Clofazimine Inhibits Human Kv1.3 Potassium Channel by Perturbing Calcium Oscillation in T Lymphocytes

The Kv1.3 potassium channel plays an essential role in effector memory T cells and has been implicated in several important autoimmune diseases including multiple sclerosis, psoriasis and type 1 diabetes. A number of potent small molecule inhibitors of Kv1.3 channel have been reported, some of which were found to be effective in various animal models of autoimmune diseases. We report herein the identification of clofazimine, a known anti-mycobacterial drug, as a novel inhibitor of human Kv1.3. Clofazimine was initially identified as an inhibitor of intracellular T cell receptor-mediated signaling leading to the transcriptional activation of human interleukin-2 gene in T cells from a screen of the Johns Hopkins Drug Library. A systematic mechanistic deconvolution revealed that clofazimine selectively blocked the Kv1.3 channel activity, perturbing the oscillation frequency of the calcium-release activated calcium channel, which in turn led to the inhibition of the calcineurin-NFAT signaling pathway. These effects of clofazimine provide the first line of experimental evidence in support of a causal relationship between Kv1.3 and calcium oscillation in human T cells. Furthermore, clofazimine was found to be effective in blocking human T cell-mediated skin graft rejection in an animal model in vivo. Together, these results suggest that clofazimine is a promising immunomodulatory drug candidate for treating a variety of autoimmune disorders

Biochar from biomass and waste

There is an increasing realisation that biomass and organic wastes are valuable feedstocks for second generation biorefining processes that give rise to platform chemicals to substitute for dwindling petrochemical resources, and for pyrolysis processes that produce syngas, bio-oil, and biochar from biomass, organic wastes, and the biorefining residuals of the future. The experimental work described has focused on physical properties and compositions of biochars produced from miscanthus (Miscanthus x giganteus), willow (Salix spp) and pine (Pinus sylvestris) at 500°C and at 400, 500, and 600°C in the case of the miscanthus. Although the morphologies of the cell structures were maintained in the pyrolysis, the surface area of the miscanthus biochar was greatly increased by heating at 600°C for 60 min. Nuclear magnetic resonance spectra showed the disappearance of evidence for the carbohydrate and lignin plant components as the pyrolysis temperature was raised, and the compositions of miscanthus biochars after heating for 10 and for 60 min at 600°C were very similar and composed of fused aromatic structures and with no traces of the aliphatic components in the starting materials. In greenhouse and growth chamber experiments the growth of maize (Zea mays L) seedlings was found to be inhibited by soil amendments with biochar from miscanthus formed at 400°C for 10 min, but stimulated by miscanthus char formed at 600°C for 60 min. In the course of discussion the relevance of the results obtained is related to the roles that soil amendments with biochar can have on soil fertility, carbon sequestration, on the emissions of greenhouse gases from soil, on fertilizer requirements, and on waste management. It is clear that biochar soil amendments can have definite agronomic and environmental benefits, but it will be essential to have clear guidelines for biochar production from various feedstocks and under varying pyrolysis parameters. It will be equally important to have a classification system for biochars that clearly indicate the product compositions that will meet acceptable standards. A case can be made for sets of standard biochars from different substrates that meet the required criteria