The RAGE Axis: A Relevant Inflammatory Hub in Human Diseases.

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.

Emerging and multifaceted potential contributions of polyphenols in the management of type 2 diabetes mellitus.

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.

The First Population-Level Description of Women Diagnosed With Invasive Breast Cancer in Costa Rica From 2008 to 2012: A Cross-Sectional Study.

INTRODUCTION: Breast cancer is the leading cause of cancer-related deaths among women worldwide. In Costa Rica, it ranks first in incidence and fourth in terms of mortality. However, there is a lack of comprehensive information on treatment patterns and outcomes for breast cancer patients in Costa Rica. METHODS: This study utilized data from the National Tumor Registry, which was merged with the Costa Rica Social Security Fund (CCSS) to ensure comprehensive access to clinical information. The study is prospective and focused on patients diagnosed with breast cancer between January 2008 and December 2012. This combined dataset allowed for a more comprehensive analysis of patient characteristics, treatment patterns, and outcomes related to breast cancer in Costa Rica. RESULTS: Among the 4775 patients diagnosed during this period, 3160 met the inclusion criteria for our study. The average age at diagnosis was 59.1 years, with 32.5% of patients being over the age of 65. Most of the patients (55.4%) identified themselves as homemakers, while 46.5% underwent core needle biopsy for diagnosis. Approximately 60% of women were diagnosed with early-stage disease (IA, IIA, and IIB), while 1.7% had metastatic disease, mainly affecting the bone. The mean interval between diagnosis and surgery was 72 days. Most patients (88.7%) received surgery as their initial treatment, and over half (54.4%) received some form of adjuvant therapy. Additionally, 85.6% of patients completed their prescribed treatment. CONCLUSION: This study provides a comprehensive and detailed description of the characteristics and treatment patterns among breast cancer patients in Costa Rica. The findings contribute to our understanding of the disease in this population and can serve as a foundation for further research and improvement in breast cancer management and care.

Contributions of the receptor for advanced glycation end products axis activation in gastric cancer.

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.

Association between diabetes and cancer. Current mechanistic insights into the association and future challenges.

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.

Receptor of advanced glycation end-products axis and gallbladder cancer: A forgotten connection that we should reconsider.

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.

The RAGE/multiligand axis: a new actor in tumor biology.

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.

Changes in the airway after mentoplasty (genioplasty): systematic review / Cambios en la vía aérea después de una mentoplastia (genioplastia): una revisión sistemática

SUMMARY: The aim of this research was to evaluate the changes obtained with the mentoplasty technique in the increase of the airway imaging. A systemic review was performed using the parameters of the prism matrix, in the PubMed, Science Direct, Redalyc database, covering the years 1984 to 2019 with the use of defined inclusion criteria. The authors independently applied the selected parameter of data extraction, study selection and risk-to-bias assessment. A total of 1,251 articles were obtained among the 3 databases, of which 10 met the inclusion criteria. The variables studied were: type of research, sample size, sex, age, dento-skeletal diagnosis, airway classification, diagnosis of obstructive sleep apnea syndrome (OSAS), type of imaging evaluation, variables evaluated in the image, pre and post-operative values, surgical technique and type of fixation used, other surgical procedures applied, and complications. In the cases of linear evaluation with cephalometric analysis (9 articles) they used PAS (posterior airspace), MP-H (mandibular plane to the hyoid) and SNB (saddle-nasion-point B), and SCSA (section area as the most relevant points, smallest cross section) and VT (total volume) in the volumetric evaluations (2 articles). The average change in posterior airspace achieved by the cited authors is 4.2 mm with standard deviation of 1.4 mm with the use of advancement mentoplasty. The most widely used technique was mentoplasty with a horizontal osteotomy by 5 authors. Based on the research there is a positive relationship between the increase in the airway and the advancement mentoplasty procedure, however, more standardized studies associated with the way of measuring and evaluating the relationship between advancement and the airway are necessary.

RESUMEN: El objetivo de esta investigación fue evaluar los cambios obtenidos con la técnica de mentoplastia en el incremento de la via aérea. Una revisión sistemática fue realizada utilizando parámetros de la matriz prisma, en PubMed, Science Direct, Redalyc database, cubriendo los años 1984 a 2019 con criterios de inclusión definidos. Los autores aplicaron de forma independiente los parámetros de selección y extracción de datos, selección de estudios y riesgos de sesgo. Un total de 1251 artículos fueron obtenidos de las 3 bases de dato, donde 10 artículos cumplieron los criterios de inclusión. Las variables estudiadas fueron: tipo de investigación, tamaño de la muestra, genero, edad, diagnóstico dento esqueletal, clasificación de la vía aérea, diagnostico de síndrome de apnea del sueño (SAOS), tipo de evaluación de la imagen, variables evaluadas en la imagen en pre y postoperatorio, técnica quirúrgica y tipo de fijación utilizada, otros procedimientos quirúrgicos y complicaciones. En el caso de la evaluación linear con cefalometria (9 artículos), usaron PAS (posterior airspace), MP-H (plano mandibular hacia el hueso hioide) y SNB (silla turca-nasion- punto B) y SCSA (sección de puntos mas relevantes, menores transfversales) y el VT (volumen total) en las evaluaciones volumétricas (2 artículos). El promedio de cambio posterior de la vía aérea citado por autores fue de 4,2 mm con una desviación estándar de 1,4 mm con el uso de la mentoplastia de avance. La técnica mas habitual fue la mentoplastia con osteotomía horizontal (5 autores). Basados en esta investigación existe una relación positiva entre el incremento de la vía aérea y el avance con genioplastia; sin embargo, mas estudios estandarizados junto con medidas definidas y la evaluación correcta del avance y la vía área son necesarios.

Pattern recognition receptors and their roles in the host response to Helicobacter pylori infection.

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.

Contribution of RAGE axis activation to the association between metabolic syndrome and cancer.

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.

Diabetes mellitus contribution to the remodeling of the tumor microenvironment in gastric cancer.

Compelling pieces of evidence derived from both clinical and experimental research has demonstrated the crucial contribution of diabetes mellitus (DM) as a risk factor associated with increased cancer incidence and mortality in many human neoplasms, including gastric cancer (GC). DM is considered a systemic inflammatory disease and therefore, this inflammatory status may have profound effects on the tumor microenvironment (TME), particularly by driving many molecular mechanisms to generate a more aggressive TME. DM is an active driver in the modification of the behavior of many cell components of the TME as well as altering the mechanical properties of the extracellular matrix (ECM), leading to an increased ECM stiffening. Additionally, DM can alter many cellular signaling mechanisms and thus favoring tumor growth, invasion, and metastatic potential, as well as key elements in regulating cellular functions and cross-talks, such as the microRNAs network, the production, and cargo of exosomes, the metabolism of cell stroma and resistance to hypoxia. In the present review, we intend to highlight the mechanistic contributions of DM to the remodeling of TME in GC.

Polyphenols and AGEs/RAGE axis. Trends and challenges.

The formation of advanced glycation end-products (AGEs) is a key pathophysiological event linked not only to the onset and progression of diabetic complications, but also to neurodegeneration, cardiovascular diseases, cancer, and others important human diseases. AGEs contributions to pathophysiology are mainly through the formation of cross-links and by engaging the receptor for advanced glycation end-products (RAGE). Polyphenols are secondary metabolites found largely in fruits, vegetables, cereals, and beverages, and during many years, important efforts have been made to elucidate their beneficial effects on human health, mainly ascribed to their antioxidant activities. In the present review, we highlighted the beneficial actions of polyphenols aimed to diminish the harmful consequences of advanced glycation, mainly by the inhibition of ROS formation during glycation, the inhibition of Schiff base, Amadori products, and subsequent dicarbonyls group formation, the activation of the glyoxalase system, as well as by blocking either AGEs-RAGE interaction or cell signaling.

Gastric Tumor Microenvironment.

A compelling body of evidence has demonstrated that gastric cancer has a very particular tumor microenvironment, a signature very suitable to promote tumor progression and metastasis. Recent investigations have provided new insights into the multiple molecular mechanisms, defined by genetic and epigenetic mechanisms, supporting a very active cross talk between the components of the tumor microenvironment and thus defining the fate of tumor progression. In this review, we intend to highlight the role of very active contributors at gastric cancer TME, particularly cancer-associated fibroblasts, bone marrow-derived cells, tumor-associated macrophages, and tumor-infiltrating neutrophils, all of them surrounded by an overtime changing extracellular matrix. In addition, the very active cross talk between the components of the tumor microenvironment, defined by genetic and epigenetic mechanisms, thus defining the fate of tumor progression, is also reviewed.

HMGB1 decreases CCR-2 expression and migration of M2 macrophages under hypoxia.

OBJECTIVE: The hypoxic milieu at tumor microenvironment is able to drive the behavior of infiltrating tumor cells. Considering that hypoxia-mediated HMGB1 release is known to promote tumor growth, as well to enhance the pro-tumoral profile of M2 macrophages by a RAGE-dependent mechanism, it is tempting to evaluate the potential contribution of HMGB1 under hypoxia to restrain M2 macrophages mobility. METHODS: CCR-2 expression was evaluated in M2 polarized macrophages by western blotting and immunocytochemistry. The secreted levels of CCL-2 and the migration capability were evaluated using an ELISA and a chemotaxis assay, respectively. RESULTS: HMGB1, under hypoxic conditions, markedly reduce both the production of CCL-2 and the expression of its receptor CCR-2; and reduced the migration capacity of M2 macrophages. CONCLUSIONS: These results provided new insights into the mechanisms that regulate M2 macrophages mobility at the tumor microenvironment.

Helicobacter Pylori Infection and Lung Cancer: 
New Insights and Future Challenges.

Helicobacter pylori (H. pylori) is the causative agent of chronic gastritis and peptic ulcer diseases and is an important risk factor for the development functional dyspepsia, peptic ulceration, gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma. H. pylori has very high rates of infection in human populations, and it is estimated that over 50% of the world population is infected. Recently, certain extra-gastric manifestations, linked to H. pylori infection, have been widely investigated. Noteworthy, a growing body of evidences supports an association between H. pylori infection with lung cancer. The present review intend to highlight not only the most recent evidences supporting this association, but also some missed points, which must be considered to validate this emerging association.

Skewed Signaling through the Receptor for Advanced Glycation End-Products Alters the Proinflammatory Profile of Tumor-Associated Macrophages.

Tumors are complex tissues composed of variable amounts of both non-cellular components (matrix proteins) and a multitude of stromal cell types, which are under an active cross-talk with tumor cells. Tumor-associated macrophages (TAMs) are the major leukocyte population among the tumor-infiltrating immune cells. Once they are infiltrated into tumor stroma they undergo a polarized activation, where the M1 and M2 phenotypes represent the two extreme of the polarization heterogeneity spectrum. It is known that TAMs acquire a specific phenotype (M2), oriented toward tumor growth, angiogenesis and immune-suppression. A growing body of evidences supports the presence of tuning mechanisms in order to skew or restraint the inflammatory response of TAMs and thus forces them to function as active tumor-promoting immune cells. The receptor of advanced glycation end-products (RAGE) is a member of the immunoglobulin protein family of cell surface molecules, being activated by several danger signals and thus signaling to promote the production of many pro-inflammatory molecules. Interestingly, this receptor is paradoxically expressed in both M1 and M2 macrophages phenotypes. This review addresses how RAGE signaling has been drifted away in M2 macrophages, and thus taking advantage of the abundance of RAGE ligands at tumor microenvironment, particularly HMGB1, to reinforce the supportive M2 macrophages strategy to support tumor growth.

Dermal Collagen Stabilization by Polyphenols and Spray Drying as an Encapsulation Strategy.

Collagen, the most abundant component in mammalian tissues, has a crucial impact at skin level. Both promotion and maintenance of cross-linked collagen at the skin are critical to sustain the functionality and appearance of that tissue. Lysyl oxidases, also known as LOX enzymes, are the major collagen cross-linking enzymes that play a pivotal role in homeostasis. This minireview summarizes evidence that describes an amino oxidase-like activity, which could be attributed to polyphenols, or where polyphenols could be required. We also discuss some available collagen formulations and the scientific evidence that describes the impact on dermal extracellular matrix. In addition, information about encapsulation strategies to carry polyphenols, and some examples are also provided.

Polyphenolic Composition and Antioxidant Activity of Aqueous and Ethanolic Extracts from Uncaria tomentosa Bark and Leaves.

Uncaria tomentosa constitutes an important source of secondary metabolites with diverse biological activities mainly attributed until recently to alkaloids and triterpenes. We have previously reported for the first-time the polyphenolic profile of extracts from U. tomentosa, using a multi-step process involving organic solvents, as well as their antioxidant capacity, antimicrobial activity on aerial bacteria, and cytotoxicity on cancer cell lines. These promising results prompted the present study using food grade solvents suitable for the elaboration of commercial extracts. We report a detailed study on the polyphenolic composition of aqueous and ethanolic extracts of U. tomentosa bark and leaves (n = 16), using High Performance Liquid Chromatography coupled with Mass Spectrometry (HPLC-DAD/TQ-ESI-MS). A total of 32 compounds were identified, including hydroxybenzoic and hydroxycinnamic acids, flavan-3-ols monomers, procyanidin dimers and trimers, flavalignans⁻cinchonains and propelargonidin dimers. Our findings showed that the leaves were the richest source of total phenolics and proanthocyanidins, in particular propelargonidin dimers. Two-way Analysis of Variance (ANOVA) indicated that the contents of procyanidin and propelargonidin dimers were significantly different (p < 0.05) in function of the plant part, and leaves extracts showed higher contents. Oxygen Radical Absorbance Capacity (ORAC) and 2,2-diphenyl-1-picrylhidrazyl (DPPH) values indicated higher antioxidant capacity for the leaves (p < 0.05). Further, correlation between both methods and procyanidin dimers was found, particularly between ORAC and propelargonidin dimers. Finally, Principal Component Analysis (PCA) analysis results clearly indicated that the leaves are the richest plant part in proanthocyanidins and a very homogenous material, regardless of their origin. Therefore, our findings revealed that both ethanol and water extraction processes are adequate for the elaboration of potential commercial extracts from U. tomentosa leaves rich in proanthocyanidins and exhibiting high antioxidant activity.

Extracellular matrix glycation and receptor for advanced glycation end-products activation: a missing piece in the puzzle of the association between diabetes and cancer.

A growing body of epidemiologic evidence suggests that people with diabetes are at a significantly higher risk of many forms of cancer. However, the molecular mechanisms underlying this association are not fully understood. Cancer cells are surrounded by a complex milieu, also known as tumor microenvironment, which contributes to the development and metastasis of tumors. Of note, one of the major components of this niche is the extracellular matrix (ECM), which becomes highly disorganized during neoplastic progression, thereby stimulating cancer cell transformation, growth and spread. One of the consequences of chronic hyperglycemia, the most frequently observed sign of diabetes and the etiological source of diabetes complications, is the irreversible glycation and oxidation of proteins and lipids leading to the formation of the advanced glycation end-products (AGEs). These compounds may covalently crosslink and biochemically modify structure and functions of many proteins, and AGEs accumulation is particularly high in long-living proteins with low biological turnover, features that are shared by most, if not all, ECM proteins. AGEs-modified proteins are recognized by AGE-binding proteins, and thus glycated ECM components have the potential to trigger Receptor for advanced glycation end-products-dependent mechanisms. The biological consequence of receptor for advanced glycation end-products activation mechanisms seems to be connected, in different ways, to drive some hallmarks of cancer onset and tumor growth. The present review intends to highlight the potential impact of ECM glycation on tumor progression by triggering receptor for advanced glycation end-products-mediated mechanisms.