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PURPOSE OF REVIEW: Atherosclerotic cardiovascular disease (ASCVD) is still the leading cause of death worldwide. Despite excellent pharmacological approaches, clinical registries consistently show that many people with dyslipidemia do not achieve optimal management, and many of them are treated with low-intensity lipid-lowering therapies. Beyond the well-known association between low-density lipoprotein cholesterol (LDL-C) and cardiovascular prevention, the atherogenicity of lipoprotein(a) and the impact of triglyceride (TG)-rich lipoproteins cannot be overlooked. Within this landscape, the use of RNA-based therapies can help the treatment of difficult to target lipid disorders. RECENT FINDINGS: The safety and efficacy of LDL-C lowering with the siRNA inclisiran has been documented in the open-label ORION-3 trial, with a follow-up of 4 years. While the outcome trial is pending, a pooled analysis of ORION-9, ORION-10, and ORION-11 has shown the potential of inclisiran to reduce composite major adverse cardiovascular events. Concerning lipoprotein(a), data of OCEAN(a)-DOSE trial with olpasiran show a dose-dependent drop in lipoprotein(a) levels with an optimal pharmacodynamic profile when administered every 12 weeks. Concerning TG lowering, although ARO-APOC3 and ARO-ANG3 are effective to lower apolipoprotein(apo)C-III and angiopoietin-like 3 (ANGPTL3) levels, these drugs are still in their infancy. In the era moving toward a personalized risk management, the use of siRNA represents a blossoming armamentarium to tackle dyslipidaemias for ASCVD risk reduction.
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Aterosclerosis , Enfermedades Cardiovasculares , Dislipidemias , Humanos , LDL-Colesterol , ARN Interferente Pequeño/uso terapéutico , ARN Interferente Pequeño/farmacología , Dislipidemias/tratamiento farmacológico , Aterosclerosis/tratamiento farmacológico , Lipoproteína(a) , Enfermedades Cardiovasculares/inducido químicamente , Proteína 3 Similar a la AngiopoyetinaRESUMEN
BACKGROUND: Depression and cardiovascular disease (CVD) are among the most common causes of disability in high-income countries, depression being associated with a 30% increased risk of future CV events. Depression is twice as common in people with diabetes and is associated with a 60% rise in the incidence of type 2 diabetes, an independent CVD risk factor. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein cholesterol, has been related to a large number of CV risk factors, including insulin resistance. Aim of this study was to investigate whether the presence of depression could affect PCSK9 levels in a population of obese subjects susceptible to depressive symptoms and how these changes may mediate a pre-diabetic risk. RESULTS: In 389 obese individuals, the Beck Depression Inventory (BDI-II) was significantly associated with PCSK9 levels. For every one-unit increment in BDI-II score, PCSK9 rose by 1.85 ng/mL. Depression was associated also with the HOMA-IR (homeostatic model assessment index of insulin resistance), 11% of this effect operating indirectly via PCSK9. CONCLUSIONS: This study indicates a possible mechanism linking depression and insulin resistance, a well-known CV risk factor, providing evidence for a significant role of PCSK9.
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Afecto , Enfermedades Cardiovasculares/etiología , Depresión/etiología , Resistencia a la Insulina , Obesidad/complicaciones , Proproteína Convertasa 9/sangre , Adulto , Biomarcadores , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/diagnóstico , Estudios Transversales , Depresión/sangre , Depresión/diagnóstico , Depresión/psicología , Femenino , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Masculino , Persona de Mediana Edad , Obesidad/sangre , Obesidad/diagnóstico , Obesidad/fisiopatología , Estudios Retrospectivos , Medición de RiesgoRESUMEN
Recent evidence suggests that ceramides can play an important pathophysiological role in the development of diabetes. Ceramides are primarily recognized as lipid bilayer building blocks, but recent work has shown that these endogenous molecules are important intracellular signalling mediators and may exert some diabetogenic effects via molecular pathways involved in insulin resistance, ß-cell apoptosis and inflammation. In the present review, we consider the available evidence on the possible roles of ceramides in diabetes mellitus and introduce eight different molecular mechanisms mediating the diabetogenic action of ceramides, categorized into those predominantly related to insulin resistance vs those mainly implicated in ß-cell dysfunction. Specifically, the mechanistic evidence involves ß-cell apoptosis, pancreatic inflammation, mitochondrial stress, endoplasmic reticulum stress, adipokine release, insulin receptor substrate 1 phosphorylation, oxidative stress and insulin synthesis. Collectively, the evidence suggests that therapeutic agents aimed at reducing ceramide synthesis and lowering circulating levels may be beneficial in the prevention and/or treatment of diabetes and its related complications.
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Ceramidas/biosíntesis , Diabetes Mellitus/metabolismo , Apoptosis/fisiología , Ceramidas/fisiología , Diabetes Mellitus/fisiopatología , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Inflamación , Resistencia a la Insulina/fisiologíaRESUMEN
The high occurrence of atherosclerotic cardiovascular disease (ASCVD) events is still a major public health issue. Although a major determinant of ASCVD event reduction is the absolute change of low-density lipoprotein-cholesterol (LDL-C), considerable residual risk remains and new therapeutic options are required, in particular, to address triglyceride-rich lipoproteins and lipoprotein(a) [Lp(a)]. In the era of Genome Wide Association Studies and Mendelian Randomization analyses aimed at increasing the understanding of the pathophysiology of ASCVD, RNA-based therapies may offer more effective treatment options. The advantage of oligonucleotide-based treatments is that drug candidates are targeted at highly specific regions of RNA that code for proteins that in turn regulate lipid and lipoprotein metabolism. For LDL-C lowering, the use of inclisiran - a silencing RNA that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis - has the advantage that a single s.c. injection lowers LDL-C for up to 6 months. In familial hypercholesterolemia, the use of the antisense oligonucleotide (ASO) mipomersen, targeting apolipoprotein (apoB) to reduce LDL-C, has been a valuable therapeutic approach, despite unquestionable safety concerns. The availability of specific ASOs lowering Lp(a) levels will allow rigorous testing of the Lp(a) hypothesis; by dramatically reducing plasma triglyceride levels, Volanesorsen (APOC3) and angiopoietin-like 3 (ANGPTL3)-LRx will further clarify the causality of triglyceride-rich lipoproteins in ASCVD. The rapid progress to date heralds a new dawn in therapeutic lipidology, but outcome, safety and cost-effectiveness studies are required to establish the role of these new agents in clinical practice.
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Dislipidemias/tratamiento farmacológico , ARN/uso terapéutico , Animales , LDL-Colesterol/sangre , Dislipidemias/sangre , Humanos , Hipolipemiantes/uso terapéutico , Lipoproteína(a)/sangre , Oligonucleótidos Antisentido/uso terapéutico , Triglicéridos/sangreRESUMEN
PURPOSE: The "Mars-500 project" allowed to evaluate the changes in psychological/physiological adaptation over a prolonged confinement, in order to gather information for future missions. Here, we evaluated the impact of confinement and isolation on body composition, glucose metabolism/insulin resistance and adipokine levels. METHODS: The "Mars-500 project" consisted of 520 consecutive days of confinement from June 3, 2010 to Nov 4, 2011. The crew was composed of six male subjects (three Russians, two Europeans, and one Chinese) with a median age of 31 years (range 27-38 years). RESULTS: During the 520-day confinement, total body mass and BMI progressively decreased, reaching a significant difference at the end (417 days) of the observation period (- 9.2 and - 5.5%, respectively). Fat mass remained unchanged. A progressive and significant increase of fasting plasma glucose was observed between 249 and 417 days (+ 10/+ 17% vs baseline), with a further increase at the end of confinement (up to + 30%). Median plasma insulin showed a non-significant early increment (60 days; + 86%). Total adiponectin halved (- 47%) 60 days after hatch closure, remaining at this nadir (- 51%) level for a further 60 days. High molecular weight adiponectin remained significantly lower from 60 to 168 days. CONCLUSIONS: Based on these data, countermeasures may be envisioned to balance the potentially harmful effects of prolonged confinement, including a better exercise program, with accurate monitoring of (1) the individual activity and (2) the relationship between body composition and metabolic derangement.
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Adiponectina/sangre , Glucemia/análisis , Composición Corporal/fisiología , Insulina/sangre , Simulación del Espacio , Estrés Fisiológico/fisiología , Adaptación Fisiológica/fisiología , Adulto , Índice de Masa Corporal , Humanos , Resistencia a la Insulina/fisiología , MasculinoRESUMEN
Nowadays, the goal in the management of type 2 diabetes mellitus (T2DM) remains personalized control of glucose. Since less than 50% of patients with T2DM achieve glycemic treatment goal and most of them take medications for comorbidities associated to T2DM, drug interactions, namely pharmacokinetic and pharmacodynamic interactions, may enhance or reduce the effect of compounds involved in hyperglycemia. Hence, clinicians should be aware of the severe complications in T2DM patients in case of a concomitant use of these medications. It is within this context that this review aims to evaluate the effect of a second drug on the pharmacokinetic of these compounds which may lead, along with several pharmacodynamic interactions, to severe clinical complications, i.e., hypoglycemia. Available drugs already approved in Europe, USA and Japan have been included.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéutico , Interacciones Farmacológicas/fisiología , Humanos , Hipoglucemiantes/farmacocinética , Insulina/uso terapéuticoRESUMEN
AIM: Critically discuss the available data, to identify the current gaps and to provide key concepts that will help clinicians in translating the biology of adipokines in the context of atherosclerosis and cardio-metabolic diseases. DATA SYNTHESIS: Adipose tissue is nowadays recognized as an active endocrine organ, a function related to the ability to secrete adipokines (such as leptin and adiponectin) and pro-inflammatory cytokines (tumor necrosis factor alpha and resistin). Studies in vitro and in animal models have observed that obesity status presents a chronic low-grade inflammation as the consequence of the immune cells infiltrating the adipose tissue as well as adipocytes. This inflammatory signature is often related to the presence of cardiovascular diseases, including atherosclerosis and thrombosis. These links are less clear in humans, where the role of adipokines as prognostic marker and/or player in cardiovascular diseases is not as clear as that observed in experimental models. Moreover, plasma adipokine levels might reflect a condition of adipokine-resistance in which adipokine redundancy occurs. The investigation of the cardio-metabolic phenotype of carriers of single nucleotide polymorphisms affecting the levels or function of a specific adipokine might help determine their relevance in humans. Thus, the aim of the present review is to critically discuss the available data, identify the current gaps and provide key concepts that will help clinicians translate the biology of adipokines in the context of atherosclerosis and cardio-metabolic diseases.
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Adipoquinas/sangre , Tejido Adiposo/metabolismo , Aterosclerosis/sangre , Enfermedades Cardiovasculares/sangre , Investigación Biomédica Traslacional , Adipoquinas/genética , Tejido Adiposo/fisiopatología , Animales , Aterosclerosis/diagnóstico , Aterosclerosis/fisiopatología , Biomarcadores/sangre , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/fisiopatología , Citocinas/sangre , Predisposición Genética a la Enfermedad , Variación Genética , Humanos , Mediadores de Inflamación/sangre , Fenotipo , Pronóstico , Receptores de Adipoquina/metabolismo , Factores de Riesgo , Transducción de SeñalRESUMEN
Extracellular vesicles (EVs) are membrane-bound particles released by all cells under physiological and pathological conditions. EVs constitute a potential tool to unravel cell-specific pathophysiological mechanisms at the root of disease states and retain the potential to act as biomarkers for cardiac diseases. By being able to carry bioactive cargo (such as proteins and miRNAs), EVs harness great potential as accessible "liquid biopsies", given their ability to reflect the state of their cell of origin. Cardiomyopathies encompass a variety of myocardial disorders associated with mechanical, functional and/or electric dysfunction. These diseases exhibit different phenotypes, including inappropriate ventricular hypertrophy, dilatation, scarring, fibro-fatty replacement, dysfunction, and may stem from multiple aetiologies, most often genetic. Thus, the aims of this narrative review are to summarize the current knowledge on EVs and cardiomyopathies (e.g., hypertrophic, dilated and arrhythmogenic), to elucidate the potential role of EVs in the paracrine cell-to-cell communication among cardiac tissue compartments, in aiding the diagnosis of the diverse subtypes of cardiomyopathies in a minimally invasive manner, and finally to address whether certain molecular and phenotypical characteristics of EVs may correlate with cardiomyopathy disease phenotype and severity.
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Lactate sits at the crossroad of metabolism, immunity, and inflammation. The expression of cellular lactate transporter MCT1 (known as Slc16a1) increases during immune cell activation to cope with the metabolic reprogramming. We investigated the impact of MCT1 deficiency on CD8+ T cell function during obesity-related inflammatory conditions. The absence of MCT1 impaired CD8+ T cell proliferation with a shift of ATP production to mitochondrial oxidative phosphorylation. In Slc16a1 f/f Tcell cre mice fed a high-fat diet, a reduction in the number of CD8+ T cells, which infiltrated epididymal visceral adipose tissue (epiWAT) or subcutaneous adipose tissue, was observed. Adipose tissue weight and adipocyte area were significantly reduced together with downregulation of adipogenic genes only in the epiWAT. Our findings highlight a distinct effect of MCT1 deficiency in CD8+ T cells in the crosstalk with adipocytes and reinforce the concept that targeting immunometabolic reprogramming in lymphocyte could impact the immune-adipose tissue axis in obesity.
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BACKGROUND: The 5'-AMP-activated protein kinase (AMPK) plays a fundamental role in regulating energy homeostasis as well as feeding and metabolism, through central and peripheral actions. AMPK is activated by conditions causing ATP depletion and by different metabolic molecules, such as adiponectin and AMPK agonist, such as 5-aminoimidazole- 4-carboxamide-1-ß-D-ribofuranoside (AICAR). AMPK activation has also been shown to affect the migration of different cell types and to participate in the central control of reproductive function, although information concerning AMPK and the development of the hypothalamic reproductive compartment is lacking. AIM: To explore whether AMPK activation by globular adiponectin (gAdipo) and AICAR may affect the migratory ability of GnRH neurons. MATERIALS AND METHODS: We used GN11 immature GnRH neurons (in vitro model system), RT-PCR and Western blot analysis, and Boyden's chamber assay. RESULTS: gAdipo did not affect FBS-stimulated migration of GN11 cells and activated AMPK through the mandatory phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and Akt, which also interact one to each other. AICAR treatment inhibited FBS-stimulated GN11 cell migration, through a long-lasting activation of AMPK. A downstream activation of ERK1/2 by AICAR was also observed and inhibition of ERK1/2 amplified AICAR-induced inhibition of migration. CONCLUSIONS: The direct, but not the indirect, activation of AMPK appears to negatively affect FBSinduced GN11 cell migration, suggesting that the final balance between pro-migratory and anti-migratory actions may also depend upon the specific sequence of intracellular signals activated by one agent.
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Proteínas Quinasas Activadas por AMP/fisiología , Aminoimidazol Carboxamida/farmacología , Movimiento Celular/efectos de los fármacos , Neuronas/fisiología , Adiponectina/farmacología , Animales , Línea Celular , Activación Enzimática , Hormona Liberadora de Gonadotropina/metabolismo , Hipotálamo/metabolismo , Ratones , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fosforilación , Receptores de Adiponectina/biosíntesisRESUMEN
BACKGROUND: Sex hormones and adipokines seem to differently interact in both genders at different ages. AIM: To comparatively evaluate the serum level of adipokines and sex hormones in healthy non-pharmacologically treated premenopausal women, post-menopausal women, and elderly women, and in age-matched men. SUBJECTS: From the historical cohort of the Brisighella Heart Study we selected 199 adult healthy subjects (males: 89; females: 110), aged 62.5±12.4 yr. Men and women included in the age-class subgroups were matched for body mass index (BMI), waist circumference, blood pressure, heart rate, fasting plasma glucose, plasma lipids. RESULTS: Leptin did not differ among various age classes in men, while pre-menopausal women displayed significantly lower serum leptin than post-menopausal women (-6.7 ± 2.2 pg/ml, p=0.036). Post-menopausal women had significantly greater serum leptin when compared with age-matched men (+13.1 ± 2.0 pg/ml, p<0.001); the same was observed for elderly women when compared with elderly men (+11.2 ± 2.3 pg/ml, p<0.001). At any age, women had significantly lower serum testosterone/estrone ratio than age-matched men (p<0.01). Serum DHEAS was inversely proportional to age in both genders. The main predictors of adiponectin level are age in men (p=0.027) and BMI in women (p=0.003). The main predictors of leptin level are BMI and the testosterone/estrone ratio in both sexes (p<0.05). The testosterone/estrone ratio is also the main predictor of ghrelin levels in women (p=0.006). CONCLUSION: Sex hormones and adipokines show specific interactions in the two genders and in different age-classes in a representative sample of adult healthy subjects.
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Adipoquinas/sangre , Hormonas Esteroides Gonadales/sangre , Posmenopausia/sangre , Premenopausia/sangre , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Estudios de Cohortes , Femenino , Humanos , Leptina/sangre , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores SexualesRESUMEN
OBJECTIVE: Exposure to airborne pollutants during pregnancy appears to be associated with uterine growth restriction and adverse neonatal outcome. Proprotein convertase subtilisin/kexin type (PCSK9), the key modulator of low-density lipoprotein (LDL) metabolism, increases following particulate matter (PM10) exposure. Because maternal cholesterol is required for fetal growth, PCSK9 levels could be used to evaluate the potential impact of airborne pollutants on fetal growth. DESIGN: A cohort of 134 healthy women during early pregnancy (11-12 weeks of gestational age) was studied. RESULTS: A significant association between circulating PCSK9 levels and three tested air pollutants (PM10, PM2.5, nitric oxide (NO2)) was found. Of importance, gestational age at birth was reduced by approximately 1 week for each 100 ng/mL rise in circulating PCSK9 levels, an effect that became more significant at the highest quartile of PM2.5 (with a 1.8 week advance in delivery date for every 100 ng/mL rise in circulating PCSK9; p for interaction = 0.026). This finding was supported by an elevation of the odds ratio for urgent cesarean delivery for each 100 ng/mL rise in PCSK9 (2.99, 95% CI, 1.22-6.57), similar trends being obtained for PM10 and NO2. CONCLUSIONS: The association between exposure to air pollutants during pregnancy and elevation in PCSK9 advances our understanding of the unforeseen influences of environmental exposure in terms of pregnancy associated disorders.
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Contaminantes Atmosféricos , Proproteína Convertasa 9 , Contaminantes Atmosféricos/análisis , Contaminantes Atmosféricos/toxicidad , Femenino , Desarrollo Fetal , Edad Gestacional , Humanos , Italia , Exposición Materna/efectos adversos , EmbarazoRESUMEN
BACKGROUND: The insulin-like growth factor-1 (IGF-1) signaling system is regulated by many factors which interact in regulating the bioavailability of IGF-I. In this context, little information is available on free IGF-1, the bioactive form of IGF-1, in amyotrophic lateral sclerosis (ALS). METHODS: We investigated the endogenous expression of IGF-1, and two related binding proteins (IGF-binding proteins, IGFBP-2 and BP-3) in serum and cerebrospinal fluid (CSF) of 54 sporadic ALS (sALS) patients. Twenty-five healthy individuals and 25 with other neurological diseases (OND) were used as controls. Total and free IGF-1, and IGFBP-3 levels were detected by immunoradiometric assay (IRMA); IGFBP-2 levels were determined by radioimmunoassay (RIA). RESULTS: Total and free IGF-1, IGFBP-2 and BP-3 serum levels were not significantly different between patients and controls, although in sALS patients free IGF-1 was negatively correlated with ALS-Functional Rating Scale-revised (ALS-FRS-R) score (r = -0.4; P = 0.046) and forced vital capacity (FVC) (r = -0.55; P < 0.04). In CSF, free IGF-1 was significantly increased in sALS patients compared with OND (P < 0.0001). CONCLUSIONS: Though in the serum we did not find significant differences amongst the three groups, IGF-1 bioavailability, represented by the free IGF-1 levels, correlated with disease severity. In the CSF, the significant increment of the free fraction of IGF-1 suggests an up-regulation of the IGF-1 system in the intrathecal compartment of sALS patients. Since IGF-1 is a trophic factor for different tissues, we speculate that high levels of the free IGF-1 in sALS might reflect a physiological defensive mechanism promoted in response to neural degeneration and/or muscle atrophy.
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Esclerosis Amiotrófica Lateral/metabolismo , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Esclerosis Amiotrófica Lateral/sangre , Esclerosis Amiotrófica Lateral/líquido cefalorraquídeo , Disponibilidad Biológica , Femenino , Humanos , Ensayo Inmunorradiométrico , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/líquido cefalorraquídeo , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/líquido cefalorraquídeo , Factor I del Crecimiento Similar a la Insulina/líquido cefalorraquídeo , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/sangre , Enfermedades del Sistema Nervioso/líquido cefalorraquídeo , Enfermedades del Sistema Nervioso/metabolismo , Radioinmunoensayo , Índice de Severidad de la EnfermedadRESUMEN
Adipose tissue synthesizes and secretes a number of cytokine hormones, defined adipokines, which have emerged as critical regulators of several metabolic functions, including energy homeostasis, insulin action and lipid metabolism. The present study is aimed at assessing the relationship between plasma concentrations of leptin and adiponectin and body composition in a cohort of 38 male professional rugby players (age: 22-35 years). Anthropometric evaluation included body mass index (BMI, range: 23.4-35.1 kg/m2) and whole body bioelectric impedance to determine absolute fat-free mass (FFM), absolute fat mass (FAT), relative percentage of fat mass (FAT percent) and fat-free mass (FFM percent). FAT percent ranged from 15 to 34 percent, corresponding to a FAT of 11.5-38.7 kg, whereas FFM range was 62.1-83.5 kg. Plasma leptin range was 1.2-4.3 ng/mL and adiponectin range was 2.0-16.6 microg/mL. Plasma leptin and adiponectin concentrations and their ratio did not correlate with BMI, nor with FAT, FAT percent, FFM and FFM percent, even after correction for BMI. The findings of this study suggest that in professional rugby players some additional factors, like neuroendocrine adaptations, other than adipose mass play a relevant role in the determination of adipokine levels, which in this group appear to be rather independent of body composition.
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Fútbol Americano/fisiología , Leptina/sangre , Adiponectina/sangre , Adiposidad , Adulto , Rendimiento Atlético/fisiología , Composición Corporal , Índice de Masa Corporal , Estudios de Cohortes , Impedancia Eléctrica , Humanos , Masculino , Adulto JovenRESUMEN
Hyperoxaluria is a pathological condition which affects long-term health of kidneys. The present study evaluates the impact of the combination of Lactobacillus amylovorus SGL 14 and the plant extract Phyllantus niruri (namely Phyllantin 14™) on dietary hyperoxaluria. Safety and efficacy of Phyllantin 14 have been evaluated in vivo. Mice C57BL6 fed a high-oxalate diet were compared to mice fed the same diet administered with Phyllantin 14 by gavage for 6 weeks. Control mice were fed a standard diet without oxalate. No adverse effects were associated to Phyllantin 14 supplementation, supporting its safety. Mice fed a high-oxalate diet developed significant hyperoxaluria and those administered with Phyllantin 14 showed a reduced level of urinary oxalate and a lower oxalate-to-creatinine ratio. Soluble and insoluble caecal oxalate were significantly lower in treated group, a finding in agreement with the colonisation study, i.e. mice were colonised with SGL 14 after 3 weeks. Microbiota analysis demonstrated that both oxalate diet and Phyllantin 14 can differently modulate the microbiota. In conclusion, our findings suggest that Phyllantin 14 supplementation represents a potential supportive approach for reducing urinary oxalate and/or for enhancing the efficacy of existing treatments.
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Dieta , Hiperoxaluria/terapia , Lactobacillus acidophilus , Oxalatos/administración & dosificación , Phyllanthus , Extractos Vegetales/uso terapéutico , Animales , Adhesión Bacteriana , Ciego/química , Modelos Animales de Enfermedad , Heces/química , Microbioma Gastrointestinal , Células HT29 , Humanos , Hiperoxaluria/tratamiento farmacológico , Hiperoxaluria/patología , Riñón/patología , Lactobacillus acidophilus/crecimiento & desarrollo , Lactobacillus acidophilus/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Oxalatos/análisis , Oxalatos/orina , Fitoterapia , ProbióticosRESUMEN
Epidemiologically, high-density lipoprotein (HDL) cholesterol levels have been inversely associated to cardiovascular (CV) events, although a Mendelian Randomisation Study had failed to establish a clear causal role. Numerous atheroprotective mechanisms have been attributed to HDL, the main being the ability to promote cholesterol efflux from arterial walls; anti-inflammatory effects related to HDL ligands such as S1P (sphingosine-1-phosphate), resolvins and others have been recently identified. Experimental studies and early clinical investigations have indicated the potential of HDL to slow progression or induce regression of atherosclerosis. More recently, the availability of different HDL formulations, with different phospholipid moieties, has allowed to test other indications for HDL therapy. Positive reports have come from studies on coronary stent biocompatibility, where the use of HDL from different sources reduced arterial cell proliferation and thrombogenicity. The observation that low HDL-C levels may be associated with an enhanced risk of heart failure (HF) has also suggested that HDL therapy may be applied to this condition. HDL infusions or apoA-I gene transfer were able to reverse heart abnormalities, reduce diastolic resistance and improve cardiac metabolism. HDL therapy may be effective not only in atherosclerosis, but also in other conditions, of relevant impact on human health.Key messagesHigh-density lipoproteins have as a major activity that of removing excess cholesterol from tissues (particularly arteries).Knowledge on the activity of high-density lipoproteins on health have however significantly widened.HDL-therapy may help to improve stent biocompatibility and to reduce peripheral arterial resistance in heart failure.
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Aterosclerosis/terapia , Insuficiencia Cardíaca/terapia , Lipoproteínas HDL , Terapia Molecular Dirigida , Animales , Materiales Biocompatibles , Terapia Genética , Humanos , Intervención Coronaria Percutánea , StentsRESUMEN
Regulation of pro-protein convertase subtilisin/kexin type 9 (PCSK9) by drugs has led to the development of a still small number of agents with powerful activity on low-density lipoprotein cholesterol levels, associated with a significant reduction of cardiovascular events in patients in secondary prevention. The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) and Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY OUTCOMES) studies, with the two available PCSK9 antagonists, i.e. evolocumab and alirocumab, both reported a 15% reduction in major adverse cardiovascular events. Regulation of PCSK9 expression is dependent upon a number of factors, partly genetic and partly associated to a complex transcriptional system, mainly controlled by sterol regulatory element binding proteins. PCSK9 is further regulated by concomitant drug treatments, particularly by statins, enhancing PCSK9 secretion but decreasing its stimulatory phosphorylated form (S688). These complex transcriptional mechanisms lead to variable circulating levels making clinical measurements of plasma PCSK9 for cardiovascular risk assessment a debated matter. Determination of total PCSK9 levels may provide a diagnostic tool for explaining an apparent resistance to PCSK9 inhibitors, thus indicating the need for other approaches. Newer agents targeting PCSK9 are in clinical development with a major interest in those with a longer duration of action, e.g. RNA silencing, allowing optimal patient compliance. Interest has been expanded to areas not only limited to low-density lipoprotein cholesterol reduction but also investigating other non-lipid pathways raising cardiovascular risk, in particular inflammation associated to raised high-sensitivity C-reactive protein levels, not significantly affected by the present PCSK9 antagonists.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticolesterolemiantes/uso terapéutico , Enfermedades Cardiovasculares/prevención & control , Dislipidemias/tratamiento farmacológico , Inhibidores de PCSK9 , Proproteína Convertasa 9/sangre , Inhibidores de Serina Proteinasa/uso terapéutico , Animales , Enfermedades Cardiovasculares/epidemiología , Resistencia a Medicamentos , Dislipidemias/sangre , Dislipidemias/enzimología , Dislipidemias/epidemiología , Regulación Enzimológica de la Expresión Génica , Humanos , Fosforilación , Proproteína Convertasa 9/genética , Tratamiento con ARN de Interferencia , Factores de RiesgoRESUMEN
INTRODUCTION: Tolerability problems in treating hypercholesterolemic patients undergoing statin treatment are of growing concern to physicians and patients, thus underlining the need for an agent with a similar mechanism but minimal side effects. A drug with a somewhat similar mechanism to statins but free of muscular side effects is ETC-1002 (bempedoic acid). It inhibits cholesterol biosynthesis at a step preceding HMG-CoA reductase, i.e. ATP citrate lyase (ACLY). A prodrug, ETC-1002 is converted to the active agent only in liver, not in skeletal muscle, and this may prevent any myotoxic activity. Area covered: The mechanism of ETC-1002 activity is described in detail, considering that ACLY inhibition markedly attenuated atherosclerosis in animal models. Clinical studies are also reported. Expert opinion: Present day LDL-C lowering treatments lead to significant reductions of cardiovascular (CV) events but, at times, the need to interrupt statin treatment appears to be dangerous due to a rapid rise in CV risk. The excellent tolerability of ETC-1002 makes it a useful alternative, either alone or as an adjunct to ezetimibe, for patients with statin intolerance needing to achieve significant CV risk reduction. ETC-1002 is also associated with a marked fall in high-sensitivity C-reactive protein.
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Anticolesterolemiantes/uso terapéutico , Ácidos Dicarboxílicos/uso terapéutico , Ácidos Grasos/uso terapéutico , Hiperlipidemias/tratamiento farmacológico , ATP Citrato (pro-S)-Liasa/antagonistas & inhibidores , ATP Citrato (pro-S)-Liasa/genética , ATP Citrato (pro-S)-Liasa/metabolismo , Animales , Anticolesterolemiantes/efectos adversos , Aterosclerosis/tratamiento farmacológico , Proteína C-Reactiva/metabolismo , Ensayos Clínicos como Asunto , Ácidos Dicarboxílicos/efectos adversos , Quimioterapia Combinada , Ezetimiba/uso terapéutico , Ácidos Grasos/efectos adversos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hígado/metabolismoRESUMEN
Statins, the most widely used drugs in the Western world, have become a pivotal component in the primary and secondary prevention of vascular diseases. Although benefits have been well documented in younger-than-75-year-old individuals, the value of statins in people aged >75years and over is controversial. The CTT meta-analysis calculated an absolute risk reduction of 0.6%/year per 38.7mg/dl reduction in LDL-C levels in patients aged >75years, that would translate into a number needed to treat of 167. However, the absolute effect of a 38.7mg/dl cholesterol lowering on the rate of annual ischemic heart disease mortality is 10-fold larger in older vs younger patients. In order to advise physician prescription, three major Guidelines have been published over the last few years, i.e. the AHA/ACC and the NLA in the US, and the ESC/EAS in Europe. Moreover, statin prescription in the elderly should also consider the cardiovascular outcomes of elderly patients reported in classical statin preventive trials which give important clues on adherence and persistence of use, as well as on drug safety. The present review discusses benefits of intensive vs moderate statin therapy, justifications for the use of aggressive lipid management in the very old and the use of statins in frail elderlies. The final decision on the therapeutic strategy with statins in elderlies at higher risk to develop cardiovascular events should be always based on a careful analysis of the patient's general health and on the presence of metabolic abnormalities or drug interactions potentially leading to risk.
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LDL-Colesterol/sangre , Enfermedad de la Arteria Coronaria/prevención & control , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Prevención Primaria/métodos , Prevención Secundaria/métodos , Anciano , Enfermedad de la Arteria Coronaria/mortalidad , Anciano Frágil , Humanos , Cumplimiento de la Medicación , Guías de Práctica Clínica como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de RiesgoRESUMEN
Inflammatory changes are responsible for maintenance of the atherosclerotic process and may underlie some of the most feared vascular complications. Among the multiple mechanisms of inflammation, the arterial deposition of lipids and particularly of cholesterol crystals is the one responsible for the activation of inflammasome NLRP3, followed by the rise of circulating markers, mainly C-reactive protein (CRP). Elevation of lipoproteins, LDL but also VLDL and remnants, associates with increased inflammatory changes and coronary risk. Lipid lowering medications can reduce cholesterolemia and CRP: patients with elevations of both are at greatest cardiovascular (CV) risk and receive maximum benefit from therapy. Evaluation of the major drug series indicates that statins exert the largest LDL and CRP reduction, accompanied by reduced CV events. Other drugs, mainly active on the triglyceride/HDL axis, for example, PPAR agonists, may improve CRP and the lipid pattern, especially in patients with metabolic syndrome. PCSK9 antagonists, the newest most potent medications, do not induce significant changes in inflammatory markers, but patients with the highest baseline CRP levels show the best CV risk reduction. Parallel evaluation of lipids and inflammatory changes clearly indicates a significant link, both guiding to patients at highest risk, and to the best pharmacological approach. Key messages Lipid lowering agents with "pleiotropic" effects provide a more effective approach to CV prevention In CANTOS study, patients achieving on-treatment hsCRP concentrations ≤2 mg/L had a higher benefit in terms of reduction in major CV events The anti-inflammatory activity of PCSK9 antagonists appears to be of a minimal extent.