NOD2-Nitric Oxide-responsive MicroRNA-146a Activates Sonic Hedgehog Signaling to Orchestrate Inflammatory Responses in Murine Model of Inflammatory Bowel Disease

Background: Genetic variants of NOD2 are linked to inflammatory bowel disease (IBD) etiology. Results: DSS model of colitis in wild-type and inducible nitric-oxide synthase (iNOS) null mice revealed that NOD2-iNOS/NO-responsive microRNA-146a targets NUMB gene facilitating Sonic hedgehog (SHH) signaling. Conclusion: miR-146a-mediated NOD2-SHH signaling regulates gut inflammation. Significance: Identification of novel regulators of IBD provides new insights into pathophysiology and development of new therapy concepts. Inflammatory bowel disease (IBD) is a debilitating chronic inflammatory disorder of the intestine. The interactions between enteric bacteria and genetic susceptibilities are major contributors of IBD etiology. Although genetic variants with loss or gain of NOD2 functions have been linked to IBD susceptibility, the mechanisms coordinating NOD2 downstream signaling, especially in macrophages, during IBD pathogenesis are not precisely identified. Here, studies utilizing the murine dextran sodium sulfate model of colitis revealed the crucial roles for inducible nitric-oxide synthase (iNOS) in regulating pathophysiology of IBDs. Importantly, stimulation of NOD2 failed to activate Sonic hedgehog (SHH) signaling in iNOS null macrophages, implicating NO mediated cross-talk between NOD2 and SHH signaling. NOD2 signaling up-regulated the expression of a NO-responsive microRNA, miR-146a, that targeted NUMB gene and alleviated the suppression of SHH signaling. In vivo and ex vivo studies confirmed the important roles for miR-146a in amplifying inflammatory responses. Collectively, we have identified new roles for miR-146a that established novel cross-talk between NOD2-SHH signaling during gut inflammation. Potential implications of these observations in therapeutics could increase the possibility of defining and developing better regimes to treat IBD pathophysiology.

Magnetic skin layer of NiO(100) probed by polarization-dependent spectromicroscopy

Using polarization-dependent x-ray photoemission electron microscopy, we have investigated the surface effects on antiferromagnetic (AFM) domain formation. Depth-resolved information obtained from our study indicates the presence of strain-induced surface AFM domains on some of the cleaved NiO(100) crystals, which are unusually thinner than bulk AFM domain wall widths (similar to 150 nm). Existence of such magnetic skin layer is substantiated by exchange-coupled ferromagnetic Fe domains in Fe/NiO(100), thereby evidencing the influence of this surface AFM domains on interfacial magnetic coupling. Our observations demonstrate a depth evolution of AFM structure in presence of induced surface strain, while the surface symmetry-breaking in absence of induced strain does not modify the bulk AFM domain structure. Realization of such thin surface AFM layer will provide better microscopic understanding of the exchange bias phenomena. (C) 2014 AIP Publishing LLC.

SIRT6 Promotes COX-2 Expression and Acts as an Oncogene in Skin Cancer

SIRT6 is a SIR2 family member that regulates multiple molecular pathways involved in metabolism, genomic stability, and aging. It has been proposed previously that SIRT6 is a tumor suppressor in cancer. Here, we challenge this concept by presenting evidence that skin-specific deletion of SIRT6 in the mouse inhibits skin tumorigenesis. SIRT6 promoted expression of COX-2 by repressing AMPK signaling, thereby increasing cell proliferation and survival in the skin epidermis. SIRT6 expression in skin keratinocytes was increased by exposure to UVB light through activation of the AKT pathway. Clinically, we found that SIRT6 was upregulated in human skin squamous cell carcinoma. Taken together, our results provide evidence that SIRT6 functions as an oncogene in the epidermis and suggest greater complexity to its role in epithelial carcinogenesis. (C) 2014 AACR.

Microbial community profiling shows dysbiosis in the lesional skin of Vitiligo subjects

Healthy human skin harbours a diverse array of microbes that comprise the skin microbiome. Commensal bacteria constitute an important component of resident microbiome and are intricately linked to skin health. Recent studies describe an association between altered skin microbial community and epidemiology of diseases, like psoriasis, atopic dermatitis etc. In this study, we compare the differences in bacterial community of lesional and non-lesional skin of vitiligo subjects. Our study reveals dysbiosis in the diversity of microbial community structure in lesional skin of vitiligo subjects. Although individual specific signature is dominant over the vitiligo-specific microbiota, a clear decrease in taxonomic richness and evenness can be noted in lesional patches. Investigation of community specific correlation networks reveals distinctive pattern of interactions between resident bacterial populations of the two sites (lesional and non-lesional). While Actinobacterial species constitute the central regulatory nodes (w.r.t. degree of interaction) in non-lesional skin, species belonging to Firmicutes dominate on lesional sites. We propose that the changes in taxonomic characteristics of vitiligo lesions, as revealed by our study, could play a crucial role in altering the maintenance and severity of disease. Future studies would elucidate mechanistic relevance of these microbial dynamics that can provide new avenues for therapeutic interventions.