Alzheimer’s disease and type 2 diabetes mellitus: Pathophysiologic and pharmacotherapeutics links

At present, Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) are two highly prevalent disorders worldwide, especially among elderly individuals. T2DM appears to be associated with cognitive dysfunction, with a higher risk of developing neurocognitive disorders, including AD. These diseases have been observed to share various pathophysiological mechanisms, including alterations in insulin signaling, defects in glucose transporters (GLUTs), and mitochondrial dysfunctions in the brain. Therefore, the aim of this review is to summarize the current knowledge regarding the molecular mechanisms implicated in the association of these pathologies as well as recent therapeutic alternatives. In this context, the hyperphosphorylation of tau and the formation of neurofibrillary tangles have been associated with the dysfunction of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways in the nervous tissues as well as the decrease in the expression of GLUT-1 and GLUT-3 in the different areas of the brain, increase in reactive oxygen species, and production of mitochondrial alterations that occur in T2DM. These findings have contributed to the implementation of overlapping pharmacological interventions based on the use of insulin and antidiabetic drugs, or, more recently, azeliragon, amylin, among others, which have shown possible beneficial effects in diabetic patients diagnosed with AD

CFTR regulates B cell activation and lymphoid follicle development

The number of LFs, BAFF+, TLR4+ and proliferation marker Ki67+ B cells in lung explants or resections from subjects with CF and normal controls was quantified by immunostaining. The role of CFTR in B cell activation and LF development was then examined in two independent cohorts of uninfected CFTR-deficient mice (Cftr -/-) and wild type controls. The number of lung LFs, B cells and BAFF+, CXCR4+, immunoglobulin G+ B cells was examined by immunostaining. Lung and splenocyte B cell activation marker and major histocompatibility complex class II (MHC class II) expression was quantified by flow cytometry. Inflammatory cytokine levels were measured in supernatants from isolated B cells from Cftr -/- and wild type mice stimulated in vitro with Pseudomonas aeruginosa lipopolysaccharide (LPS).CT/MA Cystic Fibrosis/Multiple Sclerosis Fund; May Family Trust; CF Foundation [DRUMMR0, DRUMMR1]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Thyroid alterations in type 2 diabetes mellitus

La diabetes mellitus es una de las enfermedades no transmisibles que causa más defunciones a nivel mundial. Cursa con alteraciones en el metabolismo de la glucosa derivadas de la baja disponibilidad de insulina o resistencia a su acción. Estudios recientes indican que hay una relación entre la diabetes mellitus y la disfunción tiroidea, mediada por disturbios en el eje hipotálamo – hipófisis – tiroides, reducción de la actividad deiodinasa, sinergismo de rutas mitogénicas, aumento del estado inflamatorio, el estrés oxidativo y la resistencia a la insulina. La alteración más frecuente es el hipotiroidismo subclínico y se presenta con mayor frecuencia en el sexo femenino por lo que se sugiere realizar periódicamente el perfil tiroideo a estos pacientes. Es necesario que desde la práctica clínica se tengan en cuenta estas implicaciones para brindar un tratamiento oportuno, mejorar complicaciones derivadas como las enfermedades cardiovasculares y disminuir las cifras de morbimortalidad.Diabetes mellitus is one of the world’s leading non-communicable diseases. It leads to alterations in glucose metabolism due to the low availability of insulin or resistance to its action. Recent studies indicate that there is a relationship between diabetes mellitus and thyroid dysfunction, mediated by disturbances in the hypothalamus - pituitary - thyroid axis, and reduced deiodinase activity, synergism of mitogenic routes, increased inflammatory status, oxidative stress and insulin resistance. The most frequent alteration is subclinical hypothyroidism and it occurs more frequently in women, so it is suggested to periodically perform the thyroid profile to these patients. It is necessary that in clinical practice these implications are taken into account in order to provide timely treatment, improve complications such as cardiovascular disease and reduce morbidity and mortality rates

Neprilysin: A Potential Therapeutic Target of Arterial Hypertension?

Arterial hypertension is the most prevalent chronic disease in the adult population of developed countries and it constitutes a significant risk factor in the development of cardiovascular disease, contributing to the emergence of many comorbidities, among which heart failure excels, a clinical syndrome that nowadays represents a major health problem with uncountable hospitalizations and the indolent course of which progressively worsens until quality of life decreases and lastly death occurs prematurely. In the light of this growing menace, each day more efforts are invested in the field of cardiovascular pharmacology, searching for new therapeutic options that allow us to modulate the physiological systems that appear among these pathologies. Therefore, in the later years, the study of natriuretic peptides has become so relevant, which mediate beneficial effects at the cardiovascular level such as diuresis, natriuresis, and decreasing cardiac remodeling; their metabolism is mediated by neprilysin, a metalloproteinase, widely expressed in the human and capable of catalyzing many substrates. The modulation of these functions has been studied by decades, giving room to Sacubitril, the first neprilysin inhibitor, which in conjunction with an angiotensin receptor blocker has provided a high efficacy and tolerability among patients with heart failure, for whom it has already been approved and recommended. Nonetheless, in the matter of arterial hypertension, significant findings have arisen that demonstrate the potential role that it will play among the pharmacological alternatives in the upcoming years

SGLT2i and GLP-1RA in cardiometabolic and renal diseases : from glycemic control to adipose tissue inflammation and senescence

Background. Over the last few years, the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RA) has increased substantially in medical practice due to their documented benefits in cardiorenal and metabolic health. In this sense, and in addition to being used for glycemic control in diabetic patients, these drugs also have other favorable effects such as weight loss and lowering blood pressure, and more recently, they have been shown to have cardio and renoprotective effects with anti-inflammatory properties. Concerning the latter, the individual or associated use of these antihyperglycemic agents has been linked with a decrease in proinflammatory cytokines and with an improvement in the inflammatory profile in chronic endocrine-metabolic diseases. Hence, these drugs have been positioned as first-line therapy in the management of diabetes and its multiple comorbidities, such as obesity, which has been associated with persistent inflammatory states that induce dysfunction of the adipose tissue. Moreover, other frequent comorbidities in long-standing diabetic patients are chronic complications such as diabetic kidney disease, whose progression can be slowed by SGLT2i and/or GLP-1RA. The neuroendocrine and immunometabolism mechanisms underlying adipose tissue inflammation in individuals with diabetes and cardiometabolic and renal diseases are complex and not fully understood. Summary. This review intends to expose the probable molecular mechanisms and compile evidence of the synergistic or additive anti-inflammatory effects of SGLT2i and GLP-1RA and their potential impact on the management of patients with obesity and cardiorenal compromise

Role of Endocrine-Disrupting Chemicals in the Pathogenesis of Non-Alcoholic Fatty Liver Disease: A Comprehensive Review

Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disorder, affecting around 25% of the population worldwide. It is a complex disease spectrum, closely linked with other conditions such as obesity, insulin resistance, type 2 diabetes mellitus, and metabolic syndrome, which may increase liver-related mortality. In light of this, numerous efforts have been carried out in recent years in order to clarify its pathogenesis and create new prevention strategies. Currently, the essential role of environmental pollutants in NAFLD development is recognized. Particularly, endocrine-disrupting chemicals (EDCs) have a notable influence. EDCs can be classified as natural (phytoestrogens, genistein, and coumestrol) or synthetic, and the latter ones can be further subdivided into industrial (dioxins, polychlorinated biphenyls, and alkylphenols), agricultural (pesticides, insecticides, herbicides, and fungicides), residential (phthalates, polybrominated biphenyls, and bisphenol A), and pharmaceutical (parabens). Several experimental models have proposed a mechanism involving this group of substances with the disruption of hepatic metabolism, which promotes NAFLD. These include an imbalance between lipid influx/efflux in the liver, mitochondrial dysfunction, liver inflammation, and epigenetic reprogramming. It can be concluded that exposure to EDCs might play a crucial role in NAFLD initiation and evolution. However, further investigations supporting these effects in humans are required

Increased expression of A Proliferation-inducing Ligand (APRIL) in lung leukocytes and alveolar epithelial cells in COPD patients with non small cell lung cancer: a possible link between COPD and lung cancer?

Background: Chronic Obstructive Pulmonary Disease (COPD) is characterized by an excessive activation of the adaptive immune system and, in particular, uncontrolled expansion of the B-cell pool. One of the key promoters of B cell expansion is A PRoliferation-Inducing Ligand (APRIL). APRIL has been strongly linked to non small cell lung cancer (NSCLC) onset and progression previously. However, little is known about the expression of APRIL in the lungs of COPD patients. Methods: Using immuno-fluorescence staining, the expression of APRIL was assessed in sections of lungs from 4 subjects with primary diagnosis of COPD (FEV1 33 ± 20 % predicted), 4 subjects with primary diagnosis of NSCLC, 4 subjects diagnosed with both COPD and NSCLC, smokers without COPD or NSCLC and 3 healthy never-smokers. The percentage of B cells, alveolar macrophages (AMs) and polymorphonuclear neutrophils (PMNs) in the lung and alveolar epithelial cells (AECs) that stained positively for APRIL was quantified using epi-fluorescence microscopy and image analysis software. Results: The percentage of APRIL-expressing B cells, AMs, PMNs and alveolar epithelial cells (AECs) was higher in patients having both COPD and NSCLC than in patients with either COPD or NSCLC alone, SC or NSC (p < 0.03 for all comparisons). The percentage of APRIL-expressing AMs and AECs (but not in B cells) was higher in patients with NSCLC alone than in patients with COPD alone. The percentage of APRIL-expressing AECs (but not B cells or AMs) was higher in COPD patients than in SC and NSC (p < 0.05 for all comparisons). The percentage of APRIL-expressing B cells, AMs and AECs cells was similar in NSC and SC. Conclusion: The percentage of APRIL-expressing B cells, AMs and AECs is higher in the lungs of patients with both COPD and NSCLC than in patients with COPD or NSCLC alone or control subjects. These findings suggest that APRIL may contribute to the pathogenesis of both COPD and NSCLC, and possibly to the development of NSCLC in patients with established COPD

La actividad física de ocio como factor protector para la obesidad en la población adulta del área rural de Quingeo, Cuenca-Ecuador

Introducci&oacute;n: La obesidad se considera una epidemia global, cuya prevalencia se estima que aumente dr&aacute;sticamente en los pr&oacute;ximos a&ntilde;os. Por otra parte, la actividad f&iacute;sica ha demostrado m&uacute;ltiples beneficios, entre los cuales se encuentran el ser un factor protector de riesgo cardiometab&oacute;lico. Sin embargo en las parroquias rurales de Cuenca-Ecuador no se ha evaluado el impacto que tiene la actividad f&iacute;sica sobre la obesidad.Materiales y m&eacute;todos: Se realiz&oacute; un estudio de campo, descriptivo y transversal en 530 individuos mayores a 18 a&ntilde;os de ambos sexos residentes en la parroquia Quingeo de la ciudad de Cuenca, Provincia del Azuay. La actividad f&iacute;sica fue evaluada mediante el Cuestionario Internacional de Actividad F&iacute;sica (IPAQ), dividi&eacute;ndose en actividad f&iacute;sica de hogar, trabajo, transporte y tiempo de ocio. Se clasific&oacute; a su vez seg&uacute;n el promedio de equivalentes metab&oacute;licos obtenidos (METs) en alta o baja para cada dominio. Se realiz&oacute; una regresi&oacute;n log&iacute;stica para obesidad ajustada por: sexo, grupo etario, estatus laboral, h&aacute;bito tab&aacute;quico, alcoh&oacute;lico, caf&eacute;ico, actividad f&iacute;sica de trabajo, transporte, hogar y ocio.Resultados: El 17,7% tuvo obesidad, siendo mayor en las mujeres (20,4%) comparado a los hombres (13,8%). La actividad f&iacute;sica de ocio mostr&oacute; una diferencia estad&iacute;sticamente significativa entre obesos [0 (0-1039) METs/min/sem] y no obesos [346 (0-1386) METs/min/sem] (p=0,005). Los factores que mostraron mayor influencia para la obesidad fueron el sexo femenino (OR=1,78; IC95%: 1,01-3,17; p=0,048); edad de 45 a 65 a&ntilde;os (OR=1,79; IC95%: 1,05-2,94; p=0,031), edad mayor a 65 a&ntilde;os (OR=2,09; IC95%: 1,06-4,09; p=0,032); y la actividad f&iacute;sica de ocio se comport&oacute; como un factor de protecci&oacute;n para obesidad (OR=0,46; IC95%: 0,22-1,45; p=0,038).Conclusi&oacute;n: La actividad f&iacute;sica en tiempo de ocio, se comporta como un factor protector para la obesidad en las parroquias rurales, siendo necesaria su recomendaci&oacute;n a la poblaci&oacute;n adulta general as&iacute; como a los pacientes en riesgo de las consultas de atenci&oacute;n primaria

Papel de las universidades en la promoción de la investigación en los estudiantes de pregrado

El camino hacia el éxito académico es un sendero largo y progresivo, el cual inicia desde los primeros niveles de la enseñanza y alcanza sus prim eros logros muchos años después cuando el individuo logra culminar victorioso sus estudios universitarios. Si bien el propósito de una carrera universitaria es la de entrenar al estudiante y especializarlo en una profesión específica, las necesidades socio - culturales del mundo han moldeado esta etapa, en un proceso de adquisición y producción de conocimiento científico, el cual no sólo nutre al estudiante, sino que también contribuye al desarrollo de la universidad, y en consecuencia, a la nación. La necesi dad de investigación y desarrollo científico es de vital importancia a la hora de proponer soluciones a los problemas que nos afectan tanto a nivel local como a nivel global

The quest for immunotherapy in atherosclerosis: CANTOS study, interleukin-1β and vascular inflammation

espite the monumental efforts directed into studying and describing the pathways, factors, genetic predisposition, and target-specific pharmacotherapy to atherosclerosis, ischemic heart disease, thrombotic cerebrovascular disease and peripheral artery disease are still responsible for 50% of all the deaths occurring in the developed world. The quest for a clear pathophysiology into atherosclerosis began with von Rokitansky’s incrustation theory, which evolved into the crucial role of platelets and thrombogenesis during acute coronary syndromes (1). Next, came the irritation theory postulated by Virchow, which detailed the presence of leukocytes in atherosclerotic plaques, suggesting the presence of chronic inflammation and progressive vessel deformation (1). By 1904, the term atherosclerosis was coined by Felix Jacob Marchand and 9 years later Nikolai Anichkov published that cholesterol alone can induce the vascular changes associated with atherosclerosis (1). The impeccable work performed by Anichkov and his team, paved the way to the current understanding and clinical logic used in current cardiovascular medicine (the lipid hypothesis), which for the longest period focused mainly in plasma lipids as sole culprits for atherogenesis. Genetic connection between cholesterol and heart disease came in 1939, when Müller described families with severe hypercholesterolemia and early onset cardiac disease and death (2). The recognition of hereditary hyperlipidemias and their characteristics, cemented the role on cholesterol in cardiovascular risk, along with the findings from the epidemiological mammoth, the Framingham Heart Study (3). At some point, the lipid hypothesis was “universally recognized as a law” [2002] (4), and as such, it dominated pharmacotherapy development in cardiovascular medicine