组蛋白去乙酰化酶抑制剂与肾脏疾病

组蛋白去乙酰化是组蛋白表观遗传学修饰的重要的方式之一。组蛋白去乙酰化酶(HDACs)作为调控基因的关键蛋白,其功能异常早已被证实与肿瘤、神经退行性病变、肾脏病等发生和发展关系密切,进而推动HDAC抑制剂(HDACi)的研发及临床应用。本文综述HDACs在肾脏病发生发展中的作用及HDACi在肾脏病治疗中的应用前景。     

Epigenetics and Epigenetic Alterations in Pancreatic Cancer

Pancreatic cancer remains a major therapeutic challenge. In 2008, there will be approximately 37,680 new cases and 34,290 deaths attributable to pancreatic cancer in the United States (U.S.), making it the fourth leading cause of cancer-related death. Recent comprehensive pancreatic cancer genome project found that pancreatic adenocarcinomas harbored 63 intragenic mutations or amplifications/homozygous deletions and these alterations clustered in 12 signaling pathways. In addition to widespread genetic alterations, it is now apparent that epigenetic mechanisms are also central to the evolution and progression of human cancers. Since epigenetic silencing processes are mitotically heritable, they can drive neoplastic progression and undergo the same selective pressure as genetic alterations. This review will describe recent developments in cancer epigenetics and their importance in our understanding of pancreatic adenocarcinomas.     

Differential allele expression of host defense genes, pulmonary surfactant protein-A and osteopontin, in rat

Differential allele-specific expression has been observed in several genes involved in immunity. SP-A and OPN play a role in innate host defense. To determine whether SP-A and OPN are subject to differential allele-specific regulation, we investigated their gene or allele-specific expression in various tissues. The results showed: (1) Tissue-specific expression with high levels in lung (SP-A) and kidney (OPN). (2) Differences in allele-specific expression among individuals and tissues. SP-A showed an exclusively balanced biallelic expression (BB) in lung, but both BB and imbalanced biallelic (IB) expression in colon. Allele expression of OPN was more heterogeneous, e.g. in colon BB (22%), IB (64%), and monoallelic expression (MO) (14%). (3) Differential allele-specific expression was observed in all tissues studied (OPN) or in all extrapulmonary tissues (SP-A). (4) Family studies indicated that inheritable factor(s) may be involved in the regulation of allele-specific expression. (5) Analysis of co-expression of gene-specific alleles from double heterozygous rats revealed lack of coordinate allele expression among SP-A, SP-D, and OPN. We conclude that allele-specific expression occurs among genes of innate host defense. This may yet provide another level of regulatory complexity for molecules involved in the first line of defense.     

Novel epigenetic-based therapies useful in cardiovascular medicine

Epigenetic modifications include DNA methylation, his-tone modifications, and micro RNA. Gene alterations have been found to be associated with cardiovascular diseases, and epigenetic mechanisms are continuously being studied to find new useful strategies for the clinical management of afflicted patients. Numerous cardiovascular disorders are characterized by the abnormal methylation of Cp G islands and so specific drugs that could inhibit DNA methyltransferase directly or by reducing its gene expression(e.g., hydralazine and procainamide) are currently under investigation. The anti-proliferative and anti-inflammatory properties of histone deacetylase inhibitors and their cardio-protective effects have been confirmed in preclinical studies. Furthermore, the regulation of the expression of micro RNA targets through pharmacological tools is still under development. Indeed, large controlled trials are required to establish whether current possible candidate antisense micro RNAs could offer better therapeutic benefits in clinical practice. Here, we updated therapeutic properties, side effects, and feasibility of eme-rging epigenetic-based strategies in cardiovascular diseases by highlighting specific problematic issues that still affect the development of large scale novel therapeutic protocols.     

Generating long‐lived CD8+ T‐cell memory: Insights from epigenetic programs

T‐cell‐based immunological memory has the potential to provide the host with life‐long protection against pathogen reexposure and thus offers tremendous promise for the design of vaccines targeting chronic infections or cancer. In order to exploit this potential in the design of new vaccines, it is necessary to understand how and when memory T cells acquire their poised effector potential, and moreover, how they maintain these properties during homeostatic proliferation. To gain insight into the persistent nature of memory T‐cell functions, investigators have turned their attention to epigenetic mechanisms. Recent efforts have revealed that many of the properties acquired among memory T cells are coupled to stable changes in DNA methylation and histone modifications. Furthermore, it has recently been reported that the delineating features among memory T cells subsets are also linked to distinct epigenetic events, such as permissive and repressive histone modifications and DNA methylation programs, providing exciting new hypotheses regarding their cellular ancestry. Here, we review recent studies focused on epigenetic programs acquired during effector and memory T‐cell differentiation and discuss how these data may shed new light on the developmental path for generating long‐lived CD8⁺ T‐cell memory.