Microbiota-Mitochondria Inter-Talk: A Potential Therapeutic Strategy in Obesity and Type 2 Diabetes.

The rising prevalence of obesity and type 2 diabetes (T2D) is a growing concern worldwide. New discoveries in the field of metagenomics and clinical research have revealed that the gut microbiota plays a key role in these metabolic disorders. The mechanisms regulating microbiota composition are multifactorial and include resistance to stress, presence of pathogens, diet, cultural habits and general health conditions. Recent evidence has shed light on the influence of microbiota quality and diversity on mitochondrial functions. Of note, the gut microbiota has been shown to regulate crucial transcription factors, coactivators, as well as enzymes implicated in mitochondrial biogenesis and metabolism. Moreover, microbiota metabolites seem to interfere with mitochondrial oxidative/nitrosative stress and autophagosome formation, thus regulating the activation of the inflammasome and the production of inflammatory cytokines, key players in chronic metabolic disorders. This review focuses on the association between intestinal microbiota and mitochondrial function and examines the mechanisms that may be the key to their use as potential therapeutic strategies in obesity and T2D management.

Leukocyte-Endothelium Interaction Is Associated with Fat Mass in Children.

OBJECTIVE: To study leukocyte-endothelium interaction, a measure of the initial phase of atheromatosis, in children with overweight or obesity. STUDY DESIGN: A prospective study was conducted in 77 children aged 7-16 years; 47 were children with overweight/obesity and 30 were normal weight. Polymorphonuclear neutrophils (PMNs) and peripheral blood mononuclear cells were isolated from venous blood samples and the interaction of leukocytes over a monolayer of human umbilical vein endothelial cells was analyzed using flow chamber microscopy. The variables studied included leukocyte rolling velocity, rolling flux, and adhesion to endothelial cells. These were compared between children with overweight/obesity and control children. Correlation between the measures of leukocyte-endothelium interaction and anthropometric and biochemical variables was evaluated. RESULTS: In comparison with normal weight children, the PMNs and peripheral blood mononuclear cells of the overweight/obesity group showed a reduction in rolling velocity (P = .000 and P = .001, respectively) and an increase in rolling flux (P = .001 and P = .004), and adhesion (P = .003 and P = .002). The homeostasis model of insulin resistance was correlated inversely with rolling velocity and positively with rolling flux in PMNs. C-reactive protein was correlated positively with rolling flux and adhesion in both types of leucocytes. Fat mass index was correlated with all measures of leukocyte-endothelial interaction and proved to be the main predictor of leukocyte adhesion in the multiple regression analysis (P = .001 for PMNs and P = .006 for peripheral blood mononuclear cells). CONCLUSIONS: Excess fat mass in children is related to the activation of the leukocyte-endothelium interaction, potentially contributing to the development of atherosclerosis.

Neuronal bioenergetics and acute mitochondrial dysfunction: a clue to understanding the central nervous system side effects of efavirenz.

BACKGROUND: Neurological pathogenesis is associated with mitochondrial dysfunction and differences in neuronal/glial handling of oxygen and glucose. The main side effects attributed to efavirenz involve the CNS, but the underlying mechanisms are unclear. METHODS: Human cell lines and rat primary cultures of neurons and astrocytes were treated with clinically relevant efavirenz concentration. RESULTS: Efavirenz alters mitochondrial respiration, enhances reactive oxygen species generation, undermines mitochondrial membrane potential, and reduces adenosine triphosphate (ATP) levels in a concentration-dependent fashion in both neurons and glial cells. However, it activates adenosine monophosphate-activated protein kinase only in glial cells, upregulating glycolysis and increasing intracellular ATP levels, which do not occur in neurons. To reproduce the conditions that often exist in human immunodeficiency virus-related neuroinflammatory disorders, the effects of efavirenz were evaluated in the presence of exogenous nitric oxide, an inflammatory mediator and mitochondrial inhibitor. The combination potentiated the effects on mitochondrial parameters in both neurons and glial cells, but ATP generation and lactate production were enhanced only in glial cells. CONCLUSIONS: Efavirenz affects the bioenergetics of neurons through a mechanism involving acute mitochondrial inhibition, an action exacerbated in neuroinflammatory conditions. A similar scenario of glial cells survival and degeneration of neurons with signs of mitochondrial dysfunction and oxidative stress has been associated with neurocognitive disorders.

Inhibidores de la bomba de protones y la homeostasis del calcio / Proton pump inhibitors and calcium homeostasis

Antecedentes: la asociación entre los inhibidores de la bomba de protones (IBP) y el riesgo de osteoporosis y fracturas óseas es un tema que ha originado, recientemente, bastante interés en la literatura médica. Los IBP son los fármacos de primera elección en enfermedades que evolucionan con incremento de la secreción ácida y, debido al aumento progresivo de su prescripción, su potencial toxicidad se investiga periódicamente. Objetivos: en la presente revisión se analizan las bases fisiofarmacológicas y la limitada evidencia clínica de una potencial relación entre la administración continuada de IBP y la aparición de osteoporosis y fracturas óseas. Ambas patologías, relacionadas con la homeostasis del calcio, son de gran importancia en pacientes de edad avanzada por su mal pronóstico general y las consecuencias invalidantes que conllevan.

Background: the relationship between proton pump inhibitors (PPI) and the risk of osteoporosis and bone fractures is a topic of great interest in recent medical literature. PPI are first choice drugs for diseases evolving with an increase in acid secretion. Due to their growing prescription, their potential toxicity is periodically verified. Objectives: the present review analyzes the physiopharmacological bases and limited clinical evidence of a potential relationship between continued administration of PPIs and the appearance of osteoporosis and bone fractures. Both conditions are related to calcium homeostasis, and their relevance in elderly patients is high, due to their poor general prognosis and disabling effects.

Differential effects of tenofovir/emtricitabine and abacavir/lamivudine on human leukocyte recruitment.

BACKGROUND: The association of abacavir (ABC) with cardiovascular disease has led to HIV treatment guidelines favouring the combination of tenofovir/emtricitabine (TDF/FTC) over that of ABC/lamivudine (ABC/3TC). We have analysed the effects of plasma-relevant concentrations of TDF, FTC, ABC and 3TC, individually and in clinically employed combinations, on human leukocyte accumulation. The effects of ABC, 3TC, TDF and FTC on the expression of adhesion molecules were also evaluated. METHODS: Interactions between human leukocytes - specifically peripheral blood polymorphonuclear or mononuclear cells - and human umbilical vein endothelial cells were evaluated in a flow chamber reproducing in vivo conditions. The expression of adhesion molecules was analysed by flow cytometry. RESULTS: Concentrations of TDF, FTC or 3TC mimicking those in the plasma of patients did not have any effect on human leukocyte-endothelial cell interactions, while contrasting results were obtained with ABC. This distinct pattern was reproduced when the drugs were administered in combination; namely, ABC/3TC had a significant influence on rolling and adhesion while TDF/FTC did not. However, the effects produced by ABC alone did not differ when it was combined with 3TC, which suggests the former drug was responsible for the effects observed. ABC, 3TC, TDF and FTC did not modify the expression of endothelial adhesion molecules. Conversely, only ABC enhanced the expression of leukocyte CD11b/CD18 in neutrophils and monocytes. CONCLUSIONS: Our results provide evidence that the combination TDF/FTC has a better vascular profile than ABC/3TC.

Profile of stress and toxicity gene expression in human hepatic cells treated with Efavirenz.

Hepatic toxicity and metabolic disorders are major adverse effects elicited during the pharmacological treatment of the human immunodeficiency virus (HIV) infection. Efavirenz (EFV), the most widely used non-nucleoside reverse transcriptase inhibitor (NNRTI), has been associated with these events, with recent studies implicating it in stress responses involving mitochondrial dysfunction and oxidative stress in human hepatic cells. To expand these findings, we analyzed the influence of EFV on the expression profile of selected stress and toxicity genes in these cells. Significant up-regulation was observed with Cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1), which indicated metabolic stress. Several genes directly related to oxidative stress and damage exhibited increased expression, including Methalothionein 2A (MT2A), Heat shock 70kDa protein 6 (HSPA6), Growth differentiation factor 15 (GDF15) and DNA-damage-inducible transcript 3 (DDIT3). In addition, Early growth response protein 1 (EGR1) was enhanced, whereas mRNA levels of the inflammatory genes Chemokine (C-X-C motif) ligand 10 (CXCL10) and Serpin peptidase inhibitor (nexin, plasminogen activator inhibitor type 1), member 1 (SERPINE1) decreased and increased, respectively. This profile of gene expression supports previous data demonstrating altered mitochondrial function and presence of oxidative stress/damage in EFV-treated hepatic cells, and may be of relevance in the search for molecular targets with therapeutic potential to be employed in the prevention, diagnosis and treatment of the hepatic toxicity associated with HIV therapy.

Metabolomics of the effect of AMPK activation by AICAR on human umbilical vein endothelial cells.

AMP-activated protein kinase (AMPK) is a metabolic master switch expressed in a great number of cells and tissues. AMPK is thought to modulate the cellular response to different stresses that increase cellular AMP concentration. The adenosine analog, 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside (AICAR) is an AMPK activator used in many studies to assess the effects of AMPK activation on cellular metabolism and function. However, the effect of AICAR on cell metabolism reaches many different pathways and metabolites, some of which do not seem to be fully related to AMPK activation. We have now for the first time used NMR metabolomics on human umbilical vein endothelial cells (HUVEC) for the study of the global metabolic impact of AMPK activation by AICAR. In our study, incubation with AICAR activates AMPK and is associated with, among others, broad metabolic alterations in energy metabolism and phospholipid biosynthesis. Using NMR spectroscopy and metabolic network tools, we analyzed the connections between the different metabolic switches activated by AICAR. Our approach reveals a strong interconnection between different phospholipid precursors and oxidation by-products. Metabolomics profiling is a useful tool for detecting major metabolic alterations, generating new hypotheses and provides some insight about the different molecular correlations in a complex system. The present study shows that AICAR induces metabolic effects in cell metabolism well beyond energy production pathways.

¿Es real el riesgo de osteoporosis y riesgo de fracturas con el uso crónico de inhibidores de la bomba de protones? / Chronic use of proton pump inhibitors: Is the risk of osteoporosis and fractures real?

Resumen Los inhibidores de la bomba de protones (IBP) constituyen uno de los grupos farmacológicosmás usados y su potencial toxicidad se revisa periódicamente haciendo hincapié enaspectos que en un primer momento se habían considerado secundarios. En la presente revisiónse analizan las bases fisio-farmacológicas y la limitada evidencia clínica de una potencial relaciónentre la administración continuada de IBP y la aparición de osteoporosis y fracturas óseas.Ambas patologías están claramente relacionadas con la homeostasis del calcio, y son de granimportancia en pacientes de edad avanzada por su mal pronóstico general y las consecuenciasinvalidantes que conllevan (AU)

Abstract Proton pump inhibitors (PPI) are one of the most widely used groups of drugs and theirpotential toxicity is periodically reviewed, emphasizing aspects originally considered secondary.The present review analyzes the physiological and pharmacological bases and the scarce clinicalevidence for a potential association between the continued administration of PPI and thedevelopment of osteoporosis and bone fractures. Both disorders are clearly related to calciumhomeostasis and are highly important in elderly patients due to their poor general prognosisand disabling consequences (AU)

[Chronic use of proton pump inhibitors: is the risk of osteoporosis and fractures real?]. / ¿Es real el riesgo de osteoporosis y riesgo de fracturas con el uso crónico de inhibidores de la bomba de protones?

Proton pump inhibitors (PPI) are one of the most widely used groups of drugs and their potential toxicity is periodically reviewed, emphasizing aspects originally considered secondary. The present review analyzes the physiological and pharmacological bases and the scarce clinical evidence for a potential association between the continued administration of PPI and the development of osteoporosis and bone fractures. Both disorders are clearly related to calcium homeostasis and are highly important in elderly patients due to their poor general prognosis and disabling consequences.

Seguridad e interacciones de los IBP / Security and interactions of PPIs

Los IBP han demostrado ser fármacos relativamente seguros después de muchos años de una amplia utilización. Las reacciones adversas con las que más frecuentemente se han asociado son leves y con escasa repercusión clínica. Inducen hipergastrinemia pero esta no se ha relacionado con una capacidad para inducir lesiones malignas Parece que pueden facilitar determinadas infecciones bacterianas a nivel digestivo y del aparato respiratorio, aunque este hecho no limita su prescripción dada la facilidad de su tratamiento. Desde el punto de vista farmacocinético se han descrito la posibilidad de interacciones con otros fármacos a nivel del citocromo P450, pero ello no parece tener mayor trascendencia clínica y terapéutica en general. Sin embargo, recientemente se está incidiendo por las agencias reguladoras en la hipotética interacción de los IBP (sobre todo omeprazol) con el clopidogrel generando una reducción en su efecto antiagregante. Aunque se debe seguir esta recomendación, necesitaria ser evaluado de forma específica para poder determinar su realidad clínica y las posibles alternativas existentes en los pacientes con riesgo de sangrado gastrointestinal. En último lugar se revisa su administración en situaciones especiales, objeto de discusión, como en la mujer embarazada o durante la lactancia materna...

[Safety and interactions of proton pump inhibitors: lessons learned in millions of patients]. / Seguridad e interacciones de los inhibidores de la bomba de protones: lecciones aprendidas en millones de pacientes.

After many years of widespread use, proton pump inhibitors (PPI) have been demonstrated to be relatively safe. The most frequently associated adverse reactions are mild with scarce clinical effects. These agents produce hypergastrinemia but this adverse effect has not been related to the development of malignancies. PPI seem to facilitate certain bacterial infections in the gastrointestinal and respiratory tracts. However, these infections are easily treated and therefore do not limit the prescription of PPI. From the pharmacokinetic point of view, the possibility of interactions with other drugs metabolized by the cytochrome P450 system has been described but these interactions generally seem to have little clinical or therapeutic importance. However, regulatory agencies are currently stressing the hypothetical interaction between PPI (especially omeprazole) and clopidogrel, which reduces the latter's antiplatelet effect. Although this recommendation should be followed, this interaction should be specifically evaluated to determine its clinical effect and the possible alternatives in patients at risk of gastrointestinal bleeding. Lastly, the present article reviews PPI administration in special, currently debated situations, such as in pregnant or breastfeeding women.

Seguridad e interacciones de los inhibidores de la bomba de protones: lecciones aprendidas en millones de pacientes / Safety and interactions of proton pump inhibitors: lessons learned in millions of patients

Los IBP han demostrado ser fármacos relativamente seguros después de muchos años de una amplia utilización. Las reacciones adversas con las que más frecuentemente se han asociado son leves y con escasa repercusión clínica. Inducen hipergastrinemia pero esta no se ha relacionado con una capacidad para inducir lesiones malignas Parece que pueden facilitar determinadas infecciones bacterianas a nivel digestivo y del aparato respiratorio, aunque este hecho no limita su prescripción dada la facilidad de su tratamiento. Desde el punto de vista farmacocinético se han descrito la posibilidad de interacciones con otros fármacos a nivel del citocromo P450, pero ello no parece tener mayor trascendencia clínica y terapéutica en general. Sin embargo, recientemente se está incidiendo por las agencias reguladoras en la hipotética interacción de los IBP (sobre todo omeprazol) con el clopidogrel generando una reducción en su efecto antiagregante. Aunque se debe seguir esta recomendación, necesitaria ser evaluado de forma específica para poder determinar su realidad clínica y las posibles alternativas existentes en los pacientes con riesgo de sangrado gastrointestinal. En último lugar se revisa su administración en situaciones especiales, objeto de discusión, como en la mujer embarazada o durante la lactancia materna (AU)

After many years of widespread use, proton pump inhibitors (PPI) have been demonstrated to be relatively safe. The most frequently associated adverse reactions are mild with scarce clinical effects. These agents produce hypergastrinemia but this adverse effect has not been related to the development of malignancies. PPI seem to facilitate certain bacterial infections in the gastrointestinal and respiratory tracts. However, these infections are easily treated and therefore do not limit the prescription of PPI. From the pharmacokinetic point of view, the possibility of interactions with other drugs metabolized by the cytochrome P450 system has been described but these interactions generally seem to have little clinical or therapeutic importance. However, regulatory agencies are currently stressing the hypothetical interaction between PPI (especially omeprazole) and clopidogrel, which reduces the latter’s antiplatelet effect. Although this recommendation should be followed, this interaction should be specifi cally evaluated to determine its clinical effect and the possible alternatives in patients at risk of gastrointestinal bleeding. Lastly, the present article reviews PPI administration in special, currently debated situations, such as in pregnant or breastfeeding women (AU)

Is the vagina an adequate route for the administration of hormonal contraceptives?

The vaginal route of drug administration provides women with a valid alternative to more conventional methods of contraception. Drugs absorbed in the upper part of the vagina can bypass the liver and, if metabolized, are subject to a reduced hepatic first-pass effect. Current vaginally-administered contraceptive formulations deliver similar doses of gestagens to those provided by oral methods but release lower amounts of oestrogens. This results in a systemic exposure to gestagens similar to that achieved via other routes, thereby maintaining contraceptive efficacy while limiting systemic, but not uterine, exposure to oestrogen. In this way, the probability of systemic oestrogen-related adverse effects are theoretically reduced without compromising cycle control. In addition, the fact that the effects of a contraceptive ring last a complete cycle makes it more user-friendly than other methods and results in better patient compliance. The present review will explain in detail the specificities of this route of delivery of hormonal contraception and will compare it to more classic forms of contraception received via the oral (pill), intramuscular (injected), transdermic (patch) and subcutaneous (implants) routes of administration.

Seguridad de la utilización de los inhibidores de la bomba de protones / Safety of proton pump inhibitors

La importante capacidad inhibitoria de la secreción ácida gástrica de los inhibidores de la bomba de protones (IBP) los convierte en los fármacos de elección en las enfermedades relacionadas con el ácido. La elevada prevalencia de esas enfermedades y la necesidad de mantener la administración del fármaco durante períodos muy prolongados determinan que este grupo terapéutico sea uno de los de mayor volumen de gasto para el sistema sanitario. Sin embargo, con la enorme generalización de su uso, aún siguen aflorando periódicamente reservas sobre su potencial toxicidad, una opinión basada en una cierta desconfianza sobre la especificidad de su mecanismo de acción y en la sensación consiguiente de que algo tan potente debe conllevar una contrapartida lesiva. Los IBP actúan selectivamente en el eslabón final del proceso de secreción del ácido gástrico, la H+/K+-ATPasa o bomba de protones. Esta enzima representa un paso obligado en el proceso de secreción de H+, y los IBP son muy específicos de la célula parietal, porque para actuar necesitan de un ambiente con unos valores de pH muy bajos, que sólo se dan en el canalículo secretor de esa célula. En el presente artículo se revisa los efectos adversos de los IBP, haciendo especial énfasis en los relacionados con su administración continuada y en ciertas circunstancias relacionadas con situaciones especiales de los pacientes, como la ancianidad, la insuficiencia hepática, la gestación y la lactancia materna y la infancia. Todos los IBP comercializados comparten una base química común y no hay grandes diferencias en sus potenciales efectos adversos, la posibilidad de favorecer infecciones oportunistas o su capacidad de generar interacciones farmacocinéticas con otros fármacos que, en general y cuando se las refiere, son de poca entidad. Tras 2 décadas de uso, se confirma que los IBP son fármacos muy eficaces y seguros

The significant inhibitory capacity of gastric acid secretion of PPIs makes them the drugs of choice for treating acid-related diseases. The considerable prevalence of these diseases and the need for maintaining the administration of the drug during considerably long periods results in this therapeutic group being one of the most widely used. However, in spite of their extensive use, there continue to emerge concerns about their potential toxicity; concerns surrounding the specificity of their mechanism of action and a consequential suspicion that something so potent must involve harmful effects. PPIs act selectively on the final stage of the process of gastric acid secretion, namely the H+/K+-ATPase or proton pump. This enzyme represents an essential step in the process of secretion of H+, and PPIs exert a very specific action on the parietal cell, as they need an environment with very low pH levels, which only exist in this cell. In the present article, the adverse effects of PPIs are reviewed, with special emphasis on those related to their continued administration and on the special circumstances of patients, as in the case of the elderly, those with liver failure, pregnant and breastfeeding mothers and children. All the PPIs on the market share a common chemical basis and there are no great differences in their potential adverse effects, the possibility of them promoting opportunist infections or their capacity to generate pharmacokinetic interactions with other drugs, which, if occur, are generally insignificant. After two decades of use, PPIs have proved to be very effective and safe drugs

[Safety of proton pump inhibitors]. / Seguridad de la utilización de los inhibidores de la bomba de protones.

The significant inhibitory capacity of gastric acid secretion of PPIs makes them the drugs of choice for treating acid-related diseases. The considerable prevalence of these diseases and the need for maintaining the administration of the drug during considerably long periods results in this therapeutic group being one of the most widely used. However, in spite of their extensive use, there continue to emerge concerns about their potential toxicity; concerns surrounding the specificity of their mechanism of action and a consequential suspicion that something so potent must involve harmful effects. PPIs act selectively on the final stage of the process of gastric acid secretion, namely the H+/K+-ATPase or proton pump. This enzyme represents an essential step in the process of secretion of H+, and PPIs exert a very specific action on the parietal cell, as they need an environment with very low pH levels, which only exist in this cell. In the present article, the adverse effects of PPIs are reviewed, with special emphasis on those related to their continued administration and on the special circumstances of patients, as in the case of the elderly, those with liver failure, pregnant and breastfeeding mothers and children. All the PPIs on the market share a common chemical basis and there are no great differences in their potential adverse effects, the possibility of them promoting opportunist infections or their capacity to generate pharmacokinetic interactions with other drugs, which, if occur, are generally insignificant. After two decades of use, PPIs have proved to be very effective and safe drugs.