The cytokine basis of cachexia and its treatment: are they ready for prime time?

Cachexia is a hypercatabolic condition that is often associated with the terminal stages of many diseases, in which the patient's resting metabolic rate is high and loss of muscle and fat tissue mass occur at an alarming rate. The patient also usually has concurrent anorexia, amplifying the wasting syndrome that is cachexia. The greater the extent of cachexia (regardless of underlying disease), the worse the prognosis. Efforts to treat cachexia over the years have fallen short of satisfactorily reversing the wasting syndrome. This article reviews the pathophysiology of cachexia, enumerating the different pro-inflammatory cytokines that contribute to the syndrome and attempting to illustrate their interwoven pathways. We also review the different treatments that have been explored, as well as the recent literature addressing the use of anti-cytokine therapy to treat cachexia.

Metabolic engineering through cofactor manipulation and its effects on metabolic flux redistribution in Escherichia coli.

Applications of genetic engineering or metabolic engineering have increased in both academic and industrial institutions. Most current metabolic engineering studies have focused on enzyme levels and on the effect of the amplification, addition, or deletion of a particular pathway. Although it is generally known that cofactors play a major role in the production of different fermentation products, their role has not been thoroughly and systematically studied. It is conceivable that in cofactor-dependent production systems, cofactor availability and the proportion of cofactor in the active form may play an important role in dictating the overall process yield. Hence, the manipulation of these cofactor levels may be crucial in order to further increase production. We have demonstrated that manipulation of cofactors can be achieved by external and genetic means and these manipulations have the potential to be used as an additional tool to achieve desired metabolic goals. We have shown experimentally that the NADH/NAD(+) ratio can be altered by using carbon sources with different oxidation states. We have shown further that the metabolite distribution can be influenced by a change in the NADH/NAD(+) ratio as mediated by the oxidation state of the carbon source used. We have also demonstrated that the total NAD(H/(+)) levels can be increased by the overexpression of the pncB gene. The increase in the total NAD(H/(+)) levels can be achieved even in a complex medium, which is commonly used by most industrial processes. Finally, we have shown that manipulation of the CoA pool/flux can be used to increase the productivity of a model product, isoamyl acetate.