Phosphate is a common ingredient of the daily consumed foods and is absorbed in the intestine and is excreted in the urine through the kidney to maintain the homeostatic balance. For adults, the ...Recommended Dietary Allowance (RDA) for phosphorus is around 700 mg/day. The change in dietary habits resulted in far more phosphate consumption (almost double) than the RDA, contributing to increased cardiovascular diseases, kidney diseases, and tumor formation. Due to a lack of clinical appreciation for the long‐term consequences of chronic phosphate burden on non‐communicable disorders, it is rapidly becoming a global health concern. The possible association between dysregulated phosphate metabolism and obesity is not studied in‐depth, mainly because such an association is believed to be nonexistent. However, in the animal model of obesity, serum phosphate level was higher than their non‐obese controls. In a similar observation line, significantly higher salivary phosphate levels were detected in obese children compared to normal‐weight children. Of clinical importance, despite the significant increase of salivary phosphate levels in obese children, the plasma phosphate levels did not change in samples collected from the same group of children. Such disparity between plasma and saliva raised the possibility that human salivary phosphate levels may be an early biomarker of childhood obesity.
We present the second catalog of flaring gamma-ray sources (2FAV) detected with the Fermi All-sky Variability Analysis (FAVA), a tool that blindly searches for transients over the entire sky observed ...by the Large Area Telescope (LAT) on board the Fermi Gamma-ray Space Telescope. With respect to the first FAVA catalog, this catalog benefits from a larger data set, the latest LAT data release (Pass 8), as well as from an improved analysis that includes likelihood techniques for a more precise localization of the transients. Applying this analysis to the first 7.4 years of Fermi observations, and in two separate energy bands 0.1-0.8 GeV and 0.8-300 GeV, a total of 4547 flares were detected with significance greater than (before trials), on the timescale of one week. Through spatial clustering of these flares, 518 variable gamma-ray sources were identified. Based on positional coincidence, likely counterparts have been found for 441 sources, mostly among the blazar class of active galactic nuclei. For 77 2FAV sources, no likely gamma-ray counterpart has been found. For each source in the catalog, we provide the time, location, and spectrum of each flaring episode. Studying the spectra of the flares, we observe a harder-when-brighter behavior for flares associated with blazars, with the exception of BL Lac flares detected in the low-energy band. The photon indexes of the flares are never significantly smaller than 1.5. For a leptonic model, and under the assumption of isotropy, this limit suggests that the spectrum of freshly accelerated electrons is never harder than .
The volume-regulated anion channel (VRAC) is a key player in the volume regulation of vertebrate cells. This ubiquitously expressed channel opens upon osmotic cell swelling and potentially other cues ...and releases chloride and organic osmolytes, which contributes to regulatory volume decrease (RVD). A plethora of studies have proposed a wide range of physiological roles for VRAC beyond volume regulation including cell proliferation, differentiation and migration, apoptosis, intercellular communication by direct release of signaling molecules and by supporting the exocytosis of insulin. VRAC was additionally implicated in pathological states such as cancer therapy resistance and excitotoxicity under ischemic conditions. Following extensive investigations, 5 years ago leucine-rich repeat-containing family 8 (LRRC8) heteromers containing LRRC8A were identified as the pore-forming components of VRAC. Since then, molecular biological approaches have allowed further insight into the biophysical properties and structure of VRAC. Heterologous expression, siRNA-mediated downregulation and genome editing in cells, as well as the use of animal models have enabled the assessment of the proposed physiological roles, together with the identification of new functions including spermatogenesis and the uptake of antibiotics and platinum-based cancer drugs. This review discusses the recent molecular biological insights into the physiology of VRAC in relation to its previously proposed roles.
Normal mineral ion homeostasis is tightly controlled by numerous endocrine factors that coordinately exert effects on intestine, kidney, and bone to maintain physiological balance. The importance of ...the fibroblast growth factor (FGF)-23-klotho axis in regulating mineral ion homeostasis has been proposed from recent research observations. Experimental studies suggest that 1) FGF23 is an important in vivo regulator of phosphate homeostasis, 2) FGF23 acts as a counter regulatory hormone to modulate the renal 1alpha-hydroxylase and sodium-phosphate cotransporter activities, 3) there is a trend of interrelationship between FGF23 and parathyroid hormone activities, 4) most of the FGF23 functions are conducted through the activation of FGF receptors, and 5) such receptor activation needs klotho, as a cofactor to generate downstream signaling events. These observations clearly suggest the emerging roles of the FGF23-klotho axis in maintaining mineral ion homeostasis. In this brief article, we will summarize how the FGF23-klotho axis might coordinately regulate normal mineral ion homeostasis, and how their abnormal regulation could severely disrupt such homeostasis to induce disease pathology.
There is a growing body of evidence for the effects of vitamin D on intestinal host-microbiome interactions related to gut dysbiosis and bowel inflammation. This brief review highlights the potential ...links between vitamin D and gut health, emphasizing the role of vitamin D in microbiological and immunological mechanisms of inflammatory bowel diseases. A comprehensive literature search was carried out in PubMed and Google Scholar using combinations of keywords “vitamin D,” “intestines,” “gut microflora,” “bowel inflammation”. Only articles published in English and related to the study topic are included in the review. We discuss how vitamin D (a) modulates intestinal microbiome function, (b) controls antimicrobial peptide expression, and (c) has a protective effect on epithelial barriers in the gut mucosa. Vitamin D and its nuclear receptor (VDR) regulate intestinal barrier integrity, and control innate and adaptive immunity in the gut. Metabolites from the gut microbiota may also regulate expression of VDR, while vitamin D may influence the gut microbiota and exert anti-inflammatory and immune-modulating effects. The underlying mechanism of vitamin D in the pathogenesis of bowel diseases is not fully understood, but maintaining an optimal vitamin D status appears to be beneficial for gut health. Future studies will shed light on the molecular mechanisms through which vitamin D and VDR interactions affect intestinal mucosal immunity, pathogen invasion, symbiont colonization, and antimicrobial peptide expression.
The region around the Galactic Center (GC) is now well established to be brighter at energies of a few GeV than what is expected from conventional models of diffuse gamma-ray emission and catalogs of ...known gamma-ray sources. We study the GeV excess using 6.5 yr of data from the Fermi Large Area Telescope. We characterize the uncertainty of the GC excess spectrum and morphology due to uncertainties in cosmic-ray source distributions and propagation, uncertainties in the distribution of interstellar gas in the Milky Way, and uncertainties due to a potential contribution from the Fermi bubbles. We also evaluate uncertainties in the excess properties due to resolved point sources of gamma rays. The GC is of particular interest, as it would be expected to have the brightest signal from annihilation of weakly interacting massive dark matter (DM) particles. However, control regions along the Galactic plane, where a DM signal is not expected, show excesses of similar amplitude relative to the local background. Based on the magnitude of the systematic uncertainties, we conservatively report upper limits for the annihilation cross-section as a function of particle mass and annihilation channel.
Inorganic phosphate‐induced cytotoxicity Alexander, Rachel; Debiec, Nicholas; Razzaque, Mohammad S. ...
IUBMB life,
January 2022, Letnik:
74, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Phosphate, an essential nutrient, is available in organic and inorganic forms. The balance of phosphate is central for cellular homeostasis through the genomic roles of DNA and RNA synthesis and cell ...signaling processes. Therefore, an imbalance of this nutrient, manifested, either as a deficiency or excess in phosphate levels, can result in pathology, ranging from cytotoxicity to musculoskeletal defects. Inorganic phosphate (Pi) overdosing can result in a wide spectrum of cytotoxicity processes, as noted in both animal models and human studies. These include rewired cell signaling pathways, impaired bone mineralization, infertility, premature aging, vascular calcification, and renal dysfunction. This article briefly reviews the regulation of phosphate homeostasis and elaborates on cytotoxic effects of excessive Pi, as documented in cell‐based models.
Maintenance of physiologic phosphate balance is of crucial biological importance, as it is fundamental to cellular function, energy metabolism, and skeletal mineralization. Fibroblast growth ...factor-23 (FGF-23) is a master regulator of phosphate homeostasis, but the molecular mechanism of such regulation is not yet completely understood. Targeted disruption of the Fgf-23 gene in mice (Fgf-23-/-) elicits hyperphosphatemia, and an increase in renal sodium/phosphate co-transporter 2a (NaPi2a) protein abundance. To elucidate the pathophysiological role of augmented renal proximal tubular expression of NaPi2a in Fgf-23-/- mice and to examine serum phosphate-independent functions of Fgf23 in bone, we generated a new mouse line deficient in both Fgf-23 and NaPi2a genes, and determined the effect of genomic ablation of NaPi2a from Fgf-23-/- mice on phosphate homeostasis and skeletal mineralization. Fgf-23-/-/NaPi2a-/- double mutant mice are viable and exhibit normal physical activities when compared to Fgf-23-/- animals. Biochemical analyses show that ablation of NaPi2a from Fgf-23-/- mice reversed hyperphosphatemia to hypophosphatemia by 6 weeks of age. Surprisingly, despite the complete reversal of serum phosphate levels in Fgf-23-/-/NaPi2a-/-, their skeletal phenotype still resembles the one of Fgf23-/- animals. The results of this study provide the first genetic evidence of an in vivo pathologic role of NaPi2a in regulating abnormal phosphate homeostasis in Fgf-23-/- mice by deletion of both NaPi2a and Fgf-23 genes in the same animal. The persistence of the skeletal anomalies in double mutants suggests that Fgf-23 affects bone mineralization independently of systemic phosphate homeostasis. Finally, our data support (1) that regulation of phosphate homeostasis is a systemic effect of Fgf-23, while (2) skeletal mineralization and chondrocyte differentiation appear to be effects of Fgf-23 that are independent of phosphate homeostasis.
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