RESUMEN
The prevalence of gestational diabetes mellitus (GDM) has increased in recent years, along with the higher prevalence of obesity in women of reproductive age. GDM is a pathology associated with vascular dysfunction in the fetoplacental unit. GDM-associated endothelial dysfunction alters the transfer of nutrients to the foetus affecting newborns and pregnant women. Various mechanisms for this vascular dysfunction have been proposed, of which the most studied are metabolic alterations of the vascular endothelium. However, different cell types are involved in GDM-associated endothelial dysfunction, including platelets. Platelets are small, enucleated cell fragments that actively take part in blood haemostasis and thrombus formation. Thus, they play crucial roles in pathologies coursing with endothelial dysfunction, such as atherosclerosis, cardiovascular diseases, and diabetes mellitus. Nevertheless, platelet function in GDM is understudied. Several reports show a potential relationship between platelet volume and mass with GDM; however, platelet roles and signaling mechanisms in GDM-associated endothelial dysfunction are unclear. This review summarizes the reported findings and proposes a link among altered amount, volume, mass, reactivity, and function of platelets and placenta development, resulting in fetoplacental vascular dysfunction in GDM.
Asunto(s)
Diabetes Gestacional , Enfermedades Vasculares , Embarazo , Femenino , Recién Nacido , Humanos , Diabetes Gestacional/metabolismo , Diabetes Gestacional/patología , Placenta/metabolismo , Plaquetas/metabolismo , Endotelio Vascular/metabolismo , Enfermedades Vasculares/metabolismoRESUMEN
The exposome is the cumulative measure of environmental influences and associated biological responses throughout the lifespan, including those from the environment, diet, behaviour, and endogenous processes. The exposome concept and the 2030 Agenda for the Sustainable Development Goals (SDGs) from the United Nations are the basis for understanding the aetiology and consequences of non-communicable diseases, including gestational diabetes mellitus (GDM). Pregnancy may be developed in an environment with adverse factors part of the immediate internal medium for fetus development and the external medium to which the pregnant woman is exposed. The placenta is the interface between maternal and fetal compartments and acts as a protective barrier or easing agent to transfer exposome from mother to fetus. Under and over-nutrition in utero, exposure to adverse environmental pollutants such as heavy metals, endocrine-disrupting chemicals, pesticides, drugs, pharmaceuticals, lifestyle, air pollutants, and tobacco smoke plays a determinant role in the development of GDM. This phenomenon is worsened by metabolic stress postnatally, such as obesity which increases the risk of GDM and other diseases. Clinical risk factors for GDM development include its aetiology. It is proposed that knowledge-based interventions to change the potential interdependent ecto-exposome and endo-exposome could avoid the occurrence and consequences of GDM.
Asunto(s)
Contaminantes Atmosféricos , Diabetes Gestacional , Contaminantes Ambientales , Exposoma , Embarazo , Femenino , Humanos , Diabetes Gestacional/epidemiología , Contaminantes Ambientales/toxicidad , Factores de RiesgoRESUMEN
Pregnant women may develop gestational diabetes mellitus (GDM), a disease of pregnancy characterised by maternal and fetal hyperglycaemia with hazardous consequences to the mother, the fetus, and the newborn. Maternal hyperglycaemia in GDM results in fetoplacental endothelial dysfunction. GDM-harmful effects result from chronic and short periods of hyperglycaemia. Thus, it is determinant to keep glycaemia within physiological ranges avoiding short but repetitive periods of hyper or hypoglycaemia. The variation of glycaemia over time is defined as 'glycaemia dynamics'. The latter concept regards with a variety of mechanisms and environmental conditions leading to blood glucose handling. In this review we summarized the different metrics for glycaemia dynamics derived from quantitative, plane distribution, amplitude, score values, variability estimation, and time series analysis. The potential application of the derived metrics from self-monitoring of blood glucose (SMBG) and continuous glucose monitoring (CGM) in the potential alterations of pregnancy outcome in GDM are discussed.
Asunto(s)
Diabetes Gestacional , Hiperglucemia , Glucemia , Automonitorización de la Glucosa Sanguínea , Femenino , Humanos , Recién Nacido , EmbarazoRESUMEN
A balanced communication between the mother, placenta and foetus is crucial to reach a successful pregnancy. Several windows of exposure to environmental toxins are present during pregnancy. When the women metabolic status is affected by a disease or environmental toxin, the foetus is impacted and may result in altered development and growth. Gestational diabetes mellitus (GDM) is a disease of pregnancy characterised by abnormal glucose metabolism affecting the mother and foetus. This disease of pregnancy associates with postnatal consequences for the child and the mother. The whole endogenous and exogenous environmental factors is defined as the exposome. Endogenous insults conform to the endo-exposome, and disruptors contained in the immediate environment are the ecto-exposome. Some components of the endo-exposome, such as Selenium, vitamins D and B12, adenosine, and a high-fat diet, and ecto-exposome, such as the heavy metals Arsenic, Mercury, Lead and Copper, and per- and polyfluoroakyl substances, result in adverse pregnancies, including an elevated risk of GDM or gestational diabesity. The impact of the exposome on the human placenta's vascular physiology and function in GDM and gestational diabesity is reviewed.
Asunto(s)
Diabetes Gestacional , Exposoma , Niño , Diabetes Gestacional/metabolismo , Endotelio Vascular/metabolismo , Femenino , Humanos , Placenta/metabolismo , EmbarazoRESUMEN
Gestational diabetes mellitus (GDM) shows a deficiency in the metabolism of D-glucose and other nutrients, thereby negatively affecting the foetoplacental vascular endothelium. Maternal hyperglycaemia and hyperinsulinemia play an important role in the aetiology of GDM. A combination of these and other factors predisposes women to developing GDM with pre-pregnancy normal weight, viz. classic GDM. However, women with GDM and prepregnancy obesity (gestational diabesity, GDty) or overweight (GDMow) show a different metabolic status than women with classic GDM. GDty and GDMow are associated with altered l-arginine/nitric oxide and insulin/adenosine axis signalling in the human foetoplacental microvascular and macrovascular endothelium. These alterations differ from those observed in classic GDM. Here, we have reviewed the consequences of GDty and GDMow in the modulation of foetoplacental endothelial cell function, highlighting studies describing the modulation of intracellular pH homeostasis and the potential implications of NO generation and adenosine signalling in GDty-associated foetal vascular insulin resistance. Moreover, with an increase in the rate of obesity in women of childbearing age worldwide, the prevalence of GDty is expected to increase in the next decades. Therefore, we emphasize that women with GDty and GDMow should be characterized with a different metabolic state from that of women with classic GDM to develop a more specific therapeutic approach for protecting the mother and foetus.
Asunto(s)
Diabetes Gestacional , Resistencia a la Insulina , Endotelio Vascular , Femenino , Humanos , Insulina , Placenta , EmbarazoRESUMEN
The release of protons (H+) occurs via the Na+/H+ exchanger isoform 1 (NHE1) leading to a stable intracellular pH (pHi) in MDCK cells. Chronic intake of arsenic trioxide (ATO), in the drinking water, associated with higher morbidity and mortality in neoplastic tissues. ATO increased NHE1 expression and activity, resulting in intracellular alkalization and higher MDCK cells proliferation. Since the pro-proliferative transcription factor activator protein 1 (AP-1) gets activated by al alkaline intracellular pH, a phenomenon paralleled by higher NHEs activity, we asked whether ATO-increased MDCK cells proliferation involves AP-1-dependent NHE1 activation. Cells were exposed (48 h) to ATO (0.05 µmol/L), SR11302 (1 µmol/L, AP-1 inhibitor), HOE-694 (100 nmol/L, NHE1 inhibitor) and EIPA (50 µmol/L, NHE1/NHE3 inhibitor) in the presence of S3226 (10 µmol/L, NHE3 inhibitor), concanamycin A (0.1 µmol/L, V-ATPases inhibitor), and Schering (10 µmol/L, H+/K+-ATPase inhibitor). [3H]Thymidine incorporation, cell counting, wound healing assay, and AP-1 activity were determined. The pHi was measured in cells pre-loaded (10 min) with 2,7-bicarboxyethyl-5,6-carboxyfluorescein acetoxymethyl ester (12 mmol/L) and exposed to NH4Cl (20 mmol/L). Basal pHi and recovery rate (dpHi/dt), intracellular buffer capacity (ßi) and H+ flux (JH+) were determined. NHE1 protein abundance was measured by Western blotting and immunofluorescence. ATO increased the cell growth (1.5 fold), basal pHi (0.4 pHi units), dpHi/dt (1.8 fold), JH+ (1.4 fold), AP-1 activity and NHE1 protein abundance (1.3 fold). ATO also increased (1.5 fold) the nuclear/perinuclear NHE1 immunosignal. SR11302 and HOE-694 blocked ATO effects. Thus, ATO-increased proliferation resulted from AP-1-dependent NHE1 activation in MDCK cells.
Asunto(s)
Trióxido de Arsénico/farmacología , Proliferación Celular/efectos de los fármacos , Intercambiador 1 de Sodio-Hidrógeno/biosíntesis , Factor de Transcripción AP-1/metabolismo , Animales , Perros , Células de Riñón Canino Madin DarbyRESUMEN
Gestational diabetes mellitus (GDM) is a disease of pregnancy that is associated with d-glucose intolerance and foeto-placental vascular dysfunction. GMD causes mitochondrial dysfunction in the placental endothelium and trophoblast. Additionally, GDM is associated with reduced placental oxidative phosphorylation due to diminished activity of the mitochondrial F0F1-ATP synthase (complex V). This phenomenon may result from a higher generation of reactive superoxide anion and nitric oxide. Placental mitochondrial biogenesis and mitophagy work in concert to maintain cell homeostasis and are vital mechanisms securing the efficient generation of ATP, whose demand is higher in pregnancy, ensuring foetal growth and development. Additional factors disturbing placental ATP synthase activity in GDM include pre-gestational maternal obesity or overweight, intracellular pH, miRNAs, fatty acid oxidation, and foetal (and 'placental') sex. GDM is also associated with maternal and foetal hyperinsulinaemia, altered circulating levels of adiponectin and leptin, and the accumulation of extracellular adenosine. Here, we reviewed the potential interplay between these molecules or metabolic conditions on the mechanisms of mitochondrial dysfunction in the foeto-placental unit in GDM pregnancies.
Asunto(s)
Diabetes Gestacional/metabolismo , Mitocondrias/metabolismo , Enfermedades Placentarias/metabolismo , Animales , Diabetes Gestacional/patología , Femenino , Humanos , Enfermedades Placentarias/patología , EmbarazoRESUMEN
The maintenance of the pH homeostasis is maintained by several mechanisms including the efflux of protons (H+) via membrane transporters expressed in almost all mammalian cells. Along these membrane transporters the sodium/H+ exchangers (NHEs), mainly NHE isoform 1 (NHE1), plays a key role in this phenomenon. NHE1 is under modulation by several environmental conditions (e.g. hyperglycaemia, protein kinase C activity) as well as hormones, including insulin. NHE1 activation causes intracellular alkalization in human endothelial cells leading to activation of the endothelial Nitric Oxide Synthase (eNOS) to generate NO. Intracellular alkalization is a phenomenon that also results in upregulation of the glucose transporter GLUT4 in cells that are responsive to insulin. A reduction in the removal of the extracellular D-glucose is seen in states of insulin resistance, such as in diabetes mellitus and obesity. Since insulin is a potent activator of eNOS in human endothelium, therefore causing vasodilation, and its vascular effect is reduced in insulin resistance it is likely that a defective signal to activate NHE1 in insulin target cells is expected. This phenomenon results in lower redistribution and activation of GLUT4 leading to reduced uptake of D-glucose and hyperglycaemia. The general concept of a role for NHE1, and perhaps other NHEs isoforms, in insulin resistance in the human vasculature is proposed.
Asunto(s)
Equilibrio Ácido-Base , Glucemia/metabolismo , Vasos Sanguíneos/metabolismo , Diabetes Mellitus/metabolismo , Angiopatías Diabéticas/metabolismo , Hiperglucemia/metabolismo , Resistencia a la Insulina , Insulina/sangre , Animales , Biomarcadores/sangre , Vasos Sanguíneos/fisiopatología , Diabetes Mellitus/fisiopatología , Angiopatías Diabéticas/etiología , Angiopatías Diabéticas/fisiopatología , Transportador de Glucosa de Tipo 4/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Hiperglucemia/complicaciones , Hiperglucemia/fisiopatología , Factores de Riesgo , Intercambiador 1 de Sodio-Hidrógeno/metabolismoRESUMEN
l-Arginine is taken up via the cationic amino acid transporters (system y+/CATs) and system y+L in human umbilical vein endothelial cells (HUVECs). l-Arginine is the substrate for endothelial NO synthase (eNOS) which is activated by intracellular alkalization, but nothing is known regarding modulation of system y+/CATs and system y+L activity, and eNOS activity by the pHi in HUVECs. We studied whether an acidic pHi modulates l-arginine transport and eNOS activity in HUVECs. Cells loaded with a pH-sensitive probe were subjected to 0.1-20â¯mmol/L NH4Cl pulse assay to generate pHi 7.13-6.55. Before pHi started to recover, l-arginine transport (0-20 or 0-1000⯵mol/L, 10â¯s, 37⯰C) in the absence or presence of 200⯵mol/L N-ethylmaleimide (NEM) (system y+/CATs inhibitor) or 2â¯mmol/L l-leucine (systemy+L substrate) was measured. Protein abundance for eNOS and serine1177 or threonine495 phosphorylated eNOS was determined. The results show that intracellular acidification reduced system y+L but not system y+/CATs mediated l-arginine maximal transport capacity due to reduced maximal velocity. Acidic pHi reduced NO synthesis and eNOS serine1177 phosphorylation. Thus, system y+L activity is downregulated by an acidic pHi, a phenomenon that may result in reduced NO synthesis in HUVECs.
Asunto(s)
Sistema de Transporte de Aminoácidos y+L/metabolismo , Sistema de Transporte de Aminoácidos y+/metabolismo , Arginina/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Óxido Nítrico/biosíntesis , Sistema de Transporte de Aminoácidos y+/antagonistas & inhibidores , Transporte Biológico Activo/efectos de los fármacos , Transporte Biológico Activo/fisiología , Etilmaleimida/farmacología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Concentración de Iones de HidrógenoRESUMEN
The enterotoxigenic Escherichia coli strains lead to diarrhoea in humans due to heat-labile and heat-stable (STa) enterotoxins. STa increases Cl-release in intestinal cells, including the human colonic carcinoma T84 cell line, involving increased cGMP and membrane alkalization due to reduced Na+/H+ exchangers (NHEs) activity. Since NHEs modulate intracellular pH (pHi), and NHE1, NHE2, and NHE4 are expressed in T84 cells, we characterized the STa role as modulator of these exchangers. pHi was assayed by the NH4Cl pulse technique and measured by fluorescence microscopy in BCECF-preloaded cells. pHi recovery rate (dpHi/dt) was determined in the absence or presence of 0.25 µmol/L STa (30 minutes), 25 µmol/L HOE-694 (concentration inhibiting NHE1 and NHE2), 500 µmol/L sodium nitroprusside (SNP, spontaneous nitric oxide donor), 100 µmol/L dibutyryl cyclic GMP (db-cGMP), 100 nmol/L H89 (protein kinase A inhibitor), or 10 µmol/L forskolin (adenylyl cyclase activator). cGMP and cAMP were measured in cell extracts by radioimmunoassay, and buffering capacity (ßi) and H+ efflux (JH+) was determined. NHE4 protein abundance was determined by western blotting. STa and HOE-694 caused comparable reduction in dpHi/dt and JH+ (~63%), without altering basal pHi (range 7.144-7.172). STa did not alter ßi value in a range of 1.6 pHi units. The dpHi/dt and JH+ was almost abolished (~94% inhibition) by STa + HOE-694. STa effect was unaltered by db-cGMP or SNP. However, STa and forskolin increased cAMP level. STa-decreased dpHi/dt and JH+ was mimicked by forskolin, and STa + HOE-694 effect was abolished by H89. Thus, incubation of T84 cells with STa results in reduced NHE4 activity leading to a lower capacity of pHi recovery requiring cAMP, but not cGMP. STa effect results in a causal phenomenon (STa/increased cAMP/increased PKA activity/reduced NHE4 activity) ending with intracellular acidification that could have consequences in the gastrointestinal cells function promoting human diarrhoea.
Asunto(s)
AMP Cíclico/metabolismo , Enterotoxinas/farmacología , Células Epiteliales/efectos de los fármacos , Escherichia coli , Calor , Intestinos/citología , Intercambiadores de Sodio-Hidrógeno/antagonistas & inhibidores , Adulto , Línea Celular Tumoral , GMP Cíclico/metabolismo , Estabilidad de Medicamentos , Enterotoxinas/química , Células Epiteliales/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Concentración de Iones de Hidrógeno , Cinética , Masculino , Protones , Intercambiadores de Sodio-Hidrógeno/metabolismoRESUMEN
Arsenic main inorganic compound is arsenic trioxide (ATO) presented in solution mainly as arsenite. ATO increases intracellular pH (pHi), cell proliferation and tumor growth. Sodium-proton exchangers (NHEs) modulate the pHi, with NHE1 playing significant roles. Whether ATO-increased cell proliferation results from altered NHEs expression and activity is unknown. We hypothesize that ATO increases cell proliferation by altering pHi due to increased NHEs-like transport activity. Madin-Darby canine kidney (MDCK) cells grown in 5 mmol/L D-glucose-containing DMEM were exposed to ATO (0.05, 0.5 or 5 µmol/L, 0-48 hours) in the absence or presence of 5-N,N-hexamethylene amiloride (HMA, 5-100 µmol/L, NHEs inhibitor), PD-98059 (30 µmol/L, MAPK1/2 inhibitor), Gö6976 (10 µmol/L, PKCα, ßI and µ inhibitor), or Schering 28080 (10 µmol/L, H(+)/K(+)ATPase inhibitor) plus concanamycin (0.1 µmol/L, V type ATPases inhibitor). Incorporation of [(3)H]thymidine was used to estimate cell proliferation, and counting cells with a hemocytometer to determine the cell number. The pHi was measured by fluorometry in 2,7-bicarboxyethyl-5,6-carboxyfluorescein loaded cells. The Na(+)-dependent HMA-sensitive NHEs-like mediated proton transport kinetics, NHE1 protein abundance in the total, cytoplasm and plasma membrane protein fractions, and phosphorylated and total p42/44 mitogen-activated protein kinases (p42/44(mapk)) were also determined. Lowest ATO (0.05 µmol/L, ~0.01 ppm) used in this study increased cell proliferation, pHi, NHEs-like transport and plasma membrane NHE1 protein abundance, effects blocked by HMA, PD-98059 or Gö6976. Cell-buffering capacity did not change by ATO. The results show that a low ATO concentration increases MDCK cells proliferation by NHEs (probably NHE1)-like transport dependent-increased pHi requiring p42/44(mapk) and PKCα, ßI and/or µ activity. This finding could be crucial in diseases where uncontrolled cell growth occurs, such as tumor growth, and in circumstances where ATO, likely arsenite, is available at the drinking-water at these levels.
Asunto(s)
Arsenicales/metabolismo , Proliferación Celular/efectos de los fármacos , Óxidos/metabolismo , Intercambiadores de Sodio-Hidrógeno/metabolismo , Amilorida/análogos & derivados , Análisis de Varianza , Animales , Trióxido de Arsénico , Arsenicales/farmacología , Western Blotting , Carbazoles , Recuento de Células , Fraccionamiento Celular , Perros , Flavonoides , Fluorometría , Concentración de Iones de Hidrógeno , Imidazoles , Macrólidos , Células de Riñón Canino Madin Darby , Óxidos/farmacologíaRESUMEN
In this year, we commemorate half a century of the first open-heart surgery performed in Mexico at the Military Hospital on January 11, 1957. The surgery was performed in a child with interventricular communication by Dr. Raul Baz; in this surgery a De Wall and Lillehei bubble oxygenator was used. The perfusionist was Dr. Marcelo García Cornejo. The present historical review is aimed at covering the advances in cardiology from its beginnings to the present.
Asunto(s)
Historia del Siglo XX , Circulación Extracorporea , Diseño de Equipo , Circulación Extracorporea/instrumentación , MéxicoRESUMEN
In this year, we commemorate half a century of the first open-heart surgery performed in Mexico at the Military Hospital on January 11, 1957. The surgery was performed in a child with interventricular communication by Dr. Raul Baz; in this surgery a De Wall and Lillehei bubble oxygenator was used. The perfusionist was Dr. Marcelo García Cornejo. The present historical review is aimed at covering the advances in cardiology from its beginnings to the present.