Mammalian target of rapamycin;novel insight for management of inflammatory bowel diseases

Inflammatory bowel diseases(IBDs),with blurred etiology,show a rising trend and are of global concern.Of various factors involved in IBD pathogenesis and development,inflammation has been shown to play a major role.Recognition of the molecular and cellular pathways that induce IBD is an emerging subject to develop targeted therapies.Mammalian target of rapamycin(mTOR)is one the most common receptors of many inflammatory pathways,including that of IBD.To this end,we intend to overview the mTOR inhibitors for their possible efficacy in present and future approaches to treatment of IBD.

Use of everolimus in liver transplantation

In recent years, the use of mammalian target of rapamycin inhibitors has gained traction in their use as alternative or adjunct immunosuppressants in the post-liver transplantation(LT) setting. The efficacy of everolimus(EVR) in de novo LT is established and a reasonable time to initiate EVR is 30d from LT surgery. Initiating EVR early post-LT allows for calcineurin inhibitor(CNI) reduction, thus reducing nephrotoxicity in LT recipients. However, data is inadequate on the appropriate timing for conversion from CNI to EVR maintenance in order to achieve optimal renoprotective effect without compromising drug efficacy. Adverse effects of proteinuria, hypercholesterolemia and hyperlipidemia are significantly higher as compared to standard CNI and long-term implications on graft and patient survival in LT is still unclear. Future research to explore strategies to minimise EVR adverse effects will be crucial for the success of EVR as an important alternative or adjunct immunosuppressive therapy in LT.

Targeting autophagy with small molecules for cancer therapy

Autophagy is a conserved lysosomal-dependent catabolic process that maintains the cellular homeostasis by recycling misfolded proteins and damaged organelles. It involves a series of ordered events (initiation, nucleation, elongation, lysosomal fusion and degradation) that are tightly regulated/controlled by diverse cell signals and stress. It is like a double-edged sword that can play either a protective or destructive role in cancer, by pro-survival or apoptotic cues. Recently, modulating autophagy by pharmacological agents has become an attractive strategy to treat cancer. Currently, a number of small molecules that inhibit autophagy initiation (e.g., ULK kinase inhibitors), nucleation (e.g., Vps34 inhibitors), elongation (e.g., ATG4 inhibitors) and lysosome fusion (e.g., chloroquine, hydroxyl chloroquine,etc.) are reported in pre-clinical and clinical study. Also a number of small molecules reported to induce autophagy by targeting mammalian target of rapamycin (e.g., rapamycin analogs) or adenosine 5'-monophosphate-activated protein kinase (e.g., sulforaphane). The study results suggest that many potential "druggable" targets exist in the autophagy pathway that could be harnessed for developing new cancer therapeutics. In this review, we discuss the reported autophagy modulators (inhibitors and inducers), their molecular mode of action and their applications in cancer therapy.