RESUMEN
Homeostasis of phosphorus (P), an essential macronutrient, is vital for plant growth under diverse environmental conditions. Although plants acquire P from the soil as inorganic phosphate (Pi), its availability is generally limited. Therefore, plants employ mechanisms involving various Pi transporters that facilitate efficient Pi uptake against a steep concentration gradient across the plant-soil interface. Among the different types of Pi transporters in plants, some members of the PHOSPHATE TRANSPORTER 1 (PHT1) family, present in the plasma membrane of root epidermal cells and root hairs, are chiefly responsible for Pi uptake from the rhizosphere. Therefore, accurate regulation of PHT1 expression is crucial for the maintenance of P homeostasis. Previous investigations positioned the Pi-dependent posttranslational regulation of PHOSPHATE STARVATION RESPONSE 1 (PHR1) transcription factor activity at the center of the regulatory mechanism controlling PHT1 expression and P homeostasis; however, recent studies indicate that several other factors also regulate the expression of PHT1 to modulate P acquisition and sustain P homeostasis against environmental fluctuations. Together with PHR1, several transcription factors that mediate the availability of other nutrients (such as nitrogen and zinc), light, and stress signals form an intricate transcriptional network to maintain P homeostasis under highly diverse environments. In this review, we summarize this intricate transcriptional network for the maintenance of P homeostasis under different environmental conditions, with a main focus on the mechanisms identified in Arabidopsis.
Asunto(s)
Proteínas de Transporte de Fosfato/metabolismo , Fósforo/metabolismo , Fenómenos Fisiológicos de las Plantas , Proteínas de Plantas/metabolismo , Sequías , Regulación de la Expresión Génica de las Plantas , Homeostasis , Luz , Nitrógeno/metabolismo , Proteínas de Transporte de Fosfato/genética , Fosfatos/metabolismo , Fosfatos/farmacocinética , Proteínas de Plantas/genética , Salinidad , Suelo/química , Zinc/metabolismoRESUMEN
Retrospective chart reviews have reported hypophosphatemia associated with elemental formula use in infants and children with systemic disease involving multiple diagnoses. The present study aims to evaluate the bioavailability of phosphorus from 2 commercial elemental formulas and to test our hypothesis of bioequivalence of the 2 products in healthy volunteers receiving gastric acid-suppressive medication. A single-center, double-blind, randomized, cross-over study was conducted in healthy volunteers with esomeprazole-induced hypochlorhydria. After a standardized low phosphorus meal followed by overnight fasting, subjects consumed 1 gram of phosphorus in a single oral dose of 1217 kcal of Product A (Neocate) or Product B (Elecare). The alternate product was given following a 1-week washout period. Blood and urine were collected at baseline and different time-points for up to 6 hours after product consumption. Area-under-the-curve (AUC) and peak values (Cpeak) for serum phosphate and calcium and urinary creatinine-corrected phosphate and calcium were assessed for bioequivalence of Products A and B. Results show that the geometric mean ratio (GMR) and 90% CI for serum phosphate were 1.041 (0.998-1.086) and 1.020 (0.963-1.080) for AUC0-360 and Cpeak, respectively, meeting the predetermined criteria for bioequivalence. Urinary creatinine-corrected phosphate followed a similar pattern after intake of Product A and B, but did not reach bioequivalence criteria (GMR: AUC70-370 = 1.105 (0.918-1.330); Cpeak = 1.182 (1.040-1.343)). Serum calcium concentrations (GMR: AUC0-360 = 1.002 (0.996-1.009); Cpeak = 0.991 (0.983-0.999)) and urinary creatinine-corrected calcium excretion (GMR: AUC70-370 = 1.117 (1.023-1.219); Cpeak = 1.157 (1.073-1.247)) demonstrated bioequivalence of the products. In conclusion, both elemental infant formulas showed equivalent serum phosphorus and calcium bioavailability in healthy volunteers even if combined with treatment with acid-suppressive medication.
Asunto(s)
Aminoácidos , Calcio/farmacocinética , Carbohidratos , Grasas de la Dieta , Fórmulas Infantiles , Fosfatos/farmacocinética , Aclorhidria , Adulto , Fosfatasa Alcalina/sangre , Aminoácidos/efectos adversos , Disponibilidad Biológica , Glucemia/análisis , Calcio/sangre , Calcio/orina , Carbohidratos/efectos adversos , Estudios Cruzados , Grasas de la Dieta/efectos adversos , Método Doble Ciego , Femenino , Voluntarios Sanos , Humanos , Fórmulas Infantiles/efectos adversos , Insulina/sangre , Masculino , Hormona Paratiroidea/sangre , Fosfatos/sangre , Fosfatos/orina , Equivalencia Terapéutica , Adulto JovenRESUMEN
Due to insufficient amount of soluble phosphate and poor persistence of traditional chemical phosphate fertilizers in agricultural soils, the eco-friendly and sustainable phosphorus sources for crops are urgently required. The efficient phosphate-releasing fungal strain designated y2 was isolated and identified by the internal transcribed spacer of rDNA as Penicillium oxalicum y2. When lecithin, Ca3(PO4)2, or ground phosphate rock were separately used as sole phosphorus source, different phosphate-releasing modes were observed. The strain y2 was able to release as high as 2090 mg/L soluble phosphate within 12 days of incubation with Ca3(PO4)2 as sole phosphorus source. In the culture solution, high concentration of oxalic, citric, and malic acids and high phosphatase activity were detected. The organic acids contributed to solubilizing inorganic phosphate sources, while phosphatase was in charge of the mineralization of organic phosphorus lecithin. Afterwards, the fungus culture was applied to the soil with rape growing. During 50 days of incubation, the soil's available phosphate concentration increased by three times compared with the control, the dry weight of rape increased by 78.73%, and the root length increased by 38.79%. The results illustrated that P. oxalicum y2 possessed both abilities of solubilizing inorganic phosphorus and mineralizing organic phosphorus, which have great potential application in providing biofertilizer for modern agriculture.
Asunto(s)
Penicillium/metabolismo , Fosfatos/metabolismo , Fósforo/metabolismo , Microbiología del Suelo , Disponibilidad Biológica , Brassica napus/crecimiento & desarrollo , Carbono/metabolismo , Ácidos Carboxílicos/metabolismo , ADN Espaciador Ribosómico/genética , Nitrógeno/metabolismo , Penicillium/clasificación , Penicillium/genética , Penicillium/aislamiento & purificación , Fosfatos/farmacocinética , Monoéster Fosfórico Hidrolasas/metabolismo , Filogenia , Suelo/químicaRESUMEN
Tylosin phosphate (TYL) is administered to more than 50% of U.S. beef cattle to reduce the incidence of liver abscesses but may increase the risk of macrolide-lincosamide-streptogramin-resistant bacteria disseminating from the feedlot. Limited evidence has been collected to understand how TYL affects the proportion of resistant bacteria in cattle or the feedlot environment. We created a mathematical model to investigate the effects of TYL administration on Enterococcus dynamics and examined preharvest strategies to mitigate the impact of TYL administration on resistance. The model simulated the physiological pharmacokinetics of orally administered TYL and estimated the pharmacodynamic effects of TYL on populations of resistant and susceptible Enterococcus within the cattle large intestine, feedlot pen, water trough, and feed bunk. The model parameters' population distributions were based on the available literature; 1000 Monte Carlo simulations were performed to estimate the likely distribution of outcomes. At the end of the simulated treatment period, the median estimated proportion of macrolide-resistant enterococci was only 1 percentage point higher within treated cattle compared with cattle not fed TYL, in part because the TYL concentrations in the large intestine were substantially lower than the enterococci minimum inhibitory concentrations. However, 25% of the simulated cattle had a >10 percentage point increase in the proportion of resistant enterococci associated with TYL administration, termed the TYL effect. The model predicts withdrawing TYL treatment and moving cattle to an antimicrobial-free terminal pen with a low prevalence of resistant environmental enterococci for as few as 6 days could reduce the TYL effect by up to 14 percentage points. Additional investigation of the importance of this subset of cattle to the overall risk of resistance transmission from feedlots will aid in the interpretation and implementation of resistance mitigation strategies.
Asunto(s)
Alimentación Animal/microbiología , Antibacterianos/farmacocinética , Enfermedades de los Bovinos/microbiología , Enterococcus/efectos de los fármacos , Fosfatos/farmacocinética , Tilosina/farmacocinética , Animales , Bovinos , Enfermedades de los Bovinos/transmisión , Farmacorresistencia Bacteriana/efectos de los fármacos , Microbiología de Alimentos , Macrólidos , Pruebas de Sensibilidad Microbiana , Modelos TeóricosRESUMEN
Depression and dementia are predicted to increase within aging global populations. Pathophysiological effects of phosphate toxicity, dysregulated amounts of accumulated phosphorus in body tissue, are under-investigated in association with stress, inflammation, depression, and dementia. A comparative analysis of concepts in cited sources from the research literature was used to synthesize novel themes exploring the disease-oriented neuroscience effects of phosphate toxicity. Phosphate toxicity is associated with activation of cellular stress response systems and inflammation. Cortisol released by the hypothalamic-pituitary-adrenal axis responds to stress and inflammation associated with phosphate toxicity and depression. In a reciprocal interaction, phosphate toxicity is capable of harming adrenal gland function, possibly leading to adrenal insufficiency and depression. Furthermore, Alzheimer's disease is associated with hyperphosphorylated tau which self-assembles into neurofibrillary tangles from excessive amounts of phosphate in the brain and central nervous system. Future research should investigate dietary phosphate modification to reduce potential pathophysiological effects of phosphate toxicity in stress, inflammation, depression, and cognitive decline which affects global populations.
Asunto(s)
Enfermedad de Alzheimer , Trastorno Depresivo , Hidrocortisona/metabolismo , Fosfatos , Estrés Fisiológico , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/metabolismo , Animales , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/metabolismo , Trastorno Depresivo/inducido químicamente , Trastorno Depresivo/metabolismo , Humanos , Inflamación/inducido químicamente , Inflamación/metabolismo , Fosfatos/farmacocinética , Fosfatos/toxicidadRESUMEN
Inorganic phosphate (Pi) plays a critical function in many tissues of the body: for example, as part of the hydroxyapatite in the skeleton and as a substrate for ATP synthesis. Pi is the main source of dietary phosphorus. Reduced bioavailability of Pi or excessive losses in the urine causes rickets and osteomalacia. While critical for health in normal amounts, dietary phosphorus is plentiful in the Western diet and is often added to foods as a preservative. This abundance of phosphorus may reduce longevity due to metabolic changes and tissue calcifications. In this review, we examine how dietary phosphorus is absorbed in the gut, current knowledge about Pi sensing, and endocrine regulation of Pi levels. Moreover, we also examine the roles of Pi in different tissues, the consequences of low and high dietary phosphorus in these tissues, and the implications for healthy aging.
Asunto(s)
Huesos/metabolismo , Envejecimiento Saludable/efectos de los fármacos , Fosfatos/farmacocinética , Fósforo Dietético/farmacocinética , Disponibilidad Biológica , HumanosRESUMEN
The role of root exudates has long been recognized for its potential to improve nutrient use efficiency in cropping systems. However, studies addressing the variability of root exudates involved in phosphorus solubilization across plant developmental stages remain scarce. Here, we grew Arabidopsis thaliana seedlings in sterile liquid culture with a low, medium, or high concentration of phosphate and measured the composition of the root exudate at seedling, vegetative, and bolting stages. The exudates changed in response to the incremental addition of phosphorus, starting from the vegetative stage. Specific metabolites decreased in relation to phosphate concentration supplementation at specific stages of development. Some of those metabolites were tested for their phosphate solubilizing activity, and 3-hydroxypropionic acid, malic acid, and nicotinic acid were able to solubilize calcium phosphate from both solid and liquid media. In summary, our data suggest that plants can release distinct compounds to deal with phosphorus deficiency needs influenced by the phosphorus nutritional status at varying developmental stages.
Asunto(s)
Arabidopsis/crecimiento & desarrollo , Arabidopsis/metabolismo , Fósforo/metabolismo , Exudados de Plantas/metabolismo , Raíces de Plantas/metabolismo , Fosfatos de Calcio/química , Fosfatos de Calcio/metabolismo , Fertilizantes , Fosfatos/farmacocinética , Exudados de Plantas/análisis , SolubilidadRESUMEN
Utilizing phosphate more efficiently is crucial for sustainable crop production. Highly efficient rice (Oryza sativa) cultivars have been identified and this study aims to identify metabolic markers associated with P utilization efficiency (PUE). P deficiency generally reduced leaf P concentrations and CO2 assimilation rates but efficient cultivars were reducing leaf P concentrations further than inefficient ones while maintaining similar CO2 assimilation rates. Adaptive changes in carbon metabolism were detected but equally in efficient and inefficient cultivar groups. Groups furthermore did not differ with respect to partial substitutions of phospholipids by sulfo- and galactolipids. Metabolites significantly more abundant in the efficient group, such as sinapate, benzoate and glucoronate, were related to antioxidant defence and may help alleviating oxidative stress caused by P deficiency. Sugar alcohols ribitol and threitol were another marker metabolite for higher phosphate efficiency as were several amino acids, especially threonine. Since these metabolites are not known to be associated with P deficiency, they may provide novel clues for the selection of more P efficient genotypes. In conclusion, metabolite signatures detected here were not related to phosphate metabolism but rather helped P efficient lines to keep vital processes functional under the adverse conditions of P starvation.
Asunto(s)
Metaboloma/fisiología , Oryza/fisiología , Fosfatos/metabolismo , Adaptación Fisiológica , Biomarcadores/metabolismo , Dióxido de Carbono/metabolismo , Genotipo , Metabolismo de los Lípidos , Oryza/genética , Oryza/metabolismo , Fosfatos/farmacocinética , Fosfolípidos/metabolismo , Fósforo/metabolismo , Fotosíntesis/fisiología , Hojas de la Planta/fisiología , Fosfatos de Azúcar/metabolismoRESUMEN
Background and Objectives: Muscle fatigue is characterised by (1) loss of force, (2) decreased maximal shortening velocity and (3) a greater resistance to stretch that could be due to reduced intracellular Ca2+ and increased Pi, which alter cross bridge kinetics. Materials and Methods: To investigate this, we used (1) 2,3-butanedione monoxime (BDM), believed to increase the proportion of attached but non-force-generating cross bridges; (2) Pi that increases the proportion of attached cross bridges, but with Pi still attached; and (3) reduced activating Ca2+. We used permeabilised rat soleus fibres, activated with pCa 4.5 at 15 °C. Results: The addition of 1 mM BDM or 15 mM Pi, or the lowering of the Ca2+ to pCa 5.5, all reduced the isometric force by around 50%. Stiffness decreased in proportion to isometric force when the fibres were activated at pCa 5.5, but was well maintained in the presence of Pi and BDM. Force enhancement after a stretch increased with the length of stretch and Pi, suggesting a role for titin. Maximum shortening velocity was reduced by about 50% in the presence of BDM and pCa 5.5, but was slightly increased by Pi. Neither decreasing Ca2+ nor increasing Pi alone mimicked the effects of fatigue on muscle contractile characteristics entirely. Only BDM elicited a decrease of force and slowing with maintained stiffness, similar to the situation in fatigued muscle. Conclusions: This suggests that in fatigue, there is an accumulation of attached but low-force cross bridges that cannot be the result of the combined action of reduced Ca2+ or increased Pi alone, but is probably due to a combination of factors that change during fatigue.
Asunto(s)
Hipocalcemia/diagnóstico , Fatiga Muscular/fisiología , Ejercicios de Estiramiento Muscular/fisiología , Fosfatos/efectos adversos , Animales , Modelos Animales de Enfermedad , Hipocalcemia/sangre , Cinética , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Fatiga Muscular/efectos de los fármacos , Fosfatos/farmacocinética , Ratas , Ratas WistarRESUMEN
The rabbit is a much-used experimental animal in renal tubule physiology studies. Although a monogastric mammal, the rabbit is a known hindgut fermenter. That ruminant species excrete inorganic phosphate (Pi) mainly through the digestive system while non-ruminants eliminate surplus phosphate primarily through the renal system are acknowledged facts. To understand phosphate homeostasis in the acidotic rabbit, anaesthetized animals were infused with hydrochloric acid, after which they underwent intravenous phosphate loading. Biofluids were collected during the infusion process for analysis. Plasma Pi increased (7.9 ± 1.7 mmoles.Litre-1 (N = 5) vs 2.2 ± 0.4 mmoles.Litre-1 (N = 10) pre-infusion, (p < 0.001)), while urinary phosphate excretion was also enhanced (74.4 ± 15.3 from a control value of 4.7 ± 3 µmol.min-1 (N = 9), pre-infusion, p < 0.001)) over an 82.5 minute Pi loading period. However, the fractional excretion of Pi (FePi) only increased from 14.2 ± 5.4% to a maximum of 61.7 ± 19% (N = 5) over the infusion period. Furthermore, the renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmPi/GFR) computed to 3.5 mmol.L-1, while a reading of 23.2 µmol.min-1.Kg.0.75 was obtained for the transport maximum for Pi (TmPi). The high reabsorptivity of the rabbit nephrons coupled with possibly a high secretory capacity of the salivary glands for Pi, may constitute a unique physiological mechanism that ensures the rabbit hindgut receives adequate phosphate to regulate caecal pH in favour of the resident metabolically - active microbiota. The handling of Pi by the rabbit is in keeping with the description of this animal as a monogastric, pseudo-ruminant herbivore.
Asunto(s)
Fosfatos/administración & dosificación , Fosfatos/farmacocinética , Administración Intravenosa , Animales , Tracto Gastrointestinal/metabolismo , Cinética , Fosfatos/sangre , Conejos , Saliva/metabolismoRESUMEN
Tenofovir disoproxil (TD) is very unstable in the solid state under storage conditions. Moreover, tenofovir disoproxil fumarate (TDF), a commercial salt, is chemically unstable in alkaline solution. In this study, a novel tenofovir disoproxil phosphate (TDP), with stability enhancement and bioequivalence to commercial TDF in rats and beagle dogs, has been developed as an alternative. The TDP and its tablets were easily manufactured, and its physicochemical properties, such as morphology, crystallinity, solubility, lipophilicity and stability were investigated and compared to TD and TDF. Its dissolution and pharmacokinetics were investigated in rats and beagle dogs in comparison to TD and TDF. TDP appeared as an irregularly-shaped crystalline powder with a rough surface, like TDF. However, TDP significantly improved the solubility (7.4⯱â¯1.3 vs. 28.6⯱â¯1.0â¯mg/ml), hydrophilicity (Log P, 0.58⯱â¯0.03 vs. 0.47⯱â¯0.04), and aqueous stability (drug concentration over 12â¯h at pH 6.8 84.0⯱â¯2.0% vs. 88.2⯱â¯1.5%) of TD compared to TDF. The TDP gave no significant different plasma concentrations, AUC and Cmax compared to TDF in rats (AUC, 1242.1⯱â¯584.9 vs. 825.9⯱â¯79.5â¯h·ng/ml; Cmax, 154.8⯱â¯25.4 vs. 210.9⯱â¯70.3â¯ng/ml). Moreover, the TDP-loaded tablets were stable for at least six months and provided similar dissolution and bioequivalence to the TDF-loaded commercial product in beagle dogs (AUC, 26,832.7⯱â¯4093.0 vs. 26,605.3⯱â¯2530.1â¯h·ng/ml; Cmax, 4364.0⯱â¯2061.9 vs. 4186.3⯱â¯2616.5â¯ng/ml). Therefore, as an alternative salt, the TDP would be a recommendable candidate with stability enhancement and bioequivalence to the commercial TDF.
Asunto(s)
Fosfatos/química , Cloruro de Sodio/química , Tenofovir/química , Animales , Área Bajo la Curva , Perros , Estabilidad de Medicamentos , Interacciones Hidrofóbicas e Hidrofílicas , Masculino , Fosfatos/farmacocinética , Ratas , Ratas Sprague-Dawley , Solubilidad , Comprimidos/química , Comprimidos/farmacocinética , Tenofovir/farmacocinética , Equivalencia TerapéuticaRESUMEN
The differentiation of adult stem cells is usually performed in vitro, by exposing them to specific factors. Alternatively, one can use nanocarriers containing such factors, to be internalized by the cells. In this work we have reduce the size of those carriers to the nanoscale, developing bioactive silica nanoparticles with diameters under 100â¯nm, containing calcium and phosphate ions (SiNPs-CaP). These ions, once released inside adult stem cells, induce bone cell proliferation and differentiation, and stimulate the expression of bone-related proteins in a single dose administration. The SiNPs-CaP nanomaterials were prepared through a sol-gel approach, and the ions added with a post-synthesis functionalization method. The synthesized SiNPs-CaP have narrow size distribution, good colloidal stability, and show high levels of ion incorporation. Furthermore, the SiNPs-CaP have good cytocompatibility and promote the osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSC), with alkaline phosphatase, osteopontin and osteocalcin production levels comparable to the ones obtained in standard osteogenic medium. The novel bioactive SiNPs-CaP are synthesized in a simple and fast manner and show the ability to promote osteogenic differentiation after a single dose administration, independently from external osteogenic inducers, showing great potential as carriers in bone tissue engineering applications.
Asunto(s)
Calcio/administración & dosificación , Células Madre Mesenquimatosas/citología , Nanopartículas/química , Osteogénesis/efectos de los fármacos , Fosfatos/administración & dosificación , Fosfatasa Alcalina/metabolismo , Calcio/química , Calcio/farmacocinética , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Liberación de Fármacos , Humanos , Células Madre Mesenquimatosas/efectos de los fármacos , Nanopartículas/administración & dosificación , Osteocalcina/metabolismo , Osteogénesis/fisiología , Osteopontina/metabolismo , Tamaño de la Partícula , Fosfatos/química , Fosfatos/farmacocinética , Dióxido de Silicio/químicaRESUMEN
Euphorbia species are characterized by a net of laticifers producing large amounts of triterpenes. These hydrocarbon-like metabolites can be converted into fuel by the methods of the oil industry. Euphorbia lathyris is easily grown at an industrial scale. In an attempt to increase its triterpene production, the metabolic pathways leading to isoprenoid were investigated by incorporation of 13C labeled glucose and mevalonate and 2H labeled deoxyxylulose as well as by natural abundance isotope ratio GC-MS. Latex triterpenes are exclusively synthesized via the mevalonate (MVA) pathway: this may orient future search for improving the triterpene production in E. lathyris. Phytosterols and their precursors are mainly derived from MVA pathway with a slight contribution of the methylerythritol phosphate (MEP) pathway, whereas phytol is issued from MEP pathway with a minor contribution of the MVA pathway: this is in accordance with the metabolic cross-talk between cytosolic and plastidial compartments in plants. In addition, hopenol B behaved differently from the other latex triterpenes. Its 13C isotope abundance after incorporation of 13C labeled glucose and its natural abundance δ2H signature clearly differed from those of the other latex triterpenes indicating another metabolic origin and suggesting that it may be synthesized by an endophytic fungus.
Asunto(s)
Butadienos/metabolismo , Eritritol/metabolismo , Euphorbia/metabolismo , Hongos/metabolismo , Hemiterpenos/metabolismo , Redes y Vías Metabólicas/fisiología , Ácido Mevalónico/metabolismo , Fosfatos/farmacocinética , Glucosa/metabolismo , Látex/metabolismo , Fitosteroles/metabolismo , Triterpenos/metabolismo , Xilulosa/análogos & derivados , Xilulosa/metabolismoRESUMEN
The Expert Panel assessed the safety of 28 alkyl phosphates and concluded that these ingredients are safe in the current practices of use and concentration when formulated to be nonirritating. The ingredients in the alkyl phosphate family share a common phosphate core structure, and vary by the identity of the alkyl chains attached therein. Most of the alkyl phosphates function as surfactants in cosmetic ingredients; however, the triesters function as plasticizers rather than surfactants. The Panel reviewed the available animal and clinical data to determine the safety of these ingredients.
Asunto(s)
Cosméticos/toxicidad , Fosfatos/toxicidad , Tensoactivos/toxicidad , Animales , Seguridad de Productos para el Consumidor , Humanos , Fosfatos/farmacocinética , Tensoactivos/farmacocinética , Pruebas de Toxicidad , ToxicocinéticaRESUMEN
Aluminium (Al) toxicokinetics after intramuscular (IM) injection of Al-adjuvanted vaccines is unknown. Since animal data are required for modeling and extrapolation, a rat study was conducted measuring Al in plasma and tissues after IM injection of either plain Al-hydroxide (pAH) or Al-phosphate (pAP) adjuvant (Al dose 1.25 mg), single human doses of three Al-adjuvanted vaccines (V1, V2, and V3; Al doses 0.5-0.82 mg), or vehicle (saline). A significant increase in Al plasma levels compared to controls was observed after pAP (AUC(0-80 d), mean ± SD: 2424 ± 496 vs. 1744 ± 508 µg/L*d). Percentage of Al dose released from injected muscle until day 80 was higher after pAP (66.9%) and AP-adjuvanted V3 (85.5%) than after pAH and AH-adjuvanted V1 (0 and 22.3%, resp.). Estimated absolute Al release was highest for pAP (836.8 µg per rat). Al concentration in humerus bone was increased in all groups, again strongest in the pAP group [3.35 ± 0.39 vs. 0.05 ± 0.06 µg/g wet weight (ww)]. Extrapolated amounts in whole skeleton corresponded to 5-12% of the released Al dose. Very low brain Al concentrations were observed in all groups (adjuvant group means 0.14-0.29 µg/g ww; control 0.13 ± 0.04 µg/g ww). The results demonstrate systemically available Al from marketed vaccines in rats being mainly detectable in bone. Al release appears to be faster from AP- than AH-adjuvants. Dose scaling to human adults suggests that increase of Al in plasma and tissues after single vaccinations will be indistinguishable from baseline levels.
Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Compuestos de Aluminio/administración & dosificación , Hidróxido de Aluminio/administración & dosificación , Fosfatos/administración & dosificación , Vacunas/administración & dosificación , Adyuvantes Inmunológicos/farmacocinética , Compuestos de Aluminio/farmacocinética , Hidróxido de Aluminio/farmacocinética , Animales , Área Bajo la Curva , Humanos , Inyecciones Intramusculares , Masculino , Fosfatos/farmacocinética , Ratas , Ratas Wistar , Distribución Tisular , Vacunas/farmacocinéticaRESUMEN
RIP2 kinase has been identified as a key signal transduction partner in the NOD2 pathway contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP2 kinase or its signaling partners on the NOD2 pathway that are suitable for advancement into the clinic have yet to be described. Herein, we report our discovery and profile of the prodrug clinical compound, inhibitor 3, currently in phase 1 clinical studies. Compound 3 potently binds to RIP2 kinase with good kinase specificity and has excellent activity in blocking many proinflammatory cytokine responses in vivo and in human IBD explant samples. The highly favorable physicochemical and ADMET properties of 3 combined with high potency led to a predicted low oral dose in humans.
Asunto(s)
Benzotiazoles/farmacología , Fosfatos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , Proteína Serina-Treonina Quinasa 2 de Interacción con Receptor/antagonistas & inhibidores , Animales , Benzotiazoles/química , Benzotiazoles/farmacocinética , Benzotiazoles/uso terapéutico , Colitis/tratamiento farmacológico , Perros , Descubrimiento de Drogas , Humanos , Masculino , Ratones , Simulación del Acoplamiento Molecular , Fosfatos/química , Fosfatos/farmacocinética , Fosfatos/uso terapéutico , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/química , Quinazolinas/farmacocinética , Quinazolinas/uso terapéutico , Ratas Sprague-Dawley , Proteína Serina-Treonina Quinasa 2 de Interacción con Receptor/metabolismo , Porcinos , Porcinos EnanosRESUMEN
In this study, a simple and rapid DAPI-based protocol was developed and optimized to visualize polyphosphates (polyPs) in the cyanobacterium Synechocystis sp. PCC 6803. The optimum dye concentration and incubation time were determined, and formaldehyde fixation was shown to significantly improve polyP detection in Synechocystis cells. Using the developed protocol, for the first time, it was shown that 80% of Synechocystis cells under phosphate overplus were able to accumulate phosphorus as polyP 3 min after the addition of K2HPO4. After 1 h, the number of cells with polyP began to decrease, and after 24 h, polyP granules were detected in only 30% of the cells. Thus, the Synechocystis cells appeared to be heterogeneous in their ability to accumulate and mobilize polyP. Like other photosynthetic organisms, Synechocystis synthesized less polyP in the dark than in the light. The accumulation of polyP was not inhibited under conditions of cold and heat stresses, and some cells were even able to synthesize polyP at a temperature of approximately 0 °C.
Asunto(s)
Imagen Molecular/métodos , Polifosfatos/análisis , Polifosfatos/metabolismo , Synechocystis/metabolismo , Colorantes Fluorescentes/metabolismo , Indoles/metabolismo , Luz , Fosfatos/farmacocinética , Compuestos de Potasio/farmacocinética , Synechocystis/efectos de los fármacos , TemperaturaRESUMEN
This study tested the solubilization of phosphorus by five actinobacterial strains in liquid media containing Ca3 PO4 ; AlPO4 or FePO4 as the sole phosphate source, and discusses the possible mechanisms involved in this process. P solubilization by different strains was accompanied by a significant drop in pH from 7.0 to 2.15-5.0 after 14 days. The efficiency of different strains depended on the P-source. Streptomyces spp. MM140 and MM141 were the most efficient in solubilizing Ca3 PO4 , MM136, and MM141 were the most efficient in solubilizing AlPO4 , while all strains were equally efficient in solubilizing FePO4 . Gluconic, oxalic, citric, malic, succinic, formic, and acetic acid were detected in the medium with Ca3 PO4 , while all except acetic acid were detected in the media with FePO4 or AlPO4 . Although we did not use an organic source of phosphorus in the media, all strains produced acid and alkaline phosphatase. It is concluded from this study that actinobacteria produced multiple organic acids followed by a decrease in the pH to solubilize phosphate salts. As well as producing phosphatase, these microorganisms were found to have different ways of making P available, suggesting an ecological advantage as they form part of soil microbiomes important for plants.
Asunto(s)
Actinobacteria/metabolismo , Fosfatos/metabolismo , Actinobacteria/clasificación , Disponibilidad Biológica , Ácidos Carboxílicos/metabolismo , Medios de Cultivo/química , Concentración de Iones de Hidrógeno , Fosfatos/farmacocinética , Monoéster Fosfórico Hidrolasas/metabolismo , Microbiología del Suelo , Especificidad de la Especie , Especificidad por SustratoRESUMEN
Development of slow release fertilizers by tuning dissolution kinetics can reduce the environmental impact of (micro) nutrients added to crops. Mixed metal compounds may have different dissolution kinetics and plant uptake than single metal compounds. In this study, mixed Fe(II)/Zn(II) phosphates (0-100â¯at% Zn) were prepared by aqueous precipitation and their structural characteristics and dissolution kinetics in a sand column were measured as model for divalent metal and phosphate release in soil. Three minerals were identified, namely vivianite (Fe3(PO4)2·8H2O) at 0-20â¯at% Zn, phosphophyllite (Zn2Fe(PO4)2·4H2O) at 20-79â¯at% Zn, and hopeite (Zn3(PO4)2·4H2O) at 79-100â¯at% Zn. The Fe-rich materials had high SSA of 42-64â¯m2â¯g-1, which decreased to ≤4â¯m2â¯g-1 for ≥79â¯at% Zn. The Fe K-edge and Zn K-edge XANES spectroscopy measurements show that the samples had comparable local structure and contained 13-72% of Fe as Fe(III) due to partial oxidation. In the sand column, Zn(II) and Fe(II) phosphates dissolved near-congruently at steady state (>7â¯h), whereas mixed Fe(II)/Zn(II) phosphates showed preferential release of Zn over P and Fe, likely due to reprecipitation of Fe. Pot experiments demonstrate that Zn from Fe(II)/Zn(II) phosphates is absorbed by bird's eye chili plants (C. annuum), in agreement with the preferential dissolution of Zn(II). These results may provide insight into the dissolution of other divalent metals, which not only aids in the growth of plants and resulting foodstuff but ultimately leads to reductions in environmental contamination.
Asunto(s)
Compuestos Ferrosos/farmacocinética , Minerales/química , Fosfatos/farmacocinética , Compuestos de Zinc/farmacocinética , Cationes Bivalentes/química , Precipitación Química , Compuestos Ferrosos/química , Cinética , Oxidación-Reducción , Fosfatos/química , Suelo/química , Solubilidad , Espectroscopía de Absorción de Rayos XRESUMEN
IMPACT STATEMENT: This review summarizes the work on transcellular intestinal phosphate absorption, arguing why this pathway is not the predominant pathway in humans consuming a "Western" diet. We then highlight the recent evidence which is strongly consistent with paracellular intestinal phosphate absorption mediating the bulk of intestinal phosphate absorption in humans.