these people and their family caregivers is labor‐intensive. At the same time, ageism is a big problem for older people, with and without mental disorders. Positive elements of aging, such as resilience, wisdom and prosocial behaviors, need to be highlighted and promoted, both to combat stigma and to help protect and improve mental health in older adults. The positive psychiatry of aging is not an oxymoron, but a scientific construct strongly informed by research evidence. We champion a broader concept of geriatric psychiatry – one that encompasses health as well as illness. In the present paper, we address these issues in the context of four disorders that are the greatest source of years lived with disability: neurocognitive disorders, major depression, schizophrenia, and substance use disorders. We emphasize the need for implementation of multidisciplinary team care, with comprehensive assessment, clinical management, intensive outreach, and coordination of mental, physical and social health services. We also underscore the need for further research into moderators and mediators of treatment response variability. Because optimal care of older adults with mental disorders is both patient‐focused and family‐centered, we call for further research into enhancing the well‐being of family caregivers. To optimize both the safety and efficacy of pharmacotherapy, further attention to metabolic, cardiovascular and neurological tolerability is much needed, together with further development and testing of medications that reduce the risk for suicide. At the same time, we also address positive aging and normal cognitive aging, both as an antidote to ageism and as a catalyst for change in the way we think about aging per se and late‐life mental disorders more specifically. It is in this context that we provide directions for future clinical care and research.