Mechanisms of DNA repair and mutagenesis are defined on the basis of relatively few proteins acting on DNA, yet the identities and functions of all proteins required are unknown. Here, we identify the network that underlies mutagenic repair of DNA breaks in stressed Escherichia coli and define functions for much of it. Using a comprehensive screen, we identified a network of ≥93 genes that function in mutation. Most operate upstream of activation of three required stress responses (RpoS, RpoE, and SOS, key network hubs), apparently sensing stress. The results reveal how a network integrates mutagenic repair into the biology of the cell, show specific pathways of environmental sensing, demonstrate the centrality of stress responses, and imply that these responses are attractive as potential drug targets for blocking the evolution of pathogens.

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Lipoteichoic acid (LTA) induces neuroinflammatory molecules, contributing to the pathogenesis of neurodegenerative diseases. Therefore, suppression of neuroinflammatory molecules could be developed as a therapeutic method. Although previous data supports an immune-modulating effect of curcumin, the underlying signaling pathways are largely unidentified. Here, we investigated curcumin’s anti-neuroinflammatory properties in LTA-stimulated BV-2 microglial cells. Inflammatory cytokine tumor necrosis factor-α [TNF-α, prostaglandin E2 (PGE2), and Nitric Oxide (NO] secretion in LTA-induced microglial cells were inhibited by curcumin. Curcumin also inhibited LTA-induced inducible NO synthases (iNOS) and cyclooxygenase-2 (COX-2) expression. Subsequently, our mechanistic studies revealed that curcumin inhibited LTA-induced phosphorylation of mitogen-activated protein kinase (MAPK) including ERK, p38, Akt and translocation of NF-κB. Furthermore, curcumin induced hemeoxygenase (HO)-1HO-1 and nuclear factor erythroid 2-related factor 2 (Nrf-2) expression in microglial cells. Inhibition of HO-1 reversed the inhibition effect of HO-1 on inflammatory mediators release in LTA-stimulated microglial cells. Taken together, our results suggest that curcumin could be a potential therapeutic agent for the treatment of neurodegenerative disorders via suppressing neuroinflammatory responses.

Mucus-secreting cells of the stomach epithelium provide a protective barrier against damage that might result from bacterial colonization or other stimuli. Impaired barrier function contributes to chronic inflammation and cancer. Knock-out mice for the epithelium-specific transcription factor Spdef (also called Pdef) have defects in terminal differentiation of intestinal and bronchial secretory cells. We sought to determine the physiologic function of Spdef in the stomach, another site of significant levels of Spdef expression. We used in situ hybridization and immunohistochemistry to localize Spdef-expressing cells in the mouse stomach; targeted gene disruption to generate mice lacking Spdef; and histologic, immunologic, and transcriptional profiling approaches to determine the requirements of Spdef in stomach epithelial homeostasis. The Ets protein family in humans and mice contains nearly 30 transcription factors. Loss of several family members in knock-out mice reveals their critical requirement in embryogenesis, morphogenesis, and cell differentiation (1-3). Deregulated expression or activation of Ets factors is also linked to various human cancers (4, 5), highlighting their importance in disease. Ets proteins were first studied in detail in lymphocytes and neurons (6, 7). Their role in epithelial cells gained attention after we and others identified four additional Ets factors: Elf3 (Ese1), Elf5 (Ese2), Ehf (Ese3), and Spdef (Pdef) (8 -10). These factors are virtually restricted to epithelial cells, but each shows a distinct tissue distribution, with further restriction to distinct cell subsets or differentiation stages (11), suggesting specialized roles in different lineages.Spdef is unique among Ets proteins for its distinct DNA binding specificity and restricted expression in hormone-regulated prostate, mammary, endometrial and ovarian epithelia, salivary gland, trachea, lungs, and digestive tract (9, 12). Spdef function has been studied in cancer cell migration and prostate, ovarian, and breast cancer (13-16); its role in normal tissues is starting to emerge. Exposure to intratracheal allergens or IL-13 leads to excess mucus production as a result of Spdef-dependent goblet cell differentiation, whereas Spdef expression in transgenic bronchial epithelium causes goblet cell hyperplasia and mucus hypersecretion (17), defects related to human lung diseases. Spdef Ϫ/Ϫ mice show defective differentiation of pulmonary goblet cells and intestinal Paneth and goblet cells, together with deregulation of secretory cell-specific genes (18,19).After gastrointestinal mucosal progenitors commit to a particular cell fate, they undergo additional differentiation steps before acquiring the unique ability to absorb nutrients or secrete enzymes, mucus, acid, hormones, or antimicrobial peptides. Combinations of cell type-specific and broadly expressed transcription factors regulate each step, as highlighted in recent reports of the roles of transcription factors Foxq1 and Mist1 in specific aspects of gastric foveolar (pit) ...