Pincer Ligands as Multifunctional Agents for Alzheimer's Copper Dysregulation and Oxidative Stress: A Computational Evaluation.

Alzheimer's disease (AD) is the most common form of dementia worldwide, affecting millions of people around the globe. AD is characterized by different pathologies being beta-amyloid (Aß) plaque formation, metal ion dysregulation, and oxidative stress (OS) central topics under investigation. Copper-Aß complexes have been shown to induce catalytic hydrogen peroxide formation and increase OS in the brain leading to neuronal death. Pincer-type compounds are tridentate ligands that coordinate metals in a planar fashion whose properties can be tuned via group substitutions, giving rise to many possibilities in catalysis and drug discovery. In this work we evaluated the potential pharmaceutical activity of 26 pincer compounds in AD's copper ion-related oxidative stress framework. In this sense, four key aspects were considered: 1) Lipinski's rule of five, 2) blood-brain barrier permeation, 3) standard reduction potential (SRP) of the formed copper complexes, and 4) the ligand's affinity towards copper cations. The evaluation of these criteria was performed by means of bioinformatic tools and electronic structure calculations at the DFT level of theory. Our results suggest that two compounds from this set are potential antioxidant agents, whereas five of them are promissory distributor-like compounds in the context of AD.

Computational Evaluation of the Potential Pharmacological Activity of Salen-Type Ligands in Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia representing from 60% to 70% of the cases globally. It is a multifactorial disease that, among its many pathological characteristics, has been found to provoke the metal ion dysregulation in the brain, along with an increase in the oxidative stress. There is proof that metallic complexes formed by the amyloid-ß peptide (Aß) and extraneuronal copper can catalyze the production of reactive oxygen species, leading to an increase in oxidative stress, promoting neuronal death. Due to this interaction, bioavailable copper has become an important redox active target to consider within the search protocols of multifunctional agents for AD's treatment. OBJECTIVE: In this study, we examined by using bioinformatics and electronic structure calculations the potential application of 44 salen-type copper chelating ligands and 12 further proposed molecules as possible multifunctional agents in the context of AD. METHODS: The candidates were evaluated by combining bioinformatic tools and electronic structure calculations, which allowed us to classify the molecules as potential antioxidants, redistributor-like compounds, and the newly proposed suppressor mechanism. RESULTS: This evaluation demonstrate that salen-type ligands exhibit properties suitable for interfering in the chain of copper-induced oxidative stress reactions present in AD and potential redistributor and suppressor activity for copper ions. Finally, a novel set of plausible candidates is proposed and evaluated. CONCLUSION: According to the evaluated criteria, a subset of 13 salen-type candidates was found to exhibit promissory pharmacological properties in the AD framework and were classified according to three plausible action mechanisms.

Tromboembolismo pulmonar asociado a COVID-19 en paciente con síndrome de May-Thurner / COVID-19-associated Pulmonary Thromboembolism in a Patient with May-Thurner Syndrome

Introducción: El síndrome de May-Thurner es una enfermedad cuya prevalencia real es desconocida. Suele ser asintomática y las manifestaciones clínicas aparecen en el contexto de las complicaciones asociadas a la enfermedad. La aproximación diagnóstica se realiza por medio de imágenes, donde se identifican alteraciones patognomónicas que permiten descartar diagnósticos diferenciales. Se ha demostrado que la COVID-19 genera un estado protrombótico, que en contexto del síndrome de May-Thurner puede derivar en complicaciones tromboembólicas. Objetivo: Comparar la clínica y la posible relación de la enfermedad tromboembólica venosa en el curso de la COVID-19 en pacientes con SMT. Caso clínico: Mujer de 24 años, secretaria de profesión y residente en Bucaramanga. Presentó un cuadro clínico de 20 días de evolución que inició con rinorrea hialina, tos ocasional y mialgias; cinco días después manifestó fiebre no cuantificada y tos con expectoración hemoptoica. Conclusiones: Dentro de la fisiopatología de la infección por SARS-CoV-2 se desarrollan mecanismos procoagulantes, lo cual incrementa el riesgo de eventos trombóticos en pacientes con o sin factores de riesgo(AU)

Introduction: May-Thurner syndrome is a disease whose actual prevalence is unknown. It is usually asymptomatic and clinical manifestations appear in the context of complications associated with the disease. The diagnostic approach is performed by imaging, where pathognomonic alterations are identified to rule out differential diagnoses. It has been demonstrated that COVID-19 generates a prothrombotic state, which particularly in patients with May-Thurner syndrome would lead to thromboembolic complications. Objective: To compare the clinical and possible relationship of venous thromboembolic disease in the course of COVID-19 in patients with May-Thurner syndrome. Clinical case: 24-year-old woman, secretary by profession and resident in Bucaramanga, Colombia. She presented a clinical picture of 20 days of evolution that began with hyaline rhinorrhea, occasional cough and myalgias; five days later she manifested unquantified fever and cough with hemoptotic expectoration. Conclusions: Within the pathophysiology of SARS-CoV-2 infection, procoagulant mechanisms develop, which increases the risk of thrombotic events in patients with or without risk factors(AU)

Role of Metal Cations of Copper, Iron, and Aluminum and Multifunctional Ligands in Alzheimer's Disease: Experimental and Computational Insights.

Alzheimer's disease (AD) is the most common form of dementia, affecting millions of people around the world. Even though the causes of AD are not completely understood due to its multifactorial nature, some neuropathological hallmarks of its development have been related to the high concentration of some metal cations. These roles include the participation of these metal cations in the production of reactive oxygen species, which have been involved in neuronal damage. In order to avoid the increment in the oxidative stress, multifunctional ligands used to coordinate these metal cations have been proposed as a possible treatment to AD. In this review, we present the recent advances in experimental and computational works aiming to understand the role of two redox active and essential transition-metal cations (Cu and Fe) and one nonbiological metal (Al) and the recent proposals on the development of multifunctional ligands to stop or revert the damaging effects promoted by these metal cations.

Nutrition care as a health policy in the 21st century: A phenomenological study.

BACKGROUND: Addressing the high prevalence of disease-related malnutrition (DRM) requires political will. The aim of this study is to define DRM as a health public policy issue from the point of view of the stakeholders. METHODS: We conducted a qualitative phenomenological study consisting of grey data search and individual semi-structured in-depth interviews with stakeholders (policy-makers, academics, and civil society organization representatives) from 17 Latin American countries. The analyzed themes reflected ideas repeatedly found across the interviews. RESULTS: 26 respondents were interviewed (5 policy-makers, 18 academics, 3 civil society organizations representatives). The grey data research and interviews showed that Brazil and Costa Rica were the only countries in the Region that had developed a specific public health policy addressing DRM and nutrition care issues. The rest of the Latin American countries had a nutrition policy which neither addressed DRM specifically nor included nutrition care, with important heterogeneity existing in terms of national regulation of selected nutritional care categories. Stakeholder opinions allowed to identify heterogeneity in the understanding of the nature and causes of DRM, confusing DRM with malnutrition caused by food insecurity and lack of food availability. Policy in the field of clinical nutrition can be addresses from two approaches: interdisciplinarity and a human rights-based approach. CONCLUSION: DRM is an unaddressed problem by health policy. Due to internal and external factor related to the health systems DRM has not been able to become a public policy issue. The study highlights the need for the development of public policy in clinical nutrition aimed at improving access to nutrition care.

Computational Design of Copper Ligands with Controlled Metal Chelating, Pharmacokinetics, and Redox Properties for Alzheimer's Disease.

BACKGROUND: Redox active metal cations, such as Cu2 +, have been related to induce amyloid plaques formation and oxidative stress, which are two of the key events in the development of Alzheimer's disease (AD) and others metal promoted neurodegenerative diseases. In these oxidative events, standard reduction potential (SRP) is an important property especially relevant in the reactive oxygen species formation. OBJECTIVE: The SRP is not usually considered for the selection of drug candidates in anti-AD treatments. In this work, we present a computational protocol for the selection of multifunctional ligands with suitable metal chelating, pharmacokinetics, and redox properties. METHODS: The filtering process is based on quantum chemical calculations and the use of in silico tools. Calculations of SRP were performed by using the M06-2X density functional and the isodesmic approach. Then, a virtual screening technique (VS) was used for similar structure search. RESULTS: Protocol application allowed the assessment of chelating, drug likeness, and redox properties of copper ligands. Those molecules showing the best features were selected as molecular scaffolds for a VS procedure in order to obtain related compounds. After applying this process, we present a list of candidates with suitable properties to prevent the redox reactions mediated by copper(II) ion. CONCLUSION: The protocol incorporates SRP in the filtering stage and can be effectively used to obtain a set of potential drug candidates for AD treatments.

Assessment of the isodesmic method in the calculation of standard reduction potential of copper complexes.

Molecular phenomena involving electron transfer and reduction/oxidation processes are of the utmost importance in chemistry. However, accurate computational calculations of standard reduction potentials (SRPs) for transition metal complexes are still challenging. For this reason, some computational strategies have been proposed in order to overcome the main limitations in SRP calculations for copper complexes. However, these strategies are limited to particular coordination spheres and do not represent a general methodology. In this work, we present standard reduction potential calculations for copper complexes in aqueous solution covering a wide range of coordination spheres. These calculations were performed using the M06-2X density functional, and by employing the direct and isodesmic approaches. Result analysis reveals that values obtained with the use of the isodesmic method are in better agreement with experimental values than those obtained from the direct method (mean unsigned error 0.39 V with the direct and 0.08 V with the isodesmic method). This approach provides values with errors comparable to the experimental uncertainty due to the proper cancellation of computational errors. These results strongly suggest the isodesmic approach as an adequate methodology for the calculation of SRPs for copper complexes with diverse coordination spheres. Graphical Abstract Comparison between direct and isodesmic methods in the calculation of standard reduction potentials for copper complexes using DFT methods.

Hiperplasia fibrosa inflamatória provocada por uma prótese parcial removível / Inflammatory fibrous hyperplasia caused by removable partial prosthesis ­ a case report

A hiperplasia fibrosa inflamatória (HFI) é um crescimento gengival que tem como principal causa etiológica o uso de próteses inadequadas ou mal adaptadas. A HFI é uma lesão exofítica benigna de tecido epitelial e conjuntivo fibroso. Seu tratamento de eleição é a exérese cirúrgica e a remoção do agente irritante. Este trabalho teve como objetivo relatar um caso clínico de hiperplasia gengival inflamatória diagnosticada em uma paciente, leucoderma e com 38 anos de idade, que procurou atendimento na Clínica de Periodontia do Sindicato dos Dentistas de Mato Grosso do Sul (Sioms). Após a remoção cirúrgica da lesão e análise histopatológica, o estudo concluiu que o tratamento aplicado neste caso é o mais efetivo para esta patologia, contudo, deve haver avaliações periódicas da prótese para evitar recidiva da lesão.

Inflammatory fibrous hyperplasia (HFI) is a gingival overgrowth that has as its main etiological cause the use of inappropriate or poorly fitting dentures. The HFI is a benign exophytic lesion of epithelial and connective fibrous tissues. The treatment of choice of choice is surgical excision and removal of the irritant. This study aimed to report a clinical case of inflammatory gingival hyperplasia diagnosed in a 38 years-old female patient who sought care in Union Periodontics Clinic of Mato Grosso do Sul Dentists (Sioms). After surgical removal of the lesion and histopathologic analysis the treatment applied in this case is the most effective for this condition, however, periodic reviews must be made to avoid recurrent fibrotic lesions.