Certain forward and backward modifications are facilitated by a set of enzymes which are known as HATs and HDACs. They maintain a balanced acetylation of the histone proteins. A decrease in the quantity of HATs leads to excess deacetylation of histone proteins. This further stimulates the neuronal degeneration. HDAC inhibitors like Valporate, Vorinostat and ITF2357 help in treating neuronal disorders.
NEUROPROTECTIVE NATURE OF ITF2357
A mouse suffering from head injury was chosen and was examined after the treatment with ITF2357. It is a hydroxamic acid derivative which did not show any organ toxicity under physiological conditions. After administration at a concentration of 1.5 mg/kg/day, the pain in the joints was reduced significantly. It inhibits the damage to the tissues after 24 hours of administration. It brings down the degeneration of the neuronal tissues and reduces the lesion volume. The acetylation of the histone H3 proteins is stimulated. An injury decreases the levels of the HSP70 kDa and pAkt. This decrease in the levels is halted by ITF2357. This is also accompanied with the increase in p53 levels as a result of which the cells are cleared out by the process of apoptosis, at an increased rate .
ITF2357 DOWN REGULATES MUTATION IN JAK2
Mutation within the Jak2 kinase (replacement of valine residue with phenyl alanine) is associated with polycythemia vera. ITF2357 shows specific action against those cells showing this mutation. Low concentrations of ITF2357 ranging from 0.0010.01μM were enough to control the growth of these mutated cells. The concentration of ITF2357 required to inhibit the growth of the normal or tumor cells was found to be at least 100 -250 times greater. In fact ITF2357 stimulates the outgrowth of the unmutated colonies. The total and p JAK2V617F molecules disappear totally after the administration of ITF2357. The phosphorylated levels of STAT5 and STAT3 were also found to be significantly reduced. The mRNA of JAK2V617F was inhibited from getting modified within granulocytes. On the whole this inhibitor checks the proliferation of cells showing JAK2V617F mutation hence downmodulating the mutated protein .
ITF2357 REDUCES THE SYNTHESIS OF CYTOKINES
The proapoptotic signals are suppressed in many cases of cancers as a result of which the cells become resistant to cell death. Agents like SAHA or trichostatin A which inhibit HDACs stimulate the expression of these genes. This later promotes apoptosis or terminal differentiation. These inhibitors bind to the zinc atom in the catalytic pocket and hence inhibit its catalytic properties. Within the LPS stimulated PMBCs, ITF2357 reduced the levels of TNFα, IL-1β, IFNγ and IL-1α at different concentrations. It decreases the mRNA levels of TNFα .
ITF2357 PROTECTS Β ISLETS
ITF2357 targets HDACs belonging to class I and II. During diabetes various proinflammatory cytokines are produced which destroy the β-islet cell. ITF2357 acts both as HDAC inhibitor and anti-inflammatory agent. The effect of ITF2357 was further confirmed after noticing the increase in the insulin synthesis. It decreases the apoptosis of β-islet cells drastically .
In a nut shell ITF2357 not only checks the growth of tumors but is also helpful in controlling the rate of diabetes and neuronal degeneration.
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1. Shein NA, Grigoriadis N, et al. Histone deacetylase inhibitor ITF2357 is neuroprotective, improves functional recovery, and induces glial apoptosis following experimental traumatic brain injury. The FASEB Journal Dec 2009; 23(12): 4266-4275.
2. V Guerini, V Barbui, et al. The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2V617FThe HDAC inhibitor ITF2357 downmodulates JAK2V617F. Leukemia 2008 April; 22, 740-747.
3. Flavio Leoni, Gianluca Fossati, et al. The Histone Deacetylase Inhibitor ITF2357 Reduces Production of Pro-Inflammatory Cytokines In Vitro and Systemic Inflammation In Vivo. Mol Med 2005 Jan-Dec; 11(1-12): 115.
4. Lewis EC, Blaabjerg L, et al. The oral histone deacetylase inhibitor ITF2357 reduces cytokines and protects islet β cells in vivo and in vitro. Mol Med 2011 May-Jun; 17(5-6):369-77.
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