Studies were carried out on some biological activities of Helicobacter pylori porins in vitro. We extracted and purified a porin with an apparent molecular mass of 30 kDa. Human polymorphonuclear leukocytes preincubated with H. pylori porins showed a decrease of chemotaxis, of adherence to nylon wool, and of chemiluminescence. Used as chemotaxins in place of zymosan-activated serum or as chemotaxinogens in place of zymosan, the porins induced polymorphonuclear leukocyte migration. Human monocytes and lymphocytes cultivated in the presence of H. pylori porins released cytokines. Release of the various cytokines studied was obtained with differentiated kinetics and at various porin concentrations. Starting only 3 h after culture, tumor necrosis factor alpha is released quickly, reaching a peak at 18 h, at a porin concentration of 1 ,ug/ml/106 cells. Interleukin-6 (IL-6) appears later, with a peak at 10 ,ug/ml/106 cells, while IL-8 is released after 6 h of culture, with a peak at 24 h, at a porin concentration of 10 FLg/ml/106 cells. Lymphocytes stimulated by H. pylori porins release gamma interferon after 18 h of culture at higher concentrations of porins (20 ,ig/ml/106 cells). Granulocyte macrophage colony-stimulating factor is released from 6 to 48 h at a concentration of 1 p.g/ml/106 cells, while both IL-3 and IL-4 are released after 18 h of culture at different porin concentrations (0.1 and 1 ttg/ml/106 cells, respectively). Our results lead us to think that during H. pylori infection, surface components, porins in particular, are able to induce a series of chain reactions ranging from the inflammatory to the immunological responses.

Introduction The major hallmark of inflammation is the recruitment and activation of leucocytes, especially polymorphonuclear neutrophils (PMNs), which results from a complex interplay among these cells and the vascular endothelium [1-3] and accounts for destruction of foreign pathogens on one hand, and breakdown and remodelling of inflamed tissues on the other hand [4]. Inflammation is triggered and sustained by pro-inflammatory cytokines as well as prostaglandins and gaseous radicals, such as nitric oxide [4-6], which are produced locally by the inflammation-induced enzymes cyclooxygenase-2 (COX-2) and nitric oxide synthase (iNOS). Most of the classical anti-inflammatory drugs target the endogenous production of these pro-inflammatory mediators. In this context, the sulphated proteoglycan heparin can be also regarded as a non-conventional anti-inflammatory molecule, as it has several biological actions independent of its well-known anti-coagulant activity, including the modulation of extracellular matrix synthesis, cell proliferation, angiogenesis and inflammation [7-11]. In particular, heparin has been shown to inhibit pro-inflammatory cytokine production by human monocytes stimulated Summary Low molecular weight heparin derivatives are characterized by low anti-coagulant activity and marked anti-inflammatory effects that allow for these molecules to be viewed as a new class of non-steroidal anti-inflammatory drugs (NSAIDs). We show here that K5NOSepiLMW, an O-sulphated heparin-like semi-synthetic polymer of the D-glucuronic acid-N-acetyleparoson disaccharide unit with low molecular weight, has marked anti-inflammatory effects in a rat model of acute inflammation, the carrageenan-induced pleurisy, commonly used to test NSAID efficacy. A 30-min. pre-treatment with K5NOSepiLMW (0.1, 0.5 and 1 mg/kg b.wt., given intrapleurally) attenuated the recruitment of leucocytes in the lung tissue and the pleural exudate, inhibited the induction of inducible nitric oxide syn-thase and cyclooxygenase-2 (COX-2), thereby abating the generation of nitric oxide and pro-inflammatory prostaglandins such as PgE2 and PGF1, reduced the inflammation-induced nitroxidative lung tissue injury, as shown by tissue thiobarbituric acid-reactive substances and nitrotyrosine, and blunted the local generation of cytokines such as interleukin-1 and tumour necrosis factor-. All these parameters were markedly increased by intrapleural carrageenan in the absence of any pre-treatment. The anti-inflammatory action of K5NOSepiLMW is specific, as judged by the lack of therapeutic effects of B4/110, a biologically inactive cognate polysaccharide, given in the place of the authentic molecule. Moreover, K5NOSepiLMW showed similar effects as celecoxib (1 mg/kg b.wt), a COX-2 inhibitor and well-known NSAID. This study provides further insight into the mechanisms underlying the beneficial effects of heparin derivatives in inflammation and identifies K5NOSepiLMW as a novel, promising anti-inflammatory drug.

Passive transport of molecules through nanopores is characterized by the interaction of molecules with pore internal walls and by a general crowding effect due to the constricted size of the nanopore itself, which limits the presence of molecules in its interior. The molecule–pore interaction is treated within the diffusion approximation by introducing the potential of mean force and the local diffusion coefficient for a correct statistical description. The crowding effect can be handled within the Markov state model approximation. By combining the two methods, one can deal with complex free energy surfaces taking into account crowding effects. We recapitulate the equations bridging the two models to calculate passive currents assuming a limited occupancy of the nanopore in a wide range of molecular concentrations. Several simple models are analyzed to clarify the consequences of the model. Eventually, a biologically relevant case of transport of an antibiotic molecule through a bacterial porin is used to draw conclusions (i) on the effects of crowding on transport of small molecules through biological channels, and (ii) to demonstrate its importance for modelling of cellular transport.

After adjusting for observed risk factors, statin initiation versus glaucoma drug initiation was associated with a reduced risk of CRC in men but not in women. While this study is subject to many limitations, it corroborates a previous study that found sex differences in the association between statins and CRC.

No abstract

Background: Aumolertinib is a novel, irreversible third generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI). APOLLO, a pivotal phase II singlearm study (NCT02981108), has demonstrated progression-free survival (PFS) benefit with a favorable safety profile in pretreated EGFR T790M positive NSCLC patients.Methods: Adult pts received aumolertinib 110 mg once daily until disease progression. Treatment beyond progression was allowed if clinical benefit was expected. The primary endpoint was objective response rate by independent central review. Secondary endpoints included PFS, OS and safety. Explore endpoints included the drug resistance mechanism.

Introduction The major hallmark of inflammation is the recruitment and activation of leucocytes, especially polymorphonuclear neutrophils (PMNs), which results from a complex interplay among these cells and the vascular endothelium [1][2][3] Summary Low molecular weight heparin derivatives are characterized by low anti-coagulant activity and marked anti-inflammatory effects that allow for these molecules to be viewed as a new class of non-steroidal anti-inflammatory drugs (NSAIDs). We show here that K5NOSepiLMW, an O-sulphated heparin-like semi-synthetic polymer of the D-glucuronic acid-N-acetyleparoson disaccharide unit with low molecular weight, has marked anti-inflammatory effects in a rat model of acute inflammation, the carrageenan-induced pleurisy

No abstract