Mitigating Alzheimer’s disease with natural polyphenols: a review

According to Alzheimer’s Disease International (ADI), nearly 50 million people worldwide were living with dementia in 2017, and this number is expected to triple by 2050. Despite years of research in this field, the root cause and mechanisms responsible for Alzheimer’s disease (AD) have not been fully elucidated yet. Moreover, promising preclinical results have repeatedly failed to translate into patient treatments. Until now, none of the molecules targeting AD has successfully passed the Phase III trial. Although natural molecules have been extensively studied, they normally require high concentrations to be effective; alternately, they are too large to cross the blood-brain barrier (BBB). In this review, we report on AD treatment strategies, with a virtually exclusive focus on green chemistry (natural phenolic molecules). These include therapeutic strategies for decreasing amyloid- β (Aβ) production, preventing and/or altering A β aggregation, and reducing oligomers cytotoxicity such as curcumin, (-)- epigallocatechin-3-gallate (EGCG), morin, resveratrol, tannic acid, and other natural green molecules. We also examinewhether consideration should be given to potential candidates used outside of medicine and nutrition, through a discussion of two intermediate-sized green molecules, with very similar molecular structures and key properties, which exhibit potential in mitigating Alzheimer’s disease

Polyphenol-peptide interactions in mitigation of Alzheimer’s disease : role of biosurface-induced aggregation

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder, responsible for nearly two-thirds of all dementia cases. In this review, we report the potential AD treatment strategies focusing on natural polyphenol molecules (green chemistry) and more specifically on the inhibition of polyphenol-induced amyloid aggregation/disaggregation pathways: in bulk and on biosurfaces. We discuss how these pathways can potentially alter the structure at the early stages of AD, hence delaying the aggregation of Aβ and tau. We also discuss multidisciplinary approaches, combining experimental and modelling methods, that can better characterize the biochemical and biophysical interactions between proteins and phenolic ligands. In addition to the surface-induced aggregation, which can occur on surfaces where protein can interact with other proteins and polyphenols, we suggest a new concept referred as “confinement stability”. Here. on the contrary, the adsorption of Aβ and tau on biosurfaces other than Aβ- and tau-fibrils, e.g. red blood cells (RBCs), can lead to confinement stability that minimizes the aggregation of Aβ and tau. Overall, these mechanisms may participate directly or indirectly in mitigating neurodegenerative diseases, by preventing protein self-association, slowing down the aggregation processes, and delaying the progression of AD

Molecular interactions of tannic acid with proteins associated with SARS-CoV-2 infectivity

The overall impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on our society is unprecedented. The identification of small natural ligands that could prevent the entry and/or replication of the coronavirus remains a pertinent approach to fight the coronavirus disease (COVID-19) pandemic. Previously, we showed that the phenolic compounds corilagin and 1,3,6-tri-O-galloyl-β-D-glucose (TGG) inhibit the interaction between the SARS-CoV-2 spike protein receptor binding domain (RBD) and angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 target receptor on the cell membrane of the host organism. Building on these promising results, we now assess the effects of these phenolic ligands on two other crucial targets involved in SARS-CoV-2 cell entry and replication, respectively: transmembrane protease serine 2 (TMPRSS2) and 3-chymotrypsin like protease (3CLpro) inhibitors. Since corilagin, TGG, and tannic acid (TA) share many physicochemical and structural properties, we investigate the binding of TA to these targets. In this work, a combination of experimental methods (biochemical inhibition assays, surface plasmon resonance, and quartz crystal microbalance with dissipation monitoring) confirms the potential role of TA in the prevention of SARS-CoV-2 infectivity through the inhibition of extracellular RBD/ACE2 interactions and TMPRSS2 and 3CLpro activity. Moreover, molecular docking prediction followed by dynamic simulation and molecular mechanics Poisson–Boltzmann surface area (MMPBSA) free energy calculation also shows that TA binds to RBD, TMPRSS2, and 3CLpro with higher affinities than TGG and corilagin. Overall, these results suggest that naturally occurring TA is a promising candidate to prevent and inhibit the infectivity of SARS-CoV-2

Synthetic Plasmodium-Like Hemozoin Activates the Immune Response: A Morphology - Function Study

Increasing evidence points to an important role for hemozoin (HZ), the malaria pigment, in the immunopathology related to this infection. However, there is no consensus as to whether HZ exerts its immunostimulatory activity in absence of other parasite or host components. Contamination of native HZ preparations and the lack of a unified protocol to produce crystals that mimic those of Plasmodium HZ (PHZ) are major technical limitants when performing functional studies with HZ. In fact, the most commonly used methods generate a heterogeneous nanocrystalline material. Thus, it is likely that such aggregates do not resemble to PHZ and differ in their inflammatory properties. To address this issue, the present study was designed to establish whether synthetic HZ (sHZ) crystals produced by different methods vary in their morphology and in their ability to activate immune responses. We report a new method of HZ synthesis (the precise aqueous acid-catalyzed method) that yields homogeneous sHZ crystals (Plasmodium-like HZ) which are very similar to PHZ in their size and physicochemical properties. Importantly, these crystals are devoid of protein and DNA contamination. Of interest, structure-function studies revealed that the size and shape of the synthetic crystals influences their ability to activate inflammatory responses (e.g. nitric oxide, chemokine and cytokine mRNA) in vitro and in vivo. In summary, our data confirm that sHZ possesses immunostimulatory properties and underline the importance of verifying by electron microscopy both the morphology and homogeneity of the synthetic crystals to ensure that they closely resemble those of the parasite. Periodic quality control experiments and unification of the method of HZ synthesis are key steps to unravel the role of HZ in malaria immunopathology

Mechanisms of flocculation with poly(ethylene oxide) and novel cofactors : theory and experiment

In modern papermaking, the use of retention aids, which help to effectively incorporate fines and fillers into a sheet of paper, is widespread. Various single, dual and multi-component retention aid systems are available, one example of which is poly(ethylene oxide) and cofactor, the topic of this thesis. The mechanisms by which such systems function are still poorly understood, thus making the optimization of wet-end papermaking a complex problem. Without a knowledge of the basic mechanisms of these retention aids, costly trial-and-error runs have to be performed. The aim of this thesis is to use Molecular Mechanics (MM) and Semiempirical Molecular Orbital Theories to test the original ideas and theories, postulating that the association of PEO and cofactor is essential for the flocculation of cellulose fibre fines and that the driving force for association is hydrogen bonding. These theoretical methods provide structures and energies not easily obtainable from experiment, and predict properties and interactions that can be tested experimentally.Gas phase calculations, using the PM3 Semiempirical Molecular Orbital Theory, of the interactions between non-ionic poly (ethylene oxide) (PEO), with three model cofactors, (gallic acid, beta-1-O-Galloyl-3,6-(R)-hexahydroxydiphenoyl-D-Glucose (corilagin) and 1,3,6-Tri-O-Galloyl-beta-D-Glucose (TGG)), showed that the delocalised molecular orbitals (DLMO), which describe the bonding between the n-mer (PEO)n and cofactors, cover the complete complexes. The DLMOs which cover R-OH···O or R-CH···O, traditionally considered as hydrogen bonds, show a distinct "pinch", a decrease of the electron density between the H···O atoms. Calculations of Gibbs free energy, entropy and enthalpy show that the PEO/cofactor complexes do not form at room temperature, because the loss of entropy exceeds the increase in enthalpy. Even though bond lengths, bond angles, DLMOs and electron densities for the PEO/cofactor complexes are consistent with the definition of hydrogen bonds, the number of intermolecular R-OH···O and R-CH···O bonds does not correlate with the enthalpy of association of the complexes, indicating that other interactions predominate in the bonding mechanism for this type of system. Moreover this thesis shows that the original idea that the main mechanism of complexation is hydrogen bonding, is incorrect

Découpage, automates et réception (aspects du cinéma et de ses débuts (1886-1915))

Cette thèse s inscrit dans la mouvance qui, depuis une trentaine d années, fait du cinéma des premiers temps* un champ prolifique et spécifique au sein des études cinématographiques. À la suite de mon mémoire, qui visait à catégoriser, dans une perspective essentiellement historique, les différents types de regards sollicités de la part de l instance spectatorielle au cours de la période, cette thèse de doctorat vise à développer les aspects à la fois plus théoriques et épistémiques de la question et à ouvrir sur la question du découpage. On verra, entre autres, les horizons d attente du cinéma des débuts : l illusion de la Mort vaincue, le cinéma comme automate et la peur du train qui fonce sur les spectateurs. On critiquera le concept de dispositif en rapport avec la réception. L objectif premier est de penser la transformation du découpage durant cette période, afin de comprendre comment s est constitué, pour ne pas dire cristallisé, le langage du cinéma dit institutionnel. Cet objectif ne peut être atteint sans la prise en compte de la réception dans une perspective diachronique.This thesis is a part of the movement over the last thirty years that has made the study of early cinema a prolific and specific area within film studies. Following my Master s thesis, which aimed to categorize from an historical perspective the different kinds of gazes produced by the instance of spectatorship during the early period, this doctoral thesis aims to develop both the theoretical and epistemic sides of the same question and to elaborate on the question of decoupage. We will consider, among other topics, the horizons of expectation of early films: the illusion of defeated Death, film as automaton and the fear of the on-coming train. We will criticize the concept of apparatus when applied to that of spectatorship. Our primary objective is to analyze the transformation of decoupage during this period, in order to better understand how the language of institutional film was developed, if not crystallized. This objective cannot be reached without careful consideration of spectatorship from a diachronic perspective.PARIS3-BU (751052102) / SudocSudocFranceCanadaFRC

Corilagin and 1,3,6-Tri-O-galloyl-β -D-glucose : potential inhibitors of SARS-CoV-2 variants

The COVID-19 disease caused by the virus SARS-CoV-2, first detected in December 2019, is still emerging through virus mutations. Although almost under control in some countries due to effective vaccines that are mitigating the worldwide pandemic, the urgency to develop additional vaccines and therapeutic treatments is imperative. In this work, the natural polyphenols corilagin and 1,3,6-tri-Ogalloy-β-D-glucose (TGG) are investigated to determine the structural basis of inhibitor interactions as potential candidates to inhibit SARS-CoV-2 viral entry into target cells. First, the therapeutic potential of the ligands are assessed on the ACE2/wild-type RBD. We first use molecular docking followed by molecular dynamics, to take into account the conformational flexibility that plays a significant role in ligand binding and that cannot be captured using only docking, and then analyze more precisely the affinity of these ligands using MMPBSA binding free energy. We show that both ligands bind to the ACE2/wild-type RBD interface with good affinities which might prevent the ACE2/RBD association. Second, we confirm the potency of these ligands to block the ACE2/RBD association using a combination of surface plasmon resonance and biochemical inhibition assays. These experiments confirm that TGG and, to a lesser extent, corilagin, inhibit the binding of RBD to ACE2. Both experiments and simulations show that the ligands interact preferentially with RBD, while weak binding is observed with ACE2, hence, avoiding potential physiological side-effects induced by the inhibition of ACE2. In addition to the wild-type RBD, we also study numerically three RBD mutations (E484K, N501Y and E484K/N501Y) found in the main SARS-CoV-2 variants of concerns. We find that corilagin could be as effective for RBD/E484K but less effective for the RBD/N501Y and RBD/E484K-N501Y mutants, while TGG strongly binds at relevant locations to all three mutants, demonstrating the significant interest of these molecules as potential inhibitors for variants of SARSCoV-2

Bionanocomposites with Enhanced Physical Properties from Curli Amyloid Assemblies and Cellulose Nanofibrils

Proteinaceous amyloid fibrils are one of the stiffest biopolymers due to their extensive cross-β-sheet quaternary structure, whereas cellulose nanofibrils (CNFs) exhibit interesting properties associated with their nanoscale size, morphology, large surface area, and biodegradability. Herein, CNFs were supplemented with amyloid fibrils assembled from the Curli-specific gene A (CsgA) protein, the main component of bacterial biofilms. The resulting composites showed superior mechanical properties, up to a 7-fold increase compared to unmodified CNF films. Wettability and thermogravimetric analyses demonstrated high surface hydrophobicity and robust thermal tolerance. Bulk spectroscopic characterization of CNF-CsgA films revealed key insights into the molecular organization within the bionanocomposites. Atomic force microscopy and photoinduced force microscopy revealed the high-resolution location of curli assemblies into the CNF films. This novel sustainable and cost-effective CNF-based bionanocomposites supplemented with intertwined bacterial amyloid fibrils opens novel directions for environmentally friendly applications demanding high mechanical, water-repelling properties, and thermal resistance