1,720,972 research outputs found
Editorial on: Genetic Determinants and Prediction of Antibiotic Resistance Phenotypes in Helicobacter pylori
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A new serotonin 2A receptor antagonist with potential benefits in Non-Alcoholic Fatty Liver Disease
No full textPeripheral 5-hydroxytryptamine 2A receptor (5-HT2AR) could be a new pharmacological target for NASH, an evolution of NAFLD characterized by hepatic steatosis, cytoskeletal alterations, and hepatic inflammation that can arise with or without fibrosis. SJT4a is a synthetic β-carboline antagonist for 5-HT2AR developed by SJT molecular research to treat NASH. We performed a combined in silico/in vivo study on this potential drug to elucidate its activity and possible mechanism of action. The in silico protocol compares SJT4a with four known 5-HT2AR ligands with different activities (LSD, methiothepin, zotepine, risperidone). We performed molecular docking calculations, evaluation of binding energy by AI-based methods and Molecular Dynamics simulations of the five ligand-target complexes. Moreover, we used a pseudo-semantic analysis to evaluate the potential mechanism of action of SJT4a. In silico predictions and pseudo-semantic analysis suggested antagonistic activity for SJT4a. The in silico prediction was confirmed by [3H]-5HT radioligand binding together with SJT4a competition analysis in CHO-K1 cell cultures expressing 5-HT2AR. SJT4a was then tested in vivo. We investigated the effect of 8 weeks of treatment with SJT4A on metabolic parameters, liver pathology, NAFLD activity score, and fibrosis stage in male DIO-NASH C57BL/6 J mice diet-induced obesity fed with an obesogenic diet compared with DIO-NASH and LEAN-CHOW vehicles. In our tests, SJT4a showed intense activity in diminishing the most relevant hallmarks of NASH in the DIO-NASH mice model. We proposed a possible mode of action for SJT4a based on its 5-HT2AR antagonist activity
The Protecting Activity of RIPACUT®: A New Therapeutic Approach Preserving Epithelial Health Based on the Combination of Iceland Lichen Extract, Silver Salt, and Sodium Hyaluronate
No full textEpithelial integrity and function must be maintained in a dynamic healthy equilibrium, keeping unaltered the oxidative and inflammatory conditions and the microbiome of the cutaneous layers. Beside the skin, other mucous membranes can be injured, such as the nasal and anal ones, because of the contact with the external environment. Here, we detected the effects of RIPACUT®, a combination of Iceland lichen extract, silver salt and sodium hyaluronate that individually act in diverse biological ways. The findings we obtained on keratinocytes, nasal and intestinal epithelial cells reveal that this combination showed a marked antioxidant activity, further assessed by the DPPH assay. Additionally, by analyzing the release of the IL-1β, TNF-α and IL-6 cytokines, we proved the anti-inflammatory effect of RIPACUT®. In both cases, the main preserving action was due to Iceland lichen. We also observed a notable antimicrobial activity mediated by the silver compound. These data suggest that RIPACUT® could signify the basis for an attractive pharmacological approach to maintaining healthy epithelial conditions. Interestingly, this may be extended to the nasal and anal areas where it protects against oxidative, inflammatory and infectious insults. Thus, these outcomes encourage the creation of sprays or creams for which sodium hyaluronate can guarantee a surface film-forming effect
Comparative Evaluation of Antimicrobial, Antiamoebic, and Antiviral Efficacy of Ophthalmic Formulations
No full textThe extensive use of ophthalmic antibiotics is contributing to the appearance of resistant bacterial strains, which require prolonged and massive treatments with consequent detrimental outcomes and adverse effects. In addition to these issues, antibiotics are not effective against parasites and viruses. In this context, antiseptics could be valuable alternatives. They have nonselective mechanisms of action preventing bacterial resistance and a broad spectrum of action and are also effective against parasites and viruses. Here, we compare the in vitro antibacterial, antiameobic, and antiviral activities of six ophthalmic formulations containing antiseptics such as povidone-iodine, chlorhexidine, and thymol against Gram-positive and Gram-negative bacteria, the amoeba Acanthamoeba castellanii, and two respiratory viruses, HAdV-2 and HCoV-OC43. The results suggest that, among all the tested formulations, Dropsept, consisting of Vitamin E TPGS-based (tocopheryl polyethylene glycol succinate) in combination with the antiseptic chlorhexidine, is the one with the highest range of activities, as it works efficiently against bacteria, amoeba, and viruses. On the other hand, the solution containing PVA (polyvinyl alcohol) and thymol showed a promising inhibitory effect on Pseudomonas aeruginosa, which causes severe keratitis. Given its high efficiency, Dropsept might represent a valuable alternative to the widely used antibiotics for the treatment of ocular infections. In addition to this commercial eye drop solution, thymol-based solutions might be enrolled for their natural antimicrobial and antiamoebic effect
Gastric TFF1 Expression from Acute to Chronic Helicobacter Infection
Full text linkTFF1, a mucin-associated secreted peptide of gastric mucous cells, is known as a protective agent for stomach epithelium under different stimuli, but its role upon Helicobacter infection is still not clear. In this paper we characterized TFFs expression, with particular attention to TFF1, under Helicobacter infection in gastric cell lines. A mouse model was used to distinguish TFF1 mRNA expression between acute and chronic stages of Helicobacter infection. Our results show that TFF1 expression is induced in infected cells; in addition, the inflammatory response upon Helicobacter infection is inversely associated to pre-existing TFF1 protein levels. In infected mice, TFF1 is initially upregulated in gastric antrum in the acute phase of infection, along with IL-1β and IL-6. Then, expression of TFF1 is gradually silenced when the infection becomes chronic and IFN-γ, CXCL5, and CXCL15 reach higher levels. Our data suggest that TFF1 might help cells to counteract bacteria colonization and the development of a chronic inflammation
Helicobacter pylori Pathogen-Associated Molecular Patterns: Friends or Foes?
No full textMicrobial infections are sensed by the host immune system by recognizing signature molecules called Pathogen-Associated Molecular Patterns—PAMPs. The binding of these biomolecules to innate immune receptors, called Pattern Recognition Receptors (PRRs), alerts the host cell, ac- tivating microbicidal and pro-inflammatory responses. The outcome of the inflammatory cascade depends on the subtle balance between the bacterial burn and the host immune response. The role of PRRs is to promote the clearance of the pathogen and to limit the infection by bumping inflammatory response. However, many bacteria, including Helicobacter pylori, evolved to escape PRRs’ recognition through different camouflages in their molecular pattern. This review examines all the different types of H. pylori PAMPs, their roles during the infection, and the mechanisms they evolved to escape the host recognition
A Novel Vitamin E TPGS-Based Formulation Enhances Chlorhexidine Bioavailability in Corneal Layers
No full textKeratitis is a severe condition characterized by inflammation of the cornea following a local trauma. The most common ocular disease is the bacterial one, which requires an antibiotic treatment. The major limitation of this therapy is the resistance of the antibiotic. For this reason, alternative procedures have been developed and consist of antimicrobial molecules. One of the most used is the chlorhexidine gluconate, which has shown activity versus Gram-positive and Gram-negative bacteria and fungi. In addition to its efficiency, chlorhexidine shows low toxicity levels for mammalian cells and is a low-cost molecule. Despite its multiple benefits, chlorhexidine, if used at concentrations higher than 0.02% (w/w), can cause local eye irritation. Additionally, its poor penetrability through the cornea makes necessary frequent instillation of eye drops for a prolonged time. Due to these limitations, alternative drug delivery strategies are required. Here, we report a novel formulation based on the combination of d-alpha-tocopherol polyethylene glycol 1000 succinate with chlorhexidine, which results in higher accumulation of the drug in human corneas measured by liquid chromatography and strong antimicrobial activity. Moreover, this formulation does not cause any toxic effect on human cells and is well tolerated by rabbit eyes. Therefore this novel formulation represents a good candidate for the treatment of keratitis that overcomes the risk of antibiotic resistance
Study of bio-molecar interaction: a) Mapping of the interaction between STAT1 and flavonoids; b) Role of PDIA6-BiP complex in the regulation of the unfolded protein response
Full text link2010 - 2011Mapping of the interaction between STAT1 and flavonoids
Abstract
An experimental approach is described, in the first part of this Ph.D. work, for determining protein-small molecule non-covalent ligand binding sites and protein conformational changes induced by ligand binding. The methodology utilizes a combination of multiple technical approaches: limited proteolysis, MALDI TOF MS, circular dichroism and Surface Plasmon Resonance (SPR) to determine the binding sites in signal transducer and activator of transcription 1, STAT1 (87kDa)-flavonoid (Epigallocatechin-3-gallate, Myricetin and Delphinidin, about 500 Da) non-covalent complex. Comparing relative ion abundances of peptides released from the limited proteolysis of STAT1 and the STAT1-flavonoid complex after 0, 5, 15 and 30 minutes of digestion revealed that the binding of flavonoid induced a significant change in surface topology of STAT1. An increase in ion abundance and a different peptide profile suggest that the flavonoids obstruct the access of the proteases to one or both termini of specific peptides, identifying flavonoids binding region. Taken together, MALDI MS and SPR data led us to assume that the binding sites are close to Tyrosine 701 and that the flavonoids probably act disturbing the phosphorylation of TYR701 and the following dimerization and activation of STAT1.
PDIA6-BiP complex: role in the regulation of the unfolded protein response
Abstract
The unfolded proteins response (UPR) induced in many experimental settings is an extremely strong response that usually leads to cell death rather than to restoration of the ER homeostasis. Because the outcome of UPR signaling determines cell fate, a key unresolved molecular question is how UPR signaling is attenuated. Indeed, it is often under-appreciated that UPR signaling in response to stress is transient and is attenuated. Recently it has been proved that yeast UPR matches its output to the magnitude of the stress by regulating the duration of IRE1 signaling. An ER protein, known as binding immunoglobulin protein (BiP), binding to UPR sensors regulates their deactivation. Our idea, described in the second part of this Ph.D. work, is that there is another luminal ER factor, which interacts with the UPR sensors and is involved in attenuation of their activities. This factor is protein disulphide isomerase 6, PDIA6 (also known as P5), a poorly understood member of the protein disulfide isomerase (PDI) family, whose absence, according to our data, confers hypersensitivity to ER stress because one of its main action is tied to the sensing of UPR, rather than to the consequences of UPR signaling. We thought that PDIA6 uses its protein disulfide isomerase activity to interact specifically with UPR sensors in the ER lumen and attenuate their activities, thus regulating the duration of ER stress signaling. [edited by author]X n.s
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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