COVID-19 and Alzheimer's Disease: Neuroinflammation, Oxidative Stress, Ferroptosis, and Mechanisms Involved.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by marked cognitive decline, memory loss, and spatio-temporal troubles and, in severe cases, lack of recognition of family members. Neurological symptoms, cognitive disturbances, and the inflammatory frame due to COVID-19, together with long-term effects, have fueled renewed interest in AD based on similar damage. COVID-19 also caused the acceleration of AD symptom onset. In this regard, the morbidity and mortality of COVID-19 were reported to be increased in patients with AD due to multiple pathological changes such as excessive expression of the viral receptor angiotensin-converting enzyme 2 (ACE2), comorbidities such as diabetes, hypertension, or drug-drug interactions in patients receiving polypharmacy and the high presence of proinflammatory molecules. Furthermore, the release of cytokines, neuroinflammation, oxidative stress, and ferroptosis in both diseases showed common underlying mechanisms, which together worsen the clinical picture and prognosis of these patients.

Resonance structure contributions, flexibility, and frontier molecular orbitals (HOMO-LUMO) of pelargonidin, cyanidin, and delphinidin throughout the conformational space: application to antioxidant and antimutagenic activities.

This research refers to the study and understanding of the conformational space of the positive-charged anthocyanidin structures in relation with the known chemical reactivities and bioactivities of these compounds. Therefore, the planar (P) and nonplanar (Z) conformers of the three hydroxylated anthocyanidins pelargonidin, cyanidin, and delphinidin were analyzed throughout the conformational space at the B3LYP/6-311 ++ G** level of theory. The outcome displayed eleven new conformers for pelargonidin, fifty-four for cyanidin, and thirty-one for delphinidin. Positive-charged quinoidal structures showed a significant statistical weight in the conformational space, thus coexisting simultaneously with other resonance structures, such that under certain reaction conditions, the anthocyanidins behave as positive-charged quinoidal structures instead of oxonium salts. The calculations of the permanent dipole moment and the polarizability showed relationships with the quantity and arrangement of hydroxyls in the structure. In addition, theoretical calculations were used to analyze the frontier molecular orbitals (HOMO-LUMO) of the three anthocyanidins. The novel conception of this work lies in the fact that dipole moment, polarizability, and HOMO-LUMO values were related to the reactivity/bioactivity of these three anthocyanidins. HOMO-LUMO energy gaps were useful to explain the antioxidant activity, while the percent atom contributions to HOMO were appropriate to demonstrate the antimutagenic activity as enzyme inhibitors, as well as the steric and electrostatic requirements to form the pharmacophore. Delphinidin was the strongest antioxidant anthocyanidin, and pelargonidin the best anthocyanidin with antimutagenic activity.

Dietary anthocyanins balance immune signs in osteoarthritis and obesity - update of human in vitro studies and clinical trials.

Anthocyanins are known to change ligand-receptor bindings, cell membrane permeability, and intracellular signaling pathways. The beneficial effects of dietary anthocyanins have been chronologically demonstrated in interventional and observational studies, including fourteen human chondrocyte studies and related cell culture assays, nineteen human clinical trials in osteoarthritis patients, seven in vivo obesity assays, nineteen in vitro assays in preadipocytes and related cells, and twenty-two clinical trials in overweight/obese subjects, which are critically discussed in this update. Strawberries, cherries, berries, pomegranate, tropical fruits, rosehip, purple rice, purple corn, red beans, and black soybean, together with cyanidin, delphinidin, malvidin, peonidin, some 3-O-glycosides, metabolites, and acylated anthocyanins from a potato cultivar have shown the best outcomes. The set of these five key tests and clinical trials, taken together, contributes to the understanding of the underlying mechanisms and pathways involved. Furthermore, this set shows the value of anthocyanins in counteracting the progression of osteoarthritis/obesity. The interplay between the inflammation of osteoarthritis and obesity, and the subsequent regulation/immunomodulation was performed through isolated and food anthocyanins. The antioxidant, anti-inflammatory, and immunomodulatory properties of anthocyanins explain the findings of the studies analyzed. However, further interventional studies should be conducted to finally establish the appropriate doses for anthocyanin supplementation, dose-response, and length of consumption, to include dietary recommendations for osteoarthritis/obese patients for preventive and management purposes.

Neuroproteomics Chip-Based Mass Spectrometry and Other Techniques for Alzheimer's Disease Biomarkers - Update.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease of growing interest given that there is cognitive damage and symptom onset acceleration. Therefore, it is important to find AD biomarkers for early diagnosis, disease progression, and discrimination of AD and other diseases. OBJECTIVE: The objective of this study is to update the relevance of mass spectrometry for the identification of peptides and proteins involved in AD useful as discriminating biomarkers. METHODS: Proteomics and peptidomics technologies that show the highest possible specificity and selectivity for AD biomarkers are analyzed, together with the biological fluids used. In addition to positron emission tomography and magnetic resonance imaging, MALDI-TOF mass spectrometry is widely used to identify proteins and peptides involved in AD. The use of protein chips in SELDI technology and electroblotting chips for peptides makes feasible small amounts (µL) of samples for analysis. RESULTS: Suitable biomarkers are related to AD pathology, such as intracellular neurofibrillary tangles; extraneuronal senile plaques; neuronal and axonal degeneration; inflammation and oxidative stress. Recently, peptides were added to the candidate list, which are not amyloid-ß or tau fragments, but are related to coagulation, brain plasticity, and complement/neuroinflammation systems involving the neurovascular unit. CONCLUSION: The progress made in the application of mass spectrometry and recent chip techniques is promising for discriminating between AD, mild cognitive impairment, and matched healthy controls. The application of this technique to blood samples from patients with AD has shown to be less invasive and fast enough to determine the diagnosis, stage of the disease, prognosis, and follow-up of the therapeutic response.

Uncommon Noninvasive Biomarkers for the Evaluation and Monitoring of the Etiopathogenesis of Alzheimer's Disease.

BACKGROUND: Alzheimer´s disease (AD) is the most widespread dementia in the world, followed by vascular dementia. Since AD is a heterogeneous disease that shows several varied phenotypes, it is not easy to make an accurate diagnosis, so it arises when the symptoms are clear and the disease is already at an advanced stage. Therefore, it is important to find out biomarkers for early AD diagnosis that facilitate treatment or slow down the disease. Classic biomarkers are obtained from cerebrospinal fluid and plasma, along with brain imaging by positron emission tomography. Attempts have been made to discover uncommon biomarkers from other body fluids, which are addressed in this update. OBJECTIVE: This update aims to describe recent biomarkers from minimally invasive body fluids for the patients, such as saliva, urine, eye fluid or tears. METHODS: Biomarkers were determined in patients versus controls by single tandem mass spectrometry and immunoassays. Metabolites were identified by nuclear magnetic resonance and microRNAs with genome-wide high-throughput real-time polymerase chain reaction-based platforms. RESULTS: Biomarkers from urine, saliva, and eye fluid were described, including peptides/proteins, metabolites, and some microRNAs. The association with AD neuroinflammation and neurodegeneration was analyzed, highlighting the contribution of matrix metalloproteinases, the immune system and microglia, as well as the vascular system. CONCLUSION: Unusual biomarkers have been developed, which distinguish each stage and progression of the disease, and are suitable for the early AD diagnosis. An outstanding relationship of biomarkers with neuroinflammation and neurodegeneration was assessed, clearing up concerns about the etiopathogenesis of AD.

QSAR studies of the antioxidant activity of anthocyanins.

Through experimental information available from antioxidant assays of seventeen anthocyanins, and six common anthocyanidins, quantitative structure-activity relationships (QSAR) have been established in the present work. The antioxidant bioactivity has been predicted in three different lipid environments: emulsified and bulk oil (methyl linoleate) (in vitro tests) at concentrations of 50 and 250 µM, and 50 µM of the inhibitor, respectively, and in human LDL (low-density lipoprotein; "bad cholesterol") (ex vivo test) at concentrations of 2.5, 10, and 25 µM of the inhibitor. Radical scavenging activity was predicted in the assay with the 1,1-diphenyl-2-picrylhydrazyl radical (DPPH·). The QSAR models developed for each test and concentration used allowed to obtain prospective information on the constitutional and topological molecular characteristics for anthocyanin/anthocyanidin compounds. Therefore, the antioxidant activity was predicted for twenty-one compounds with unknown experimental values, leading for some of them to a favorable predicted bioactivity.

Z-Isomers of (4α→6″, 2α→O→1″)-phenylflavan substituted with R'=R=OH. Conformational properties, electronic structure and aqueous solvent effects.

Procyanidins are highly hydroxylated polymers known as antioxidant compounds, thereby exhibiting beneficial effects. These compounds are protective agents against oxidative stress and the damage induced by free radicals in membranes and nucleic acids. This paper describes a study of the conformational space of (4α→6″, 2α→O→1″)-phenylflavan substituted with R'=R=OH as part of a larger study of similar structures with different substitutions. The relationships between aqueous solution-vacuum variations of some properties were studied, as well as the stabilization and reactivity of (4α→6″, 2α→O→1″)-phenylflavan substituted with R'=R=H, R'=H, R=OH, R'=R=OH, and (+)-catechin. The variations in geometric parameters and electronic properties due to conformational changes, as well as the effects of substituents and polar solvents, were evaluated and analyzed. Bader's theory of atoms in molecules was applied to characterize intramolecular interactions, along with a natural bond orbital analysis for each conformer described. The molecular electrostatic potential was rationalized by charge delocalization mechanisms and interatomic intramolecular interactions, relating them to the structural changes and topological properties of the electron charge density. Molecular polarizability and permanent electric dipole moment values were estimated. The results show the importance of a knowledge of the conformational space, and values for each conformer. Based on our previous results, we showed the existence of electron charge delocalization mechanisms acting cooperatively as "delocalization routes", showing interactions between different rings not even sharing the same plane. These "delocalization routes" were more effective for (4α→6″, 2α→O→1″)-phenylflavan substituted with R'=R=OH than for (+)-catechin, and are proposed as adding insight into the structure-antioxidant activity relationship of flavans.

Exploratory conformational study of (+)-catechin. Modeling of the polarizability and electric dipole moment.

The extension of the study of the conformational space of the structure of (+)-catechin at the B3LYP/6-31G(d,p) level of theory is presented in this paper. (+)-Catechin belongs to the family of the flavan-3-ols, which is one of the five largest phenolic groups widely distributed in nature, and whose biological activity and pharmaceutical utility are related to the antioxidant activity due to their ability to scavenge free radicals. The effects of free rotation around all C-O bonds of the OH substituents at different rings are taken into account, obtaining as the most stable conformer, one that had not been previously reported. One hundred seven structures, and a study of the effects of charge delocalization and stereoelectronic effects at the B3LYP/6-311++G(d,p) level are reported by natural bond orbital analysis, streamlining the order of these structures. For further analysis of the structural and molecular properties of this compound in a biological environment, the calculation of polarizabilities, and the study of the electric dipole moment are performed considering the whole conformational space described. The results are analyzed in terms of accumulated knowledge for (4α → 6″, 2α → O → 1″)-phenylflavans and (+)-catechin in previous works, enriching the study of both types of structures, and taking into account the importance of considering the whole conformational space in modeling both the polarizability and the electric dipole moment, also proposing to define a descriptive subspace of only 16 conformers.

Structure and electronic properties of (+)-catechin: aqueous solvent effects.

We report a study of the structure of (+)-catechin, which belongs to the family of the flavan-3-ols-one of the five most widely distributed phenolic groups. The biological activities and pharmaceutical utility of these compounds are related to antioxidant activity due to their ability to scavenge free radicals. A breakthrough in the study of the conformational space of this compound, so far absent in the literature, is presented herein. A detailed analysis of the electronic distribution, charge delocalization effects, and stereoelectronic effects is presented following application of the theory of atoms in molecules (AIM) and natural bond orbital analysis. The stability order, and the effects of electron delocalization in the structures were analyzed in depth. The molecular electrostatic potential (MEP) was also obtained, assessing changes in the electronic distribution in aqueous solution, the effects of the solvent on the intrinsic electronic properties, and molecular geometry. The effect of the aqueous solvent on MEP was also quantified, and rationalized by charge delocalization mechanisms, relating them to structural changes and topological properties of the electronic charge density. To further analyze the effects of the aqueous solvent, as well as investigating the molecular and structural properties of these compounds in a biological environment, the polarizabilities for all conformers characterized were also calculated. All results were interpreted on the basis of our accumulated knowledge on (4α→6", 2α→O→1")-phenylflavans in previous reports, thus enriching and deepening the analysis of both types of structure.

Naturally-occurring dimers of flavonoids as anticarcinogens.

Biflavonoids are dimers of flavonoid moieties linked by a C-C or C-O-C bond. Simple, complex, rearranged, natural and ketalized Diels-Alder adducts, benzofuran derivatives, and spirobiflavonoids are some of the structural groups of biflavonoids. These compounds are mainly distributed in the Gymnosperms, Angiosperms (monocots and dicots), ferns (Pteridophyta), and mosses (Bryophyta). Biflavonoids have shown a variety of biological activities, including anticancer, antibacterial, antifungal, antiviral, antiinflammatory, analgesic, antioxidant, vasorelaxant, anticlotting, among others. This work is focused on probably the most potentially relevant biological activity of biflavonoids, the anticancer activity and the involved mechanisms of action, such as induction of apoptosis [inhibition of cyclic nucleotide phosphodiesterases; effects on NF-κB family of transcription factors; activation of caspase(s); inhibition effects on bcl-2 expression, and upregulation of p53 and caspase-3 gene expression]; inhibition of angiogenesis [anti-proliferative effects; activation of Rho-GTPases and ERK signaling pathways; inhibition of FASN activity]; inhibition of pre-mRNA splicing; inhibition of human DNA topoisomerases I and II-α; anti-inflammatory/ immunoregulatory effects [inhibition of XO; inhibition of proinflammatory enzymes, such as PLA2 and COX; effects on cytokines mediated COX-2 and iNOS expression]; modulation of immune response; inhibition of protein tyrosine phosphorylation; antioxidant and analgesic activities in relation to the anticarcinogen behavior. For that reason the structures and anticarcinogenic activities of 83 biflavonoids are thoroughly discussed. The results of this work indicate that biflavonoids strongly affect the cancer cells with little effect on normal cell proliferation, suggesting a therapeutic potential against cancer.

Amino acid profiles and quantitative structure-property relationship models as markers for Merlot and Torrontés wines.

Quantitative structure-property relationships (QSPRs) were applied to the aminograms obtained by HPLC in our laboratories for Torrontés and Merlot wines. Dragon theoretical descriptors were derived for a set of optimized amino acid structures with the purpose of establishing QSPR models. The statistical Replacement Method was used for designing the best multi-parametric linear regression models, which included structural features selected from a pool containing 1497 constitutional, topological, geometrical or electronic molecular descriptors. Predicted QSPR results were in good agreement with experimental amino acid profiles. The developed QSPR approach showed to be of practical value for distinguishing each wine varietal, and for calculating experimentally non-available amino acid concentrations of Torrontés and Merlot wines. It was also useful for assessing wine authenticity; the models were especially suitable for Merlot and Torrontés wines.

(Iso)flav(an)ones, chalcones, catechins, and theaflavins as anticarcinogens: mechanisms, anti-multidrug resistance and QSAR studies.

Flavonoids have shown anticarcinogenic activity in cancer cell lines, animal models, and some human studies. Quantitative structure-activity relationship (QSAR) models have become useful tools for identification of promising lead compounds in anticancer drug development. However, epidemiological and clinical studies are still scarce. Compounds with flavonoid scaffold have been the subject of many mechanistic studies in cells, but information on human chemopreventive properties is still missing. The knowledge of the mechanisms of action, anti-multidrug resistance, and QSAR studies on flavonoids and related compounds may help to enhance research on these compounds and their bioactivity. Therefore, once the issue is introduced, the mechanisms involved, and QSAR studies developed to predict the activity and toxicity of these chemicals to biological systems are discussed. QSAR studies on flavonoids as inhibitors of breast cancer resistance protein (BCRP/ABCG2), 17ß-hydroxysteroid dehydrogenase (17ß-HSD), PIM-1 kinase and cyclin-dependent kinases (CDKs) are analyzed. Combined treatment of flavonoids with TRAIL and current chemotherapy agents is also discussed as a promising cancer chemoprevention and/or therapy.

Structural and electronic properties of Z isomers of (4α→6´´,2α→O→1´´)-phenylflavans substituted with R = H, OH and OCH3 calculated in aqueous solution with PCM solvation model.

In the search for new antioxidants, flavan structures called our attention, as substructures of many important natural compounds, including catechins (flavan-3-ols), simple and dimeric proanthocyanidins, and condensed tannins. In this work the conformational space of the Z-isomers of (4α→6´´, 2α→O→1´´)-phenylflavans substituted with R = H, OH and OCH(3) was scanned in aqueous solution, simulating the solvent by the polarizable continuum model (PCM). Geometry optimizations were performed at B3LYP/6-31 G level. Electronic distributions were analyzed at a better calculation level, thus improving the basis set (6-311++G). A topological study based on Bader´s theory (atoms in molecules) and natural bond orbital (NBO) framework was performed. Furthermore, molecular electrostatic potential maps (MEPs) were obtained and thoroughly analyzed. The stereochemistry was discussed, and the effect of the solvent was addressed. Moreover, intrinsic properties were identified, focusing on factors that may be related to their antioxidant properties. Hyperconjugative and inductive effects were described. The coordinated NBO/AIM analysis allowed us to rationalize the changes of MEPs in a polar solvent. To investigate the molecular and structural properties of these compounds in biological media, the polarizabilities and dipolar moments were predicted which were further used to enlighten stability and reactivity properties. All conformers were taken into account. Relevant stereoelectronic aspects were described for understanding the stabilization and antioxidant function of these structures.

In vivo long-term kinetics of radiolabeled n,n-dimethyltryptamine and tryptamine.

UNLABELLED: N,N-dimethyltryptamine (DMT), a strong psychodysleptic drug, has been found in higher plants, shamanic hallucinogenic beverages, and the urine of schizophrenic patients. The aim of this work was to gain better knowledge on the relationship between this drug and hallucinogenic processes by studying DMT behavior in comparison with tryptamine. METHODS: (131)I-labeled DMT and tryptamine were injected into rabbits. γ-Camera and biodistribution studies were performed. Brain uptake, plasma clearance, and renal excretion were assessed for each indolealkylamine. RESULTS: DMT and tryptamine showed different behavior when brain uptake, residence time, and excretion were compared. Labeled DMT entered the brain 10 s after injection, crossed the blood-brain barrier, and bound to receptors; then it was partially renally excreted. It was detected in urine within 24 h after injection and remained in the brain, even after urine excretion ceased; up to 0.1% of the injected dose was detected at 7 d after injection in the olfactory bulb. In contrast, tryptamine was rapidly taken up in the brain and fully excreted 10 min after injection. CONCLUSION: To our knowledge, this is the first demonstration that exogenous DMT remains in the brain for at least 7 d after injection. Although labeled DMT and tryptamine behave as agonists for at least 5-hydroxytryptamine 2A receptor, 5-hydroxytryptamine 2C receptor, trace amine-associated receptor, and σ-1 putative receptor targets, binding to the latter can explain the different behavior of labeled DMT and tryptamine in the brain. The persistence in the brain can be further explained on the basis that DMT and other N,N-dialkyltryptamines are transporter substrates for both the plasma membrane serotonin transporter and the vesicle monoamine transporter 2. Furthermore, storage in vesicles prevents DMT degradation by monoamine oxidase. At high concentrations, DMT is taken up by the serotonin transporter and further stored in vesicles by the vesicle monoamine transporter 2, to be released under appropriate stimuli. Moreover, the (131)I-labeling proved to be a useful tool to perform long-term in vivo studies.

Theoretical study of Z isomers of A-type dimeric proanthocyanidins substituted with R=H, OH and OCH3: stability and reactivity properties.

The stereochemistry of A-type dimeric proanthocyanidins was studied, focusing on the factors that determine it, and the changes that occur with R = OCH3, R' = H, and R = OH, R' = H as substituents, starting with the study of the conformational space of each species. Using molecular dynamics at a semiempirical level, and complementing with functional density calculations, two conformers of lowest energy were characterized for R = H, eight conformers for R = OH, and three conformers for R = OCH3. Electronic distributions were analyzed at a higher calculation level, thus improving the basis set. Intramolecular interactions were examined and characterized by the theory of atoms in molecules (AIM). Detailed natural bond orbitals (NBO) analysis allowed the description of subtle stereoelectronic aspects of fundamental importance for understanding the stabilization and antioxidant function of these structures. The study was enriched by a deep analysis of maps of molecular electrostatic potential (MEP). The coordinated analysis of MEP, together with the NBO and AIM results, allowed us to rationalize novel distribution aspects of the potential created in the space around a molecule.

QSAR study of flavonoids and biflavonoids as influenza H1N1 virus neuraminidase inhibitors.

We performed a predictive analysis based on Quantitative Structure-Activity Relationships (QSAR) of a very important property of flavonoids which is the inhibition (IC50) of influenza H1N1 virus neuraminidase. The best linear model constructed from 20 molecular structures incorporated four molecular descriptors, selected from more than a thousand geometrical, topological, quantum-mechanical and electronic types of descriptors. The obtained model suggests that the activity depends on the electric charges, masses and polarizabilities of the atoms present in the molecule as well as its conformation. The model showed good predictive ability established by the theoretical and external test set validations.

Conformational and electronic (AIM/NBO) study of unsubstituted A-type dimeric proanthocyanidin.

UNLABELLED: The conformational space of the unsubstituted A-type dimeric proanthocyanidin was scanned using molecular dynamics at a semiempirical level, and complemented with functional density calculations. The lowest energy conformers were obtained. Electronic distributions were analysed at a higher calculation level, thus improving the basis set. A topological study based on Bader's theory ( AIM: atoms in molecules) and natural bond orbital (NBO) framework was performed. Furthermore, molecular electrostatic potential maps (MEPs) were obtained and analysed. NMR chemical shifts were calculated at ab initio level and further compared with previous experimental values; coupling constants were also calculated. The stereochemistry of the molecule is thoroughly discussed, revealing the key role that hyperconjugative interactions play in defining experimental trends. These results show the versatility of geminal spin-spin coupling (2)J(C-1',O) as a probe for stereochemical studies of proanthocyanidins.

Vibrational spectra, NMR and theoretical studies of the enantiomers and rotamers of alpha-cypermethrin.

NMR, infrared and Raman vibrational spectra of alpha-cypermethrin have been measured at room temperature. Infrared spectra were also recorded to low temperature. The spectra were analyzed by means of ab initio calculations. The conformational space of both enantiomers and some rotamers A, B and C of alpha-cypermethrin has been scanned using molecular dynamics and complemented with functional density calculations that optimize the geometry of the lowest-energy conformers of each species as obtained in the simulations. The vibrational frequencies and the 1H and 13C NMR chemical shifts were assigned using functional density calculations. The molecular electrostatic potential maps were obtained and analyzed.

In vitro anthelmintic activity of Melia azedarach naturalized in Argentina.

The anthelmintic activity of the drupe extracts of Melia azedarach L. (Meliaceae) growing in Argentina was tested against tapeworms, hookworms, nodular worms and earthworms, and was shown to be better than the standards piperazine phosphate and hexylresorcinol against tapeworms and hookworms, respectively.

High-performance capillary electrophoresis analysis of mate infusions prepared from stems and leaves of Ilex paraguariensis using automated micellar electrokinetic capillary chromatography.

An automated micellar electrokinetic capillary chromatographic method has been developed in order to determine xanthines, e.g. caffeine, theobromine and theophylline, and chlorogenic acid in samples of yerba mate (Ilex paraguariensis). The target constituents were detected by photodiode array, and quantified by an external standard method. In addition, each constituent was collected separately and identified by EIMS. The method has been used to analyse 30 samples of mate infusions prepared at 30 and 75 degrees C with milled leaves and stems of 14 commercial brands which had been subjected to different elaboration processes. Suspended powdered material of each infusion was also analysed after three sieving steps. There was a remarkable difference in the relative xanthine composition of the finely suspended material, the amount of which varied according to the yerba mate brand, the elaboration process and the temperature of the infusion. The importance of these results with respect to gastrointestinal disorders which have been observed by habitual consumers of mate are discussed.