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The treatment of hypertension has improved in the last century; attention has been directed to restoring several altered pathophysiological mechanisms. However, regardless of the current treatments, it is difficult to control blood pressure. Uncontrolled hypertension is responsible for several cardiovascular complications, such as chronic renal failure, which is frequently observed in hypertensive patients. Therefore, new approaches that may improve the control of arterial blood pressure should be considered to prevent serious cardiovascular disorders. The contribution of purinergic receptors has been acknowledged in the pathophysiology of hypertension; this review describes the participation of these receptors in the alteration of kidney function in hypertension. Elevated interstitial ATP concentrations are essential for the activation of renal purinergic receptors; this becomes a fundamental pathway that leads to the development and maintenance of hypertension. High ATP levels modify essential mechanisms implicated in the long-term control of blood pressure, such as pressure natriuresis, the autoregulation of the glomerular filtration rate and renal blood flow, and tubuloglomerular feedback responses. Any alteration in these mechanisms decreases sodium excretion. ATP stimulates the release of vasoactive substances, causes renal function to decline, and induces tubulointerstitial damage. At the same time, a deleterious interaction involving angiotensin II and purinergic receptors leads to the deterioration of renal function.

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In this study, we investigated whether severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein may modify angiotensin-converting enzyme 2 (ACE2) activity in the plasma, heart, kidney, liver, lung, and six brain regions (amygdala, brain stem, cortex, hippocampus, hypothalamus, and striatum) of diabetic and hypertensive rats. We determine ACE2 activity in the plasma and lysates of heart, kidney, liver, lung, and six brain regions. MLN-4760 inhibits ACE2 activity in the plasma and all organs. On the other hand, soluble ACE2 (sACE2) activity increased in the plasma of diabetic rats, and there was no change in the plasma of hypertensive rats. ACE2 activity was augmented in the liver, brain stem, and striatum, while it decreased in the kidney, amygdala, cortex, and hippocampus of diabetic rats. ACE2 activity increased in the kidney, liver, and lung, while it decreased in the heart, amygdala, cortex, and hypothalamus of hypertensive rats. We measured the ACE2 content via enzyme-linked immunosorbent assay and found that ACE2 protein levels increased in the heart, while it decreased in the plasma, kidney, brain stem, cortex, hippocampus, hypothalamus, and striatum of diabetic rats. ACE2 protein levels decreased in the brain stem, cortex, hippocampus, and hypothalamus of hypertensive rats. Our data showed that the spike protein enhanced ACE2 activity in the liver and lungs of diabetic rats, as well as in the heart and three of the brain regions (cortex, hypothalamus, and striatum) of hypertensive rats.

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Hypertension is a major risk of morbidity and mortality in patients when it is uncontrolled. In spite of improved therapies currently available for blood pressure control, their complications are far away from being accomplished. Therefore, chronic renal failure is frequently observed in hypertensive patients. Thus, insights on mechanisms that may contribute to arterial pressure control should be studied to prevent life-threatening cardiovascular disorders. Purinergic receptors have been recognized in the physiopathology of hypertension; this review summarizes their participation in the renal abnormalities of the kidney in hypertension. Several studies have suggested the activation of renal purinergic receptors under an elevated interstitial ATP milieu as a fundamental pathway that leads to generation and maintained hypertension. Elevated ATP concentration alters fundamental mechanisms involved in the long-term control of blood pressure such as pressure natriuresis, autoregulation of glomerular filtration rate and renal blood flow, as well as increased tubule-glomerular feedback responses, overall, these alterations decrease sodium excretion; in addition, the expression of ATP receptors is modified. Under a genetical background, ATP induces the production of vasoactive compounds, decreases renal function and induces tubulointerstitial injury before glomerular damage. Simultaneously, a deleterious interaction between angiotensin II and purinergic receptors lead to the progression of renal damage.

La hipertensión arterial descontrolada es un factor de riesgo muy relevante para el desarrollo de complicaciones cardiovasculares graves. A pesar de los recursos disponibles en la actualidad, el control de la hipertensión arterial y sus complicaciones dista mucho de lograrse. Por ello, sus secuelas continúan siendo catastróficas, como la insuficiencia renal crónica. De ahí la relevancia de reconocer factores que pudieran modificarse para evitar esta complicación. Recientemente se ha propuesto que los receptores purinérgicos contribuyen en forma importante en las alteraciones renales que ocurren en la hipertensión arterial; en esta revisión se resume brevemente su papel. En varios estudios se ha demostrado que cuando existen concentraciones elevadas de ATP en el intersticio renal, la activación de los receptores purinérgicos constituye una vía fundamental en la generación y la persistencia de hipertensión arterial. Las concentraciones elevadas de ATP alteran mecanismos fundamentales asociados en el control de la presión arterial, como el mecanismo de natriuresis de presión, la autorregulación del flujo renal y la filtración glomerular, así como el aumento en la sensibilidad del mecanismo de retroalimentación tubuloglomerular. La alteración de estos mecanismos contribuye a la disminución de la excreción urinaria de sodio. Además, se modifica la expresión de receptores de ATP (purinérgicos). Bajo la influencia de alteraciones genéticas, el ATP estimula la producción de compuestos vasoactivos y en conjunto producen una disminución de la función renal y lesión tubulointersticial antes de que se lesione el glomérulo. Al mismo tiempo, la interacción de la angiotensina II y los receptores purinérgicos favorece la progresión del daño renal.

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BACKGROUND: Preservation of organ function and viability is a crucial factor for survival in cardiogenic shock (CS) patients. There is not information enough on cytoprotective substances that may delay organs damage in CS. We hypothesize that cytidine-5-diphosphocholine (CDP-choline) can act as a cytoprotective pharmacological measure that diminishes the target organ damage. So, we aimed to perform a review of works carried out in our institution to evaluate the effect of therapeutic cytoprotection of the CDP-choline. SUMMARY: CDP-choline is an intermediate metabolite in the synthesis of phosphatidylcholine. It is also a useful drug for the treatment of acute ischaemic stroke, traumatic brain injury, and neurodegenerative diseases and has shown an excellent pharmacological safety profile as well. We review our institution's work and described the cytoprotective effects of CDP-choline in experimental models of heart, liver, and kidney acute damage, where this compound was shown to diminish reperfusion-induced ventricular arrhythmias, oxidative stress, apoptotic cell death, inflammation, lactic acid levels and to preserve mitochondrial function. KEY MESSAGES: We propose that additional research is needed to evaluate the impact of cytoprotective therapy adjuvant to mitigate target organ damage in patients with CS.

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The objective of this study was to investigate whether the activity of enzymes involved in sphingolipid catabolism could be biomarkers to predict early renal damage in streptozotocin (STZ)-induced diabetic rats and Angiotensin II (Ang II)-induced hypertension rats. Diabetic and hypertensive rats had no changes in plasma creatinine concentration. However, transmission electron microscopy (TEM) analysis showed slight ultrastructural changes in the glomeruli and tubular epithelial cells from diabetic and hypertensive rats. Our results show that the acid sphingomyelinase (aSMase) and neutral sphingomyelinase (nSMase) activity increased in the urine of diabetic rats and decreased in hypertensive rats. Only neutral ceramidase (nCDase) activity increased in the urine of diabetic rats. Furthermore, the immunofluorescence demonstrated positive staining for the nSMase, nCDase, and sphingosine kinase (SphK1) in glomerular mesangial cells, proximal tubule, ascending thin limb of the loop of Henle, thick ascending limb of Henle's loop, and principal cells of the collecting duct in the kidney. In conclusion, our results suggest that aSMase and nCDase activity in urine could be a novel predictor of early slight ultrastructural changes in the nephron, aSMase and nCDase as glomerular injury biomarkers, and nSMase as a tubular injury biomarker in diabetic and hypertensive rats.

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(1) Background: Previous studies have enriched high-density lipoproteins (HDL) using cholesteryl esters in rabbits with a three-quarter reduction in functional renal mass, suggesting that the kidneys participate in the cholesterol homeostasis of these lipoproteins. However, the possible role of the kidneys in lipoprotein metabolism is still controversial. To understand the role of the kidneys in regulating the HDL lipid content, we determined the turnover of HDL-cholesteryl esters in rabbits with a three-quarter renal mass reduction. (2) Methods: HDL subclass characterization was conducted, and the kinetics of plasma HDL-cholesteryl esters, labeled with tritium, were studied in rabbits with a 75% reduction in functional renal mass (Ntx). (3) Results: The reduced renal mass triggered the enrichment of cholesterol, specifically cholesteryl esters, in HDL subclasses. The exchange of cholesteryl esters between HDL and apo B-containing lipoproteins (VLDL/LDL) was not significantly modified in Ntx rabbits. Moreover, the cholesteryl esters of HDL and VLDL/LDL fluxes from the plasmatic compartment tended to decrease, but they only reached statistical significance when both fluxes were added to the Nxt group. Accordingly, the fractional catabolic rate (FCR) of the HDL-cholesteryl esters was lower in Ntx rabbits, concomitantly with its accumulation in HDL subclasses, probably because of the reduced mass of renal cells requiring this lipid from lipoproteins.

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Resumen Los esfingolípidos (esfingomielina, glucolípidos y gangliósidos) se localizan en las membranas celulares, el plasma y las lipoproteínas. En pacientes con enfermedades cardiovasculares, renales y metabólicas, el perfil de los esfingolípidos y sus metabolitos (ceramida, esfingosina y esfingosina-1-fosfato) se modifica, y estos cambios pueden explicar las alteraciones en algunas respuestas celulares, como la apoptosis. Además, se ha sugerido que la esfingosina y la esfingosina-1-fosfato previenen la COVID-19. En esta revisión también se mencionan brevemente las técnicas que permiten el estudio de los esfingolípidos y sus metabolitos.

Abstract Sphingolipids (sphingomyelin, glycolipids, gangliosides) are located in cell membranes, plasma, and lipoproteins. In patients with cardiovascular, renal, and metabolic diseases, the profile of sphingolipids and their metabolites (ceramide, sphingosine, and sphingosine-1-phosphate) is modified, and these changes may explain the alterations in some cellular responses such as apoptosis. Furthermore, sphingosine and sphingosine-1-phosphate have been suggested to prevent COVID-19. This review also briefly mentions the techniques that allow us to study sphingolipids and their metabolites.

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Sphingolipids (sphingomyelin, glycolipids, gangliosides) are located in cell membranes, plasma, and lipoproteins. In patients with cardiovascular, renal, and metabolic diseases, the profile of sphingolipids and their metabolites (ceramide, sphingosine, and sphingosine-1-phosphate) is modified, and these changes may explain the alterations in some cellular responses such as apoptosis. Furthermore, sphingosine and sphingosine-1-phosphate have been suggested to prevent COVID-19. This review also briefly mentions the techniques that allow us to study sphingolipids and their metabolites.

Los esfingolípidos (esfingomielina, glucolípidos y gangliósidos) se localizan en las membranas celulares, el plasma y las lipoproteínas. En pacientes con enfermedades cardiovasculares, renales y metabólicas, el perfil de los esfingolípidos y sus metabolitos (ceramida, esfingosina y esfingosina-1-fosfato) se modifica, y estos cambios pueden explicar las alteraciones en algunas respuestas celulares, como la apoptosis. Además, se ha sugerido que la esfingosina y la esfingosina-1-fosfato previenen la COVID-19. En esta revisión también se mencionan brevemente las técnicas que permiten el estudio de los esfingolípidos y sus metabolitos.

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The profile of sphingomyelin and its metabolites shows changes in the plasma, organs, and tissues of patients with cardiovascular, renal, and metabolic diseases. The objective of this study was to investigate the effect of empagliflozin on the levels of sphingomyelin and its metabolites, as well as on the activity of acid and neutral sphingomyelinase (aSMase and nSMase) and neutral ceramidase (nCDase) in the plasma, kidney, heart, and liver of streptozotocin-induced diabetic and Angiotensin II (Ang II)-induced hypertension rats. Empagliflozin treatment decreased hyperglycemia in diabetic rats whereas blood pressure remained elevated in hypertensive rats. In diabetic rats, empagliflozin treatment decreased sphingomyelin in the plasma and liver, ceramide in the heart, sphingosine-1-phosphate (S1P) in the kidney, and nCDase activity in the plasma, heart, and liver. In hypertensive rats, empagliflozin treatment decreased sphingomyelin in the plasma, kidney, and liver; S1P in the plasma and kidney; aSMase in the heart, and nCDase activity in the plasma, kidney, and heart. Our results suggest that empagliflozin downregulates the interaction of the de novo pathway and the catabolic pathway of sphingolipid metabolism in the diabetes, whereas in Ang II-dependent hypertension, it only downregulates the sphingolipid catabolic pathway.

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BACKGROUND: Heterogeneity and focalization are the most common epidemiological characteristics of endemic countries in the Americas, where malaria transmission is moderate and low. During malaria elimination, the first step is to perform a risk stratification exercise to prioritize interventions. This study aimed to identify malaria risk strata in the ecoepidemiological regions of Colombia. METHODS: This was a descriptive and retrospective study using cumulative malaria cases in 1,122 municipalities of Colombia from 2010 to 2019. To identify the strata, the criteria proposed by PAHO were adapted. To classify the receptive areas (strata 2, 3, and 4) and nonreceptive areas (stratum 1), 1,600 m above sea level, ecotypes, main malaria vector presence, Plasmodium species prevalence and occurrence of malaria cases were used. The area occupied by the receptive municipalities, the cumulative burden, and the at-risk population in the regions were calculated. RESULTS: Ninety-one percent of the Colombian territory is receptive to the transmission of malaria and includes 749 municipalities with 9,734,271 (9,514,243-9,954,299) million at-risk inhabitants. Stratum 4 accounted for 96.7% of the malaria burden, and cases were concentrated primarily in the Pacific and Uraba-Bajo Cauca-Sinu-San Jorge regions. Plasmodium vivax predominates in most of the receptive municipalities, except in the municipalities of the Pacific region, where P. falciparum predominates. Anopheles albimanus, An. nuneztovari s.l., and An. darlingi were the main vectors in receptive areas. CONCLUSIONS: In Colombia, 91.2% of the territory is receptive to the transmission of malaria and is characterized by being both heterogeneous and focused. Stratum 4 contains the greatest burden of disease, with a relatively greater proportion of municipalities with a predominance of P. vivax. However, there is a low proportion of municipalities with P. falciparum mainly in the Pacific region. These findings suggest that the latter be prioritized within the malaria elimination plan in Colombia.

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RESUMEN Introducción: El uso de los fármacos modificadores de la enfermedad (FAME) en pacientes con artritis reumatoide (AR) es esencial para alcanzar y mantener un control adecuado de la enfermedad y prevenir un daño funcional irreversible. Sin embargo, la tasa de adherencia a la terapia farmacológica varía entre el 20% y el 107%. Esta variabilidad puede deberse a los métodos de medición utilizados en los diferentes estudios. Objetivo: Evaluar la adherencia global al tratamiento oral con FAME en pacientes con AR mediante el autodiligenciamiento del cuestionario Compliance Questionnaire on Rheumatology (CQR) y la actividad de la enfermedad e identificar los factores potenciales asociados con la baja adherencia. Métodos: Estudio descriptivo transversal que incluyó pacientes mayores de 18 años con AR clasificados por criterios ACR-EULAR 2010, con prescripción de FAME durante al menos 3 meses y control con reumatólogo en el último año. Los participantes llenaron el cuestionario CQR y se les indagó acerca del conocimiento de la enfermedad, la percepción sobre el tratamiento, los efectos adversos, el índice de comorbilidad de Charlson, el índice global de apoyo social, el número de medicamentos y FAME prescritos, el acceso a los servicios de salud y la actividad de la enfermedad por DAS 28 o CDAI. Se definió como buena adherencia un punto de corte de CQR >80 y ausencia de actividad (remisión o actividad baja). Para la búsqueda de factores asociados con adherencia se analizaron los datos por medio de mediana y rango intercuartílico, así como frecuencias y proporciones. La comparación entre los grupos de adherentes y no adherentes se hizo con comparaciones absolutas, por medio de test de Mann-Whitney para las variables continuas y chi-cuadrado (para valores esperados > 5), o Fisher (para valor esperado < 5) para variables categóricas, tomando como nivel de significancia un valor de p<0,05. Se utilizaron OR y sus respectivos intervalos de confianza al 95% (IC95%). Resultados: De los 170 participantes incluidos, el 50% (n = 85) tuvo un valor de CQR mayor de 80 (buena adherencia). La mayoría de los pacientes se encontraba en remisión (60,6%) o baja actividad de la enfermedad (17%). El análisis posterior únicamente encontró asociación estadísticamente significativa entre adherencia medida por CQR y el número de amigos (p = 0,0012) y entre adherencia medida por actividad de la enfermedad y el índice de soporte social global (p = 0,004). Conclusiones: Este estudio muestra un nivel de adherencia similar al reportado en otras poblaciones, lo cual puede deberse a comportamientos propios de nuestra población, aunque los autores percibieron dificultades reportadas por los pacientes para entender los enunciados del instrumento en todos los niveles de escolaridad. Únicamente las variables de soporte social tuvieron una asociación estadísticamente significativa con la adherencia, asociación descrita en la literatura. Se requieren más estudios para evaluar las características operacionales del CQR en nuestra población.

ABSTRACT Introduction: The use of disease modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA) is essential in order to achieve and maintain adequate disease control, and thus preventing irreversible functional damage. However, the rate of adherence to drug therapy has been reported to be between 20% and 107%. This variability may be due to the measurement methods used in the different studies. Objective: To test the overall medication adherence to oral treatment with DMARD in patients with RA using the self-report Spanish version Compliance Questionnaire on Rheumatology (CQR) and to identify potential factors associated with non-adherence. Methods: A cross-sectional descriptive study was conducted that included patients older than 18 years with RA diagnosed according to the ACR-EULAR 2010 criteria. They also had to have been prescribed oral DMARD for the previous 3 months, and had been seen by a rheumatologist in the last year. Patients completed the CQR to assess adherence, and were asked about disease knowledge, perception about treatment, side effects, Charlson Comorbidity Index, global index of social support, number of medications and DMARD prescribed, access to health resources, and disease activity measured by DAS 28 or CDAI. Good adherence was defined as a cut-off point of CQR > 80 or non-activity (remission or low activity). In the search for factors associated with adherence, the data were analysed using means of median and interquartile range, as well as frequencies and proportions. The comparison between adherent and non-adherent groups was performed using absolute comparisons, with the Mann-Whitney test for continuous, and chi-squared (for expected values > 5), or Fisher (for expected values < 5) tests for categorical variables, taking as a level of significance a value of P < .05. OR and their respective 95% confidence intervals (95% CI) were used. Results: Of 170 participants included, 50% (n = 85) had a value greater than 80% (good drug adherence). Most patients had remission (60.6%) or low disease activity (17%). The subsequent analysis showed statistically significant association between adherence measured by CQR and the number of friends (P = .0012). An association was also found between disease activity as an indirect indicator of adherence and the global social support index (P = .004). Conclusions: This study found a similar level of adherence to that reported in other populations, which could be due to the behaviour of our population, although the authors perceived difficulties reported by patients in understanding the statements of the questionnaire at all levels of education. Only the social support variables had a statistically significant relationship with adherence, which had also been described in the literature. Further studies are required to evaluate the operational characteristics of the CQR in our population.

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Introducción: Se han publicados pocos informes sobre el seguimiento a largo plazo de la reparación quirúrgica de una amputación parcial. Algunos estudios de largo plazo han registrado tasas similares de discapacidad entre los pacientes con amputaciones y los sometidos a operación reconstructiva. Objetivo: Informar un caso clínico de una amputación traumática parcial de una extremidad superior con recuperación funcional después de 13 años de seguimiento. Caso clínico: Paciente masculino de ocho años con traumatismo grave en la extremidad superior izquierda, desprendimiento de los músculos bíceps y tríceps y una fractura diafisaria oblicua del húmero distal. La fractura se fijó de manera transitoria con alambres de Kirschner de 2.0 mm, seguido de inmovilización con aparato de Sarmiento y al final se realizó reducción abierta y fijación interna con placa de compresión dinámica de 3.5 mm. La integridad muscular y neurovascular permitió la reparación microquirúrgica del nervio radial y la rehabilitación neuromuscular. Conclusiones: Este informe clínico representa un caso de una recuperación funcional excelente atestiguada a través de un periodo de seguimiento de 13 años.

Introduction: There are just a few reports that deal with long-term outcomes of a partial amputation surgical repair. Long-term studies have reported similar rates of disability among patients with amputations and those that have been undergoing reconstructive surgery. Objective: The purpose of this report is describing a clinical case of a patient with partial traumatic amputation of an upper limb with an excellent functional recovery after 13 years of follow-up. Clinical case: The case of an 8 year old male patient with severe trauma to the upper left limb is described. The lesions included an oblique diaphyseal open fracture of the distal region of the humerus, along with detachment of the biceps and triceps muscles. The fracture was fixed transiently with 2.0 mm Kirschner's wire followed by immobilization with Sarmiento's brace, and finally, open reduction and internal fixation with a 3.5 mm dynamic compression plate were performed. The muscular and neurovascular integrity allowed microsurgical repair of the radial nerve and neuromuscular rehabilitation. Conclusion: This clinical report represents a case with an excellent functional recovery witnessed through a 13-year follow-up period.

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Glomerular arteriolar vasoconstriction and tubulointerstitial injury are observed before glomerular damage occurs in models of hypertension. High interstitial ATP concentrations, caused by the increase in arterial pressure, alter renal mechanisms involved in the long-term control of blood pressure, autoregulation of glomerular filtration rate and blood flow, tubuloglomerular feedback (TGF) responses, and sodium excretion. Elevated ATP concentrations and augmented expression of P2X receptors have been demonstrated under a genetic background or induction of hypertension with vasoconstrictor peptides. In addition to the alterations of the microcirculation in the hypertensive kidney, the vascular actions of elevated intrarenal angiotensin II levels may be mitigated by the administration of broad purinergic P2 antagonists or specific P2Y12, P2X1, and P2X7 receptor antagonists. Furthermore, the prevention of tubulointerstitial infiltration with immunosuppressor compounds reduces the development of salt-sensitive hypertension, indicating that tubulointerstitial inflammation is essential for the development and maintenance of hypertension. Inflammatory cells also express abundant purinergic receptors, and their activation by ATP induces cytokine and growth factor release that in turn contributes to augment tubulointerstitial inflammation. Collectively, the evidence suggests a pathophysiological activation of purinergic P2 receptors in angiotensin-dependent hypertension. Coexistent increases in intrarenal angiotensin II and activates Ang II AT1 receptors, which interacts with over-activated purinergic receptors in a complex manner, suggesting convergence of their post-receptor signaling processes.

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Previous studies demonstrated modifications of high-density lipoproteins (HDL) structure and apolipoprotein (apo) A-I catabolism induced by the atorvastatin and fenofibrate combination. However, it remains unknown whether such structural and metabolic changes of HDL were related to an improvement of the HDL-cholesteryl esters (HDL-CE) metabolism. Therefore, we determined the structure of HDL and performed kinetic studies of HDL-CE radiolabeled with tritium in rabbits treated with atorvastatin, fenofibrate, and a combination of both drugs. The atorvastatin and fenofibrate combination increased the HDL size and the cholesterol and phospholipid plasma concentrations of the largest HDL subclasses. Moreover, the relative amount of unsaturated fatty acids contained in HDL increased, in detriment of saturated fatty acids as determined by gas chromatography-mass spectrometry. The transfers of cholesteryl esters (CE) from HDL to very low-density lipoproteins/low-density lipoproteins (VLDL/LDL) and vice versa were enhanced with atorvastatin, alone or in combination. Moreover, the direct elimination of CE from plasma via VLDL/LDL decreased with fenofibrate, whereas the direct elimination of CE via HDL augmented with the combination treatment. Taken together, the rise of unsaturated fatty acid content and the size increase of HDL, suggest that atorvastatin and fenofibrate induce more fluid HDL particles, which in turn favor an enhanced CE exchange between HDL and VLDL/LDL. Our results contribute to a better understanding of the relationship between the structure and function of HDL during the use of anti-dyslipidemic drugs.

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Cell-based therapy has become a resource for the treatment of cardiovascular diseases; however, there are some conundrums to achieve. In vitro cardiomyocyte generation could be a solution for scaling options in clinical applications. Variability on cardiac differentiation in previously reported studies from adipose tissue-derived mesenchymal stem cells (ASCs) and the lack of measuring of the cardiomyocyte differentiation efficiency motivate the present study. Here, we improved the ASC-derived cardiomyocyte-like cell differentiation efficiency with a directed cardiomyocyte differentiation protocol: BMP-4 + VEGF (days 0-4) followed by a methylcellulose-based medium with cytokines (IL-6 and IL-3) (days 5-21). Cultures treated with the directed cardiomyocyte differentiation protocol showed cardiac-like cells and "rosette-like structures" from day 7. The percentage of cardiac troponin T- (cTnT-) positive cells was evaluated by flow cytometry to assess the cardiomyocyte differentiation efficiency in a quantitative manner. ASCs treated with the directed cardiomyocyte differentiation protocol obtained a differentiation efficiency of up to 44.03% (39.96%±3.78) at day 15 without any enrichment step. Also, at day 21 we observed by immunofluorescence the positive expression of early, late, and cardiac maturation differentiation markers (Gata-4, cTnT, cardiac myosin heavy chain (MyH), and the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCa2)) in cultures treated with the directed cardiomyocyte differentiation protocol. Unlike other protocols, the use of critical factors of embryonic cardiomyogenesis coupled with a methylcellulose-based medium containing previously reported cardiogenic cytokines (IL-6 and IL-3) seems to be favorable for in vitro cardiomyocyte generation. This novel efficient culture protocol makes ASC-derived cardiac differentiation more efficient. Further investigation is needed to identify an ASC-derived cardiomyocyte surface marker for cardiac enrichment.

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Osteocalcin is no longer regarded as a molecule exclusive to bone remodeling and osteogenesis, but as a hormone with manifold functions. The discovery of the interaction of osteocalcin with the G protein­coupled receptor family C group 6­member A (GPRC6A) receptor has accompanied the characterization of several roles that this peptide serves in body regulation and homeostasis. These roles include the modulation of memory in the brain, fertility in the testis, fat accumulation in the liver, incretins release in the intestine and adaptation to exercise in muscle, in addition to the well­known effects on ß­cell proliferation, insulin release and adiponectin secretion. The aim of the present review was to provide a practical update of the multi­organ effects that osteocalcin exerts through its interaction with GPRC6A and the clinical implications of this.

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Oxidative stress and redox status play a central role in the link between insulin resistance (IR) and lipotoxicity in metabolic syndrome. This mechanistic link may involve alterations in the glutathione redox state. We examined the effect of glycine supplementation to diet on glutathione biosynthesis, oxidative stress, IR, and insulin cell signaling in liver from sucrose-fed (SF) rats characterized by IR and oxidative stress. Our hypothesis is that the correction of glutathione levels by glycine treatment leads to reduced oxidative stress, a mechanism associated with improved insulin signaling and IR. Glycine treatment decreases the levels of oxidative stress markers in liver from SF rats and increases the concentrations of glutathione (GSH) and γ-glutamylcysteine and the amount of γ-glutamylcysteine synthetase (γ-GCS), a key enzyme of GSH biosynthesis in liver from SF rats. In liver from SF rats, glycine also decreases the insulin-induced phosphorylation of insulin receptor substrate-1 (ISR-1) in serine residue and increases the phosphorylation of insulin receptor ß-subunit (IR-ß) in tyrosine residue. Thus, supplementing diets with glycine to correct GSH deficiency and to reduce oxidative stress provides significant metabolic benefits to SF rats by improving insulin sensitivity.

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The potential cause-effect relationship between uric acid plasma concentrations and HDL functionality remains elusive. Therefore, this study aimed to explore the effect of oxonic acid (OA)-induced hyperuricemia on the HDL size distribution, lipid content of HDL subclasses, and apo AI turnover, as well as HDL functionality in New Zealand white rabbits. Experimental animals received OA 750 mg/kg/day by oral gavage during 21 days. The HDL-apo AI fractional catabolic rate (FCR) was determined by exogenous labeling with 125I, and HDL subclasses were determined by sequential ultracentrifugation and PAGE. Paraoxonase-1 activity (PON-1) and the effect of HDL on relaxation of aorta rings in vitro were determined as an indication of HDL functionality. Oxonic acid induced a sixfold increase of uricemia (0.84 ± 0.06 vs. 5.24 ± 0.12 mg/dL, P < 0.001), and significant decreases of triglycerides and phospholipids of HDL subclasses, whereas HDL size distribution and HDL-cholesterol remained unchanged. In addition, HDL-apo AI FCR was significantly higher in hyperuricemic rabbits than in the control group (0.03697 ± 0.0038 vs. 0.02605 ± 0.0017 h-1 respectively, P < 0.05). Such structural and metabolic changes were associated with lower levels of PON-1 activities and deleterious effects of HDL particles on endothelium-mediated vasodilation. In conclusion, hyperuricemia is associated with structural and metabolic modifications of HDL that result in impaired functionality of these lipoproteins. Our data strongly suggest that uric acid per se exerts deleterious effects on HDL that contribute to increase the risk of atherosclerosis.

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The catabolism and structure of high-density lipoproteins (HDL) may be the determining factor of their atheroprotective properties. To better understand the role of the kidney in HDL catabolism, here we characterized HDL subclasses and the catabolic rates of apo A-I in a rabbit model of proteinuria. Proteinuria was induced by intravenous administration of doxorubicin in New Zealand white rabbits (n = 10). HDL size and HDL subclass lipids were assessed by electrophoresis of the isolated lipoproteins. The catabolic rate of HDL-apo A-I was evaluated by exogenous radiolabelling with iodine-131. Doxorubicin induced significant proteinuria after 4 weeks (4.47 ± 0.55 vs. 0.30 ± 0.02 g/L of protein in urine, P < 0.001) associated with increased uremia, creatininemia, and cardiotoxicity. Large HDL2b augmented significantly during proteinuria, whereas small HDL3b and HDL3c decreased compared to basal conditions. HDL2b, HDL2a, and HDL3a subclasses were enriched with triacylglycerols in proteinuric animals as determined by the triacylglycerol-to-phospholipid ratio; the cholesterol content in HDL subclasses remained unchanged. The fractional catabolic rate (FCR) of [(131)I]-apo A-I in the proteinuric rabbits was faster (FCR = 0.036 h(-1)) compared to control rabbits group (FCR = 0.026 h(-1), P < 0.05). Apo E increased and apo A-I decreased in HDL, whereas PON-1 activity increased in proteinuric rabbits. Proteinuria was associated with an increased number of large HDL2b particles and a decreased number of small HDL3b and 3c. Proteinuria was also connected to an alteration in HDL subclass lipids, apolipoprotein content of HDL, high paraoxonase-1 activity, and a rise in the fractional catabolic rate of the [(131)I]-apo A-I.

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The anti-atherogenic properties of high-density lipoproteins (HDLs) may be related to their structure and metabolism. The HDL physicochemical characteristics that determine their plasma clearance during treatment with statins and fibrates are not well understood. In this study, we analyzed HDL-apo AI fractional catabolic rates (FCRs), size distributions, and the lipid composition of the HDL subclasses in New Zealand white rabbits with exogenous dyslipidemia that received low doses of atorvastatin and fenofibrate. Hypercholesterolemia decreased only partially with the combination of both drugs. HDL size distribution shifted toward larger particles among the groups of rabbits that received atorvastatin, fenofibrate, or their combination, compared with both the control group and the dyslipidemic group. The HDL subclasses were significantly rich in cholesterol in each of the groups compared with controls. The structural changes noted in the HDL subclasses were not associated with impaired plasma paraoxonase-1 (PON1) activity. The groups receiving monotherapy and the drug combination group were all associated with a higher apo AI FCR value compared with both the dyslipidemic rabbits and the control group. In conclusion, the combination of atorvastatin and fenofibrate induced a more favorable HDL subclass profile than did the individual use of these drugs. Similarly, the apo AI FCR values were augmented in every group receiving drug treatment (either monotherapy or combination therapy) in the setting of hypercholesterolemia. The anti-atherogenic properties of HDLs, excluding their capacity to bind PON1, may be enhanced by the structural and metabolic modifications induced by the combination of atorvastatin and fenofibrate.

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