Mechanism of action and potential applications of selective inhibition of microsomal prostaglandin E synthase-1-mediated PGE2 biosynthesis by sonlicromanol's metabolite KH176m.

Increased prostaglandin E2 (PGE2) levels were detected in mitochondrial disease patient cells harboring nuclear gene mutations in structural subunits of complex I, using a metabolomics screening approach. The increased levels of this principal inflammation mediator normalized following exposure of KH176m, an active redox-modulator metabolite of sonlicromanol (KH176). We next demonstrated that KH176m selectively inhibited lipopolysaccharide (LPS) or interleukin-1ß (IL-1ß)-induced PGE2 production in control skin fibroblasts. Comparable results were obtained in the mouse macrophage-like cell line RAW264.7. KH176m selectively inhibited mPGES-1 activity, as well as the inflammation-induced expression of mPGES-1. Finally, we showed that the effect of KH176m on mPGES-1 expression is due to the inhibition of a PGE2-driven positive feedback control-loop of mPGES-1 transcriptional regulation. Based on the results obtained we discuss potential new therapeutic applications of KH176m and its clinical stage parent drug candidate sonlicromanol in mitochondrial disease and beyond.

Disease and security: the effect of emerging and re-emerging diseases.

This article examines the role of emerging new and re-emerging diseases in the failure of the 'Health for All by 2000' concept. The gap between infection and control has widened instead of closing, which has definite military and security implications. It is argued that there is a direct link between disease and the social order, and that the traditional view of development first, followed by an increase in health status, must change. However, the political will and the necessary resources to combat emerging and re-emerging diseases are still lacking in many countries. Through the improper use of treatments and dosages, most notably antibiotics, new strains of previously eradicated diseases are appearing. Added to this are new patterns of relationships between man, his environment and the occurrence of disease leading to new diseases making their appearance. There is a direct relationship between war and disease, making disease something with political, military and security relevance. The aspect of intelligence which has the task of predicting the future, now has to take note of the occurrence of disease and its effects.