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In 1992, a transcendental report suggested that the receptor of advanced glycation end-products (RAGE) functions as a cell surface receptor for a wide and diverse group of compounds, commonly referred to as advanced glycation end-products (AGEs), resulting from the non-enzymatic glycation of lipids and proteins in response to hyperglycemia. The interaction of these compounds with RAGE represents an essential element in triggering the cellular response to proteins or lipids that become glycated. Although initially demonstrated for diabetes complications, a growing body of evidence clearly supports RAGE's role in human diseases. Moreover, the recognizing capacities of this receptor have been extended to a plethora of structurally diverse ligands. As a result, it has been acknowledged as a pattern recognition receptor (PRR) and functionally categorized as the RAGE axis. The ligation to RAGE leads the initiation of a complex signaling cascade and thus triggering crucial cellular events in the pathophysiology of many human diseases. In the present review, we intend to summarize basic features of the RAGE axis biology as well as its contribution to some relevant human diseases such as metabolic diseases, neurodegenerative, cardiovascular, autoimmune, and chronic airways diseases, and cancer as a result of exposure to AGEs, as well as many other ligands.

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Type 2 diabetes mellitus (T2DM) is recognized as a serious public health concern with a considerable impact on human life, long-term health expenditures, and substantial health losses. In this context, the use of dietary polyphenols to prevent and manage T2DM is widely documented. These dietary compounds exert their beneficial effects through several actions, including the protection of pancreatic islet ß-cell, the antioxidant capacities of these molecules, their effects on insulin secretion and actions, the regulation of intestinal microbiota, and their contribution to ameliorate diabetic complications, particularly those of vascular origin. In the present review, we intend to highlight these multifaceted actions and the molecular mechanisms by which these plant-derived secondary metabolites exert their beneficial effects on type 2 diabetes patients.

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Collagen, the most abundant structural protein found in mammals, plays a vital role as a constituent of the extracellular matrix (ECM) that surrounds cells. Collagen fibrils are strengthened through the formation of covalent cross-links, which involve complex enzymatic and non-enzymatic reactions. Lysyl oxidase (LOX) is responsible for catalyzing the oxidative deamination of lysine and hydroxylysine residues, resulting in the production of aldehydes, allysine, and hydroxyallysine. These intermediates undergo spontaneous condensation reactions, leading to the formation of immature cross-links, which are the initial step in the development of mature covalent cross-links. Additionally, non-enzymatic glycation contributes to the formation of abnormal cross-linking in collagen fibrils. During glycation, specific lysine and arginine residues in collagen are modified by reducing sugars, leading to the creation of Advanced Glycation End-products (AGEs). These AGEs have been associated with changes in the mechanical properties of collagen fibers. Interestingly, various studies have reported that plant polyphenols possess amine oxidase-like activity and can act as potent inhibitors of protein glycation. This review article focuses on compiling the literature describing polyphenols with amine oxidase-like activity and antiglycation properties. Specifically, we explore the molecular mechanisms by which specific flavonoids impact or protect the normal collagen cross-linking process. Furthermore, we discuss how these dual activities can be harnessed to generate properly cross-linked collagen molecules, thereby promoting the stabilization of highly organized collagen fibrils.

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Compelling shreds of evidence derived from both clinical and experimental research have demonstrated the crucial contribution of receptor for advanced glycation end products (RAGE) axis activation in the development of neoplasms, including gastric cancer (GC). This new actor in tumor biology plays an important role in the onset of a crucial and long-lasting inflammatory milieu, not only by supporting phenotypic changes favoring growth and dissemination of tumor cells, but also by functioning as a pattern-recognition receptor in the inflammatory response to Helicobacter pylori infection. In the present review, we aim to highlight how the overexpression and activation of the RAGE axis contributes to the proliferation and survival of GC cells as and their acquisition of more invasive phenotypes that promote dissemination and metastasis. Finally, the contribution of some single nucleotide polymorphisms in the RAGE gene as susceptibility or poor prognosis factors is also discussed.

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Compelling pieces of epidemiological, clinical, and experimental research have demonstrated that Diabetes mellitus (DM) is a major risk factor associated with increased cancer incidence and mortality in many human neoplasms. In the pathophysiology context of DM, many of the main classical actors are relevant elements that can fuel the different steps of the carcinogenesis process. Hyperglycemia, hyperinsulinemia, metabolic inflammation, and dyslipidemia are among the classic contributors to this association. Furthermore, new emerging actors have received particular attention in the last few years, and compelling data support that the microbiome, the epigenetic changes, the reticulum endoplasmic stress, and the increased glycolytic influx also play important roles in promoting the development of many cancer types. The arsenal of glucose-lowering therapeutic agents used for treating diabetes is wide and diverse, and a growing body of data raised during the last two decades has tried to clarify the contribution of therapeutic agents to this association. However, this research area remains controversial, because some anti-diabetic drugs are now considered as either promotors or protecting elements. In the present review, we intend to highlight the compelling epidemiological shreds of evidence that support this association, as well as the mechanistic contributions of many of these potential pathological mechanisms, some controversial points as well as future challenges.

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Compelling evidence derived from clinical and experimental research has demonstrated the crucial contribution of chronic inflammation in the development of neoplasms, including gallbladder cancer. In this regard, data derived from clinical and experimental studies have demonstrated that the receptor of advanced glycation end-products (RAGE)/AGEs axis plays an important role in the onset of a crucial and long-lasting inflammatory milieu, thus supporting tumor growth and development. AGEs are formed in biological systems or foods, and food-derived AGEs, also known as dietary AGEs are known to contribute to the systemic pool of AGEs. Once they bind to RAGE, the activation of multiple and crucial signaling pathways are triggered, thus favoring the secretion of several proinflammatory cytokines also involved in the promotion of gallbladder cancer invasion and migration. In the present review, we aimed to highlight the relevance of the association between high dietary AGEs intakes and high risk for gallbladder cancer, and emerging data supporting that dietary intervention to reduce gallbladder cancer risk is a very attractive approach that deserves much more research efforts.

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The receptor for advanced glycation end-products (RAGE) is a multiligand binding and single-pass transmembrane protein which actively participates in several chronic inflammation-related diseases. RAGE, in addition to AGEs, has a wide repertoire of ligands, including several damage-associated molecular pattern molecules or alarmins such as HMGB1 and members of the S100 family proteins. Over the last years, a large and compelling body of evidence has revealed the active participation of the RAGE axis in tumor biology based on its active involvement in several crucial mechanisms involved in tumor growth, immune evasion, dissemination, as well as by sculpturing of the tumor microenvironment as a tumor-supportive niche. In the present review, we will detail the consequences of the RAGE axis activation to fuel essential mechanisms to guarantee tumor growth and spreading.

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RESUMEN El equilibrio del corazón en los deportistas favorece una estabilidad morfológica y funcional que propicie parámetros de función cardiovascular en rangos de normalidad, manifestado en adecuados valores de: tensión arterial sistólica y diastólica, frecuencia cardíaca, respiratoria y aptitud física para el entrenamiento y actividades diarias. Debido a los sacrificios biológicos que esto implica, los atletas retirados de polo acuático sufren de adaptaciones morfofuncionales cardiovasculares que deben ser atendidas cuando aceptan el retiro y pasan al desentrenamiento deportivo, que constituye una estrategia profiláctica y terapéutica para el cuidado de la salud de los atletas. Se proponen intervenciones tempranas, con programaciones de trabajo aerobio, para equilibrar las adaptaciones morfofuncionales cardiovasculares en atletas retirados del alto rendimiento.

ABSTRACT The balance of the heart in athletes favors morphological and functional stability that favors cardiovascular function parameters within normal ranges, manifested in adequate values of: systolic and diastolic blood pressure, heart rate, respiratory rate and physical fitness for training and daily activities. Due to the biological sacrifices that this implies, retired water polo athletes suffer from cardiovascular morphofunctional adaptations that must be addressed when they accept retirement and move on to sports detraining, which constitutes a prophylactic and therapeutic strategy for the health care of athletes. Early interventions are proposed, with aerobic work schedules, to balance cardiovascular morphofunctional adaptations in retired high-performance athletes.

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La investigación se refiere a un estudio de la rentabilidad de la acción del viraje del estilo libre en nadadoras escolares. El objetivo para la investigación se centró en evaluar las características temporales durante la acción del viraje en nadadoras de la categoría 13 y 14 años de la provincia de Sancti Spíritus. Para la recogida de la información, se utilizaron los métodos del nivel empírico: la observación científica, así como la de medición. Se utilizaron dos cámaras de videos, ubicadas en serie, y una cámara subacuática marca Sony. Para el análisis temporal, se requirió del software Kinovea, ver 0.9.3. Se aplicó el test de 15 m. para comprobar la rentabilidad del viraje. Se pudo comprobar una pobre efectividad de este elemento técnico en el estilo libre en las nadadoras evaluadas, lo que mostró, de forma generalizada, deficiencias durante la fase de impulso y se comprobó la formación de ángulos muy abiertos de las piernas que favoreció un déficit en la utilización de la potencia de las piernas durante el empuje de la pared, aspecto este que ayudó a disminuir el deslizamiento y comenzar a realizar los movimientos de salida a la superficie de forma prematura, aumentó el tiempo de forma general en la ejecución del viraje, concluyendo que para las categorías escolares es oportuno obtener ángulos entre las articulaciones de tobillos, rodillas y cadera en el rango de los 90° y 110° al momento de iniciar el impulso de la pared.

A pesquisa diz respeito a um estudo sobre a rentabilidade da ação de viragem em estilo livre em nadadores escolares. O objectivo da investigação foi centrado na avaliação das características temporárias durante a ação de viragem em nadadores de 13 e 14 anos de idade na província de Sancti Spíritus. Para a recolha de informação, foram empregues métodos empíricos: observação científica e medição. Foram instaladas duas câmaras de vídeo, colocadas em série, e uma câmara subaquática Sony. Para a análise temporal, foi utilizado o software Kinovea, ver 0.9.3. O teste de 15 m foi executado para verificar a relação custo-benefício da curva. Foi possível constatar uma baixa eficácia deste elemento técnico no estilo livre dos nadadores avaliados, que mostraram, em geral, deficiências durante a fase de impulso e a formação de ângulos de pernas muito abertos que favoreceram um défice na utilização da força das pernas durante o impulso para a parede, Este aspecto permitiu reduzir o deslizamento e começar a realizar os movimentos de saída para a superfície antecipadamente, aumentou o tempo total na execução da curva, concluindo-se que para as categorias escolares é adequado obter ângulos entre o calcanhar, o joelho e as articulações da anca na gama de 90° e 110° no momento de iniciar o impulso da parede.

The research refers to a study of the profitability of the freestyle turning action in school swimmers. The objective of the research was focused on evaluating the temporal characteristics during the action of the turn in swimmers of the 13 and 14 years old category in the province of Sancti Spíritus. For the collection of information, the empirical level methods used were: scientific observation, as well as measurement. Two video cameras, placed in series, and a Sony underwater camera were used. For the temporal analysis, the Kinovea software, ver 0.9.3, was used. The 15 m test was applied to check the profitability of the turn. It was possible to verify a poor effectiveness of this technical element in the freestyle in the swimmers evaluated, which showed, in a generalized way, deficiencies during the impulse phase and the formation of very open angles of the legs that favored a deficit in the use of the power of the legs during the wall push, This aspect helped to decrease the sliding and to begin to perform the exit movements to the surface prematurely, increased the time in general in the execution of the turn, concluding that for the school categories it is appropriate to obtain angles between the ankle, knee and hip joints in the range of 90° and 110° at the moment of initiating the wall push.

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En la formación deportiva, tener presente cómo desarrollar la fuerza en tierra y su transferencia al medio acuático es de vital importancia en la formación de los atletas que comienzan la práctica del polo acuático. La presente investigación tuvo como objetivo determinar cómo los ejercicios de transferencia de fuerza influyen en las acciones motrices del polo acuático, lo que ayudaría a una adecuada conducción del proceso de formación deportiva de las atletas investigadas. Para lograr las metas propuestas, los autores se apoyaron en métodos teóricos y empíricos, se utilizó la herramienta de la estadística descriptiva (cálculo porcentual) para procesar la información, tomando como muestra a atletas que se iniciaban en el polo acuático en el área deportiva masiva de Polo Acuático. Para ello, se realizó una encuesta a entrenadores y se analizaron sus opiniones y criterios durante la conducción de este proceso. El resultado final es que son insuficientes los conocimientos de cómo seleccionar los ejercicios para que se desarrolle una transferencia positiva al medio acuático de los ejercicios de fuerza en tierra. No dominan los métodos, procedimientos, contenidos y metodologías, a partir de las investigaciones realizadas sobre el principio y ejercicios de transferencia. Entre las conclusiones más relevantes de esta investigación, se encuentran los referentes teóricos sobre los ejercicios de transferencia de fuera en tierra al medio acuático, lo que aportará desde la teoría una argumentación sólida para su aplicación a la práctica.

No treino desportivo, é de importância primordial ter em conta como evoluir a força em terra e a sua transferência para o meio aquático ou entorno hídrico, no treino dos atletas iniciantes na prática de pólo aquático. O objectivo desta investigação era descobrir como os exercícios de transferência de força influenciam as ações motoras no pólo aquático, o que contribuiria para a correta condução do processo de treino desportivo dos atletas inquiridos. Para alcançar os objectivos propostos, os autores apoiaram-se em métodos teóricos e empíricos, recorrendo à ferramenta da estatística descritiva (cálculo de percentagens) para processar a informação, tomando como modelo os atletas que estavam a começar no pólo aquático no campo do pólo aquático de desportos coletivos. Para este efeito, foi realizado um inquérito com os treinadores e as suas opiniões e critérios foram analisados durante a realização deste processo. O resultado final é que não há conhecimentos suficientes sobre como escolher exercícios para desenvolver uma transferência positiva de força em terra, para o ambiente aquático. Não dominam os métodos, procedimentos, conteúdos e metodologias, com base na investigação efetuada sobre o princípio e exercícios de transferência. Entre as conclusões mais relevantes desta investigação figuram as referências teóricas sobre os exercícios de transferência da terra para o meio aquático, que fornecerão da teoria uma argumentação sólida para a sua aplicação à prática.

In sports training, having in mind how to develop strength on land and its transfer to the aquatic environment is of vital importance in the training of athletes who begin the practice of water polo. The present research had the objective of determining how the strength transfer exercises influence the motor actions of water polo, which would help in an adequate conduction of the sports training process of the female athletes studied. To achieve the proposed goals, the authors relied on theoretical and empirical methods, the descriptive statistics tool (percentage calculation) was used to process the information, taking as a sample athletes who were starting in water polo in the massive sports area of Water Polo. For this purpose, a survey was made to coaches and their opinions and criteria were analyzed during the conduction of this process. The final result is that there is insufficient knowledge of how to select exercises so that a positive transfer to the aquatic environment of strength exercises on land is developed. They do not master the methods, procedures, contents and methodologies, based on the research carried out on the principle and exercises of transfer. Among the most relevant conclusions of this research are the theoretical references on the transfer exercises from land to the aquatic environment, which will provide from the theory a solid argumentation for its application to practice.

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BACKGROUND: Information is scarce on Early Childhood Caries (ECC) in Mexican preschool children and its impact on quality of life. AIM: To evaluate the ECC prevalence and its impact on OHRQoL in 3-5 years-old Mexican children according to disease severity. DESIGN: Caries was determined at two thresholds: (1) children with at least one caries lesion (ICDAS-1-6) and (2) children with at least one lesion in dentin (ICDAS-3-6). OHRQoL was assessed through the Mexican Early Childhood Oral Health Impact Scale (M-ECOHIS). Associations among caries severity, M-ECOHIS, and other variables were assessed by ordinal logistic regression. RESULTS: A total of 409 children participated (53.8% girls, 46.2% boys). Caries prevalence was 82.2% considering all lesions, and 45.0% for dentinal lesions. Significant linear trends (p < .05) among caries levels and categories of exposure were found for socioeconomic variables, dietary habits, and toothbrushing habits. Attending rural private schools (OR = 1.39, 95%CI = 1.11-1.72; p < .01), two main meals/day (OR = 2.75, 95%CI = 1.26-6.03; p = .01) and unsupervised toothbrushing (OR = 3.20, 95%CI = 1.96-5.24; p < .01) increased the risk to have high caries severity levels. M-ECOHIS scores were statistically significant associated with caries levels (χ2 (4)  = 175.85, p < .01; trend across groups z = 12.63 Prob > |z| < 0.01). CONCLUSIONS: M-ECOHIS was significantly associated with caries severity. Type of school, age groups, parents' educational level, family income, and living conditions were correlated with caries, showing how distinctive risk indicators were associated with different caries stages.

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Helicobacter pylori (H. pylori) infection is highly prevalent, affecting 4.4 billion people globally. This pathogen is a risk factor in the pathogenesis of more than 75% of worldwide cases of gastric cancer. Pattern recognition receptors are essential in the innate immune response to H. pylori infection. They recognize conserved pathogen structures and myriad alarmins released by host cells in response to microbial components, cytokines or cellular stress, thus triggering a robust proinflammatory response, which is crucial in H. pylori-induced gastric carcinogenesis. In this review, we intend to highlight the main pattern recognition receptors involved in the recognition and host response to H. pylori, as well as the main structures recognized and the subsequent inflammatory response.

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Most chronic modern non-transmissible diseases seem to begin as the result of low-grade inflammation extending over prolonged periods of time. The importance of diet as a source of many pro-inflammatory compounds that could create and sustain such a low-grade inflammatory state cannot be ignored, particularly since we are constantly exposed to them during the day. The focus of this review is on specific components of the diet associated with inflammation, specifically advanced glycation end products (AGEs) that form during thermal processing of food. AGEs are also generated in the body in normal physiology and are widely recognized as increased in diabetes, but many people are unaware of the potential importance of exogenous AGEs ingested in food. We review experimental models, epidemiologic data, and small clinical trials that suggest an important association between dietary intake of these compounds and development of an inflammatory and pro-oxidative state that is conducive to chronic diseases. We compare dietary intake of AGEs with other widely known dietary patterns, such as the Mediterranean and the Dietary Approaches to Stop Hypertension (DASH) diets, as well as the Dietary Inflammation Index (DII). Finally, we delineate in detail the pathophysiological mechanisms induced by dietary AGEs, both direct (i.e., non-receptor-mediated) and indirect (receptor-mediated).

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RESUMEN En la actualidad, en Cuba, muchos atletas que llegan a su edad de retiro no realizan procesos de desentrenamiento deportivo, lo que repercute en su estado de salud a mediano plazo; estos comienzan a sufrir de enfermedades crónicas no transmisibles, además de depresión y estados psicológicos no adecuados. La presente investigación tuvo como objetivo determinar las insuficiencias que se derivan en la conducción del proceso de desentrenamiento deportivo en atletas retirados. Para lograr las metas propuestas, los autores se apoyaron en métodos teóricos y empíricos; se utiliza la herramienta de la estadística descriptiva (cálculo porcentual) para procesar la información, tomando como muestra a atletas juveniles retirados de polo acuático, médicos deportivos, psicólogos y fisioterapeutas de medicina deportiva, a los que se les aplicaron entrevistas y analizaron sus opiniones durante la conducción de este proceso. El resultado final fue que es insuficiente el conocimiento de cómo realizar este proceso de desentrenamiento deportivo en la muestra estudiada, no dominan cabalmente los métodos, procedimientos, contenidos y metodologías, a partir de las investigaciones y preparaciones metodológicas sobre el tema que es vital en el deporte de alto rendimiento. Entre las conclusiones más relevantes de este trabajo, se encuentra que los referentes teóricos del desentrenamiento deportivo en la actualidad no cumplen las expectativas de los atletas que se retiran en las diversas agrupaciones deportivas y los atletas cuando se retiran no poseen información de cómo realizar este proceso.

RESUMO Atualmente, em Cuba, muitos atletas que atingem sua idade de aposentadoria não realizam processos de destreinamento esportivo, o que afeta sua saúde a médio prazo; eles começam a sofrer de doenças crônicas não transmissíveis, assim como depressão e estados psicológicos não adequados. A presente investigação tinha como objetivo determinar as insuficiências que derivam na condução do processo de destreinamento esportivo em atletas aposentados. Para atingir os objetivos propostos, os autores se basearam em métodos teóricos e empíricos; a ferramenta estatística descritiva (cálculo percentual) foi utilizada para processar as informações, tomando como amostra atletas juvenis de pólo aquático, aposentados; médicos esportivos, psicólogos e fisioterapeutas de medicina esportiva, aos quais foram aplicadas entrevistas e analisadas suas opiniões durante a condução deste processo. O resultado final foi que não há conhecimento suficiente de como realizar este processo de destreinamento do esporte na amostra estudada, eles não dominam totalmente os métodos, procedimentos, conteúdos e metodologias, baseados em pesquisas e preparativos metodológicos sobre o tema que é vital no esporte de alto rendimento. Dentre as conclusões mais relevantes deste trabalho, constata-se que as referências teóricas de desvalorização do esporte atualmente não atendem às expectativas dos atletas que se aposentam em vários grupos esportivos e os atletas quando se aposentam não têm informações sobre como realizar este processo.

ABSTRACT At present, in Cuba, many athletes who reach their retirement age do not carry out sports detraining processes, which affects their health in the medium term; they begin to suffer from chronic non-communicable diseases, as well as depression and inadequate psychological states. The objective of this research was to determine the inadequacies derived from the conduction of the sports detraining process in retired athletes. To achieve the proposed goals, the authors relied on theoretical and empirical methods; the descriptive statistics tool (percentage calculation) was used to process the information, taking as a sample retired youth water polo athletes, sports doctors, psychologists and sports medicine physiotherapists, to whom interviews were applied and their opinions during the conduction of this process were analyzed. The final result was that there is insufficient knowledge of how to carry out this sports detraining process in the sample studied, they do not fully master the methods, procedures, contents and methodologies, based on the research and methodological preparations on the subject that is vital in high performance sports. Among the most relevant conclusions of this work, it is found that the theoretical references of sports detraining currently do not meet the expectations of the athletes who retire in the various sports groups and the athletes when they retire do not have information on how to carry out this process.

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Compelling evidence supports the crucial role of the receptor for advanced glycation end-products (RAGE) axis activation in many clinical entities. Since the beginning of the coronavirus disease 2019 pandemic, there is an increasing concern about the risk and handling of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in inflammatory gastrointestinal disorders, such as inflammatory bowel diseases (IBD). However, clinical data raised during pandemic suggests that IBD patients do not have an increased risk of contracting SARS-CoV-2 infection or develop a more severe course of infection. In the present review, we intend to highlight how two potentially important contributors to the inflammatory response to SARS-CoV-2 infection in IBD patients, the RAGE axis activation as well as the cross-talk with the renin-angiotensin system, are dampened by the high expression of soluble forms of both RAGE and the angiotensin-converting enzyme (ACE) 2. The soluble form of RAGE functions as a decoy for its ligands, and soluble ACE2 seems to be an additionally attenuating contributor to RAGE axis activation, particularly by avoiding the transactivation of the RAGE axis that can be produced by the virus-mediated imbalance of the ACE/angiotensin II/angiotensin II receptor type 1 pathway.

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Compelling pieces of evidence derived from both clinical and experimental research has demonstrated the crucial role of the receptor for advanced-glycation end-products (RAGE) in orchestrating a plethora of proinflammatory cellular responses leading to many of the complications and end-organ damages reported in patients with diabetes mellitus (DM). During the coronavirus disease 2019 (COVID-19) pandemic, many clinical reports have pointed out that DM increases the risk of COVID-19 complications, hospitalization requirements, as well as the overall severe acute respiratory syndrome coronavirus 2 case-fatality rate. In the present review, we intend to focus on how the basal activation state of the RAGE axis in common preexisting conditions in DM patients such as endothelial dysfunction and hyperglycemia-related prothrombotic phenotype, as well as the contribution of RAGE signaling in lung inflammation, may then lead to the increased mortality risk of COVID-19 in these patients. Additionally, the cross-talk between the RAGE axis with either another severe acute respiratory syndrome coronavirus 2 receptor molecule different of angiotensin-converting enzyme 2 or the renin-angiotensin system imbalance produced by viral infection, as well as the role of this multi-ligand receptor on the obesity-associated low-grade inflammation in the higher risk for severe illness reported in diabetes patients with COVID-19, are also discussed.

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Far beyond the compelling proofs supporting that the metabolic syndrome represents a risk factor for diabetes and cardiovascular diseases, a growing body of evidence suggests that it is also a risk factor for different types of cancer. However, the involved molecular mechanisms underlying this association are not fully understood, and they have been mainly focused on the individual contributions of each component of the metabolic syndrome such as obesity, hyperglycemia, and high blood pressure to the development of cancer. The Receptor for Advanced Glycation End-products (RAGE) axis activation has emerged as an important contributor to the pathophysiology of many clinical entities, by fueling a chronic inflammatory milieu, and thus supporting an optimal microenvironment to promote tumor growth and progression. In the present review, we intend to highlight that RAGE axis activation is a crosswise element on the potential mechanistic contributions of some relevant components of metabolic syndrome into the association with cancer.

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Obesity is an increasing problem in developed and developing countries. Individuals with obesity have a higher risk of several diseases, such as cardiovascular disease, increased risk of insulin resistance, type 2 diabetes, infertility, degenerative disorders, and also certain types of cancer. Adipose tissue (AT) is considered an extremely active endocrine organ, and the expansion of AT is accompanied by the infiltration of different types of immune cells, which induces a state of low-grade, chronic inflammation and metabolic dysregulation. Even though the exact mechanism of this low-grade inflammation is not fully understood, there is clear evidence that AT-infiltrating macrophages (ATMs) play a significant role in the pro-inflammatory state and dysregulated metabolism. ATMs represent the most abundant class of leukocytes in AT, constituting 5% of the cells in AT in individuals with normal weight. However, this percentage dramatically increases up to 50% in individuals with obesity, suggesting an important role of ATMs in obesity and its associated complications. In this review, we discuss current knowledge of the function of ATMs during steady-state and obesity and analyze its contribution to different obesity-associated diseases, highlighting the potential therapeutic target of ATMs in these pathological conditions.

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BACKGROUND AND AIMS: Gallbladder cancer (GBC) is a neglected disease with substantial geographical variability: Chile shows the highest incidence worldwide, while GBC is relatively rare in Europe. Here, we investigate the causal effects of risk factors considered in current GBC prevention programs as well as C-reactive protein (CRP) level as a marker of chronic inflammation. APPROACH AND RESULTS: We applied two-sample Mendelian randomization (MR) using publicly available data and our own data from a retrospective Chilean and a prospective European study. Causality was assessed by inverse variance weighted (IVW), MR-Egger regression, and weighted median estimates complemented with sensitivity analyses on potential heterogeneity and pleiotropy, two-step MR, and mediation analysis. We found evidence for a causal effect of gallstone disease on GBC risk in Chileans (P = 9 × 10-5 ) and Europeans (P = 9 × 10-5 ). A genetically elevated body mass index (BMI) increased GBC risk in Chileans (P = 0.03), while higher CRP concentrations increased GBC risk in Europeans (P = 4.1 × 10-6 ). European results suggest causal effects of BMI on gallstone disease (P = 0.008); public Chilean data were not, however, available to enable assessment of the mediation effects among causal GBC risk factors. CONCLUSIONS: Two risk factors considered in the current Chilean program for GBC prevention are causally linked to GBC risk: gallstones and BMI. For Europeans, BMI showed a causal effect on gallstone risk, which was itself causally linked to GBC risk.

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