br Conclusion and future perspectives

Conclusion and future perspectives In the setting of myocardial I/R stress, HDAC activity is induced and contributes to myocardial injury. HDAC inhibition appears to protect the Shikonin from I/R injury by activating a variety of pro-survival molecular pathways. From a clinical relevance standpoint, it is critical that HDAC inhibition remains effective when delivered at the time of reperfusion, the point in time at which a patient is in contact with the healthcare system. Thus, we submit that the FDA-approved HDAC inhibitor, SAHA, holds promise as a therapeutic agent that now warrants testing in a clinical trial (Fig. 1). Multiple signaling pathways have been implicated in the cardioprotective actions of HDAC inhibition (Fig. 2). It is important to recognize that the increase in pro-survival pathways, or decrease in cell death pathways, are potentially confounded by survival bias. Additional mechanistic studies are needed to delineate the critical process whereby HDAC activity contributes to I/R injury and suppression of that activity is protective. Possible avenues to explore include induction of cytoprotective autophagy, preservation of mitochondrial homeostasis, regulation of metabolic flux, and suppression of oxidative stress (Fig. 3). Recently, increases in histone methylation by SUV39h1 have been shown to reduce infarct size in diabetic rats [45]. Thus, manipulation of histone methylation may emerge as another therapeutic target [46]. Whereas a large body of evidence now points to robust cardioprotective benefits, SAHA remains to be tested in preclinical models that incorporate comorbidities, such as diabetes and hypertension. Furthermore, whether SAHA's cardioprotective effects on infarct size translate into improved clinical outcomes in terms of mortality and morbidity remains to be defined (Fig. 3). In the end, we submit that time is ripe for a first-in-human trial – a biological experiment in the human model – to determine whether SAHA reduces infarct size in patients presenting with STEMI.
Declaraction of interests
Introduction The epigenetic phenomenon consists of DNA methylation, RNA modification, RNA interference, histone modification and genomic imprinting. Among these, the modification on DNA and nucleosomal histone has been widely recognized to have significant impact on cancer.2, 3 The acetylation status of lysine residue of the histone has been proved to be regulated by histone deacetylases (HDACs) and histone acetyltransferase (HATs). HDACs are a class of enzymes that remove the acetyl groups from the ε-amino groups of lysine residues located in the N-terminal of the core histones, which will result in closed chromatin configuration and downregulated genes expression, including tumor suppressor genes. Besides, HDACs can catalyze the deacetylation of some non-histone proteins, which could influence protein stability and location, protein-DNA interaction and protein-protein interaction.4, 5 To date, 18 HDACs have been identified in humans. Based on the sequence homology to the yeast original enzymes and domain organization, HDACs are classified into four classes. Among these, Class I (HDAC1/2/3/8), Class II (HDAC4/5/6/7/9/10) and Class IV (HDAC11) are Zn2+ dependent, while Class III (SIRT1-7) is NAD+ dependent. The Zn2+ dependent HDACs play important roles in the processes of tumorigenesis which mainly contain: 1. Promotion on tumor cell proliferation and invasion; 2. Promotion on tumor angiogenesis; 3. Enhancement of cancer cells’ resistance to chemotherapy and radiotherapy; 4. Inhibition on differentiation and apoptosis of tumor cells. HDACIs have been proved to induce apoptosis, differentiation and cell cycle arrest as well as suppression on cell migration. Thus HDACIs have become the hot topic in the field of antitumor research. Currently, five HDACIs, vorinostat (SAHA), romidepsin (FK228), belinostat (PXD101), Chidamide and panobinostat (LBH589) have been approved by the FDA or CFDA. The first four were approved for the treatment of cutaneous T-cell lymphoma (CTCL) or peripheral T-cell lymphoma (PTCL), while the fifth, panobinostat was for combination therapy of recurrent multiple myeloma with bortezomib and dexamethasone. Most HDACIs share the common pharmacophore model which consists of three parts: a cap part, a zinc binding group (ZBG), and a linker part connecting ZBG and cap part (Fig. 1). The development of HDACIs are mainly modifications on the three parts, especially the cap part and the linker part, which significantly determine the activity and the selectivity of compounds.