RESUMEN

Hand, foot, and mouth disease (HFMD) is a highly contagious disease with several outbreaks in Asian-Pacific countries, including Thailand. With such epidemic characteristics and potential economic impact, HFMD is a significant public health issue in Thailand. Generally, contagious/infectious diseases' transmission dynamics vary across geolocations due to different socioeconomic situations, demography, and lifestyles. Hence, a nationwide comprehensive model of the disease's epidemic dynamics can provide information to understand better and predict a potential outbreak of this disease and efficiently and effectively manage its impact. However, there is no nationwide and comprehensive (i.e., the inclusion of reinfections in the model) model of HFDM dynamics for Thailand. This paper has endeavoured to promote nationwide comprehensive modelling of HFMD's epidemic dynamics and comprehend the reinfection cases. We have formulated the SEIRS epidemiological model with dynamic vitals, including reinfections, to explore this disease's prevalence. We also introduced periodic seasonality to reproduce the seasonal effect. The pattern of spread of this disease is uneven across the provinces in Thailand, so we used K-means clustering algorithm to cluster those provinces into three groups (i.e., highly, moderately, and least affected levels). We also analysed health records collected from district hospitals, which suggest significant reinfection cases. For example, we found that 11% (approximately) of infectious patients return for repeat treatment within the study period. We also performed sensitivity analysis which indicates that the basic reproduction number (R 0) is sensitive to the rate of transmission (ß) and the rate at which infected people recover (γ). By fitting the model with HFMD confirmed data for the provinces in each cluster, the basic reproduction number (R 0) was estimated to be 2.643, 1.91, and 3.246 which are greater than 1. Based on this high R 0, this study recommends that this disease will persist in the coming years under identical cultural and environmental conditions.

Asunto(s)

Enfermedad de Boca, Mano y Pie/epidemiología , Adolescente , Algoritmos , Número Básico de Reproducción/estadística & datos numéricos , Niño , Preescolar , Biología Computacional , Simulación por Computador , Brotes de Enfermedades/estadística & datos numéricos , Femenino , Enfermedad de Boca, Mano y Pie/transmisión , Humanos , Lactante , Recién Nacido , Masculino , Modelos Biológicos , Modelos Estadísticos , Prevalencia , Reinfección/epidemiología , Estaciones del Año , Tailandia/epidemiología

RESUMEN

Cancer is a complex disease that deregulates cellular functions at various molecular levels (e.g., DNA, RNA, and proteins). Integrated multi-omics analysis of data from these levels is necessary to understand the aberrant cellular functions accountable for cancer and its development. In recent years, Deep Learning (DL) approaches have become a useful tool in integrated multi-omics analysis of cancer data. However, high dimensional multi-omics data are generally imbalanced with too many molecular features and relatively few patient samples. This imbalance makes a DL based integrated multi-omics analysis difficult. DL-based dimensionality reduction technique, including variational autoencoder (VAE), is a potential solution to balance high dimensional multi-omics data. However, there are few VAE-based integrated multi-omics analyses, and they are limited to pancancer. In this work, we did an integrated multi-omics analysis of ovarian cancer using the compressed features learned through VAE and an improved version of VAE, namely Maximum Mean Discrepancy VAE (MMD-VAE). First, we designed and developed a DL architecture for VAE and MMD-VAE. Then we used the architecture for mono-omics, integrated di-omics and tri-omics data analysis of ovarian cancer through cancer samples identification, molecular subtypes clustering and classification, and survival analysis. The results show that MMD-VAE and VAE-based compressed features can respectively classify the transcriptional subtypes of the TCGA datasets with an accuracy in the range of 93.2-95.5% and 87.1-95.7%. Also, survival analysis results show that VAE and MMD-VAE based compressed representation of omics data can be used in cancer prognosis. Based on the results, we can conclude that (i) VAE and MMD-VAE outperform existing dimensionality reduction techniques, (ii) integrated multi-omics analyses perform better or similar compared to their mono-omics counterparts, and (iii) MMD-VAE performs better than VAE in most omics dataset.

Asunto(s)

Biología Computacional/métodos , Aprendizaje Profundo , Epigenómica/métodos , Perfilación de la Expresión Génica/métodos , Genómica/métodos , Neoplasias Ováricas/genética , Transcriptoma , Análisis por Conglomerados , Estudios de Cohortes , Análisis de Datos , Epigénesis Genética , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Ováricas/clasificación , Neoplasias Ováricas/mortalidad , Pronóstico

RESUMEN

The study was undertaken to find out the correlation of elevated B-type Natriuretic Peptide (BNP) levels with the severity of coronary artery disease in patients with unstable angina and NSTEMI. This cross sectional analytical study was carried out in the department of cardiology, National Institute of Cardiovascular Diseases, Dhaka during a period of August 2011 to June 2012. A total of 100 consecutive patients with unstable angina and NSTEMI undergoing coronary angiography were included in the study. BNP assay was done by Architect system, a chemo luminescent microparticle immunoassay (CMIA). CAG was done by conventional method within 14 days of index hospital admission. Study patients were divided into two groups on the basis of BNP levels. In Group I, BNP Levels were ≤80pg/ml and in Group II, BNP levels were elevated >80pg/ml. with 50 patients in each group. Angiographic severity of CAD was assessed by vessel score and Friesinger score. Vessel score showed single vessel was involved in 21(47.7%) patients while multi vessel in 23(52.3%) patients was found in Group I. On the contrary 11(22.4%) single vessel patients and 38(77.6%) multivessel patients were found in Group II. There was significant association between vessel involvement (p=0.01). Friesinger score revealed that less severe CAD was found in 22(44%) patients and significant severe CAD in 28(56.0%) patients in Group I. On the contrary 7(14.0%) less severe CAD patients and 43(86.0%) severe CAD patients were found in Group II. There was significant difference between severity of CAD among the study groups (p=0.01). There was linear correlation between BNP pg/ml and coronary artery disease severity in terms of Vessel score (r=0.38, p=0.01) and Friesinger score (r=0.51, p=0.01). The present study concluded that increased BNP level >80pg/ml was significantly associated with the presence and severity of CAD in patient with UA and NSTEMI.

Asunto(s)

Angina Inestable/sangre , Enfermedad de la Arteria Coronaria/sangre , Isquemia Miocárdica/sangre , Péptido Natriurético Encefálico/sangre , Adulto , Anciano , Angiografía Coronaria , Estudios Transversales , Humanos , Persona de Mediana Edad

RESUMEN

Taking good care of elderly is a major challenge of our society, and thus identification of potential drug targets to reduce age-associated disease burden is desirable. α-klotho(-/-) (α-kl) is a short-lived mouse model that displays multiple phenotypes resembling human aging-related syndromes. Such ageing phenotype of α-kl(-/-) mice is associated with activation of a proteolytic enzyme, Calpain-1. We hypothesized that uncontrolled activation of calpain-1 might be causing age-related phenotypes in α-kl-deficient mice. We found that daily administration of BDA-410, a calpain-1 inhibitor, strikingly ameliorated multiple aging-related phenotypes. Treated mice showed recovery of reproductive ability, increased body weight, reduced organ atrophy, and suppression of ectopic calcifications, bone mineral density reduction, pulmonary emphysema and senile atrophy of skin. We also observed ectopic expression of FGF23 in calcified arteries of α-kl(-/-) mice, which might account for the clinically observed association of increased FGF23 level with increased risk of cardiovascular mortality. These findings allow us to propose that modulation of calpain-1 activity is a potential therapeutic option for delaying age-associated organ pathology, particularly caused by the dysregulation of mineral ion homeostasis.

Asunto(s)

Envejecimiento , Glucuronidasa/deficiencia , Sulfonamidas/farmacología , Animales , Calpaína/antagonistas & inhibidores , Calpaína/metabolismo , Evaluación Preclínica de Medicamentos , Femenino , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Glucuronidasa/genética , Humanos , Proteínas Klotho , Masculino , Ratones Noqueados , Fenotipo , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/metabolismo , Sulfonamidas/uso terapéutico , Calcificación Vascular/sangre , Calcificación Vascular/tratamiento farmacológico

RESUMEN

Cardiac fibroblasts (CFs) produce and degrade the myocardial extracellular matrix and are critical in maladaptive ventricular remodeling that can result in heart failure (HF). ß-Arrestins are important signaling molecules involved in ß-adrenergic receptor (ß-AR) desensitization and can also mediate signaling in a G protein-independent fashion. We hypothesize that ß-arrestins play an important role in the regulation of adult human CF biology with regard to myofibroblast transformation, increased collagen synthesis, and myocardial fibrosis which are important in the development of HF. ß-Arrestin1 & 2 expression is significantly upregulated in adult human CF isolated from failing left ventricles and ß-AR signaling is uncoupled with loss of ß-agonist-mediated inhibition of collagen synthesis versus normal control CF. Knockdown of either ß-arrestin1 or 2 restored ß-AR signaling and ß-agonist mediated inhibition of collagen synthesis. Overexpression of ß-arrestins in normal CF led to a failing phenotype with increased baseline collagen synthesis, impaired ß-AR signaling, and loss of ß-agonist-mediated inhibition of collagen synthesis. ß-Arrestin knockdown in failing CF diminished TGF-ß stimulated collagen synthesis and also inhibited ERK phosphorylation. Overexpression of ß-arrestins in normal CF increased basal ERK1/2 and Smad2/3 phosphorylation and enhanced TGF-ß-stimulated collagen synthesis. This was prevented by pre-treatment with a MEK1/2 inhibitor. Enhanced ß-arrestin signaling appears to be deleterious in CF by promoting a pro-fibrotic phenotype via uncoupling of ß-AR signaling as well as potentiating ERK and Smad signaling. Targeted inhibition of ß-arrestins in CF may represent a therapeutic strategy to prevent maladaptive myocardial fibrosis.

Asunto(s)

Arrestinas/fisiología , Colágenos Fibrilares/biosíntesis , Miocardio/patología , Miofibroblastos/fisiología , Remodelación Ventricular , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Insuficiencia Cardíaca/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas , Receptores Adrenérgicos beta/metabolismo , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta/fisiología , beta-Arrestinas

RESUMEN

A disproportionate expansion of white adipose tissue and abnormal recruitment of adipogenic precursor cells can not only lead to obesity but also impair glucose metabolism, which are both common causes of insulin resistance and diabetes mellitus. The development of novel and effective therapeutic strategies to slow the progression of obesity, diabetes mellitus and their associated complications will require improved understanding of adipogenesis and glucose metabolism. Klotho might have a role in adipocyte maturation and systemic glucose metabolism. Klotho increases adipocyte differentiation in vitro, and mice that lack Klotho activity are lean owing to reduced white adipose tissue accumulation; moreover, mice that lack the Kl gene (which encodes Klotho) are resistant to obesity induced by a high-fat diet. Knockout of Kl in leptin-deficient Lep(ob/ob) mice reduces obesity and increases insulin sensitivity, which lowers blood glucose levels. Energy metabolism might also be influenced by Klotho. However, further studies are needed to explore the possibility that Klotho could be a novel therapeutic target to reduce obesity and related complications, and to determine whether and how Klotho might influence the regulation and function of a related protein, ß-Klotho, which is also involved in energy metabolism.

Asunto(s)

Metabolismo Energético/fisiología , Glucuronidasa/metabolismo , Animales , Metabolismo Energético/genética , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/genética , Factores de Crecimiento de Fibroblastos/metabolismo , Glucuronidasa/genética , Humanos , Resistencia a la Insulina/genética , Resistencia a la Insulina/fisiología , Proteínas Klotho , Leptina/genética , Leptina/metabolismo , Obesidad/genética , Obesidad/metabolismo

RESUMEN

The molecular interactions of fibroblast growth factor 23 (FGF23), klotho and vitamin D coordinate to regulate the delicate phosphate levels of the body. Vitamin D can induce both FGF23 and klotho synthesis to influence renal phosphate balance. In the presence of klotho, FGF23 protein gains bioactivity to influence systemic phosphate homeostasis. Experimental studies have convincingly shown that in the absence of klotho, FGF23 is unable to regulate in vivo phosphate homeostasis. Furthermore, genetic inactivation of FGF23, klotho or both of the genes have resulted in markedly increased renal expression of 1-alpha hydroxylase [1α(OH)ase] and concomitant elevated serum levels of 1,25, dihydroxyvitamin D [1,25(OH)(2)D] in the mutant mice. Vitamin D can induce the expression of both FGF23 and klotho while, FGF23 can suppress renal expression of 1α(OH)ase to reduce 1,25(OH)(2)D activity. In this brief chapter, I will summarize the possible in vivo interactions of FGF23, klotho and vitamin D, in the light of recent mouse genetics studies.

Asunto(s)

Factores de Crecimiento de Fibroblastos/genética , Factores de Crecimiento de Fibroblastos/metabolismo , Glucuronidasa/genética , Glucuronidasa/metabolismo , Vitamina D/metabolismo , Animales , Factor-23 de Crecimiento de Fibroblastos , Humanos , Enfermedades Renales/genética , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Proteínas Klotho , Ratones , Unión Proteica , Transducción de Señal

RESUMEN

OBJECTIVE: The adverse effects of metabolic disorders in obesity have been extensively studied; however, the pathologic effects of hyperphosphatemia or phosphate toxicity in obesity have not been studied in similar depth and detail, chiefly because such an association is thought to be uncommon. Studies have established that the incidence of obesity-associated nephropathy is increasing. Because hyperphosphatemia is a major consequence of renal impairment, this study determines the in vivo effects of hyperphosphatemia in obesity. METHODS AND RESULTS: We genetically induced hyperphosphatemia in leptin-deficient obese (ob/ob) mice by generating ob/ob and klotho double knockout [ob/ob-klotho(-/-)] mice. As a control, we made ob/ob mice with hypophosphatemia by generating ob/ob and 1-alpha hydroxylase double knockout [ob/ob-1α(OH)ase(-/-)] mice. Compared to the wild-type mice, all three obese background mice, namely ob/ob, ob/ob-klotho(-/-), and ob/ob-1α(OH)ase(-/-) mice developed hypercholesterolemia. In addition, the hyperphosphatemic, ob/ob-klotho(-/-) genetic background induced generalized tissue atrophy and widespread soft-tissue and vascular calcifications, which led to a shorter lifespan; no such changes were observed in the hypophosphatemic, ob/ob-1α(OH)ase(-/-) mice. Significantly, in contrast to the reduced survival of the ob/ob-klotho(-/-) mice, lowering serum phosphate levels in ob/ob-1α(OH)ase(-/-) mice showed no such compromised survival, despite both mice being hypercholesterolemic. CONCLUSION: These genetic manipulation studies suggest phosphate toxicity is an important risk factor in obesity that can adversely affect survival.

Asunto(s)

Hipercolesterolemia/mortalidad , Hiperfosfatemia/genética , Obesidad/mortalidad , Animales , Calcitriol/sangre , Calcitriol/metabolismo , Calcio/sangre , Calcio/metabolismo , Colesterol/sangre , Colesterol/metabolismo , Glucuronidasa/genética , Hipercolesterolemia/etiología , Hipercolesterolemia/patología , Hiperfosfatemia/complicaciones , Proteínas Klotho , Leptina/genética , Ratones , Ratones Noqueados , Obesidad/etiología , Obesidad/patología , Fosfatos/sangre

RESUMEN

Klotho is a multifunctional protein involved in numerous biological functions, ranging from mineral ion metabolism to signaling activities. Recent studies have identified klotho as a target gene for peroxisome proliferator-activated receptor-γ (PPAR-γ), a master regulator of adipocyte differentiation, and an adipogenesis-promoting factor. In a similar line of observation, eliminating klotho function from mice resulted in the generation of lean mice with almost no detectable fat tissue. In contrast to the klotho-knockout mice (11.7±0.3 g at 9 wk), leptin-deficient (ob/ob) mice are severely obese (49.3±0.6 g at 9 wk), due to excessive fat accumulation. To study the in vivo role of klotho in obesity, we have generated and characterized ob/ob mice lacking klotho activity [ob/ob-klotho double-knockout (DKO) mice]. The ob/ob mice started to get bigger from 3 wk onward and gained almost 2 times more weight than their wild-type (WT) counterparts (WT vs. ob/ob: 34.8±1.3 vs. 65.5±1.2 g at 21 wk). The generated ob/ob-klotho DKO mice were not only viable throughout their adulthood but also showed markedly reduced fat tissue accumulation compared to their ob/ob littermates. The ob/ob-klotho DKO mice had significantly (P<0.01) less retroperitoneal, mesenteric, and epididymal fat accumulation, compared to their ob/ob counterparts. Similarly, the fatty liver that was consistently observed in the ob/ob mice was eliminated in the ob/ob-klotho DKO mice. Such structural improvement in the liver was also evident from markedly reduced fasting blood glucose levels in ob/ob-klotho DKO mice, compared to their ob/ob counterparts (ob/ob vs. ob/ob-klotho DKO: 266 ± 36 vs. 65±2 mg/dl). Finally, to study whether the absence of klotho can induce resistance to high-fat-diet-induced obesity, we provided a high-fat (60%) diet to klotho-knockout mice and compared them with normal-fat (20%) diet-fed klotho-knockout mice. No significant difference in body weight was detected in klotho-knockout mice fed either the normal-fat diet or high-fat diet, while WT mice fed the high-fat diet gradually gained body weight, compared to the normal-fat-diet-fed counterparts. The results of our dietary and genetic manipulation studies provide in vivo evidence for a role of klotho in obesity and offer a novel target to manipulate obesity and associated complications.

Asunto(s)

Glucemia/genética , Glucemia/metabolismo , Dieta , Glucosa/metabolismo , Glucuronidasa/antagonistas & inhibidores , Obesidad/genética , Tejido Adiposo/metabolismo , Animales , Colesterol/sangre , Grasas de la Dieta , Hígado Graso/metabolismo , Hígado Graso/patología , Expresión Génica , Glucuronidasa/genética , Glucuronidasa/metabolismo , Proteínas Klotho , Leptina/genética , Leptina/metabolismo , Hígado/química , Hígado/metabolismo , Longevidad , Ratones , Ratones Noqueados , Obesidad/prevención & control , PPAR gamma/metabolismo , Triglicéridos/sangre , Aumento de Peso

RESUMEN

Vitamin D is a multifunctional hormone that can affect many essential biological functions, ranging from the immune regulation to mineral ion metabolism. A close association between altered activity of vitamin D and vascular calcification has been reported in various human diseases, including in patients with atherosclerosis, osteoporosis, and chronic kidney disease (CKD). Vascular calcification is a progressive disorder and is a major determinant of morbidity and mortality of the affected patients. Experimental studies have shown that excessive vitamin D activities can induce vascular calcification, and such vascular pathology can be reversed by reducing vitamin D activities. The human relevance of these experimental studies is not clear, as vitamin D toxicity is relatively rare in the general population. Contrary to the relationship between vitamin D and vascular calcification, in experimental uremic models, low levels of vitamin D were shown to be associated with extensive vascular calcification, a phenomenon that is very similar to the vascular pathology seen in patients with CKD. The current treatment approach of providing vitamin D analogs to patients with CKD often poses a dilemma, as studies linked vitamin D treatment to subsequent vascular calcification. Recent genetic studies, however, have shown that vascular calcification can be prevented by reducing serum phosphate levels, even in the presence of extremely high serum 1,25-dihydroxyvitamin D and calcium levels. This article will briefly summarize the dual effects of vitamin D in vascular calcification and will provide evidence of vitamin D-dependent and -independent vascular calcification.

Asunto(s)

Calcinosis/metabolismo , Enfermedades Vasculares/metabolismo , Vitamina D/metabolismo , Animales , Calcinosis/etiología , Calcinosis/prevención & control , Calcio/metabolismo , Humanos , Riñón/metabolismo , Fosfatos/metabolismo , Receptores de Calcitriol/metabolismo , Transducción de Señal , Enfermedades Vasculares/etiología , Enfermedades Vasculares/prevención & control , Vitamina D/efectos adversos , Vitamina D/uso terapéutico

RESUMEN

Phosphorus is an essential nutrient required for critical biological reactions that maintain the normal homoeostatic control of the cell. This element is an important component of different cellular structures, including nucleic acids and cell membranes. Adequate phosphorus balance is vital for maintaining basic cellular functions, ranging from energy metabolism to cell signalling. In addition, many intracellular pathways utilize phosphate ions for important cellular reactions; therefore, homoeostatic control of phosphate is one of the most delicate biological regulations. Impaired phosphorus balance can affect the functionality of almost every human system, including musculoskeletal and cardiovascular systems, ultimately leading to an increase in morbidity and mortality of the affected patients. Human and experimental studies have found that delicate balance among circulating factors, like vitamin D, PTH (parathyroid hormone) and FGF23 (fibroblast growth factor 23), are essential for regulation of physiological phosphate balance. Dysregulation of these factors, either alone or in combination, can induce phosphorus imbalance. Recent studies have shown that suppression of the FGF23-klotho system can lead to hyperphosphataemia with extensive tissue damage caused by phosphate toxicity. The cause and consequences of phosphate toxicity will be briefly summarized in the present review.

Asunto(s)

Fosfatos/efectos adversos , Animales , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/fisiología , Glucuronidasa/fisiología , Homeostasis/fisiología , Humanos , Proteínas Klotho , Fosfatos/metabolismo , Fosfatos/toxicidad

RESUMEN

Klotho has profound effects on phosphate metabolism, but the mechanisms of how Klotho affects phosphate homeostasis is unknown. We detected Klotho in the proximal tubule cell, brush border, and urinary lumen, where phosphate homeostasis resides. Increasing Klotho in the kidney and urine chronically by transgenic overexpression or acutely by intravenous infusion caused hypophosphatemia, phosphaturia from decreased proximal phosphate reabsorption, and decreased activity and protein of the principal renal phosphate transporter NaPi-2a. The phosphaturic effect was present in FGF23-null mice, indicating a direct action distinct from Klotho's known role as a coreceptor for FGF23. Direct inhibition of NaPi-2a by Klotho was confirmed in cultured cells and in cell-free membrane vesicles characterized by acute inhibition of transport activity followed by decreased cell surface protein. Transport inhibition can be mimicked by recombinant beta-glucuronidase and is associated with proteolytic degradation and reduced surface NaPi-2a. The inhibitory effect of Klotho on NaPi-2a was blocked by beta-glucuronidase inhibitor but not by protease inhibitor. Klotho is a novel phosphaturic substance that acts as an enzyme in the proximal tubule urinary lumen by modifying glycans, which cause decreased transporter activity, followed by proteolytic degradation and possibly internalization of NaPi-2a from the apical membrane.

Asunto(s)

Glucuronidasa/metabolismo , Túbulos Renales/enzimología , Animales , Células Cultivadas , Factor-23 de Crecimiento de Fibroblastos , Glucuronidasa/antagonistas & inhibidores , Glucuronidasa/genética , Glucuronidasa/farmacología , Glicoproteínas/farmacología , Homeostasis/efectos de los fármacos , Homeostasis/genética , Hipofosfatemia Familiar/inducido químicamente , Immunoblotting , Inmunohistoquímica , Proteínas Klotho , Ratones , Ratones Transgénicos , Microscopía Fluorescente , Microscopía Inmunoelectrónica , Microvellosidades/metabolismo , Fosfatos/metabolismo , Inhibidores de Proteasas/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/genética , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/metabolismo

RESUMEN

Identifying factors that accelerate the aging process can provide important therapeutic targets for slowing down this process. Misregulation of phosphate homeostasis has been noted in various skeletal, cardiac, and renal diseases, but the exact role of phosphate toxicity in mammalian aging is not clearly defined. Phosphate is widely distributed in the body and is involved in cell signaling, energy metabolism, nucleic acid synthesis, and the maintenance of acid-base balance by urinary buffering. In this study, we used an in vivo genetic approach to determine the role of phosphate toxicity in mammalian aging. Klotho-knockout mice (klotho(-/-)) have a short life span and show numerous physical, biochemical, and morphological features consistent with premature aging, including kyphosis, uncoordinated movement, hypogonadism, infertility, severe skeletal muscle wasting, emphysema, and osteopenia, as well as generalized atrophy of the skin, intestine, thymus, and spleen. Molecular and biochemical analyses suggest that increased renal activity of sodium-phosphate cotransporters (NaPi2a) leads to severe hyperphosphatemia in klotho(-/-) mice. Genetically reducing serum phosphate levels in klotho(-/-) mice by generating a NaPi2a and klotho double-knockout (NaPi2a(-/-)/klotho(-/-)) strain resulted in amelioration of premature aging-like features. The NaPi2a(-/-)/klotho(-/-) double-knockout mice regained reproductive ability, recovered their body weight, reduced their organ atrophy, and suppressed ectopic calcifications, with the resulting effect being prolonged survival. More important, when hyperphosphatemia was induced in NaPi2a(-/-)/klotho(-/-) mice by feeding with a high-phosphate diet, premature aging-like features reappeared, clearly suggesting that phosphate toxicity is the main cause of premature aging in klotho(-/-) mice. The results of our dietary and genetic manipulation studies provide in vivo evidence for phosphate toxicity accelerating the aging process and suggest a novel role for phosphate in mammalian aging.

Asunto(s)

Envejecimiento/metabolismo , Glucuronidasa/fisiología , Fosfatos/metabolismo , Fosfatos/toxicidad , Envejecimiento/efectos de los fármacos , Envejecimiento/genética , Animales , Peso Corporal/genética , Peso Corporal/fisiología , Calcio/sangre , Creatinina/sangre , Genotipo , Glucuronidasa/genética , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Mucosa Intestinal/metabolismo , Intestinos/patología , Riñón/metabolismo , Riñón/patología , Proteínas Klotho , Pulmón/metabolismo , Pulmón/patología , Ratones , Ratones Noqueados , Fosfatos/administración & dosificación , Fosfatos/sangre , Piel/metabolismo , Piel/patología , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/genética , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/metabolismo

RESUMEN

Carbonaceous material (CM) particles are the principal vectors transporting polycyclic aromatic hydrocarbons (PAHs) into urban waters via runoff; however, characteristics of CM particles in urban watersheds and their relative contributions to PAH contamination remain unclear. Our objectives were to identify the sources and distribution of CM particles in an urban watershed and to determine the types of CMs that were the dominant sources of PAHs in the lake and stream sediments. Samples of soils, parking lot and street dust, and streambed and lake sediment were collected from the Lake Como watershed in Fort Worth, Texas. Characteristics of CM particles determined by organic petrography and a significant correlation between PAH concentrations and organic carbon in coal tar, asphalt, and soot indicate that these three CM particle types are the major sources and carriers of PAHs in the watershed. Estimates of the distribution of PAHs in CM particles indicate that coal-tar pitch, used in some pavement sealcoats, is a dominant source of PAHs in the watershed, and contributes as much as 99% of the PAHs in sealed parking lot dust, 92% in unsealed parking lot dust, 88% in commercial area soil, 71% in streambed sediment, and 84% in surficial lake sediment.

Asunto(s)

Carbono/análisis , Alquitrán/análisis , Monitoreo del Ambiente , Agua Dulce/análisis , Hidrocarburos Policíclicos Aromáticos/análisis , Contaminantes Químicos del Agua/análisis , Texas , Abastecimiento de Agua/análisis

RESUMEN

BACKGROUND: Klotho-knockout mice (klotho(-/-)) have increased renal expression of sodium/phosphate cotransporters (NaPi2a), associated with severe hyperphosphatemia. Such serum biochemical changes in klotho(-/-) mice lead to extensive soft-tissue anomalies and vascular calcification. To determine the significance of increased renal expression of the NaPi2a protein and concomitant hyperphosphatemia and vascular calcification in klotho(-/-) mice, we generated klotho and NaPi2a double-knockout (klotho(-/-)/NaPi2a(-/-)) mice. METHODS AND RESULTS: Genetic inactivation of NaPi2a activity from klotho(-/-) mice reversed the severe hyperphosphatemia to mild hypophosphatemia or normophosphatemia. Importantly, despite significantly higher serum calcium and 1,25-dihydroxyvitamin D levels in klotho(-/-)/NaPi2a(-/-) mice, the vascular and soft-tissue calcifications were reduced. Extensive soft-tissue anomalies and cardiovascular calcification were consistently noted in klotho(-/-) mice by 6 weeks of age; however, these vascular and soft-tissue abnormalities were absent even in 12-week-old double-knockout mice. Klotho(-/-)/NaPi2a(-/-) mice also regained body weight and did not develop the generalized tissue atrophy often noted in klotho(-/-) single-knockout mice. CONCLUSIONS: Our in vivo genetic manipulation studies have provided compelling evidence for a pathological role of increased NaPi2a activities in regulating abnormal mineral ion metabolism and soft-tissue anomalies in klotho(-/-) mice. Notably, our results suggest that serum phosphate levels are the important in vivo determinant of calcification and that lowering serum phosphate levels can reduce or eliminate soft-tissue and vascular calcification, even in presence of extremely high serum calcium and 1,25-dihydroxyvitamin D levels. These in vivo observations have significant clinical importance and therapeutic implications for patients with chronic kidney disease with cardiovascular calcification.

Asunto(s)

Vasos Sanguíneos/patología , Huesos/patología , Calcinosis , Calcio/sangre , Hipofosfatemia/genética , Fosfatos/sangre , Vitamina D/análogos & derivados , Animales , Femenino , Glucuronidasa/genética , Glucuronidasa/metabolismo , Humanos , Hipofosfatemia/sangre , Hipofosfatemia/patología , Proteínas Klotho , Masculino , Ratones , Ratones Noqueados , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/genética , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/metabolismo , Vitamina D/sangre

RESUMEN

Appropriate levels of phosphate in the body are maintained by the coordinated regulation of the bone-derived growth factor FGF23 and the membrane-bound protein Klotho. The endocrine actions of FGF23, in association with parathyroid hormone and vitamin D, mobilize sodium-phosphate cotransporters that control renal phosphate transport in proximal tubular epithelial cells. The availability of an adequate amount of Klotho is essential for FGF23 to exert its phosphaturic effects in the kidney. In the presence of Klotho, FGF23 activates downstream signaling components that influence the homeostasis of phosphate, whereas in the absence of this membrane protein, it is unable to exert such regulatory effects, as demonstrated convincingly in animal models. Several factors, including phosphate and vitamin D, can regulate the production of both FGF23 and Klotho and influence their functions. In various acquired and genetic human diseases, dysregulation of FGF23 and Klotho is associated with vascular and skeletal anomalies owing to altered phosphate turnover. In this Review, I summarize how the endocrine effects of bone-derived FGF23, in coordination with Klotho, can regulate systemic phosphate homeostasis, and how an inadequate balance of these molecules can lead to complications that are caused by abnormal mineral ion metabolism.

Asunto(s)

Factores de Crecimiento de Fibroblastos/metabolismo , Glucuronidasa/metabolismo , Homeostasis/fisiología , Fosfatos/fisiología , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Factores de Crecimiento de Fibroblastos/genética , Glucuronidasa/genética , Homeostasis/genética , Humanos , Proteínas Klotho , Fosfatos/metabolismo

RESUMEN

Hyp mice possess a mutation that inactivates the phosphate-regulating gene, which is homologous to the endopeptidases of the X-chromosome (PHEX). The mutation is associated with severe hypophosphatemia due to excessive urinary phosphate wasting. Such urinary phosphate wasting in Hyp mice is associated with an increased serum accumulation of fibroblast growth factor (FGF) 23. We wanted to determine the biological significance of increased serum FGF23 levels and concomitant hypophosphatemia in Hyp mice and to evaluate whether FGF23 activity could be modified by manipulating klotho (a cofactor of FGF23 signaling). We generated Hyp and klotho double-mutant mice (Hyp/klotho(-/-)). Severe hypophosphatemia of Hyp mice was reversed to hyperphosphatemia in Hyp/klotho(-/-) double mutants, despite the fact that the double mutants showed significantly increased serum levels of FGF23. Hyperphosphatemia in Hyp/klotho(-/-) mice was associated with increased renal expression of sodium/phosphate cotransporter 2a (NaPi2a) protein. Exogenous injection of bioactive parathyroid hormone 1-34 down-regulated renal expression of NaPi2a and consequently reduced serum levels of phosphate in Hyp/klotho(-/-) mice. Moreover, in contrast to the Hyp mice, the Hyp/klotho(-/-) mice showed significantly higher serum levels of 1,25-dihydroxyvitamin D and developed extensive calcification in soft tissues and vascular walls. Furthermore, compared with the Hyp mice, Hyp/klotho(-/-) mice were smaller in size, showed features of generalized tissue atrophy, and generally died by 15-20 wk of age. Our in vivo studies provide genetic evidence for a pathological role of increased FGF23 activities in regulating abnormal phosphate homeostasis in Hyp mice. Moreover, these results suggest that even when serum levels of FGF23 are significantly high, in the absence of klotho, FGF23 is unable to regulate systemic phosphate homeostasis. Our in vivo observations have significant clinical implications in diseases associated with increased FGF23 activity and suggest that the functions of FGF23 can be therapeutically modulated by manipulating the effects of klotho.

Asunto(s)

Factores de Crecimiento de Fibroblastos/sangre , Glucuronidasa/fisiología , Hipofosfatemia/metabolismo , Endopeptidasa Neutra Reguladora de Fosfato PHEX/fisiología , Animales , Calcio/sangre , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/fisiología , Hipofosfatemia/genética , Proteínas Klotho , Ratones , Ratones Noqueados , Fosfatos/sangre , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/metabolismo , Vitamina D/análogos & derivados , Vitamina D/sangre

RESUMEN

The effect of salinity on morphological characters of salt tolerant genotypes PVSB9, PVSB19, PNR381, PNR519, Iratom24 and salt sensitive genotype NS15 along with one standard check salt tolerant rice cultivar Pokkali were assessed in two factors Completely Randomized Design with four replications. Seven rice genotypes in combination with six levels of salinity (0, 3, 6, 9, 12 and 15 dS m(-1)) were randomly assigned in 168 experimental plastic pots. The different morphological characters studied include plant height, total number of tillers, Root Dry Weight (RDW), Shoot Dry Weight (SDW) and Total Dry Matter (TDM) content of the selected rice genotypes in view to evaluate their response at different salinity levels. The results on the effect of morphological characters indicated that plant height, total tillers, root, shoot and total dry matter were significantly decreased by the application of salinity. The genotypes Pokkali, PVSB9, PVSB19 showed significantly higher values and the lowest value of all these characters were recorded in NS15. A sharp decrease in percent relative-plant height, RDW, SDW, TDM, total tillers were found in susceptible genotype NS 15 after 3 dS m(-1) level of salinity, but these characters were found to decrease slowly in tolerant genotypes.

Asunto(s)

Oryza/genética , Oryza/fisiología , Tolerancia a la Sal/genética , Genotipo , Oryza/anatomía & histología , Raíces de Plantas/anatomía & histología , Brotes de la Planta/anatomía & histología , Distribución Aleatoria , Salinidad

RESUMEN

Changes in the expression of klotho, a beta-glucuronidase, contribute to the development of features that resemble those of premature aging, as well as chronic renal failure. Klotho knockout mice have increased expression of the sodium/phosphate cotransporter (NaPi2a) and 1alpha-hydroxylase in their kidneys, along with increased serum levels of phosphate and 1,25-dihydroxyvitamin D. These changes are associated with widespread soft-tissue calcifications, generalized tissue atrophy, and a shorter lifespan in the knockout mice. To determine the role of the increased vitamin D activities in klotho knockout animals, we generated klotho and 1alpha-hydroxylase double-knockout mice. These double mutants regained body weight and developed hypophosphatemia with a complete elimination of the soft-tissue and vascular calcifications that were routinely found in klotho knockout mice. The markedly increased serum fibroblast growth factor 23 and the abnormally low serum parathyroid hormone levels, typical of klotho knockout mice, were significantly reversed in the double-knockout animals. These in vivo studies suggest that vitamin D has a pathologic role in regulating abnormal mineral ion metabolism and soft-tissue anomalies of klotho-deficient mice.

Asunto(s)

25-Hidroxivitamina D3 1-alfa-Hidroxilasa/deficiencia , Calcinosis , Glucuronidasa/deficiencia , Homeostasis , Minerales/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/genética , Animales , Peso Corporal , Glucuronidasa/genética , Hipofosfatemia/etiología , Proteínas Klotho , Ratones , Ratones Noqueados , Vitamina D/fisiología