Gallic acid is a known antioxidant and has anti-inflammatory activity in addition to other biological activities, but GA efficiency is restricted due to low permeability and low oral bioavailability. This study was designed to investigate the solubility, permeability, oral bioavailability, enzymatic stability with cytochrome CYP2D6, antioxidant and anti-inflammatory activity of novel gallic acid sulfonamide derivatives; TMBS, and THBS. In addition, a novel in silico permeability model was designed to predict the permeability and bioavailability of eighty derivatives of GA. In sillico prediction of intestinal permeability of GA derivative indicated an increase in permeability with increased lipophilicity and decreased aqueous solubility, replacing the carboxylic group with sulfonamide group has increased intestinal permeability. A significant (P <0.01) increase was observed in the permeability of TMBS and THBS over GA, in both gastric fluids and HIEC cells. TMBS was O-demethylated by CYP2D6. TMBS had greater ROS scavenging activity than GA in HIEC-6 cells. There was a significant (P< 0.05) increase in anti-inflammatory activity of THBS, and TMBS compared to ibuprofen. TMBS, and THBS had better oral bioavailability than GA. This data suggests that the in silico permeability model can be used in the future to study new candidate of gallic acid, and further in vivo and clinical investigations are required to introduce TMBS and THBS as a new antioxidant and anti-inflammatory drugs.

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<p>The crossing of host barriers (intestinal, blood-brain, and placental) is a critical step for systemic infections caused by entero-invasive pathogens. In the intestine, the epithelial cells are the first line of defense against enteric pathogens. <i>Listeria monocytogenes</i> is a facultative-intracellular foodborne pathogen that first crosses the intestinal barrier to cause a systemic infection. However, the underlying mechanism is not well understood.</p><p><br></p> <p>We demonstrate that <i>Listeria</i> adhesion protein (LAP) promotes the translocation of <i>L. monocytogenes </i>across the intestinal barrier in mouse models (A/J and C57BL/6). Relative to the wild-type (WT; serotype 4b) or the isogenic bacterial invasion protein Internalin A mutant (Δ<i>inlA</i>) strain, the <i>lap^─</i> strain showed significant defect in translocation across the intestinal barrier and colonization of the mesenteric-lymph nodes, liver and spleen in the early phase of infection (24 h and 48 h). LAP induces intestinal epithelial barrier dysfunction for increased translocation as evidenced by increased permeability to 4-kDa FITC-dextran (FD4), a marker of paracellular permeability, in the serum and urine of WT and Δ<i>inlA</i>- infected mice and across Caco-2 cell barrier, but not the <i>lap^─</i> mutant strain. Microscopic examination confirmed localization of the WT and Δ<i>inlA</i> strains in the tight junction, a crucial barrier of intestinal paracellular permeability, in the mouse ileal tissue but the <i>lap^─</i> strain remained confined in the lumen. LAP also upregulates TNF-α and IL-6 in intestinal epithelia of mice and in Caco-2 cells for increased permeability. </p><p><br></p> <p>Investigation of the underlying molecular mechanisms of LAP-mediated increase in intestinal permeability by using <i>lap^─</i> mutant strain, purified LAP and shRNA-mediated Hsp60 suppression, we demonstrate that LAP interacts with its host receptor, Hsp60, and activates the canonical NF-κB signaling, which in turn facilitates myosin light-chain kinase (MLCK)-mediated opening of the epithelial barrier via the cellular redistribution of major epithelial junctional proteins claudin-1, occludin, and E-cadherin. Pharmacological inhibition of NF-κB or MLCK in cells or genetic ablation of MLCK in mice (C57BL/6) prevents mislocalization of epithelial junctional proteins, intestinal permeability and <i>L. monocytogenes</i> translocation across the intestinal barrier.</p> <p><br></p><p>Furthermore, LAP also promotes <i>L. monocytogenes </i>translocation across the intestinal barrier and systemic dissemination in a Mongolian gerbil that are permissive to the bacterial invasion proteins; InlA-and InlB-mediated pathways; similar to that in humans. We show a direct LAP-dependent and InlA-independent pathway<i> </i>for <i>L. monocytogenes</i> paracellular translocation across the intestinal epithelial cells that do not express luminally accessible E-cadherin. Additionally, we show a functional InlA/E-cadherin interaction pathway that aids <i>L. monocytogenes</i> translocation by targeting cells with luminally accessible E-cadherin such as cells at the site of epithelial cell extrusion, epithelial folds and mucus-expelling goblet cells. Thus, <i>L. monocytogenes</i> uses LAP to exploit epithelial innate defense in the early phase of infection to cross the intestinal epithelial barrier, independent of other invasion proteins.</p><p><br></p> <p>This work fills a critical gap in our understanding of <i>L. monocytogenes </i>pathogenesis and sheds light to the complex interplay between host-pathogen interactions for bacterial crossing of the crucial intestinal barrier.</p> <br>

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