Innovative pathological network-based multitarget approaches for Alzheimer's disease treatment.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and is a major health threat globally. Its prevalence is forecasted to exponentially increase during the next 30 years due to the global aging population. Currently, approved drugs are merely symptomatic, being ineffective in delaying or blocking the relentless disease advance. Intensive AD research describes this disease as a highly complex multifactorial disease. Disclosure of novel pathological pathways and their interconnections has had a major impact on medicinal chemistry drug development for AD over the last two decades. The complex network of pathological events involved in the onset of the disease has prompted the development of multitarget drugs. These chemical entities combine pharmacological activities toward two or more drug targets of interest. These multitarget-directed ligands are proposed to modify different nodes in the pathological network aiming to delay or even stop disease progression. Here, we review the multitarget drug development strategy for AD during the last decade.

Developmental outcome of electroencephalographic findings in SYNGAP1 encephalopathy.

SYNGAP1 haploinsufficiency results in a developmental and epileptic encephalopathy (DEE) causing generalized epilepsies accompanied by a spectrum of neurodevelopmental symptoms. Concerning interictal epileptiform discharges (IEDs) in electroencephalograms (EEG), potential biomarkers have been postulated, including changes in background activity, fixation-off sensitivity (FOS) or eye closure sensitivity (ECS). In this study we clinically evaluate a new cohort of 36 SYNGAP1-DEE individuals. Standardized questionnaires were employed to collect clinical, electroencephalographic and genetic data. We investigated electroencephalographic findings, focusing on the cortical distribution of interictal abnormalities and their changes with age. Among the 36 SYNGAP1-DEE cases 18 presented variants in the SYNGAP1 gene that had never been previously reported. The mean age of diagnosis was 8 years and 8 months, ranging from 2 to 17 years, with 55.9% being male. All subjects had global neurodevelopmental/language delay and behavioral abnormalities; 83.3% had moderate to profound intellectual disability (ID), 91.7% displayed autistic traits, 73% experienced sleep disorders and 86.1% suffered from epileptic seizures, mainly eyelid myoclonia with absences (55.3%). A total of 63 VEEGs were revised, observing a worsening of certain EEG findings with increasing age. A disorganized background was observed in all age ranges, yet this was more common among older cases. The main IEDs were bilateral synchronous and asynchronous posterior discharges, accounting for ≥50% in all age ranges. Generalized alterations with maximum amplitude in the anterior region showed as the second most frequent IED (≥15% in all age ranges) and were also more common with increasing age. Finally, diffuse fast activity was much more prevalent in cases with 6 years or older. To the best of our knowledge, this is the first study to analyze EEG features across different age groups, revealing an increase in interictal abnormalities over infancy and adolescence. Our findings suggest that SYNGAP1 haploinsufficiency has complex effects in human brain development, some of which might unravel at different developmental stages. Furthermore, they highlight the potential of baseline EEG to identify candidate biomarkers and the importance of natural history studies to develop specialized therapies and clinical trials.

The Melatonin Derivative ITH13001 Prevents Hypertension and Cardiovascular Alterations in Angiotensin II-Infused Mice.

Inflammatory mechanisms and oxidative stress seem to contribute to the pathogenesis of hypertension. ITH13001 is a melatonin-phenyl-acrylate hybrid that moderately induces the antioxidant transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) and has a potent oxidant scavenging effect compared with other derivatives of its family. Here we investigated the effect of ITH13001 on hypertension and the associated cardiovascular alterations. Angiotensin II (AngII)-infused mice were treated with ITH13001 (1 mg/kg per day, i.p.) for 2 weeks. The ITH13001 treatment prevented: 1) the development of hypertension, cardiac hypertrophy, and increased collagen and B-type natriuretic peptide (Bnp) expression in the heart; 2) the reduction of elasticity, incremental distensibility, fenestrae area, intraluminal diameter, and endothelial cell number in mesenteric resistance arteries (MRA); 3) the endothelial dysfunction in aorta and MRA; 4) the plasma and cardiovascular oxidative stress and the reduced aortic nitric oxide (NO) bioavailability; 5) the increased cardiac levels of the cytokines interleukin (IL)-1ß, IL-6, and C-C motif chemokine ligand 2 (Ccl2), the T cell marker cluster of differentiation 3 (Cd3), the inflammasome NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3), the proinflammatory enzymes inducible nitric oxide synthase (iNOS) and COX-2, the toll-like receptor 4 (TLR4) adapter protein myeloid differentiation primary response 88 (MyD88), and the nuclear factor kappa B (NF-κB) subunit p65; 6) the greater aortic expression of the cytokines tumor necrosis factor alpha (Tnf-α), Ccl2 and IL-6, Cd3, iNOS, MyD88, and NLRP3. Although ITH13001 increased nuclear Nrf2 levels and heme oxygenase 1 (HO-1) expression in vascular smooth muscle cells, both cardiac and vascular Nrf2, Ho-1, and NADPH quinone dehydrogenase 1 (Nqo1) levels remained unmodified irrespective of AngII infusion. Summarizing, ITH13001 improved hypertension-associated cardiovascular alterations independently of Nrf2 pathway activation, likely due to its direct antioxidant and anti-inflammatory properties. Therefore, ITH13001 could be a useful therapeutic strategy in patients with resistant hypertension. SIGNIFICANCE STATEMENT: Despite the existing therapeutic arsenal, only half of the patients treated for hypertension have adequately controlled blood pressure; therefore, the search for new compounds to control this pathology and the associated damage to end-target organs (cerebral, cardiac, vascular, renal) is of particular interest. The present study demonstrates that a new melatonin derivative, ITH13001, prevents hypertension development and the associated cardiovascular alterations due to its antioxidant and anti-inflammatory properties, making this compound a potential candidate for treatment of resistant hypertensive patients.

High-resolution temporal monitoring of rare earth elements in acidic drainages from an abandoned sulphide mine (iberian pyrite belt, Spain).

Rare earth elements (REE) are strategic elements due to their economic importance. However, the studies dedicated to the distribution and behaviour of REE in aquatic systems have been scarce until a few decades ago. This work studies the seasonal variations of REE concentrations in acid mine drainage (AMD) affected water courses and the factors controlling their mobility under different hydrological conditions. To address this issue, a high-resolution sampling was performed for two years in selected sampling sites. REE concentrations were very high (median values of 2.7-3.4 mg/L, maximum of 7.0 mg/L). These values are several orders of magnitude higher than those found in natural waters, highlighting the importance of AMD processes on the release of REE to the hydrosphere. No good correlations were found between pH and REE concentration, while REE correlated positively (r Spearman coefficient of 0.78-0.94) with EC and negatively (r -0.88 to -0.90) with discharge in AMD-affected streams. A conservative behaviour of REE was observed due to the strongly acidic conditions observed in the study area. The waters also showed an enrichment in MREEs over LREEs and HREEs (mean values of GdN/LaN>1.8 and YbN/GdN < 0.7), typical of AMD waters. An asymmetry in the content of LREE and HREE was observed in AMD samples studied, which could be explained by the preferential dissolution of LREE or HREE-enriched minerals within each waste heaps. Multivariate analysis suggests the influence of Mn-rich minerals existent in the study area as a potential source of LREE.

Socialización de experiencias y logros en la salud pública y la Colaboración Médica Cubana desde las redes sociales. Venezuela 2021-2022

Introducción: Las redes sociales son formas de interacción social, que fomentan un intercambio dinámico entre personas, grupos e instituciones en contextos disímiles. Objetivo: Socializar la experiencia y los logros de la salud pública y la Colaboración Médica Cubana desde las redes sociales en Venezuela desde enero de 2021 hasta octubre de 2022. Métodos: Se realiza una investigación de tipo observacional descriptiva en el periodo comprendido desde enero de 2021 hasta octubre de 2022 y aplicado en la Misión Médica Cubana en Venezuela con una población de 14 213 profesionales de la salud dividida en 24 estados. Resultados: En el año 2021 se realizaron 21 tuitazos con un millón 876 898 tuits. Para el año 2022 Facebook se comportó con 32 489 seguidores, Twiter con 16 832, Instagram Cubacooperave, 3 905, Yotube.com/c/cubacooperave 2 830, Tiktok 890 y Telegram 371 suscriptores. Se realizaron 26 actividades nacionales, 11 Tuitazos y 15 Jornadas en las Redes, 144 en TV, 200 en Radio y 100 en la Prensa escrita. Conclusiones: El reto es utilizar la posibilidad que ofrece la tecnología para ampliar los horizontes del uso de las redes sociales, realizar acciones de alfabetización informacional dirigidas a los gestores y usuarios de las mismas en pos de una divulgación adecuada del trabajo en la Misión Médica Cubana en Venezuela.

Introduction: Social networks are forms of social interaction that foster a dynamic exchange among people, groups, and institutions in dissimilar contexts. Objective: To socialize the experience and achievements of public health and the Cuban Medical Collaboration in social networks in Venezuela from January 2021 to October 2022. Method: An observational descriptive research was conducted from January 2021 to October 2022 and applied to the Cuban Medical Mission in Venezuela in a population of 14 213 health professionals divided into 24 states. Results: In the year 2021, there was a total of 21 tweets with 1 876 898 tweets published. In 2022, the Facebook network had 32 489 followers; Twitter, 16 832; Instragram Cubacooperave, 3 905; the Yotube.com/c/Cubacooperave channel, 2 830; Tik Tok, 890; and Telegram had 371 subscribers. A total of 26 national activities such as 11 Tuits, 15 Network Events; 144 TV, 200 Radio, and 100 written Press activities were performed. Conclusions: The challenge is to use the possibility offered by technology to broaden the horizons of the use of social networks, as well as to establish information literacy actions directed towards the managers and users of these networks for the sake of an adequate dissemination of the work carried out by the Cuban Medical Mission in Venezuela.

[Remitting seronegative symetrical synovitis with pitting edema. One case report]. / Sinovitis simétrica seronegativa remitente con edema y fóvea. Presentación de un caso.

Background: RS3PE (remitting seronegative symmetrical synovitis with edema and pitting) is a rare entity of unknown etiology that has been related to genetic predisposition due to the presence of HLA-A2 in 50% of cases and less frequently HLA-B7. Its pathogenesis is unknown, but it has been related to growth factors, and some mediators (TNF, IL-6). It is common in elderly people and the course of this illness presents with acute symmetrical polyarthritis, accompanied by edema in hands and feet. The diagnosis requires a high index of suspicion and to differentiate it from other entities such as rheumatoid arthritis, complex regional pain syndrome, rheumatic polymyalgia, in addition to ruling out malignant neoplasms, since there are many reports of its association with both solid and hematological neoplasms, being of bad prognosis when there is association. When there is no association with cancer, it responds well to the use of low doses of steroids and its prognosis is usually favorable. Clinical case: 80-year-old woman with an acute onset with polyarthralgia, functional limitation associated with pitting edema in hands and feet. After approaching the patient and ruling out associated neoplasms, it was diagnosed RS3PE. It was managed with prednisone, observing a good response, with remission of the manifestations at 6 weeks and subsequent suspension of the steroid. Conclusions: RS3PE is a rare entity, and a high index of suspicion is required for the diagnosis. A complete approach is important to rule out cancer in patients affected with this syndrome. Prednisone continues to be the best therapeutic option.

Introducción: la RS3PE (sinovitis simétrica seronegativa remitente con edema y fóvea) es una entidad rara de etiología desconocida que se ha relacionado con predisposición genética por la presencia de HLA-A2 en el 50% de los casos y con menor frecuencia HLA-B7. Se desconoce su patogenia, pero se ha relacionado con factores de crecimiento y algunos mediadores (TNF, IL-6). Se presenta en personas de edad avanzada, cursa con poliartritis aguda simétrica, acompañada de edema en manos y pies. El diagnóstico requiere de un alto índice de sospecha y diferenciarlo de otras entidades como artritis reumatoide, síndrome de dolor regional complejo, polimialgia reumática, además de descartar neoplasias malignas, ya que existen muchos reportes de su asociación con neoplasias tanto sólidas como hematológicas y es de mal pronóstico cuando existe asociación. Cuando no existe asociación con cáncer tiene buena respuesta al uso de dosis bajas de esteroides y su pronóstico suele ser favorable. Caso clínico: mujer de 80 años con un cuadro de inicio agudo con poliartralgias, limitación funcional asociada a edema de manos y pies con fóvea. Después del abordaje y de descartar neoplasias asociadas, se diagnosticó RS3PE. Se manejó con prednisona y hubo buena respuesta, con remisión de las manifestaciones a las 6 semanas y suspensión posterior del esteroide. Conclusiones: la RS3PE es una entidad rara y para diagnosticarla se requiere un alto índice de sospecha. Es importante el abordaje completo para descartar cáncer en los pacientes afectados con este síndrome. La prednisona continúa siendo la mejor opción terapéutica.

Wildfire effects on the hydrogeochemistry of a river severely polluted by acid mine drainage.

This study evaluates for the first time the impact of a large wildfire on the hydrogeochemistry of a deeply AMD-affected river at the beginning of the wet season. To accomplish this, a high-resolution water monitoring campaign was performed within the basin coinciding with the first rainfalls after summer. Unlike similar events recorded in AMD-affected areas, where dramatic increases in most dissolved element concentrations, and decreases in pH values are observed as a result of evaporitic salts flushing and the transport of sulfide oxidation products from mine sites, a slight increase in pH values (from 2.32 to 2.88) and decrease in element concentrations (e.g.; Fe: 443 to 205 mg/L; Al: 1805 to 1059 mg/L; sulfate: 22.8 to 13.3 g/L) was observed with the first rainfalls after the fire. The washout of wildfire-ash deposited in the riverbanks and the drainage area, constituted by alkaline mineral phases, seems to have counterbalanced the usual behavior and patterns of the river hydrogeochemistry during autumn. Geochemical results indicate that a preferential dissolution occurs during ash washout (K > Ca > Na), with a quick release of K followed by an intense dissolution of Ca and Na. On the other hand, in unburnt zones parameters and concentrations vary to a lesser extent than burnt areas, being the washout of evaporitic salts the dominant process. With subsequent rainfalls ash plays a minor role on the river hydrochemistry. Elemental ratios (Fe/SO4 and Ca/Mg) and geochemical tracers in both ash (K, Ca and Na) and AMD (S) were used to prove the importance of ash washout as the dominant geochemical process during the study period. Geochemical and mineralogical evidences point to intense schwertmannite precipitation as the main driver of reduction in metal pollution. The results of this study shed light on the response of AMD-polluted rivers to certain climate change effects, since climate models predict an increase in the number and intensity of wildfires and torrential rain events, especially in Mediterranean climates.

KEAP1-NRF2 protein-protein interaction inhibitors: Design, pharmacological properties and therapeutic potential.

The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is considered the master regulator of the phase II antioxidant response. It controls a plethora of cytoprotective genes related to oxidative stress, inflammation, and protein homeostasis, among other processes. Activation of these pathways has been described in numerous pathologies including cancer, cardiovascular, respiratory, renal, digestive, metabolic, autoimmune, and neurodegenerative diseases. Considering the increasing interest of discovering novel NRF2 activators due to its clinical application, initial efforts were devoted to the development of electrophilic drugs able to induce NRF2 nuclear accumulation by targeting its natural repressor protein Kelch-like ECH-associated protein 1 (KEAP1) through covalent modifications on cysteine residues. However, off-target effects of these drugs prompted the development of an innovative strategy, the search of KEAP1-NRF2 protein-protein interaction (PPI) inhibitors. These innovative activators are proposed to target NRF2 in a more selective way, leading to potentially improved drugs with the application for a variety of diseases that are currently under investigation. In this review, we summarize known KEAP1-NRF2 PPI inhibitors to date and the bases of their design highlighting the most important features of their respective interactions. We also discuss the preclinical pharmacological properties described for the most promising compounds.

Sistema de actividades para desarrollar la competencia intercultural en la Facultad de Ciencias Médicas "Enrique Cabrera", La Habana

Introducción: La lengua influye en el modo de pensar, vivir y relacionarse de cada uno de sus hablantes debido a su papel en el reflejo de las prácticas de cada colectivo humano y la transmisión de conocimientos. Esto significa que la comunicación y el aprendizaje de inglés como lengua extranjera incluyen los elementos de la cultura reflejados en esta lengua. Objetivo: Realizar un sistema de actividades para desarrollar la competencia intercultural en estudiantes de Medicina de la Facultad de Ciencias Médicas "Enrique Cabrera", La Habana, Cuba. Método: Se propone un sistema de actividades mediante un temario de prueba, estudio documental, recopilación e información durante toda la etapa del proceso investigativo. Fueron empleados varios métodos de investigación, en los métodos empíricos, la observación la encuesta y la entrevista. En los métodos teóricos el análisis histórico-lógico, el enfoque sistémico y la modelación, así como los procedimientos lógicos del pensamiento y los métodos matemáticos-estadísticos. Resultados: El aprendizaje del inglés como lengua internacional y de los saberes interculturales correspondientes es especialmente válido en la asignatura de inglés, basado en un sistema de actividades, para la formación de los futuros galenos, quienes deben aprender a comunicarse en esa lengua, lo que implica dominar los contenidos interculturales que permiten una interacción eficiente con personas, autoridades, organizaciones y obras de los países donde realizan sus funciones. Conclusiones: El aprendizaje del inglés como lengua internacional y de los saberes interculturales correspondientes, a través de un sistema de actividades, resulta primordial en la formación de estudiantes de Medicina de la Facultad de Ciencias Médicas "Enrique Cabrera".

Introduction: Language influences the way of thinking, living and the relationships of speakers because its role for reflecting the realities of each human group and the transmission of knowledge. This means that the communication and learning of English as foreign language includes elements present in the language culture. Objective: To design a system of activities to build the intercultural competence in medical students of the Facultad de Ciencias Médicas Enrique Cabrera, La Habana, Cuba. Method: A system of activities is proposed supported by test agenda, documentary study, collection and information gathered through whole research process. Several research methods were used in the study, for instance, the empirical methods (comprising the observational, survey, and interview methods), the theoretical methods (historical-logical analysis, the systemic approach and modeling), also were used the logical thinking procedures and mathematical-statistical methods. Results: Learning English as international language and the corresponding intercultural knowledge has a great value in the English subject. This learning process was supported by the application of a system of activities for training of future doctors, who must learn to communicate in this language, which implies mastering the intercultural contents that allow them to interact efficiently with people, authorities, organizations and works in the countries where they perform their functions. Conclusions: Learning English as international language and the corresponding intercultural knowledge, using a system of activities, is essential for training of medical students at the Facultad de Ciencias Médicas Enrique Cabrera.

Introdução: A língua influencia a forma de pensar, viver e se relacionar de cada um de seus falantes devido ao seu papel de refletir as práticas de cada grupo humano e a transmissão de conhecimentos. Isso significa que a comunicação e o aprendizado do inglês como língua estrangeira incluem os elementos da cultura refletidos nesse idioma. Objetivo: Realizar um sistema de atividades para desenvolver a competência intercultural em estudantes de Medicina da Facultad de Ciencias Médicas "Enrique Cabrera", Havana, Cuba. Método: Propõe-se um sistema de atividades por meio de agenda de teste, estudo documental, compilação e informação durante toda a etapa do processo investigativo. Foram utilizados vários métodos de investigação, nos métodos empíricos, a observação, o inquérito e a entrevista. Nos métodos teóricos, a análise histórico-lógica, a abordagem sistémica e a modelação, bem como os procedimentos de pensamento lógico e os métodos matemático-estatísticos. Resultados: Aprender inglês como língua internacional e o correspondente conhecimento intercultural é especialmente válido na disciplina de inglês, baseada em um sistema de atividades, para a formação de futuros médicos, que devem aprender a se comunicar nessa língua, o que implica o domínio intercultural conteúdo que permite uma interação eficiente com pessoas, autoridades, organizações e obras nos países onde desempenham suas funções. Conclusões: A aprendizagem do inglês como língua internacional e o conhecimento intercultural correspondente, através de um sistema de atividades, é essencial na formação dos estudantes de medicina da Faculdade de Medicina "Enrique Cabrera Cossío".

Stream-pit lake interactions in an abandoned mining area affected by acid drainage (Iberian Pyrite Belt).

Opencast mining of sulfide ore deposits may lead to the formation of anthropogenic acidic lakes with highly polluted waters. In these systems, it is crucial to understand the hydrological connections between surface and groundwater and their contribution to the pollutant load delivered to the downgradient streams. This study characterizes the interactions between surface and groundwater in an acidic pit lake using different geochemical tracers (i.e., REE and other trace metals). The San Telmo pit lake, located in one of the most pollutant sources of the Iberian Pyrite Belt (IPB), can be considered as a flow-through pit lake except during dry periods, when it behaves as a terminal lake due to lower inputs by surface waters and higher outputs by evaporation. Results based on geochemical tracers indicate that the main inputs to the pit lake come from surface waters, with minor groundwater inputs rich in As, Cr, Cu, Fe and Pb. The contaminant load released from the mining area is very high (e.g., median values of 520 kg/day of Fe and 38 kg/day of Zn), causing the degradation of the fluvial network downstream. Most of released pollutants come from waste dumps located at the W of the mining zone (~50-70% of Al, Cd, Mg, Mn, Ni, SO4 and Zn and > 70% for Cu, Cr, Fe and, V), while the contribution of the water coming out the pit lake and other dumps is much lower. Thus, remediation efforts to improve the area and fluvial courses downstream must focus on the W waste dumps.

Climate vulnerability assessment of key fishery resources in the Northern Humboldt Current System.

The Northern Humboldt Current System sustains one of the most productive fisheries in the world. However, climate change is anticipated to negatively affect fish production in this region over the next few decades, and detailed analyses for many fishery resources are unavailable. We implemented a trait-based Climate Vulnerability Assessment based on expert elicitation to estimate the relative vulnerability of 28 fishery resources (benthic, demersal, and pelagic) to the impacts of climate change by 2055; ten exposure factors (e.g., temperature, salinity, pH, chlorophyll) and 13 sensitivity attributes (biological and population-level traits) were used. Nearly 36% of the species assessed had "high" or "very high" vulnerability. Benthic species were ranked the most vulnerable (gastropod and bivalve species). The pelagic group was the second most vulnerable; the Pacific chub mackerel and the yellowfin tuna were amongst the most vulnerable pelagic species. The demersal group had the relatively lowest vulnerability. This study allowed identification of vulnerable fishery resources, research and monitoring priorities, and identification of the key exposure factors and sensitivity attributes which are driving that vulnerability. Our findings can help fishery managers incorporate climate change into harvest level and allocation decisions, and assist stakeholders plan for and adapt to a changing future.

Resveratrol-Based MTDLs to Stimulate Defensive and Regenerative Pathways and Block Early Events in Neurodegenerative Cascades.

By replacing a phenolic ring of (E)-resveratrol with an 1,3,4-oxadiazol-2(3H)-one heterocycle, new resveratrol-based multitarget-directed ligands (MTDLs) were obtained. They were evaluated in several assays related to oxidative stress and inflammation (monoamine oxidases, nuclear erythroid 2-related factor, quinone reductase-2, and oxygen radical trapping) and then in experiments of increasing complexity (neurogenic properties and neuroprotection vs okadaic acid). 5-[(E)-2-(4-Methoxyphenyl)ethenyl]-3-(prop-2-yn-1-yl)-1,3,4-oxadiazol-2(3H)-one (4e) showed a well-balanced MTDL profile: cellular activation of the NRF2-ARE pathway (CD = 9.83 µM), selective inhibition of both hMAO-B and QR2 (IC50s = 8.05 and 0.57 µM), and the best ability to promote hippocampal neurogenesis. It showed a good drug-like profile (positive in vitro central nervous system permeability, good physiological solubility, no glutathione conjugation, and lack of PAINS or Lipinski alerts) and exerted neuroprotective and antioxidant actions in both acute and chronic Alzheimer models using hippocampal tissues. Thus, 4e is an interesting MTDL that could stimulate defensive and regenerative pathways and block early events in neurodegenerative cascades.

Are leading urban centers predisposed to global risks- A analysis of the global south from COVID-19 perspective.

COVID-19 initially spread among prominent global cities and soon to the urban centers of countries across the globe. While cities are the hotbeds of activities, they also seem highly exposed to global risks including the pandemic. Using the case of COVID-19 and the World Risk Index framework, this paper examines if the leading cities from the global south are inherently vulnerable and exposed to global risks and can they exacerbate the overall risk of their respective nations. Compared against their respective national averages, most of the 20 cities from 10 countries analyzed in this paper, have higher exposure, lower adaptive capacity, higher coping capacity and varied susceptibility. As this relative understanding is based on respective national averages which are often lower than the global standards, even high performance on certain indicators may still result in elevated predisposition. This paper concludes that the leading urban centers from the global south are highly likely to be predisposed to global risks due to their inherent vulnerability and exposure, and many of the drivers of this predisposition are related to the process of urbanization itself. This predisposition can enhance the overall exposure and vulnerability of the nation in which they are located.

Novel Series of Dual NRF2 Inducers and Selective MAO-B Inhibitors for the Treatment of Parkinson's Disease.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease. It is characterized by a complex network of physiopathological events where oxidative stress plays a central role among other factors such as neuroinflammation and protein homeostasis. Nuclear factor-erythroid 2 p45-related factor 2 (NRF2) has a multitarget profile itself as it controls a plethora of cellular processes involved in the progression of the disease. In this line, we designed a novel family of 2-(1H-indol-3-yl)ethan-1-amine derivatives as NRF2 inducers with complementary activities. Novel compounds are based on melatonin scaffold and include, among other properties, selective monoamine oxidase B (MAO-B) inhibition activity. Novel multitarget compounds exhibited NRF2 induction activity and MAO-B selective inhibition, combined with anti-inflammatory, antioxidant, and blood-brain barrier permeation properties. Furthermore, they exert neuroprotective properties against oxidative stress toxicity in PD-related in vitro. Hit compound 14 reduced oxidative stress markers and exerted neuroprotection in rat striatal slices exposed to 6-hydroxydopamine or rotenone. In conclusion, we developed a promising family of dual NRF2 inducers and selective MAO-B inhibitors that could serve as a novel therapeutic strategy for PD treatment.

Enantioselective Synthesis and Pharmacological Evaluation of Aza-CGP37157-Lipoic Acid Hybrids for the Treatment of Alzheimer's Disease.

Hybrids based on an aza-analogue of CGP37157, a mitochondrial Na+/Ca2+ exchanger antagonist, and lipoic acid were obtained in order to combine in a single molecule the antioxidant and NRF2 induction properties of lipoic acid and the neuroprotective activity of CGP37157. The four possible enantiomers of the hybrid structure were synthesized by using as the key step a fully diastereoselective reduction induced by Ellman's chiral auxiliary. After computational druggability studies that predicted good ADME profiles and blood-brain permeation for all compounds, the DPPH assay showed moderate oxidant scavenger capacity. Following a cytotoxicity evaluation that proved the compounds to be non-neurotoxic at the concentrations tested, they were assayed for NRF2 induction capacity and for anti-inflammatory properties and measured by their ability to inhibit nitrite production in the lipopolysaccharide-stimulated BV2 microglial cell model. Moreover, the compounds were studied for their neuroprotective effect in a model of oxidative stress achieved by treatment of SH-SY5Y neuroblastoma cells with the rotenone-oligomycin combination and also in a model of hyperphosphorylation induced by treatment with okadaic acid. The stereocenter configuration showed a critical influence in NRF2 induction properties, and also in the neuroprotection against oxidative stress experiment, leading to the identification of the compound with S and R configuration as an interesting hit with a good neuroprotective profile against oxidative stress and hyperphosphorylation, together with a relevant anti-neuroinflammatory activity. This interesting multitarget profile will be further characterized in future work.

Free nipple graft: current indications and applications of a centenary breast surgery technique ­ an integrative review

Introduction: Free nipple graft is a mammaplasty technique first described about 100 years ago. Its indication, restricted to reduction mammoplasty earlier, has been expanding into areas in mastology intervention, such as transgender and oncological surgery. Aim: The aim of this study was to evaluate the efficacy and outcomes of the technique. Methods: Electronic literature search was conducted, using PubMed and LILACS databases. The search strategy consisted of the keywords, MeSH terms, and free text words and variants for the free nipple graft and its application in reduction and mammaplasty, transgender, and oncoplastic surgery. Results: A total of 397 articles were found and, after inclusion and exclusion criteria, 15 were selected. Their outcomes have been shown, despite lack of standardized scores, as well as clinical trials to postulate better scientific evidence on its use and indications, that the technique, analyzed in over 1290 patients, achieved high safety rates and reproducibility. Conclusion: Aesthetics and patients satisfaction were found positive, as recommended by the authors in different studies discussed in this article.