Welcome, I am Bill Sullivan, the online leader for The Synaptic Leap's Toxoplasma research community. You can find out more about my work at the laboratory web site.
Toxoplasma gondii is a protozoan (single-celled) parasite that has permanently infected tens of millions of people in the world. A normal immune response typically controls infection promptly, but the parasite persists as a latent cyst within host tissues. Tissue cysts can form in brain, heart, and skeletal muscle tissue. If immunity should become compromised due to disease (such as AIDS) or immunosuppressive therapies (e.g., cancer chemotherapy or organ transplantation), the acute stage of infection may recrudesce. Thus, Toxoplasma is a significant opportunisitc pathogen. However, there are instances when Toxoplasma threatens normal, healthy individuals as well. For example, Toxoplasma can cause abortion or congenital birth defects; this may occur if a woman becomes infected for the first time during pregnancy. Additionally, emerging studies have demonstrated intriguing alterations in host organism behavior upon infection, or correlations with neurological disorders such as schizophrenia.
Toxoplasma infection may be picked up from cats (the definitive host) or contaminated food/water. People at significant risk (HIV+ or pregnant individuals) should cook meat thoroughly, wash vegetables, and avoid cat litter boxes and gardening.
If you're studying Toxoplasma, I encourage you to make all or portions of your project open. Invite others to help or add their thoughts to your project. Simply create a "child page" to our current project page to begin. Or if you're still in the brainstorming phase, post a blog and invite others you know working in the field to participate online.
This looks like a great application. Have you defined what you are making open from your lab? What kind of contributions are you asking for?
This sounds interesting. For the chemists here, do you have any lead references for structures we should be looking at? It would be good if someone could post some structures of promising inhibitors to get the mental gears in motion.
Have you tried sodium butyrate?
Cell. 1978 May;14(1):105-13. Sodium butyrate inhibits histone deacetylation in cultured cells. Candido EP, Reeves R, Davie JR.
At Sullivan Lab, have you tried it and rejected it? Not yet tried it? Have reasons why it would not be suitable? Etc . . .
Have you tried valproic acid?
Have you tried valproic acid? If so, what sorts of results?
however,most of the paper before conclude that p300 act as tumor repressor.how ever there still some report assert that p300 also can promter cancer cell growth.yet,i think we should consider the balance of HAT activity of p300 in cancer cell.low level or high level of p300 both contribut to cancer prolification. and so could we imagine that the histone acetyalase inhibitor may be a durg to cure cancer or to inhibitor cancer deterioration?
Thanks for the comments. There are reports that certain HDAC inhibitors are indeed effective against the parasites (e.g. apicidin). There is concern about the selective toxicity, but more studies are warranted to examine other HDACs in turn. We've not focused on this area, but rather the HATs.
What I should have asked would be something more like this. Even though Because sodium butyrateinhibits and also hyperacetylates, doesboth, have you considered it or tried it?
As to substances which blow hot and cold -- i.e., de-acetylate and hyper-acetylate -- perhaps an analogy would be vitamin C, which can be a pro-oxidant or an anti-oxidant. It alldepends on the circumstances.
J Nutr. 2003 Jul;133(7 Suppl):2485S-2493S. Inhibition of histone deacetylase activity by butyrate. Davie JR.
This article reviews the effects of the short-chain fatty acid butyrate on histone deacetylase (HDAC) activity. Sodium butyrate has multiple effects on cultured mammalian cells that include inhibition of proliferation, induction of differentiation and induction or repression of gene expression.
The observation that butyrate treatment of cells results in histone hyperacetylation initiated a flurry of activity that led to the discovery that butyrate inhibits HDAC activity.
Butyrate has been an essential agent for determining the role of histone acetylation in chromatin structure and function. Interestingly, inhibition of HDAC activity affects the expression of only 2% of mammalian genes.
Promoters of butyrate-responsive genes have butyrate response elements, and the action of butyrate is often mediated through Sp1/Sp3 binding sites (e.g., p21(Waf1/Cip1)).
We demonstrated that Sp1 and Sp3 recruit HDAC1 and HDAC2, with the latter being phosphorylated by protein kinase CK2.
A model is proposed in which inhibition of Sp1/Sp3-associated HDAC activity leads to histone hyperacetylation and transcriptional activation of the p21(Waf1/Cip1) gene; p21(Waf1/Cip1) inhibits cyclin-dependent kinase 2 activity and thereby arrests cell cycling.
Pending the cell background, the nonproliferating cells may enter differentiation or apoptotic pathways. The potential of butyrate and HDAC inhibitors in the prevention and treatment of cancer is presented.
Valproate enhances imatinib-lnduced growth arrest and apoptosis in chronic myeloid leukemia cells. MOROTTI, et al.