Pi Levels Research Articles

Effectiveness of Emamectin Benzoate and Propiconazole for Protecting Picea engelmannii (Pinales: Pinaceae) from Mortality Attributed to Dendroctonus rufipennis (Coleoptera: Curculionidae) in Wyoming

Spruce beetle, Dendroctonus rufipennis Kirby (Coleoptera: Curculionidae), causes significant mortality of mature spruce, Picea spp. (Pinales: Pinaceae), in western North America. We evaluated the effectiveness of two formulations of bole injections of emamectin benzoate (TREE-äge® G4 and TREE-äge R10; Arborjet, Inc., Woburn, MA) alone and combined with propiconazole (Propizol®; Arborjet, Inc.) for protecting Engelmann spruce, Picea engelmannii Parry ex Engelm., from mortality attributed to colonization by D. rufipennis. Treatments were injected 16–19 July 2017, and levels of Pi. engelmannii mortality were determined for 2018 and 2019. Each experimental tree (n = 30, including an untreated control group) was baited with aggregation pheromone (frontalin) June–September 2018. All surviving treated Pi. engelmannii and a second untreated control group were baited June–September 2019. Both TREE-äge G4 and TREE-äge R10 significantly reduced levels of Pi. engelmannii mortality compared with the untreated control; however, protection was limited to one field season. Protection was increased to two field seasons by combining TREE-äge G4 and TREE-äge R10 with Propizol. The addition of Propizol, a triazole fungicide, likely reduced the progression of blue stain within treated Pi. engelmannii increasing tree health and resistance to D. rufipennis.

High transcriptome plasticity drives phosphate starvation responses in tomato

Tomato is an important vegetable crop and fluctuating available soil phosphate (Pi) level elicits several morpho-physiological responses driven by underlying molecular responses. Therefore, understanding these molecular responses at the gene and isoform levels has become critical in the quest for developing crops with improved Pi use efficiency. A quantitative time-series RNA-seq analysis was performed to decipher the global transcriptomic changes that accompany Pi starvation in tomato. Apart from changes in the expression levels of genes, there were also alterations in the expression of alternatively-spliced transcripts. Physiological responses such as anthocyanin accumulation, reactive oxygen species generation and cell death are obvious 7 days after Pi deprivation accompanied with the maximum amount of transcriptional change in the genome making it an important stage for in-depth study while studying Pi stress responses (PSR). Our study demonstrates that transcriptomic changes under Pi deficiency are dynamic and complex in tomato. Overall, our study dwells on the dynamism of the transcriptome in eliciting a response to adapt to low Pi stress and lays it bare. Findings from this study will prove to be an invaluable resource for researchers using tomato as a model for understanding nutrient deficiency.

RGS14 regulates PTH- and FGF23-sensitive NPT2A-mediated renal phosphate uptake via binding to the NHERF1 scaffolding protein

Phosphate homeostasis, mediated by dietary intake, renal absorption, and bone deposition, is incompletely understood because of the uncharacterized roles of numerous implicated protein factors. Here, we identified a novel role for one such element, regulator of G protein signaling 14 (RGS14), suggested by genome-wide association studies to associate with dysregulated Pi levels. We show that human RGS14 possesses a carboxy-terminal PDZ ligand required for sodium phosphate cotransporter 2a (NPT2A) and sodium hydrogen exchanger regulatory factor-1 (NHERF1)–mediated renal Pi transport. In addition, we found using isotope uptake measurements combined with bioluminescence resonance energy transfer assays, siRNA knockdown, pull-down and overlay assays, and molecular modeling that secreted proteins parathyroid hormone (PTH) and fibroblast growth factor 23 inhibited Pi uptake by inducing dissociation of the NPT2A–NHERF1 complex. PTH failed to affect Pi transport in cells expressing RGS14, suggesting that it suppresses hormone-sensitive but not basal Pi uptake. Interestingly, RGS14 did not affect PTH-directed G protein activation or cAMP formation, implying a postreceptor site of action. Further pull-down experiments and direct binding assays indicated that NPT2A and RGS14 bind distinct PDZ domains on NHERF1. We showed that RGS14 expression in human renal proximal tubule epithelial cells blocked the effects of PTH and fibroblast growth factor 23 and stabilized the NPT2A–NHERF1 complex. In contrast, RGS14 genetic variants bearing mutations in the PDZ ligand disrupted RGS14 binding to NHERF1 and subsequent PTH-sensitive Pi transport. In conclusion, these findings identify RGS14 as a novel regulator of hormone-sensitive Pi transport. The results suggest that changes in RGS14 function or abundance may contribute to the hormone resistance and hyperphosphatemia observed in kidney diseases.

Effect of Serum Phosphate on the Prognosis of Septic Patients: A Retrospective Study Based on MIMIC-IV Database.

ObjectiveTo assess the effect of serum inorganic phosphate (Pi) on the prognosis of patients with sepsis.MethodsA retrospective analysis of patients with sepsis selected from the Medical Information Mart for Intensive Care (MIMIC)-IV database was performed. Sepsis was diagnosed according to the Third International Consensus Definition for sepsis and septic shock (Sepsis-3). The time-weighted values of the serum Pi measurements within the first 24 h of sepsis were analyzed. The association between serum Pi and in-hospital mortality was evaluated with a generalized linear model (log-binomial model).ResultsThe analysis of 11,658 patients from six intensive care units (ICUs) showed a nearly linear correlation between serum Pi and in-hospital mortality in all patients with sepsis, especially in those with acute kidney injury (AKI). The increase of serum Pi was related to a higher risk of AKI, higher norepinephrine doses, ICU mortality, and in-hospital mortality. The generalized linear model showed that serum Pi was an independent predictor for in-hospital mortality in all patients with sepsis even within the normal range. The adjusted risk ratios (RRs) were also significant in subgroup analyses according to kidney function, gender, respiratory infection, vasopressor use, and Sequential Organ Failure Assessment (SOFA) score.ConclusionHigher levels of serum Pi, even within the normal range, were significantly associated with a higher risk of in-hospital mortality in patients with sepsis regardless of kidney function, gender, respiratory infection, vasopressor use, and SOFA score.

Evaluation of bone strength using finite-element analysis in patients with ossification of the posterior longitudinal ligament

Patients with ossification of the posterior longitudinal ligament (OPLL) are often reported to have increased bone mineral density (BMD). The bone strength of the proximal femur measured by quantitative computed tomography-based finite element analysis (QCT/FEA) is reportedly comparable between healthy subjects with and without OPLL. However, the bone strength in symptomatic OPLL patients remains unknown. To investigate bone strength measured by QCT/FEA in symptomatic patients with OPLL. A single-center prospective observational study. A total of 157 patients with cervical or thoracic compressive myelopathy were included in the study. We analyzed patients' characteristics, Japanese Orthopedic Association (JOA) score, serum laboratory tests including calcium (Ca), inorganic phosphate (Pi), and bone turnover markers, BMD of the proximal femur and lumbar spine measured using dual-energy X-ray absorptiometry, and predicted bone strength (PBS) of the proximal femur and lumbar spine measured using QCT/FEA. Eligible patients were divided into the non-OPLL and OPLL groups. We compared the patients' characteristics, JOA scores, laboratory data, BMD, and PBS of the proximal femur and lumbar spine between the non-OPLL and OPLL groups among total, male, and female patients by performing Fisher's exact test for categorical variables and the unpaired t test for continuous variables. Then, we used the inverse probability weighted logistic regression model after calculating propensity scores to compare the bone metabolism-associated markers, BMD, and PBS measurements between the groups. Among the eligible 157 patients, 68 were in the non-OPLL group and 89 were in the OPLL group. Compared with the non-OPLL group, the OPLL group had a significantly younger age and higher BMI in the total, male, and female patients. The JOA scores in the total and female patients were significantly higher in the OPLL group than in the non-OPLL group. The OPLL group showed significantly lower Ca levels in the female patients and significantly lower Pi levels in the total or male patients compared with the non-OPLL group in the inverse probability weighting method. The BMD of the proximal femur and lumbar spine and the PBS of the proximal femur were significantly higher in the OPLL group than in the non-OPLL group. There were no significant differences in the PBS and BMD between the male subgroups. However, the BMD and PBS of the proximal femur and lumbar spine were significantly higher in the OPLL females than in the non-OPLL females. Hyperostosis of the posterior longitudinal ligament in OPLL was associated with higher bone strength by QCT/FEA, especially in female OPLL patients.

Fetal cerebral three-dimensional power Doppler vascularization indices and their relationships with maternal glucose levels in pregnancies complicated with gestational diabetes.

ObjectivesWe aimed to evaluate fetal cerebral circulation using three-dimensional power Doppler (3DPD) vascular indices and to study their relationships with maternal lipid and glycaemic profiles.MethodsCase–control study in women with and without gestational diabetes mellitus (GDM) at 28–32 weeks in which feto-maternal Doppler study and 3DPD cerebral vascularization indices (FI, VI and VFI) were determined. Maternal lipid and glycaemic profiles were also analysed. Both groups were compared and the correlations of the 3DPD indices with studied variables were analysed.ResultsThere were significant differences between groups in cerebral FI (p= 0.02), mean maternal Uterine artery PI (p= 0.009) and glucose levels (p= 0.001), being higher in the GDM group. Significant negative correlations were found in GDM group between VFI and MCA PI (p = 0.02) and between VI and MCA PI (p= 0.01). In the GDM group we found a negative significant correlation between FI, VI, VFI and maternal glucose (r= −0.52, p<0.001; r= −0.32, p=0.03 and r= −0.36, p= 0.01, respectively).ConclusionsFetal cerebral FI values were higher in GDM pregnancies. All 3DPD vascular indices showed an inverse correlation with maternal glucose levels. These findings support the view that GDM may also represent a fetal vascular disorder influencing fetal neurodevelopment.

Plasma Membrane Phosphatidylinositol-4-Phosphate Is Not Necessary for Candida albicans Viability yet Is Key for Cell Wall Integrity and Systemic Infection.

ABSTRACTPhosphatidylinositol phosphates are key phospholipids with a range of regulatory roles, including membrane trafficking and cell polarity. Phosphatidylinositol-4-phosphate [PI(4)P] at the Golgi apparatus is required for the budding-to-filamentous-growth transition in the human-pathogenic fungus Candida albicans; however, the role of plasma membrane PI(4)P is unclear. We have investigated the importance of this phospholipid in C. albicans growth, stress response, and virulence by generating mutant strains with decreased levels of plasma membrane PI(4)P, via deletion of components of the PI-4-kinase complex, i.e., Efr3, Ypp1, and Stt4. The amounts of plasma membrane PI(4)P in the efr3Δ/Δ and ypp1Δ/Δ mutants were ∼60% and ∼40%, respectively, of that in the wild-type strain, whereas it was nearly undetectable in the stt4Δ/Δ mutant. All three mutants had reduced plasma membrane phosphatidylserine (PS). Although these mutants had normal yeast-phase growth, they were defective in filamentous growth, exhibited defects in cell wall integrity, and had an increased exposure of cell wall β(1,3)-glucan, yet they induced a range of hyphal-specific genes. In a mouse model of hematogenously disseminated candidiasis, fungal plasma membrane PI(4)P levels directly correlated with virulence; the efr3Δ/Δ mutant had wild-type virulence, the ypp1Δ/Δ mutant had attenuated virulence, and the stt4Δ/Δ mutant caused no lethality. In the mouse model of oropharyngeal candidiasis, only the ypp1Δ/Δ mutant had reduced virulence, indicating that plasma membrane PI(4)P is less important for proliferation in the oropharynx. Collectively, these results demonstrate that plasma membrane PI(4)P levels play a central role in filamentation, cell wall integrity, and virulence in C. albicans.

Phosphate-induced resistance to pathogen infection in Arabidopsis.

SUMMARYIn nature, plants are concurrently exposed to a number of abiotic and biotic stresses. Our understanding of convergence points between responses to combined biotic/abiotic stress pathways remains, however, rudimentary. Here we show that MIR399 overexpression, loss‐of‐function of PHOSPHATE2 (PHO2), or treatment with high phosphate (Pi) levels is accompanied by an increase in Pi content and accumulation of reactive oxygen species (ROS) in Arabidopsis thaliana. High Pi plants (e.g., miR399 overexpressors, pho2 mutants, and plants grown under high Pi supply) exhibited resistance to infection by necrotrophic and hemibiotrophic fungal pathogens. In the absence of pathogen infection, the expression levels of genes in the salicylic acid (SA)‐ and jasmonic acid (JA)‐dependent signaling pathways were higher in high Pi plants compared to wild‐type plants grown under control conditions, which is consistent with increased levels of SA and JA in non‐infected high Pi plants. During infection, an opposite regulation in the two branches of the JA pathway (ERF1/PDF1.2 and MYC2/VSP2) occurs in high Pi plants. Thus, while pathogen infection induces PDF1.2 expression in miR399 OE and pho2 plants, VSP2 expression is downregulated by pathogen infection in these plants. This study supports the notion that Pi accumulation promotes resistance to infection by fungal pathogens in Arabidopsis, while providing a basis to better understand interactions between Pi signaling and hormonal signaling pathways for modulation of plant immune responses.

The efficacy and safety of different doses of calcitriol combined with neutral phosphate in X-linked hypophosphatemia: a prospective study

SummaryThe present study was the first prospective cohort evaluated the efficacy and safety of different doses of calcitriol in XLH children. The results suggested that a dose of 40 ng/kg/day calcitriol, compared with 20 ng/kg/day, was more effective in relieving the rickets, with similar safety outcomes. Further investigations were expected to set more dose groups.IntroductionDose recommended for calcitriol in X-linked hypophosphatemia (XLH) varies in different studies. Therefore, we aimed to compare the efficacy as well as the safety of 20 ng/kg/d and 40 ng/kg/d calcitriol in Chinese XLH pediatrics population.MethodsA 2-year, randomized, open-label, prospective study recruited 68 XLH children, which were randomized to receive either 40 ng/kg/day or 20 ng/kg/day calcitriol. Efficacy endpoints were the total Thacher ricket severity score (RSS) change from baseline to month 12 and 24, the difference in serum TALP level, fasting serum phosphate level, body height Z-score, and frequency of dental abscess. Safety assessments were done using renal ultrasound nephrocalcinosis grades (0–4), fasting serum and 24 h urine calcium level, and the occurrence of hyperparathyroidism.ResultsThe decrease in the total RSS from baseline was more significant in the high-dose group at 12 (difference 0.87, p = 0.049) and 24 month (difference 1.23, p = 0.011). The serum TALP level was significantly lower in the high-dose group at 6 months. Pi level, height Z-score change, frequency of dental abscess and ratio of de novo nephrocalcinosis were comparable. A lower incidence of secondary hyperparathyroidism was seen in the high-dose group (p < 0.0001).ConclusionFor the first time in this prospective cohort, 40 ng/kg/d calcitriol was shown to be the more effective therapy in XLH children than the 20 ng/kg/d. Moreover, 40 ng/kg/d calcitriol was not associated with increasing adverse events.Trial registrationClinicalTrials.gov Identifier: NCT 03,820,518.

PDGF-BB is involved in phosphate regulation via the phosphate transporters in human neuroblastoma SH-SY5Y cells

Inorganic phosphate (Pi) is the second most abundant inorganic ion in the body. Since abnormalities in Pi metabolism are risk factors for various diseases, serum Pi levels are strictly controlled. Type-III sodium-dependent Pi transporters, PiT-1 (encoded by SLC20A1) and PiT-2 (encoded by SLC20A2), are distributed throughout the tissues of the body, including the central nervous system, and are known to be responsible for extracellular to intracellular Pi transport. Platelet-derived growth factor (PDGF) is a major growth factor of mesenchymal cells. PDGF-BB, a homodimer of PDGF-B, regulates intracellular Pi by increasing PiT-1 expression in vascular smooth muscle cells. However, the effects of PDGF-BB on Pi transporters in neurons have yet to be reported. Here, we investigated the effect of PDGF-BB on Pi transporters in human neuroblastoma SH-SY5Y cells. PDGF-BB did not induce SLC20A1 mRNA expression, but it increased the intracellular uptake of Pi via PiT-1 in SH-SY5Y cells. Among the signaling pathways associated with PDGF-BB, AKT signaling was shown to be involved in the increase in Pi transport. In addition, the PDGF-BB-induced increase in Pi mediated neuroprotective effects in SLC20A2-suppressed cells, in an invitro model of the pathological condition found in idiopathic basal ganglia calcification. Moreover, the increase in Pi uptake was found to occur through promotion of intracellular PiT-1 translocation to the plasma membrane. Overall, these results indicate that PDGF-BB exerts neuroprotective effects via Pi transport, and they demonstrate the potential utility of PDGF-BB against abnormal Pi metabolism in neurons.

Npt2a as a target for treating hyperphosphatemia.

Hyperphosphatemia results from an imbalance in phosphate (Pi) homeostasis. In patients with and without reduced kidney function, hyperphosphatemia is associated with cardiovascular complications. The current mainstays in the management of hyperphosphatemia are oral Pi binder and dietary Pi restriction. Although these options are employed in patients with chronic kidney disease (CKD), they seem inadequate to correct elevated plasma Pi levels. In addition, a paradoxical increase in expression of intestinal Pi transporter and uptake may occur. Recently, studies in rodents targeting the renal Na+/Pi cotransporter 2a (Npt2a), responsible for ∼70% of Pi reabsorption, have been proposed as a potential treatment option. Two compounds (PF-06869206 and BAY-767) have been developed which are selective for Npt2a. These Npt2a inhibitors significantly increased urinary Pi excretion consequently lowering plasma Pi and PTH levels. Additionally, increases in urinary excretions of Na+, Cl− and Ca2+ have been observed. Some of these results are also seen in models of reduced kidney function. Responses of FGF23, a phosphaturic hormone that has been linked to the development of left ventricular hypertrophy in CKD, are ambiguous. In this review, we discuss the recent advances on the role of Npt2a inhibition on Pi homeostasis as well as other pleiotropic effects observed with Npt2a inhibition.

An effective in-gel assay protocol for the assessment of acid phosphatase (ACPase) isoform expression in the fungus Serendipita indica.

The induction of acid phosphatase (ACPase) in the mycorrhizal fungi is an adaptive survival mechanism to cope in a low-phosphate environment. A mycorrhizal fungi Serendipita indica can induce the ACPase enzyme and enhance the phosphate (Pi) level to the host plant through Pi-solubilization mechanism, both intracellular and extracellular (media) levels. The spectrophotometer technique has been widely and commonly used to measure the ACPase enzyme activity in all microorganisms and plants using pNPP as a substrate. However, this technique cannot be useful when studying the involvement of ACPase isoforms in Pi-solubilization. In this article, we developed a single method to identify and express the ACPase isoforms of S. indica that contribute to the Pi-nutrition in the plant. This is native-PAGE electrophoresis with the in-gel assay and staining to detect the isoforms of the ACPase enzyme. The dark red-brown color developed after staining indicates the non-denatured (native) ACPase enzyme. This method utilized a modified minimal media for the de-repression of P-responsive genes such as ACPases with minimum salt contamination in the samples. This method will be helpful for the characterization of secretory and intracellular ACPases in fungi.

Effects of Short-Term Phosphate Loading on Aerobic Capacity under Acute Hypoxia in Cyclists: A Randomized, Placebo-Controlled, Crossover Study.

The aim of this study was to evaluate the effects of sodium phosphate (SP) supplementation on aerobic capacity in hypoxia. Twenty-four trained male cyclists received SP (50 mg·kg−1 of FFM/day) or placebo for six days in a randomized, crossover study, with a three-week washout period between supplementation phases. Before and after each supplementation phase, the subjects performed an incremental exercise test to exhaustion in hypoxia (FiO2 = 16%). Additionally, the levels of 2,3-diphosphoglycerate (2,3-DPG), hypoxia-inducible factor 1 alpha (HIF-1α), inorganic phosphate (Pi), calcium (Ca), parathyroid hormone (PTH) and acid-base balance were determined. The results showed that phosphate loading significantly increased the Pi level by 9.0%, whereas 2,3-DPG levels, hemoglobin oxygen affinity, buffering capacity and myocardial efficiency remained unchanged. The aerobic capacity in hypoxia was not improved following SP. Additionally, our data revealed high inter-individual variability in response to SP. Therefore, the participants were grouped as Responders and Non-Responders. In the Responders, a significant increase in aerobic performance in the range of 3–5% was observed. In conclusion, SP supplementation is not an ergogenic aid for aerobic capacity in hypoxia. However, in certain individuals, some benefits can be expected, but mainly in athletes with less training-induced central and/or peripheral adaptation.

Root response of soybean genotypes to low phosphorus availability from juvenile to adult vegetative stages

ABSTRACT Due to the rapid exhaustion of global phosphorus (P) resources, P-efficient crops are required. In this study, we used various soybean genotypes collected from around the world and investigated the morphophysiological responses of their roots to low-P conditions at the cotyledon emergence (VE), unifoliate leaves emergence (VC), and fourth trifoliate leaflet emergence (V4) growth stages. First, we compared the growth of 81 soybean genotypes under different P conditions at the VC stage. The root morphology of most genotypes did not differ according to P conditions. However, GmWMC138 showed increased root weight under low-P conditions at the VC stage, and was therefore selected for further comparative analysis with genotypes with similar seed weights. Four selected genotypes were compared in terms of their seed storage P content and responses of plant growth and phytase and acid phosphatase activities to low-P conditions at the VE and VC stages. The inorganic-P (Pi) levels and shoot growth at the VE and VC stages of GmWMC138 were less affected by low-P conditions compared to the other genotypes. In this genotype, root fresh weight at the VC stage, phytase activity in roots at the VE stage, and acid phosphatase activity in roots at the VC stage increased under low-P conditions. The differences in these enzyme activities may have led to the maintenance of root Pi content and subsequent increase in the root fresh weight at the VC stage under low-P conditions. In addition, the low-P responses of growth and P content at the V4 stage were compared among the selected genotypes. In GmWMC138, fine-root length increased and total P content was maintained under low-P conditions compared to normal-P conditions. These results imply that in soybeans morphological changes in roots in response to low-P conditions at juvenile growth stages, such as the VE and VC stages, may contribute to P-deficiency tolerance in subsequent growth stages, such as the V4 stage.

Association between Volatile Sulfur Compounds Prevotella intermedia and Matrix Metalloproteinase-8 Expression

Objective: To determine the correlation between levels of methyl mercaptan (CH3SH) hydrogen sulfide (H2S), the proportion of Prevotella intermedia (Pi), and matrix metalloproteinase-8 (MMP-8) gene expression levels in periodontitis patients accompanied by halitosis. Material and Methods: Samples were obtained from gingival crevicular fluid (GCF) in the deepest pocket and by swabbing in the tongue coating area in patients with periodontitis presenting with halitosis (n = 23) and healthy subjects as controls (n = 7). The values of CH3SH and H2S were obtained using Oral Chroma. The proportion of Pi and MMP-8 expression levels were evaluated using PCR-RT. All the result was statistically analyzed using SPSS software. Results: The levels of CH3SH and H2S in participants with PD ≥ 6 mm showed a robust negative correlation with the proportion of P. intermedia in GCF and tongue coating. No statistically significant association was detected between CH3SH and H2S levels and MMP-8 expression levels (p>0.05). Conclusion: There is no association between CH3SH and H2S levels, the proportion of P. intermedia, and MMP-8 expression in patients with periodontitis accompanied by halitosis.

Advances in understanding of phosphate homeostasis and related disorders.

Inorganic phosphate (Pi) in the mammalian body is balanced by its influx and efflux through the intestines, kidneys, bones, and soft tissues, at which several sodium/Pi co-transporters mediate its active transport. Pi homeostasis is achieved through the complex counter-regulatory feedback balance between fibroblast growth factor 23 (FGF23), 1,25-dihydroxyvitamin D (1,25(OH)2D), and parathyroid hormone. FGF23, which is mainly produced by osteocytes in bone, plays a central role in Pi homeostasis and exerts its effects by binding to the FGF receptor (FGFR) and αKlotho in distant target organs. In the kidneys, the main target, FGF23 promotes the excretion of Pi and suppresses the production of 1,25(OH)2D. Deficient and excess FGF23 result in hyperphosphatemia and hypophosphatemia, respectively. FGF23-related hypophosphatemic rickets/osteomalacia include tumor-induced osteomalacia and various genetic diseases, such as X-linked hypophosphatemic rickets. Coverage by the national health insurance system in Japan for the measurement of FGF23 and the approval of burosumab, an FGF23-neutralizing antibody, have had a significant impact on the diagnosis and treatment of FGF23-related hypophosphatemic rickets/osteomalacia. Some of the molecules responsible for genetic hypophosphatemic rickets/osteomalacia are highly expressed in osteocytes and function as local regulators of FGF23 production. A number of systemic factors also regulate FGF23 levels. Although the mechanisms responsible for Pi sensing in mammals have not yet been elucidated in detail, recent studies have suggested the involvement of FGFR1. The further clarification of the mechanisms by which osteocytes detect Pi levels and regulate FGF23 production will lead to the development of better strategies to treat hyperphosphatemic and hypophosphatemic conditions.

Etelcalcetide controls secondary hyperparathyroidism and raises sclerostin levels in hemodialysis patients previously uncontrolled with cinacalcet

There is scarce clinical experience with etelcalcetide in patients with secondary hyperparathyroidism uncontrolled with cinacalcet. The effect of etelcalcetide on serum sclerostin levels remains to be clarified. Prospective cohort study in prevalent hemodialysis patients with uncontrolled sHPT under cinacalcet for at least 3 months, mean parathyroid hormone (PTH) > 800 pg/mL and calcium (Ca) > 8.3 mg/dL. Etelcalcetide 5 mg IV/HD was initiated after cinacalcet washout. Levels of PTH, Ca, and phosphorus (Pi) followed monthly for 6 months. Plasma sclerostin levels measured before etelcalcetide treatment and after 6 months. Thirty-four patients were enrolled, 19 (55.9%) male gender. Mean age 60.7 (± 12.3) years; median time on HD 82.5 (7–296) months and median cinacalcet dose was 180 mg/week (Interquartile Range: 180–270). Serum Ca, Pi and PTH levels showed a significant reduction after etelcalcetide treatment from 8.8 mg/dL, 5.4 mg/dL and 1005 pg/mL to 8.1 mg/dL (p = 0.08), 4.9 mg/dL (p = 0.01) and 702 pg/mL (p < 0.001), respectively. Median etelcalcetide dose remained at 5 mg/HD. Plasma sclerostin concentration increased from 35.66 pmol/L (IQR11.94–54.58) to 71.05 pmol/L (IQR54.43–84.91) (p < 0.0001). Etelcalcetide improved sHPT control in this group of patients, previously under cinacalcet treatment, and significantly increased plasma sclerostin concentration. The impact of etelcalcetide treatment on sclerostin levels is a novel finding. Existe escasa experiencia clínica sobre el uso de etelcalcetida en pacientes con hiperparatiroidismo secundario no controlado con cinacalcet. Asimismo, el efecto de la etelcalcetida sobre los niveles de esclerostina aún no ha sido aclarado. Realizamos un estudio de cohorte prospectivo en pacientes en hemodiálisis (HD) con hiperparatiroidismo secundario no controlado con cinacalcet durante al menos 3 meses, hormona paratiroidea media > 800 pg/ml y calcio (Ca) > 8,3 mg/dl. Tras un periodo de lavado, se inició administración intravenosa de etelcalcetida 5 mg/HD y se realizó un seguimiento mensual de los niveles de hormona paratiroidea, Ca y fósforo (Pi) durante 6 meses. Además, los niveles de esclerostina plasmática fueron medidos antes del tratamiento con etelcalcetida y después de 6 meses. Se incluyeron 34 pacientes, 19 (55,9%) de sexo masculino. Edad media 60,7 ± 12,3 años; la mediana de tiempo en HD fue 82,5 (7-296) meses y la mediana de la dosis de cinacalcet fue de 180 mg/semana (rango intercuartílico 180-270). Los niveles séricos de Ca, Pi y hormona paratiroidea mostraron una reducción significativa después del tratamiento con etelcalcetida desde 8,8 mg/dl, 5,4 mg/dl y 1005 pg/ml hasta 8,1 mg/dl (p = 0,08), 4,9 mg/dl (p = 0,01) y 702 pg/mL (p< 0,001) respectivamente. La dosis media de etelcalcetida se mantuvo en 5 mg/HD. La concentración de esclerostina plasmática aumentó de 35,66 pmol/L (rango intercuartílico 11,94-54,58) a 71,05 pmol/L (rango intercuartílico 54,43-84,91; p < 0,0001). En este grupo de pacientes previamente en tratamiento con cinacalcet, la etelcalcetida mejoró el control de hiperparatiroidismo secundario y resultó en un aumento de la concentración plasmática de esclerostina. El efecto del tratamiento con etelcalcetida sobre los niveles de esclerostina es un hallazgo novedoso.

A Dual-Control Strategy by Phosphate Ions and Local Microviscosity for Tracking Adenosine Triphosphate Metabolism in Mitochondria and Cellular Activity Dynamically.

Adenosine triphosphate (ATP) acts as the main energy source for growth and development in organisms, and the disorder reflects the mitochondrial damage to a large extent. Therefore, an efficient tool for the evaluation of the ATP metabolic level is important to track mitochondrial health, providing an additional perspective for an in-depth long-term study on living activities. Herein, a twisted intramolecular charge transfer (TICT) framework is utilized to build up a sensitive receptor, Mito-VP, with a negligible background to target mitochondrial ATP metabolism by monitoring the phosphate ion (Pi) level upon ATP hydrolysis under the overall consideration of the structural and functional features of mitochondria. The responsive fluorescence could be lighted on under the dual control of Pi and local microviscosity, and the two steps of ATP hydrolysis could be captured through fluorescence. In addition to the well-behaved mitochondrial targeting, the energy metabolism at cellular and organism levels has been clarified via mitosis and zebrafish development, respectively.

Association of Serum Phosphate with Low Handgrip Strength in Patients with Advanced Chronic Kidney Disease.

Muscle wasting and hyperphosphatemia are becoming increasingly prevalent in patients who exhibit a progressive decline in kidney function. However, the association between serum phosphate (Pi) level and sarcopenia in advanced chronic kidney disease (CKD) patients remains unclear. We compared the serum Pi levels between advanced CKD patients with (n = 51) and those without sarcopenia indicators (n = 83). Low appendicular skeletal muscle mass index (ASMI), low handgrip strength, and low gait speed were defined per the standards of the Asian Working Group for Sarcopenia. Mean serum Pi level was significantly higher in advanced CKD patients with sarcopenia indicators than those without sarcopenia indicators (3.88 ± 0.86 vs. 3.54 ± 0.73 mg/dL; p = 0.016). Univariate analysis indicated that serum Pi was negatively correlated with ASMI, handgrip strength, and gait speed. Multivariable analysis revealed that serum Pi was significantly associated with handgrip strength (standardized β = −0.168; p = 0.022) and this association persisted even after adjustments for potential confounders. The optimal serum Pi cutoff for predicting low handgrip strength was 3.65 mg/dL, with a sensitivity of 82.1% and specificity of 56.6%. In summary, low handgrip strength is common in advanced CKD patients and serum Pi level is negatively associated with handgrip strength.

In vivo magnetic resonance spectrometry imaging demonstrates comparable adaptation of brain energy metabolism to metabolic stress induced by 72 h of fasting in depressed patients and healthy volunteers

Major depressive disorder (MDD) is characterized by dysregulation of stress systems and by abnormalities in cerebral energy metabolism. Stress induction has been shown to impact neurometabolism in healthy individuals. Contrarily, neurometabolic changes in response to stress are insufficiently investigated in MDD patients. Metabolic stress was induced in MDD patients (MDD, N=24) and in healthy individuals (CTRL, N=22) by application of an established fasting protocol in which calorie intake was omitted for 72h. Both study groups were comparable regarding age, gender distribution, and body mass index (BMI). Fasting-induced effects on brain high-energy phosphate levels and membrane phospholipid metabolism were assessed using phosphorus-31 magnetic resonance spectroscopy (31P-MRS). Two-way repeated measures ANOVAs did not reveal significant interaction effects (group x fasting) or group differences in adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi), phosphomonoesters (PME), phosphodiesters (PDE), or pH levels between MDD and CTRL. Fasting, independent of group, significantly increased ATP and decreased Pi levels and an overall increase in PME/PDE ratio as marker for membrane turnover was observed. Overall these results indicate reactive changes in cerebral energetics and in membrane phospholipid metabolism in response to fasting. The observed effects did not significantly differ between CTRL and MDD, indicating that neurometabolic adaptation to metabolic stress is preserved in MDD patients.