Extracellular aspartic protease SAP2 of Candida albicans yeast cleaves human kininogens and releases proinflammatory peptides, Met-Lys-bradykinin and des-Arg(9)-Met-Lys-bradykinin

Bradykinin-related peptides, universal mediators of inflammation collectively referred to as the kinins, are often produced in excessive amounts during microbial infections. We have recently shown that the yeast Candida albicans, the major fungal pathogen to humans, can exploit two mechanisms to enhance kinin levels at the sites of candidial infection, one depending on adsorption and activation of the endogenous kinin-generating system of the host on the fungal cell wall and the other relying on cleavage of kinin precursors, the kininogens, by pathogen-secreted proteases. This work aimed at assigning this kininogenase activity to the major secreted aspartic protease of C. albicans (SAP2). The purified SAP2 was shown to cleave human kininogens, preferably the low molecular mass form (LK) and optimally in an acidic environment (pH 3.5-4.0), and to produce two kinins, Met-Lys-bradykinin and its derivative, {[}Hydroxyproline(3)]-Met-Lys-bradykinin, both of which are capable of interacting with cellular bradykinin receptors of the B2 subtype. Additionally, albeit with a lower yield, des-Arg(9)-Met-Lys-bradykinin, an effective agonist of B1-subtype receptors, was released. The pathophysiological potential of these kinins and des-Arg-kinin was also proven by presenting their ability to stimulate human promonocytic cells U937 to release proinflammatory interleukin 1 beta (IL-1 beta) and IL-6

Adhesive protein-mediated crosstalk between <i>Candida albicans</i> and <i>Porphyromonas gingivalis</i> in dual species biofilm protects the anaerobic bacterium in unfavorable oxic environment

Abstract The oral cavity contains different types of microbial species that colonize human host via extensive cell-to-cell interactions and biofilm formation. Candida albicans —a yeast-like fungus that inhabits mucosal surfaces—is also a significant colonizer of subgingival sites in patients with chronic periodontitis. It is notable however that one of the main infectious agents that causes periodontal disease is an anaerobic bacterium— Porphyromonas gingivalis. In our study, we evaluated the different strategies of both pathogens in the mutual colonization of an artificial surface and confirmed that a protective environment existed for P. gingivalis within developed fungal biofilm formed under oxic conditions where fungal cells grow mainly in their filamentous form i.e. hyphae. A direct physical contact between fungi and P. gingivalis was initiated via a modulation of gene expression for the major fungal cell surface adhesin Als3 and the aspartic proteases Sap6 and Sap9. Proteomic identification of the fungal surfaceome suggested also an involvement of the Mp65 adhesin and a “moonlighting” protein, enolase, as partners for the interaction with P. gingivalis. Using mutant strains of these bacteria that are defective in the production of the gingipains—the proteolytic enzymes that also harbor hemagglutinin domains—significant roles of these proteins in the formation of bacteria-protecting biofilm were clearly demonstrated

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Allergic Rhinitis and its Impact on Asthma (ARIA) Phase 4 (2018) : Change management in allergic rhinitis and asthma multimorbidity using mobile technology

Allergic Rhinitis and its Impact on Asthma (ARIA) has evolved from a guideline by using the best approach to integrated care pathways using mobile technology in patients with allergic rhinitis (AR) and asthma multimorbidity. The proposed next phase of ARIA is change management, with the aim of providing an active and healthy life to patients with rhinitis and to those with asthma multimorbidity across the lifecycle irrespective of their sex or socioeconomic status to reduce health and social inequities incurred by the disease. ARIA has followed the 8-step model of Kotter to assess and implement the effect of rhinitis on asthma multimorbidity and to propose multimorbid guidelines. A second change management strategy is proposed by ARIA Phase 4 to increase self-medication and shared decision making in rhinitis and asthma multimorbidity. An innovation of ARIA has been the development and validation of information technology evidence-based tools (Mobile Airways Sentinel Network [MASK]) that can inform patient decisions on the basis of a self-care plan proposed by the health care professional.Peer reviewe

Adherence to treatment in allergic rhinitis using mobile technology. The MASK Study

Background: Mobile technology may help to better understand the adherence to treatment. MASK-rhinitis (Mobile Airways Sentinel NetworK for allergic rhinitis) is a patient-centred ICT system. A mobile phone app (the Allergy Diary) central to MASK is available in 22 countries. Objectives: To assess the adherence to treatment in allergic rhinitis patients using the Allergy Diary App. Methods: An observational cross-sectional study was carried out on all users who filled in the Allergy Diary from 1 January 2016 to 1 August 2017. Secondary adherence was assessed by using the modified Medication Possession Ratio (MPR) and the Proportion of days covered (PDC) approach. Results: A total of 12143 users were registered. A total of 6949 users reported at least one VAS data recording. Among them, 1887 users reported >= 7 VAS data. About 1195 subjects were included in the analysis of adherence. One hundred and thirty-six (11.28%) users were adherent (MPR >= 70% and PDC = 70% and PDC = 1.50) and 176 (14.60%) were switchers. On the other hand, 832 (69.05%) users were non-adherent to medications (MPR Conclusion and clinical relevance: Adherence to treatment is low. The relative efficacy of continuous vs on-demand treatment for allergic rhinitis symptoms is still a matter of debate. This study shows an approach for measuring retrospective adherence based on a mobile app. This also represents a novel approach for analysing medication-taking behaviour in a real-world setting.Peer reviewe

Correlation between work impairment, scores of rhinitis severity and asthma using the MASK-air (R) App

Background In allergic rhinitis, a relevant outcome providing information on the effectiveness of interventions is needed. In MASK-air (Mobile Airways Sentinel Network), a visual analogue scale (VAS) for work is used as a relevant outcome. This study aimed to assess the performance of the work VAS work by comparing VAS work with other VAS measurements and symptom-medication scores obtained concurrently. Methods All consecutive MASK-air users in 23 countries from 1 June 2016 to 31 October 2018 were included (14 189 users; 205 904 days). Geolocalized users self-assessed daily symptom control using the touchscreen functionality on their smart phone to click on VAS scores (ranging from 0 to 100) for overall symptoms (global), nose, eyes, asthma and work. Two symptom-medication scores were used: the modified EAACI CSMS score and the MASK control score for rhinitis. To assess data quality, the intra-individual response variability (IRV) index was calculated. Results A strong correlation was observed between VAS work and other VAS. The highest levels for correlation with VAS work and variance explained in VAS work were found with VAS global, followed by VAS nose, eye and asthma. In comparison with VAS global, the mCSMS and MASK control score showed a lower correlation with VAS work. Results are unlikely to be explained by a low quality of data arising from repeated VAS measures. Conclusions VAS work correlates with other outcomes (VAS global, nose, eye and asthma) but less well with a symptom-medication score. VAS work should be considered as a potentially useful AR outcome in intervention studies.Peer reviewe

Calix[4]arènes phosphoniums et ammoniums (Synthèse et étude des interactions ligand-anion)

Ces travaux de thèse portent sur des dérivés des calix[4]arènes porteurs de fonctions chargées positivement, des phosphoniums et des ammoniums. Il comporte quatre chapitres. Le premier expose les propriétés particulières des anions et fait le point sur des données bibliographiques concernant leurs interactions avec des ligands acycliques (chélands et podands) et macrocycliques (coronands, cryptands, porphyrines, calixarènes, ). Le second rapporte la synthèse et la caractérisation des nouveaux composés obtenus et détaille la partie expérimentale. Le troisième chapitre présente l étude des interactions entre ces ligands et une grande variété d anions (I-, NO3 -, SCN-, ClO4 -, SO4 2-, S2O3 2-, CrO4 2-, MoO4 2-, Cr2O7 2-) en solution en utilisant différentes techniques, la RMN du proton et du phosphore 31 dans le chloroforme et l acétonitrile, la spectrophotométrie UV-VIS dans le méthanol et l acétonitrile, la microcalorimétrie et l extraction liquide-liquide. Le quatrième chapitre est consacré à l application de ces ligands dans des électrodes sélectives à membranes (ISE)...Aniony odgrywają znaczącą rolę w procesach biologicznych i chemicznych. Wykorzystywane są w wielu gałęziach przemysłu: galwanotechnice, przemyśle tworzyw sztucznych, wytwarzaniu nawozów sztucznych czy środków pirotechnicznych. Ma to odzwierciedlenie we wzrastającym zanieczyszczeniu środowiska takimi substancjami, które nierzadko trudne są do oznaczenia i oddzielenia. Nadmiar fosforanów i azotanów w ściekach wywoływać może eutrofizację w zbiornikach wodnych. Zaburzenia równowagi chlorkowej w komórce wywołują groźne choroby. Nadchlorany które prócz dużej rozpuszczalności w wodzie rozpuszczają się również w tłuszczach mają zdolność do kumulowania się w organizmie. Ich obecność powoduje zaburzenia wzrostu oraz obniżenie czynności tarczycy ze względu na ich duże podobieństwo do anionu jodkowego. Dlatego możliwość dokładnego, selektywnego oznaczania stężeń anionów w różnorakich próbkach jest tak bardzo ważne. Szczególne właściwości anionów, takie jak: zróżnicowana geometria jonów, rozmiary znacznie większe od rozmiarów kationów, mały ładunek w stosunku do promienia, możliwość zmiany stopnia utlenienia atomu centralnego anionu, zróżnicowana kwasowość hydrolizujących soli większości anionów sprawia, że projektowanie receptorów anionów stanowi dla chemika duże wyzwanie.Celem badań była synteza ligandów selektywnych na aniony, charakteryzujących się wysoką lipofilowością, i ich zastosowanie jako materiału aktywnego w czujnikach chemicznych, membranowych elektrodach jonoselektywnych. Celem było również poznanie istoty oddziaływań pomiędzy anionami a badanymi ligandami. Praca polegała na projektowaniu i syntezie nowych związków o właściwościach jonoforowych, opartych na szkielecie p-tertbutylokaliks[4]arenu i zawierających naładowane grupy amoniowe lub fosfoniowe.Praca zredagowana jest w formie 4 rozdziałów poprzedzonych krótkim wstępem. W pierwszym rozdziale zaprezentowano szczególne właściwości anionów, które sprawiają, że projektowanie receptorów anionów stanowi dla chemika duże wyzwanie. W I części usystematyzowane zostały rodzaje oddziaływań między ligandami a anionami. Przedstawiono w nim również przykłady ligandów oddziałujących z anionami, zebrane na podstawie najnowszej literatury.Cześć druga pracy przedstawia dokładny opis syntez amoniowych i fosfonowych pochodnych p-tert-butylokaliks[4]arenu oraz substratów do ich syntezy (związki S, S1 S6). Syntezowano cztery amoniowe pochodne kaliks[4]arenu (związki 1 4) oraz jedenaście pochodnych fosfonowych ( 5 8 oraz 5a, 6a, 6b, 7a, 8a, 8b, 10) różniących się między sobą zarówno rodzajem grupy osfoniowej jak i rodzajem przeciwjonu. Związki fosfoniowe oparte na strukturze kaliks[4]arenu nie były dotychczas syntezowane. By zbadać wpływ preorganizowanej struktury kaliks[4]arenu na właściwości kompleksujące badanych ligandów syntezowano monomer 0 zawierający jedną grupę trifenylofosfoniową. Budowę wszystkich związków potwierdzono spektroskopią 1H NMR oraz 31P NMR, spektrometrią mas i analizą elementarną ...STRASBOURG-Sc. et Techniques (674822102) / SudocSTRASBOURG-Bib.Central Recherche (674822133) / SudocSudocFranceF

Synthèse et étude des propriétés complexantes de dérivés amides et hydroxamiques des calix[4]arènes et de leurs analogues thiocarbonylés

Afin de pouvoir suivre les teneurs en cations de métaux lourds toxiques pour les organismes vivants tels que Pb2+ ou Cd2+, il est nécessaire de concevoir des composés hautement sélectifs. Ce travail porte sur la synthèse et l étude de dérivés amides et hydroxyamides de calix[4]arènes et de leurs analogues thiocarbonylés. Vingt sept dérivés (thioamides, amides, hydroxamates et acides hydroxamiques) ont été obtenus. Différentes techniques ont permis l étude des interactions entre ces ligands et des cations métalliques: spectroscopie RMN du 1H, diffraction des rayons X, extraction liquid-liquid, spectrophotométrie d absorption dans l UV, potentiométrie et microcalorimétrie. Le remplacement des atomes d oxygène des amides tertiaires par des atomes de soufre conduit à des composés très sélectifs pour Ag+ et Pb2+ par rapport aux cations des groupes I et II. Les dérivés acides hydroxamiques extraient très efficacement Fe3+ et Cu2+. Des résultats intéressants ont été obtenus avec ces composés permettant d envisager l'élimination et la séparation de Pb2+ d'autres métaux toxiques comme Cd2+. De plus, l utilisation de ces ligands pourrait permettre de séparer Cu2+ de Zn2+ et Ni2+ qui sont souvent présents simultanément. Les dérivés thioamides et hydroxamates ont été utilisés comme éléments sensibles dans la membrane d électrodes sélectives (ISEs). Les électrodes basées sur des dérivés thioamides, en particulier sur les composés porteurs de fonctions piperidinyles et morpholinyles devraient permettre le développement d outils analytiques prometteurs pour le contrôle des niveaux de pollution en Pb2+ dans les eaux naturelles et les eaux potables.The need of monitoring and controlling the concentration of heavy metal ions such as Pb2+ or Cd2+, which have toxic effects on all living organisms inspires chemists to synthesise more and more selective compounds. The aim of this work was the synthesis of amide and hydroxyamide derivatives of calix[4]arenes and their thiocarbonyl analogues. Nine thioamide derivatives as well as their respective amide derivatives, five hydroxamate derivatives and four calix[4]arene-hydroxamic acids were obtained. Studies of ligands interaction with metal cations were investigated using different techniques: 1H NMR spectroscopy, X-ray diffraction, liquid-liquid extraction, UV absorption spectrophotometry, potentiometry and microcalorimetry. The replacement of the oxygen atoms by sulphur atoms in the tertiary amide structures led to compounds highly selective for Ag+ and Pb2+ over I and II group of cations. Hydroxamic acids of calix[4]arene occurred to be efficient extractants for Fe3+ and Cu2+. Moreover, very important results obtained with these compounds could find an application in the context of the removal and separation of Pb2+ from other toxic metals such as Cd2+. In addition, these ligands could be used to separate Cu2+ from Ni2+ and Zn2+, which are often found together. Selectivity of thioamide and hydroxamate derivatives was assessed using these ligands as sensor materials in ion-selective membrane electrodes. Electrodes based on calix[4]arene-thioamides, particularly on compounds bearing piperidinyl and morpholinyl substituents are promising analytical tools for monitoring Pb2+ concentration in natural and drinking waters.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF