Modulation of transcription factors by small molecules in ß-cell development and differentiation.

Transcription factors regulate gene expression and play crucial roles in development and differentiation of pancreatic ß-cell. The expression and/or activities of these transcription factors are reduced when ß-cells are chronically exposed to hyperglycemia, which results in loss of ß-cell function. Optimal expression of such transcription factors is required to maintain normal pancreatic development and ß-cell function. Over many other methods of regenerating ß-cells, using small molecules to activate transcription factors has gained insights, resulting in ß-cells regeneration and survival. In this review, we discuss the broad spectrum of transcription factors regulating pancreatic ß-cell development, differentiation and regulation of these factors in normal and pathological states. Also, we have presented set of potential pharmacological effects of natural and synthetic compounds on activities of transcription factor involved in pancreatic ß-cell regeneration and survival. Exploring these compounds and their action on transcription factors responsible for pancreatic ß-cell function and survival could be useful in providing new insights for development of small molecule modulators.

Host cell transcriptomic response to the multidrug-resistant Mycobacterium tuberculosis clonal outbreak Beijing strain reveals its pathogenic features.

The upsurge of multidrug-resistant infections has rendered tuberculosis the principal cause of death among infectious diseases. A clonal outbreak multidrug-resistant triggering strain of Mycobacterium tuberculosis was identified in Kanchanaburi Province, labelled "MKR superspreader," which was found to subsequently spread to other regions, as revealed by prior epidemiological reports in Thailand. Herein, we showed that the MKR displayed a higher growth rate upon infection into host macrophages in comparison with the H37Rv reference strain. To further elucidate MKR's biology, we utilized RNA-Seq and differential gene expression analyses to identify host factors involved in the intracellular viability of the MKR. A set of host genes function in the cellular response to lipid pathway was found to be uniquely up-regulated in host macrophages infected with the MKR, but not those infected with H37Rv. Within this set of genes, the IL-36 cytokines which regulate host cell cholesterol metabolism and resistance against mycobacteria attracted our interest, as our previous study revealed that the MKR elevated genes associated with cholesterol breakdown during its growth inside host macrophages. Indeed, when comparing macrophages infected with the MKR to H37Rv-infected cells, our RNA-Seq data showed that the expression ratio of IL-36RN, the negative regulator of the IL-36 pathway, to that of IL-36G was greater in macrophages infected with the MKR. Furthermore, the MKR's intracellular survival and increased intracellular cholesterol level in the MKR-infected macrophages were diminished with decreased IL-36RN expression. Overall, our results indicated that IL-36RN could serve as a new target against this emerging multidrug-resistant M. tuberculosis strain.