BackgroundProtein/nucleic acid deglycase (DJ-1) and hypoxia-inducible factor-1α (HIF-1α) play significant roles in the progression of various types of cancer and are associated with the phosphatidylinositol 3-kinase (PI3K) pathway. However, their functions in colorectal cancer (CRC) have not been identified. The aim of this study was to analyze the putative signaling pathway encompassing DJ-1, PI3K, and HIF-1α in a series of CRC tissues and cell lines.PurposeThis study aimed at exploring the expression status of DJ-1 in colon cancer and its role in survival of cancer cell lines.MethodsThe expression and localization of DJ-1, PI3K-p110α, phosphorylated Akt (p-AKT), and HIF-1α were determined by immunohistochemistry in 73 resected CRC tissues. The effect of DJ-1 on cell activity was explored by in vitro knockdown and overexpression experiments in SW480 and HT-29 cells. The cells were treated with a PI3K inhibitor (LY294002 or wortmannin), and p-AKT and HIF-1α protein expression were then analyzed. Apoptosis was analyzed by flow cytometry. The expression levels of several HIF-1 target genes were assessed under hypoxic conditions by reverse transcription-PCR and Western blot. Xenograft tumor growth studies were conducted in DJ-1 knockdown or overexpression cells.ResultsHigh DJ-1 expression was found in 68.49% (50/73) of CRC tissues and associated with larger tumor size and advanced clinical stages. DJ-1 expression was positively associated with PI3K-p110α, p-AKT, and HIF-1α expression in CRC. HIF-1α and p-AKT protein levels were lower in SW480 and HT-29 cells with stable DJ-1 knockdown than in those with DJ-1 overexpression. PI3K inhibitors almost completely blocked DJ-1-induced AKT phosphorylation. However, the expression of HIF-1α was partially preserved after treatment with PI3K inhibitors. We also show that DJ-1 is necessary for the transcriptional ability of HIF-1α and CRC cell survival after hypoxic stress. Moreover, DJ-1 promoted the growth of established tumor xenografts in nude mice.ConclusionOur findings are the first to show that DJ-1 is overexpressed in CRC. We suggest a model in which DJ-1 mediates CRC cell survival by regulating the PI3K-AKT-HIF-1α pathway.

Many bacteria can develop biofilm (BF), a multicellular structure largely combining bacteria and their extracellular polymeric substances (EPS). The formation of biofilm results in an alternative existence in which microbes ensure their survival in adverse environments. Biofilm-relevant infections are more persistent, resistant to most antibiotics, and more recalcitrant to host immunity. Mycobacterium tuberculosis, the causative agent of tuberculosis, can develop biofilm, though whether M. tuberculosis can form biofilm within tuberculosis patients has yet to be determined. Here, we summarize the factors involved in the development and dispersal of mycobacterial biofilms, as well as underlying regulatory factors and inhibitors against biofilm to deepen our understanding of their development and to elucidate potential novel modes of action for future antibiotics. Key factors in biofilm formation identified as drug targets represent a novel and promising avenue for developing better antibiotics.

Intracellular survival plays a central role in the pathogenesis of Mycobacterium tuberculosis, a process which depends on an array of virulence factors to colonize and replicate within the host. The M. tuberculosis iron regulated open reading frame (ORF) rv3402c, encoding a conserved hypothetical protein, was shown to be up-regulated upon infection in both human and mice macrophages. To explore the function of this ORF, we heterologously expressed the rv3402c gene in the non-pathogenic fast-growing Mycobacterium smegmatis strain, and demonstrated that Rv3402c, a cell envelope-associated protein, was able to enhance the intracellular survival of recombinant M. smegmatis. Enhanced growth was not found to be the result of an increased resistance to intracellular stresses, as growth of the Rv3402c expressing strain was unaffected by iron depletion, H2O2 exposure, or acidic conditions. Colonization of macrophages by M. smegmatis expressing Rv3402c was associated with substantial cell death and significantly greater amount of TNF-α and IL-1β compared with controls. Rv3402c-induced TNF-α and IL-1β production was found to be mediated by NF-κB, ERK and p38 pathway in macrophages. In summary, our study suggests that Rv3402c delivered in a live M. smegmatis vehicle can modify the cytokines profile of macrophage, promote host cell death and enhance the persistence of mycobacterium within host cells.

Tuberculosis remains a serious human public health concern. The coevolution between its pathogen Mycobacterium tuberculosis and human host complicated the way to prevent and cure TB. Apoptosis plays subtle role in this interaction. The pathogen endeavors to manipulate the apoptosis via diverse effectors targeting key signaling nodes. In this paper, we summarized the effectors pathogen used to subvert the apoptosis, such as LpqH, ESAT-6/CFP-10, LAMs. The interplay between different forms of cell deaths, such as apoptosis, autophagy, necrosis, is also discussed with a focus on the modes of action of effectors, and implications for better TB control.

The epithelium of the mouse small intestine harbors an abundant CD8αα(+)TCRαβ(+) intraepithelial lymphocyte (IEL) population. This unique IEL subset is a self-reactive population that requires exposure to self-agonists for selection in the thymus, similarly to other regulatory T cell populations. After leaving the thymus, these cells directly seed the intestinal epithelium, which provides a unique combination of cellular interactions together with cytokines, nutrients, and antigens that guide the lineage-specific differentiation and function of these IELs. For instance, epithelial cells and nearby immune cells secrete a number of cytokines, including interleukin-15 (IL-15), IL-7, and transforming growth factor-β, resulting in an assortment of cellular responses, including activation of master transcription factors, cell proliferation, and cytokine secretion. Recent advances have also highlighted the importance of diet-derived substances and commensal metabolites, such as the aryl hydrocarbon receptor ligands and vitamin D, in controlling the survival and gene expression of CD8αα(+)TCRαβ(+) IELs. Furthermore, these cells function in the epithelium and require constant communication between cells in the form of cell-to-cell contacts. These interactions tune the antigen sensitivity of the TCR and maintain the quiescence of the CD8αα(+)TCRαβ(+) IELs. Finally, we discuss how these cells might contribute to tolerance and immunopathological responses in the gut. Therefore, an increased understanding of CD8αα(+)TCRαβ(+) IELs in the gut will help us understand how these cells participate in immune regulation and protection.