Investigation for the involvement of microbial FliC and DING proteins in Alzheimer's Disease and Mild Cognitive Impairment and correlation with neurodegeneration and inflammation markers

The pathology of Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI) has been linked to inflammation attributed to the microbiome, mainly originating from the oral cavity and the intestine. The goal of this research was to estimate the levels of the bacterial proteins flagellin (FliC) and bacterial DING in cerebrospinal fluid (CSF) and their correlation with neurodegeneration and inflammation markers. FliC and DING levels were evaluated in CSF of 54 AD and 47 MCI patients compared to 23 cognitively healthy individuals, using indirect ELISA. Correlation and multilinear regression analyses with the inflammatory biomarkers COX-1 and COX-2, and with the AD hallmarks, Αβ42, and tau, were conducted as well. FliC and DING proteins were found increased in the CSF of AD patients compared to the control group, while FliC of MCI patients was also elevated in comparison with controls. In addition, FliC and DING levels correlate with each other, with tau and both COX-1/2. Also, multilinear regression analyses suggest that DING is a significant determinant of FliC in CSF and vice-versa, while COX-2 determines both FliC and DING levels and COX-1 only the levels of DING. Consequently, the increase of bacterial FliC and its possible translocation to the brain is an early event in dementia, reflected in dysbiosis events found in MCI and AD patients, and possibly neuroinflammation and neurodegeneration. Additionally, increased DING in AD patients seems to be a significant part of the inflammatory events and its correlation with FliC points to a possible link between these proteins

In vitro and in silico evaluation of the inhibitory effect of a curcumin-based oxovanadium (IV) complex on alkaline phosphatase activity and bacterial biofilm formation

Abstract: The scientific interest in the development of novel metal-based compounds as inhibitors of bacterial biofilm-related infections and alkaline phosphatase (ALP) deregulating effects is continuous and rising. In the current study, a novel crystallographically defined heteroleptic V(IV)-curcumin-bipyridine (V-Cur) complex with proven bio-activity was studied as a potential inhibitor of ALP activity and bacterial biofilm. The inhibitory effect of V-Cur was evaluated on bovine ALP, with two different substrates: para-nitrophenyl phosphate (pNPP) and adenosine triphosphate (ATP). The obtained results suggested that V-Cur inhibited the ALP activity in a dose-dependent manner (IC50 = 26.91 ± 1.61 μM for ATP, IC50 = 2.42 ± 0.12 μM for pNPP) exhibiting a mixed/competitive type of inhibition with both substrates tested. The evaluation of the potential V-Cur inhibitory effect on bacterial biofilm formation was performed on Gram (+) bacteria Staphylococcus aureus (S. aureus) and Gram (−) Escherichia coli (E. coli) cultures, and it positively correlated with inhibition of bacterial ALP activity. In silico study proved the binding of V-Cur at eukaryotic and bacterial ALP, and its interaction with crucial amino acids of the active sites, verifying complex’s inhibitory potential. The findings suggested a specific anti-biofilm activity of V-Cur, offering a further dimension in the importance of metal complexes, with naturally derived products as biological ligands, as therapeutic agents against bacterial infections and ALP-associated diseases. Key points: • V-Cur inhibits bovine and bacterial alkaline phosphatases and bacterial biofilm formation. • Alkaline phosphatase activity correlates with biofilm formation. • In silico studies prove binding of the complex on alkaline phosphatase. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature

Unraveling the binding mechanism of an Oxovanadium(IV) – Curcumin complex on albumin, DNA and DNA gyrase by in vitro and in silico studies and evaluation of its hemocompatibility

An oxovanadium(IV) – curcumin based complex, viz. [VO(cur)(2,2´-bipy)(H2O)] where cur is curcumin and bipy is bipyridine, previously synthesized, has been studied for interaction with albumin and DNA. Fluorescence emission spectroscopy was used to evaluate the interaction of the complex with bovine serum albumin (BSA) and the BSA-binding constant (Kb) was calculated to be 2.56 x 105 M-1, whereas a single great-affinity binding site was revealed. Moreover, the hemocompatibility test demonstrated that the complex presented low hemolytic fraction (mostly below 1%), in all concentrations tested (0-250 μΜ of complex, 5% DMSO) assuring a safe application in interaction with blood. The binding of the complex to DNA was also investigated using absorption, fluorescence, and viscometry methods indicating a binding through a minor groove mode. From competitive studies with ethidium bromide the apparent binding constant value to DNA was estimated to be 4.82 x 106 M-1. Stern-Volmer quenching phenomenon gave a ΚSV constant [1.92 (± 0.05) x 104 M-1] and kq constant [8.33 (± 0.2) x 1011 M-1s-1]. Molecular docking simulations on the crystal structure of BSA, calf thymus DNA, and DNA gyrase, as well as pharmacophore analysis for BSA target, were also employed to study in silico the ability of [VO(cur)(2,2´-bipy)(H2O)] to bind to these target bio-macromolecules and explain the observed in vitro activity. © 2021 Elsevier Inc

A unique ternary Ce(III)-quercetin-phenanthroline assembly with antioxidant and anti-inflammatory properties.

From PubMed via Jisc Publications RouterHistory: received 2022-06-19, revised 2022-07-15, accepted 2022-07-24Publication status: ppublishQuercetin is one of the most bioactive and common dietary flavonoids, with a significant repertoire of biological and pharmacological properties. The biological activity of quercetin, however, is influenced by its limited solubility and bioavailability. Driven by the need to enhance quercetin bioavailability and bioactivity through metal ion complexation, synthetic efforts led to a unique ternary Ce(III)-quercetin-(1,10-phenanthroline) (1) compound. Physicochemical characterization (elemental analysis, FT-IR, Thermogravimetric analysis (TGA), UV-Visible, NMR, Electron Spray Ionization-Mass Spectrometry (ESI-MS), Fluorescence, X-rays) revealed its solid-state and solution properties, with significant information emanating from the coordination sphere composition of Ce(III). The experimental data justified further entry of 1 in biological studies involving toxicity, (Reactive Oxygen Species, ROS)-suppressing potential, cell metabolism inhibition in Saccharomyces cerevisiae (S. cerevisiae) cultures, and plasmid DNA degradation. DFT calculations revealed its electronic structure profile, with in silico studies showing binding to DNA, DNA gyrase, and glutathione S-transferase, thus providing useful complementary insight into the elucidation of the mechanism of action of 1 at the molecular level and interpretation of its bio-activity. The collective work projects the importance of physicochemically supported bio-activity profile of well-defined Ce(III)-flavonoid compounds, thereby justifying focused pursuit of new hybrid metal-organic materials, effectively enhancing the role of naturally-occurring flavonoids in physiology and disease. [Abstract copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

A unique ternary Ce(III)-quercetin-phenanthroline assembly with antioxidant and anti-inflammatory properties

Quercetin is one of the most bioactive and common dietary flavonoids, with a significant repertoire of biological and pharmacological properties. The biological activity of quercetin, however, is influenced by its limited solubility and bioavailability. Driven by the need to enhance quercetin bioavailability and bioactivity through metal ion complexation, synthetic efforts led to a unique ternary Ce(III)-quercetin-(1,10-phenanthroline) (1) compound. Physicochemical characterization (elemental analysis, FT-IR, Thermogravimetric analysis (TGA), UV–Visible, NMR, Electron Spray Ionization-Mass Spectrometry (ESI-MS), Fluorescence, X-rays) revealed its solid-state and solution properties, with significant information emanating from the coordination sphere composition of Ce(III). The experimental data justified further entry of 1 in biological studies involving toxicity, (Reactive Oxygen Species, ROS)-suppressing potential, cell metabolism inhibition in Saccharomyces cerevisiae (S. cerevisiae) cultures, and plasmid DNA degradation. DFT calculations revealed its electronic structure profile, with in silico studies showing binding to DNA, DNA gyrase, and glutathione S-transferase, thus providing useful complementary insight into the elucidation of the mechanism of action of 1 at the molecular level and interpretation of its bio-activity. The collective work projects the importance of physicochemically supported bio-activity profile of well-defined Ce(III)-flavonoid compounds, thereby justifying focused pursuit of new hybrid metal-organic materials, effectively enhancing the role of naturally-occurring flavonoids in physiology and disease

VRADA training system as a non-pharmacological dual intervention to alleviate symptoms of the pathophysiology of Mild Cognitive Impairment

In this study, a VR system called VRADA (VR Exercise App for Dementia and Alzheimer's Patients) was designed for physical and cognitive training forindividuals with Mild Cognitive Impairment (MCI). The inflammatory factors IL-1β and TNF-α, Alzheimer's disease (AD) hallmarks total tau, p181-tau, Αβ42 and Aβ40, the ratio of Aβ42/40 and p181-tau/Aβ42 were assessed on the blood serum of patients diagnosed with MCI to determine the effect of VRADA training. No significant differences were verified in the levels of inflammatory markers after the end of the study, however IL-1β levels of the VRADA group were significantly lower than those of the control group, at the follow-up of the study. Also, patients following VRADA intervention presented significantly higher Αβ42/Αβ40 ratio, and lower levels of Αβ42, of total tau, p-tau181, and of the crucial ratio p-tau181/Αβ42, in comparison with patients of the Control group. These results are promising for the further employment of the VRADA training during early dementia, and hopefully for halting the progression to AD