Search

Key points The cellular causes of the age‐related loss in power output and increased fatigability are unresolved. We previously observed that the depressive effects of hydrogen (H+) (pH 6.2) and inorganic phosphate (Pi) (30 mm) did not differ in muscle fibres from young and older men. However, the effects may have been saturated in the severe fatigue‐mimicking condition, potentially masking age differences in the sensitivity of the cross‐bridge to these metabolites. Thus, we compared the contractile mechanics of muscle fibres from the vastus lateralis of 13 young (20–32 years, seven women) and 12 older adults (70–90 years, six women) in conditions mimicking quiescent muscle and a range of elevated H+ (pH 6.8–6.6–6.2) and Pi (12–20–30 mm). The older adult knee extensor muscles showed hallmark signs of ageing, including 19% lower thigh lean mass, 60% lower power and a greater fatigability compared to young adult muscles. Progressively increasing concentrations of H+ and Pi in the chemically‐permeabilized fibre experiments caused a linear decrease in fibre force, velocity and power; however, the effects did not differ with age or sex. Fast fibre cross‐sectional area was 41% smaller in older compared to young adults, which corresponded with lower absolute power. Size‐specific power was greater in fibres from older compared to young adults, indicating the age‐related decline in absolute power was explained by differences in fibre size. These data suggest the age‐related loss in power is determined primarily by fast fibre atrophy in men and women, but the age‐related increase in fatigability cannot be explained by an increased sensitivity of the cross‐bridge to H+ and Pi. The causes of the age‐related loss in muscle power output and the increase in fatigability during dynamic exercise remain elusive. We show that progressively increasing concentrations of hydrogen (H+) and inorganic phosphate (Pi) causes a linear decrease in muscle fibre force, velocity and power, but the depressive effects of these metabolites on cross‐bridge function did not differ in fibres from older compared to young adults across a range of fatigue‐mimicking conditions. We also found peak absolute power did not differ in slow fibres from young and older adults but it was ∼33% lower in older adult fast fibres, which was explained entirely by age differences in fibre size. These data suggest that fast fibre atrophy is a major factor contributing to the loss in power of older men and women, but that the age‐related increase in fatigability cannot be explained by an increased sensitivity of the cross‐bridge to H+ and Pi. [ABSTRACT FROM AUTHOR]

Omecamtiv mecarbil (OM) is a small molecule that has been shown to improve the function of the slow human ventricular myosin (MyHC) motor through a complex perturbation of the thin/thick filament regulatory state of the sarcomere mediated by binding to myosin allosteric sites coupled to inorganic phosphate (Pi) release. Here, myofibrils from samples of human left ventricle (β-slow MyHC-7) and left atrium (α-fast MyHC-6) from healthy donors were used to study the differential effects of μmolar [OM] on isometric force in relaxing conditions (pCa 9.0) and at maximal (pCa 4.5) or half-maximal (pCa 5.75) calcium activation, both under control conditions (15 °C; equimolar DMSO; contaminant inorganic phosphate [Pi] ~170 μM) and in the presence of 5 mM [Pi]. The activation state and OM concentration within the contractile lattice were rapidly altered by fast solution switching, demonstrating that the effect of OM was rapid and fully reversible with dose-dependent and myosin isoform-dependent features. In MyHC-7 ventricular myofibrils, OM increased submaximal and maximal Ca2+-activated isometric force with a complex dose-dependent effect peaking (40% increase) at 0.5 μM, whereas in MyHC-6 atrial myofibrils, it had no effect or—at concentrations above 5 µM—decreased the maximum Ca2+-activated force. In both ventricular and atrial myofibrils, OM strongly depressed the kinetics of force development and relaxation up to 90% at 10 μM [OM] and reduced the inhibition of force by inorganic phosphate. Interestingly, in the ventricle, but not in the atrium, OM induced a large dose-dependent Ca2+-independent force development and an increase in basal ATPase that were abolished by the presence of millimolar inorganic phosphate, consistent with the hypothesis that the widely reported Ca2+-sensitising effect of OM may be coupled to a change in the state of the thick filaments that resembles the on–off regulation of thin filaments by Ca2+. The complexity of this scenario may help to understand the disappointing results of clinical trials testing OM as inotropic support in systolic heart failure compared with currently available inotropic drugs that alter the calcium signalling cascade. [ABSTRACT FROM AUTHOR]

Aim: Vascular aging is an important risk factor for cardiovascular diseases, including abdominal aortic aneurysm (AAA) and pathological aortic dilatation, playing a critical role in the morbidity and mortality of older adults. Vascular calcification, a phenotype of vascular aging, is frequently associated with AAA. However, this association remains unclear owing to the lack of animal models. This study investigated the effects of a high‐phosphate diet (HPD), a prominent trigger of vascular calcification in AAA. Methods: Eight‐week‐old male mice were fed either a normal diet (ND; Ca 1.18%/P 1.07% = 1.10) or an HPD (Ca 1.23%/P 1.65% = 0.75) for 4 weeks. Subsequently, AAA was induced using CaCl2 application and angiotensin II (AngII) infusion for 4 weeks. Results: The HPD resulted in more pronounced AAA formation than did the ND. Importantly, vascular calcification was observed only in the aorta of the HPD mice. Enhanced Runt‐related transcription factor 2 expression and apoptosis (downregulation of growth arrest‐specific gene 6/pAkt survival pathway), two major mechanisms of vascular calcification, were also observed. Furthermore, increased IL‐6 and F4/80 expression was observed in the aorta of HPD mice. In RAW264.7 cells, inorganic phosphate enhanced IL‐6 and IL‐1β expression under AngII priming. Ferric citrate, a phosphate binder, significantly inhibited HPD‐induced AAA formation. Conclusions: These findings suggest that HPD induces vascular calcification and AAA formation, possibly through inflammation. This murine model suggests that vascular calcification induced by phosphate burden may be a therapeutic target for vascular diseases, including AAA. Geriatr Gerontol Int 2024; 24: 973–981. [ABSTRACT FROM AUTHOR]

Although rice is one of the main sources of calories for most of the world, nearly 60% of rice is grown in soils that are low in phosphorus especially in Asia and Africa. Given the limitations of bioavailable inorganic phosphate (Pi) in soils, it is important to develop crops tolerant to low phosphate in order to boost food security. Due to the immobile nature of Pi, plants have developed complex molecular signalling pathways that allow them to discern changes in Pi concentrations in the environment and adapt their growth and development. Recently, in rice, it was shown that a specific serine–threonine kinase known as Phosphorus-starvation tolerance 1 (PSTOL1) is important for conferring low phosphate tolerance in rice. Nonetheless, knowledge about the mechanism underpinning PSTOL1 activity in conferring low Pi tolerance is very limited in rice. Post-translation modifications (PTMs) play an important role in plants in providing a conduit to detect changes in the environment and influence molecular signalling pathways to adapt growth and development. In recent years, the PTM SUMOylation has been shown to be critical for plant growth and development. It is known that plants experience hyperSUMOylation of target proteins during phosphate starvation. Here, we demonstrate that PSTOL1 is SUMOylated in planta, and this affects its phosphorylation activity. Furthermore, we also provide new evidence for the role of SUMOylation in regulating PSTOL1 activity in plant responses to Pi starvation in rice and Arabidopsis. Our data indicated that overexpression of the nonSUMOylatable version of OsPSTOL1 negatively impacts total root length and total root surface area of rice grown under low Pi. Interestingly, our data also showed that overexpression of OsPSTOL1 in a non-cereal species, Arabidopsis, also positively impacts overall plant growth under low Pi by modulating root development. Taken together our data provide new evidence for the role of PSTOL1 SUMOylation in mediating enhanced root development for tolerating phosphate-limiting conditions. [ABSTRACT FROM AUTHOR]

The focus of plant health management is shifting from synthetic chemicals to bio-agents, and endophytes are beneficial for this purpose. In the present study, we isolated eleven endophytic fungi from seven wild rice species. Independent treatment of endophytic fungi in rice showed significant improvements in plant growth, higher tillering and percent fertility, panicle number/hill and filled grain number in endophyte-inoculated plants compared to control plants. Growth promotion activities of two endophytes Curvularia lunata (NRRI EF-11) and Hypocreals sp. (NRRI EF-8) were recorded with increased rice yield. These isolates also exhibited higher plant growth promoting chemicals namely, Indole acetic acid (IAA) and Inorganic phosphate (IP) which was realised into better growth promotion in rice. The biocontrol efficacy of endophytic fungi was highest in NRRI EF-11among all isolates as indicated by inhibition of radial growth of pathogens by 76.98–77.06% and in NRRI EF-8 by 74.81–76.61%, which is due to higher production of prussic acid. Defense induction was confirmed by analyzing the expression of catalase (CAT), peroxidase (POD) and superoxide dismutase (SOD) defense enzymes, where expression of CAT, POD and SOD increased by 19.44–25.86, 2.70–3.16, 11.14–12.95 Units g−1 in treated NRRI EF-11 plants and 18.39–25.84, 2.16–2.94, 10.96–12.62 Units g−1 in treated NRRI EF-8 plants, respectively. These two endophytes have the potentiality to manage crop health in a sustainable way. [ABSTRACT FROM AUTHOR]

Many cells in high glucose repress mitochondrial respiration, as observed in the Crabtree and Warburg effects. Our understanding of biochemical constraints for mitochondrial activation is limited. Using a Saccharomyces cerevisiae screen, we identified the conserved deubiquitinase Ubp3 (Usp10), as necessary for mitochondrial repression. Ubp3 mutants have increased mitochondrial activity despite abundant glucose, along with decreased glycolytic enzymes, and a rewired glucose metabolic network with increased trehalose production. Utilizing ∆ubp3 cells, along with orthogonal approaches, we establish that the high glycolytic flux in glucose continuously consumes free Pi. This restricts mitochondrial access to inorganic phosphate (Pi), and prevents mitochondrial activation. Contrastingly, rewired glucose metabolism with enhanced trehalose production and reduced GAPDH (as in ∆ubp3 cells) restores Pi. This collectively results in increased mitochondrial Pi and derepression, while restricting mitochondrial Pi transport prevents activation. We therefore suggest that glycolytic flux-dependent intracellular Pi budgeting is a key constraint for mitochondrial repression.

This article presents the biochemical intra-skeletal-muscle basis of exercise intensity domains: moderate (M), heavy (H), very heavy (VH) and severe (S). Threshold origins are mediated by a 'Pi double-threshold' mechanism of muscle fatigue, which assumes (1) additional ATP usage, underlying muscle V̇O2 and metabolite slow components, is initiated when inorganic phosphate (Pi) exceeds a critical value (Picrit); (2) exercise is terminated because of fatigue, when Pi reaches a peak value (Pipeak); and (3) the Pi increase and additional ATP usage increase mutually stimulate each other forming a positive feedback. M/H and H/VH borders are defined by Pi on-kinetics in relation to Picrit and Pipeak. The values of the ATP usage activity, proportional to power output (PO), for the M/H, H/VH and VH/S borders are lowest in untrained muscle and highest in well-trained muscle. The metabolic range between the M/H and H/VH border (or 'H space') decreases with muscle training, while the difference between the H/VH and VH/S border (or 'VH space') is only weakly dependent on training status. The absolute magnitude of the muscle V̇O2 slow-component, absent in M exercise, rises gradually with PO to a maximal value in H exercise, and then decreases with PO in VH and S exercise. Simulations of untrained, physically active and well-trained muscle demonstrate that the muscle M/H border need not be identical to the whole-body M/H border determined from pulmonary V̇O2 on-kinetics and blood lactate, while suggesting that the biochemical origins of the H/VH border reside within skeletal muscle and correspond to whole-body critical power.

Patients with chronic kidney disease (CKD) have a high prevalence of hyperphosphatemia, where uremic toxins like inorganic phosphate (Pi) induce a cardiovascular remodeling. Related disorders like atherosclerosis bear the risk of increased morbidity and mortality. We previously found that Pi stimulates the synthesis and sulfation of the negatively charged glycosaminoglycans (GAGs) heparan sulfate and chondroitin sulfate in vascular smooth muscle cells (VSMC). Similar GAG alterations were detected in VSMC-derived exosome-like extracellular vesicles (EV). These EV showed a strong interaction with very small superparamagnetic iron oxide particles (VSOP), which are used as imaging probes for experimental magnetic resonance imaging (MRI). Hyaluronic acid (HA) represents another negatively charged GAG which is supposed to function as binding motif for VSOP as well. We investigated the effects of Pi on the amounts of HA in cells and EV and studied the HA-dependent interaction between VSOP with cells and EV. Rat VSMC were treated with elevated concentrations of Pi. CKD in rats was induced by adenine feeding. EV were isolated from culture supernatants and rat plasma. We investigated the role of HA in binding VSOP to cells and EV via cell-binding studies, proton relaxometry, and analysis of cellular signaling, genes, proteins, and HA contents. Due to elevated HA contents, VSMC and EV showed an increased interaction with VSOP after Pi stimulation. Amongst others, Pi induced hyaluronan synthase (HAS)2 expression and activation of the Wnt pathway in VSMC. An alternative upregulation of HA by iloprost and an siRNA-mediated knockdown of HAS2 confirmed the importance of HA in cells and EV for VSOP binding. The in vitro-derived data were validated by analyses of plasma-derived EV from uremic rats. In conclusion, the inorganic uremic toxin Pi induces HA synthesis in cells and EV, which leads to an increased interaction with VSOP. HA might therefore be a potential molecular target structure for improved detection of pathologic tissue changes secondary to CKD like atherosclerosis or cardiomyopathy using EV, VSOP and MRI. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Central South University is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

For cells to obtain inorganic phosphate, ectoenzymes in the plasma membrane, which contain a catalytic site facing the extracellular environment, hydrolyze phosphorylated molecules. In this study, we show that increased Pi levels in the extracellular environment promote a decrease in ecto‐phosphatase activity, which is associated with Pi‐induced oxidative stress. High levels of Pi inhibit ecto‐phosphatase because Pi generates H2O2. Ecto‐phosphatase activity is inhibited by H2O2, and this inhibition is selective for phospho‐tyrosine hydrolysis. Additionally, it is shown that the mechanism of inhibition of ecto‐phosphatase activity involves lipid peroxidation. In addition, the inhibition of ecto‐phosphatase activity by H2O2 is irreversible. These findings have new implications for understanding ecto‐phosphatase regulation in the tumor microenvironment. H2O2 stimulated by high Pi inhibits ecto‐phosphatase activity to prevent excessive accumulation of extracellular Pi, functioning as a regulatory mechanism of Pi variations in the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Alcohol consumption is associated with an increased risk of breast cancer, even at low alcohol intake levels, but public awareness of the breast cancer risk associated with alcohol intake is low. Furthermore, the causative mechanisms underlying alcohol's association with breast cancer are unknown. The present theoretical paper uses a modified grounded theory method to review the research literature and propose that alcohol's association with breast cancer is mediated by phosphate toxicity, the accumulation of excess inorganic phosphate in body tissue. Serum levels of inorganic phosphate are regulated through a network of hormones released from the bone, kidneys, parathyroid glands, and intestines. Alcohol burdens renal function, which may disturb the regulation of inorganic phosphate, impair phosphate excretion, and increase phosphate toxicity. In addition to causing cellular dehydration, alcohol is an etiologic factor in nontraumatic rhabdomyolysis, which ruptures cell membranes and releases inorganic phosphate into the serum, leading to hyperphosphatemia. Phosphate toxicity is also associated with tumorigenesis, as high levels of inorganic phosphate within the tumor microenvironment activate cell signaling pathways and promote cancer cell growth. Furthermore, phosphate toxicity potentially links cancer and kidney disease in onco‐nephrology. Insights into the mediating role of phosphate toxicity may lead to future research and interventions that raise public health awareness of breast cancer risk and alcohol consumption. Public awareness of breast cancer associated with alcohol intake is low, and causative mechanisms are unknown. The present review proposes that alcohol's association with breast cancer is mediated by phosphate toxicity, which is the accumulation of inorganic phosphate in body tissue. Alcohol burdens renal function and causes nontraumatic rhabdomyolysis that releases inorganic phosphate into serum, leading to hyperphosphatemia, phosphate toxicity, and tumorigenesis by stimulating cancer cell growth. Insights in this review may raise awareness of breast cancer risk associated with alcohol consumption. [ABSTRACT FROM AUTHOR]

We hypothesize that the V˙O2 time constant (τV˙O2) determines exercise tolerance by defining the power output associated with a "critical threshold" of intramuscular metabolite accumulation (e.g., inorganic phosphate), above which muscle fatigue and work inefficiency are apparent. Thereafter, the V˙O2 "slow component" and its consequences (increased pulmonary, circulatory, and neuromuscular demands) determine performance limits.

Although rice is one of the main sources of calories for most of the world, nearly 60% of rice is grown in soils that are low in phosphorus especially in Asia and Africa. Given the limitations of bioavailable inorganic phosphate (Pi) in soils, it is important to develop crops tolerant to low phosphate in order to boost food security. Due to the immobile nature of Pi, plants have developed complex molecular signalling pathways that allow them to discern changes in Pi concentrations in the environment and adapt their growth and development. Recently, in rice, it was shown that a specific serine–threonine kinase known as Phosphorus-starvation tolerance 1 (PSTOL1) is important for conferring low phosphate tolerance in rice. Nonetheless, knowledge about the mechanism underpinning PSTOL1 activity in conferring low Pi tolerance is very limited in rice. Post-translation modifications (PTMs) play an important role in plants in providing a conduit to detect changes in the environment and influence molecular signalling pathways to adapt growth and development. In recent years, the PTM SUMOylation has been shown to be critical for plant growth and development. It is known that plants experience hyperSUMOylation of target proteins during phosphate starvation. Here, we demonstrate that PSTOL1 is SUMOylated in planta, and this affects its phosphorylation activity. Furthermore, we also provide new evidence for the role of SUMOylation in regulating PSTOL1 activity in plant responses to Pi starvation in rice and Arabidopsis. Our data indicated that overexpression of the non-SUMOylatable version of OsPSTOL1 negatively impacts total root length and total root surface area of rice grown under low Pi. Interestingly, our data also showed that overexpression of OsPSTOL1 in a non-cereal species, Arabidopsis, also positively impacts overall plant growth under low Pi by modulating root development. Taken together our data provide new evidence for the role of PSTOL1 SUMOylation in mediating enhanced root development for tolerating phosphate-limiting conditions.

We evaluated whether task‐dependent, age‐related differences in muscle fatigue (contraction‐induced decline in normalized power) develop from differences in bioenergetics or metabolic economy (ME; mass‐normalized work/mM ATP). We used magnetic resonance spectroscopy to quantify intracellular metabolites in vastus lateralis muscle of 10 young and 10 older adults during two maximal‐effort, 4‐min isotonic (20% maximal torque) and isokinetic (120°s−1) contraction protocols. Fatigue, inorganic phosphate (Pi), and pH (p ≥ 0.213) differed by age during isotonic contractions. However, older had less fatigue (p ≤ 0.011) and metabolic perturbation (lower [Pi], greater pH; p ≤ 0.031) than young during isokinetic contractions. ME was lower in older than young during isotonic contractions (p ≤ 0.003), but not associated with fatigue in either protocol or group. Rather, fatigue during both tasks was linearly related to changes in [H+], in both groups. The slope of fatigue versus [H+] was 50% lower in older than young during isokinetic contractions (p ≤ 0.023), consistent with less fatigue in older during this protocol. Overall, regardless of age or task type, acidosis, but not ME, was the primary mechanism for fatigue in vivo. The source of the age‐related differences in contraction‐induced acidosis in vivo remains to be determined, as does the apparent task‐dependent difference in the sensitivity of muscle to [H+]. [ABSTRACT FROM AUTHOR]

Computer simulations using a dynamic model of the skeletal muscle bioenergetic system, involving the Pi-double-threshold mechanism of muscle fatigue, demonstrate that the training-induced increase in  V · O2max, increase in critical power (CP) and acceleration of primary phase II of the  V · O2 on kinetics (decrease in t0.63) is caused by elevated OXPHOS activity acting through a decrease in and slowing of the Pi (inorganic phosphate) rise during the rest-to-work transition. This change leads to attenuation of the reaching by Pi of Pipeak, peak Pi at which exercise is terminated because of fatigue. The delayed (in time and in relation to  V · O2 increase) Pi rise for a given power output (PO) in trained muscle causes Pi to reach Pipeak (in very heavy exercise) after a longer time and at a higher  V · O2; thus, exercise duration is lengthened, and  V · O2max is elevated compared to untrained muscle. The diminished Pi increase during exercise with a given PO can cause Pi to stabilize at a steady state less than Pipeak, and exercise can continue potentially ad infinitum (heavy exercise), instead of rising unceasingly and ultimately reaching Pipeak and causing exercise termination (very heavy exercise). This outcome means that CP rises, as the given PO is now less than, and not greater than CP. Finally, the diminished Pi increase (and other metabolite changes) results in, at a given PO (moderate exercise), the steady state of fluxes (including  V · O2) and metabolites being reached faster; thus, t0.63 is shortened. This effect of elevated OXPHOS activity is possibly somewhat diminished by the training-induced decrease in Pipeak. [ABSTRACT FROM AUTHOR]

Abstract We evaluated whether task‐dependent, age‐related differences in muscle fatigue (contraction‐induced decline in normalized power) develop from differences in bioenergetics or metabolic economy (ME; mass‐normalized work/mM ATP). We used magnetic resonance spectroscopy to quantify intracellular metabolites in vastus lateralis muscle of 10 young and 10 older adults during two maximal‐effort, 4‐min isotonic (20% maximal torque) and isokinetic (120°s−1) contraction protocols. Fatigue, inorganic phosphate (Pi), and pH (p ≥ 0.213) differed by age during isotonic contractions. However, older had less fatigue (p ≤ 0.011) and metabolic perturbation (lower [Pi], greater pH; p ≤ 0.031) than young during isokinetic contractions. ME was lower in older than young during isotonic contractions (p ≤ 0.003), but not associated with fatigue in either protocol or group. Rather, fatigue during both tasks was linearly related to changes in [H+], in both groups. The slope of fatigue versus [H+] was 50% lower in older than young during isokinetic contractions (p ≤ 0.023), consistent with less fatigue in older during this protocol. Overall, regardless of age or task type, acidosis, but not ME, was the primary mechanism for fatigue in vivo. The source of the age‐related differences in contraction‐induced acidosis in vivo remains to be determined, as does the apparent task‐dependent difference in the sensitivity of muscle to [H+].

Release of the ATP hydrolysis product ortophosphate (Pi) from the active site of myosin is central in chemo‐mechanical energy transduction and closely associated with the main force‐generating structural change, the power‐stroke. Despite intense investigations, the relative timing between Pi‐release and the power‐stroke remains poorly understood. This hampers in depth understanding of force production by myosin in health and disease and our understanding of myosin‐active drugs. Since the 1990s and up to today, models that incorporate the Pi‐release either distinctly before or after the power‐stroke, in unbranched kinetic schemes, have dominated the literature. However, in recent years, alternative models have emerged to explain apparently contradictory findings. Here, we first compare and critically analyze three influential alternative models proposed previously. These are either characterized by a branched kinetic scheme or by partial uncoupling of Pi‐release and the power‐stroke. Finally, we suggest critical tests of the models aiming for a unified picture. [ABSTRACT FROM AUTHOR]

In this report, we establish a straightforward method for estimating the equilibrium constant for the creatine kinase reaction (CK Keq″) over wide but physiologically and experimentally relevant ranges of pH, Mg2+ and temperature. Our empirical formula for CK Keq″ is based on experimental measurements. It can be used to estimate [ADP] when [ADP] is below the resolution of experimental measurements, a typical situation because [ADP] is on the order of micromolar concentrations in living cells and may be much lower in many in vitro experiments. Accurate prediction of [ADP] is essential for in vivo studies of cellular energetics and metabolism and for in vitro studies of ATP-dependent enzyme function under near-physiological conditions. With [ADP], we were able to obtain improved estimates of ΔGATP, necessitating the reinvestigation of previously reported ADP- and ΔGATP-dependent processes. Application to actomyosin force generation in muscle provides support for the hypothesis that, when [Pi] varies and pH is not altered, the maximum Ca2+-activated isometric force depends on ΔGATP in both living and permeabilized muscle preparations. Further analysis of the pH studies introduces a novel hypothesis around the role of submicromolar ADP in force generation. [ABSTRACT FROM AUTHOR]

Almost half of the people who die from sudden cardiac arrest have no detectable heart disease. Among children and young adults, the cause of approximately one‐third of deaths from sudden cardiac arrest remains unexplained after thorough examination. Sudden cardiac arrest and related sudden cardiac death are attributed to dysfunctional cardiac ion‐channels. The present perspective paper proposes a pathophysiological mechanism by which phosphate toxicity from cellular accumulation of dysregulated inorganic phosphate interferes with normal calcium handling in the heart, leading to sudden cardiac arrest. During cardiac muscle relaxation following contraction, SERCA2a pumps actively transport calcium ions into the sarcoplasmic reticulum, powered by ATP hydrolysis that produces ADP and inorganic phosphate end products. Reviewed evidence supports the proposal that end‐product inhibition of SERCA2a occurs as increasing levels of inorganic phosphate drive up phosphate toxicity and bring cardiac function to a sudden and unexpected halt. The paper concludes that end‐product inhibition from ATP hydrolysis is the mediating factor in the association of sudden cardiac arrest with phosphate toxicity. However, current technology lacks the ability to directly measure this pathophysiological mechanism in active myocardium, and further research is needed to confirm phosphate toxicity as a risk factor in individuals with sudden cardiac arrest. Moreover, phosphate toxicity may be reduced through modification of dietary phosphate intake, with potential for employing low‐phosphate dietary interventions to reduce the risk of sudden cardiac arrest. [ABSTRACT FROM AUTHOR]

During the initial phase of fatigue induced by repeated contractions in fast‐twitch muscle fibers, tetanic force decreases despite increasing tetanic free cytosolic [Ca2+] ([Ca2+]cyt). Here, we hypothesized that the increase in tetanic [Ca2+]cyt nevertheless has positive effects on force in early fatigue. Experiments on enzymatically isolated mouse flexor digitorum brevis (FDB) fibers showed that an increase in tetanic [Ca2+]cyt during ten 350 ms contractions required trains of electrical pulses to be elicited at short intervals (≤2 s) and at high frequencies (≥70 Hz). Mechanically dissected mouse FDB fibers showed greater decrease in tetanic force when the stimulation frequency during contractions was gradually reduced to prevent the increase in tetanic [Ca2+]cyt. Novel analyses of data from previous studies revealed an increased rate of force development in the tenth fatiguing contraction in mouse FDB fibers, as well as in rat FDB and human intercostal fibers. Mouse FDB fibers deficient in creatine kinase showed no increase in tetanic [Ca2+]cyt and slowed force development in the tenth contraction; after injection of creatine kinase to enable phosphocreatine breakdown, these fibers showed an increase in tetanic [Ca2+]cyt and accelerated force development. Mouse FDB fibers exposed to ten short contractions (43 ms) produced at short intervals (142 ms) showed increased tetanic [Ca2+]cyt accompanied by a marked (~16%) increase in the developed force. In conclusion, the increase in tetanic [Ca2+]cyt in early fatigue is accompanied by accelerated force development, which under some circumstances can counteract the decline in physical performance caused by the concomitant decrease in maximum force. [ABSTRACT FROM AUTHOR]

Microalgae are naturally adapted to the fluctuating availability of phosphorus (P) to opportunistically uptake large amounts of inorganic phosphate (Pi) and safely store it in the cell as polyphosphate. Hence, many microalgal species are remarkably resilient to high concentrations of external Pi. Here, we report on an exception from this pattern comprised by a failure of the high Pi-resilience in strain Micractinium simplicissimum IPPAS C-2056 normally coping with very high Pi concentrations. This phenomenon occurred after the abrupt re-supplementation of Pi to the M. simplicissimum culture pre-starved of P. This was the case even if Pi was re-supplemented in a concentration far below the level toxic to the P-sufficient culture. We hypothesize that this effect can be mediated by a rapid formation of the potentially toxic short-chain polyphosphate following the mass influx of Pi into the P-starved cell. A possible reason for this is that the preceding P starvation impairs the capacity of the cell to convert the newly absorbed Pi into a "safe" storage form of long-chain polyphosphate. We believe that the findings of this study can help to avoid sudden culture crashes, and they are also of potential significance for the development of algae-based technologies for the efficient bioremoval of P from P-rich waste streams. [ABSTRACT FROM AUTHOR]

This review summarizes the current understanding of the role of plasma membrane transporters in regulating intracellular inorganic phosphate ([Pi]In) in mammals. Pi influx is mediated by SLC34 and SLC20 Na+-Pi cotransporters. In non-epithelial cells other than erythrocytes, Pi influx via SLC20 transporters PiT1 and/or PiT2 is balanced by efflux through XPR1 (xenotropic and polytropic retrovirus receptor 1). Two new pathways for mammalian Pi transport regulation have been described recently: 1) in the presence of adequate Pi, cells continuously internalize and degrade PiT1. Pi starvation causes recycling of PiT1 from early endosomes to the plasma membrane and thereby increases the capacity for Pi influx; and 2) binding of inositol pyrophosphate InsP8 to the SPX domain of XPR1 increases Pi efflux. InsP8 is degraded by a phosphatase that is strongly inhibited by Pi. Therefore, an increase in [Pi]In decreases InsP8 degradation, increases InsP8 binding to SPX, and increases Pi efflux, completing a feedback loop for [Pi]In homeostasis. Published data on [Pi]In by magnetic resonance spectroscopy indicate that the steady state [Pi]In of skeletal muscle, heart, and brain is normally in the range of 1-5 mM, but it is not yet known whether PiT1 recycling or XPR1 activation by InsP8 contributes to Pi homeostasis in these organs. Data on [Pi]In in cultured cells are variable and suggest that some cells can regulate [Pi] better than others, following a change in [Pi]Ex. More measurements of [Pi]In, influx, and efflux are needed to determine how closely, and how rapidly, mammalian [Pi]In is regulated during either hyper-or hypophosphatemia. [ABSTRACT FROM AUTHOR]

Recent studies have shown that Cr uses other element transporters such as phosphate transporters to enter cells. The aim of this work is to explore the interaction between dichromate and inorganic phosphate (Pi) in the plant of Vicia faba L. To study this interaction, we used three concentrations of Dipotassium hydrogen phosphate (K 2 HPO 4) 10 mM (Pi10), 50 mM (Pi50) and 100 mM (Pi100) added alone or in combination with potassium dichromate (K 2 Cr 2 O 7) Cr + Pi10, Cr + Pi50 and Cr + Pi100. In order to investigate the impact of this interaction on morpho-physiological parameters, the biomass, chlorophyll content, proline level, H 2 O 2 level, Catalase and Ascorbate peroxidase activity and Cr-bioaccumulation has been determined. For the molecular scale, the theoretical chemistry was used via molecular docking to explore the various interactions between dichromate Cr 2 O 7 2−/HPO 4 2−/H 2 O 4 P− and the phosphate-transporter. We have selected the eukaryotic phosphate transporter (PDB: 7SP5) as the module. The results showed that K 2 Cr 2 O 7 negatively affects morpho-physiological parameters and generates oxidative damage (+84% H 2 O 2 than the control), which involved the production of antioxidant enzymes (+147% Catalase and +176% Ascorbate-peroxidase) and Proline (+108%). The addition of Pi improved the growth of Vicia faba L. and induces the partial restoration of the parameters affected by Cr (VI) to the normal levels. Also, it decreased oxidative damage and reduce Cr (VI) bioaccumulation in shoots and roots. Molecular docking has shown that the dichromate structure is more compatible and establishes more bonds with the Pi-transporter which generates a very stable complex compared to HPO 4 2−/H 2 O 4 P−. Overall, these results confirmed that there is a strong relationship between dichromate uptake and the Pi-transporter. • Competition between dichromate and Pi for the use of Pi carrier. • Dichromate is more compatible with the Pi transporter than Pi. • Dichromate crosses the Pi transporter with high selectivity. • Dichromate can inhibit the Pi transporter even at very low concentrations. [ABSTRACT FROM AUTHOR]

The subsurface flow of particular phosphate (P) has been recently regarded as a vital P transport path. Humic acid (HA) and P usually coexist in the natural environment and show a strong affinity to iron (Fe) (oxyhydr)oxide. The impact of P and HA on Fe (oxyhydr)oxide stability and transport is critical for evaluating the vertical transport of particular P and biogeochemical processes of Fe and P. This study investigated the effect of inorganic (IP) and organic (OP) phosphate on the stability and transport of ferrihydrite and goethite with HA through stability tests and column experiments. The adsorption of IP or OP on Fe (oxyhydr)oxide enhanced the stability and transport of Fe (oxyhydr)oxide, and OP showed a stronger enhancement than IP due to its stronger binding capacity and more negative surface. Compared with ferrihydrite, goethite had fewer adsorption sites for IP or OP and showed strong stability and transport at low IP (50 μM) or OP (10 μM) concentration. HA decreased IP or OP adsorption on Fe (oxyhydr)oxide through competition adsorption and electrostatic repulsion. The formed ternary phosphate-Fe (oxyhydr)oxide-HA complex showed a more negative surface and strong stability and transport. Our findings provide direct insights into the distinct role of IP and OP on Fe (oxyhydr)oxide stability and transport in the presence of HA, which provides essential information for evaluating the transport of particular Fe (oxyhydr)oxide-facilitated P in soils and subsurface environments rich in iron, phosphate, and dissolved carbon. [Display omitted] • Coupled impact of P and HA on Fe (oxyhydr)oxide transport is explored. • IP or OP loading enhanced the stability and transport of Fe (oxyhydr)oxide. • Fe (oxyhydr)oxide exhibits stronger transport with OP than with IP. • HA decreases IP or OP adsorption on Fe (oxyhydr)oxide by competition adsorption and electrostatic repulsion. [ABSTRACT FROM AUTHOR]

Computer simulations using a dynamic model of the skeletal muscle bioenergetic system, involving the Pi-double-threshold mechanism of muscle fatigue, demonstrate that the training-induced increase in V·O2max, increase in critical power (CP) and acceleration of primary phase II of the V·O2 on kinetics (decrease in t0.63) is caused by elevated OXPHOS activity acting through a decrease in and slowing of the Pi (inorganic phosphate) rise during the rest-to-work transition. This change leads to attenuation of the reaching by Pi of Pipeak, peak Pi at which exercise is terminated because of fatigue. The delayed (in time and in relation to V·O2 increase) Pi rise for a given power output (PO) in trained muscle causes Pi to reach Pipeak (in very heavy exercise) after a longer time and at a higher V·O2; thus, exercise duration is lengthened, and V·O2max is elevated compared to untrained muscle. The diminished Pi increase during exercise with a given PO can cause Pi to stabilize at a steady state less than Pipeak, and exercise can continue potentially ad infinitum (heavy exercise), instead of rising unceasingly and ultimately reaching Pipeak and causing exercise termination (very heavy exercise). This outcome means that CP rises, as the given PO is now less than, and not greater than CP. Finally, the diminished Pi increase (and other metabolite changes) results in, at a given PO (moderate exercise), the steady state of fluxes (including V·O2) and metabolites being reached faster; thus, t0.63 is shortened. This effect of elevated OXPHOS activity is possibly somewhat diminished by the training-induced decrease in Pipeak.

Qin Lan,1,2,* Yuming Zhang,3,* Fang Lin,1,2 Qingshu Meng,1,2 Nicholas Buys,4 Huimin Fan,1,2 Jing Sun3,4 1Shanghai East Hospital, Tongji University, Shanghai, People’s Republic of China; 2School of Medicine, Tongji University, Shanghai, People’s Republic of China; 3School of Medicine and Dentistry, Griffith University, Gold Coast, QLD, Australia; 4Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, Australia*These authors contributed equally to this workCorrespondence: Jing Sun, School of Medicine and Dentistry, Griffith University, Gold Coast, QLD, Australia, Tel +61756780924, Fax +61756780303, Email j.sun@griffith.edu.au Huimin Fan, Shanghai East Hospital, Tongji University, Shanghai, People’s Republic of China, Email frankfan@tongji.edu.cnPurpose: This study aimed to investigate the association between sex-specific baseline serum phosphate and the incidence of new-onset cardiometabolic disease in a cohort of Shanghai-based older Chinese individuals.Patients and Methods: A community cohort of 5000 disease-free Chinese men and women was recruited in 2013 and followed until 2017 for the development of cardiometabolic disease. Participants underwent index and follow-up health screens at the Tongji Medical School affiliated Shanghai East Hospital, including blood biochemistry analysis, anthropometric measurements, interview on health-related behaviors, and clinical evaluation.Results: Higher baseline serum phosphate (> 1.25 mmol/L) was significantly associated with new-onset type-2 diabetes mellitus (HR 1.730, 95% CI 1.127– 2.655) and metabolic syndrome (HR 0.640, 95% CI 1.085– 2.155) in women. Baseline serum phosphate was associated with age, BMI, waist circumference, SBP, total calcium, bicarbonate, and total cholesterol in women. The estimated risk of developing diabetes mellitus in women with inorganic phosphate > 1.25 mmol/L was 14.54%. Inorganic phosphate accounted for 9.2% of the variance explained in a total estimated 14.52% of variance attributed to BMI, total cholesterol, total calcium, waist circumference, and inorganic phosphate.Conclusion: Serum phosphate concentration showed sex-specific associations with diabetes and metabolic syndrome. Higher inorganic phosphate was associated with increased risk of developing diabetes mellitus in women. These findings may be important in the assessment of individualized metabolic risk.Keywords: inorganic phosphate, diabetes mellitus, metabolic syndrome, older women, cohort study

This review summarizes the current understanding of the role of plasma membrane transporters in regulating intracellular inorganic phosphate ([Pi]In) in mammals. Pi influx is mediated by SLC34 and SLC20 Na+-Pi cotransporters. In non-epithelial cells other than erythrocytes, Pi influx via SLC20 transporters PiT1 and/or PiT2 is balanced by efflux through XPR1 (xenotropic and polytropic retrovirus receptor 1). Two new pathways for mammalian Pi transport regulation have been described recently: 1) in the presence of adequate Pi, cells continuously internalize and degrade PiT1. Pi starvation causes recycling of PiT1 from early endosomes to the plasma membrane and thereby increases the capacity for Pi influx; and 2) binding of inositol pyrophosphate InsP8 to the SPX domain of XPR1 increases Pi efflux. InsP8 is degraded by a phosphatase that is strongly inhibited by Pi. Therefore, an increase in [Pi]In decreases InsP8 degradation, increases InsP8 binding to SPX, and increases Pi efflux, completing a feedback loop for [Pi]In homeostasis. Published data on [Pi]In by magnetic resonance spectroscopy indicate that the steady state [Pi]In of skeletal muscle, heart, and brain is normally in the range of 1–5 mM, but it is not yet known whether PiT1 recycling or XPR1 activation by InsP8 contributes to Pi homeostasis in these organs. Data on [Pi]In in cultured cells are variable and suggest that some cells can regulate [Pi] better than others, following a change in [Pi]Ex. More measurements of [Pi]In, influx, and efflux are needed to determine how closely, and how rapidly, mammalian [Pi]In is regulated during either hyper- or hypophosphatemia.

This study evaluated the effect of limestone solubility on the capacity of a novel consensus bacterial 6-phytase variant (PhyG) to improve phosphorus (P) and calcium (Ca) digestibility, retention, and utilization in low-Ca broiler diets containing no added inorganic phosphate (Pi). Male Ross 308 broilers (n = 1,152) were fed one of 16 experimental diets from 11 to 21 d of age in a randomized complete design (12 birds/cage, 6 cages/treatment). Diets comprised three positive controls (PC3, PC2, and PC1) containing 1.8, 1.2, or 0.6 g/kg MCP-P and 7.7, 7.0, or 6.2 g/kg Ca, respectively, and a negative control (NC) containing no added Pi (4.4 g/kg P; 2.8 g/kg phytate-P) and 5.5 g/kg Ca from either low or high solubility limestone (LSL or HSL, respectively, [with 42% and 97% solubility after 5 min at pH 3.0]), supplemented with 0, 250, 500, 1,000, or 2,000 FTU/kg of PhyG. Fecal samples collected on days 18 to 20 and ileal digesta collected on day 21 were analyzed for titanium dioxide, Ca, P, and phytate (IP6, inositol hexakisphosphate). Tibias (day 21) were analyzed for ash content. Data were analyzed by factorial analysis (2 limestone solubilities × 4 MCP-P levels and 2 limestone solubilities × 5 phytase dose levels) and exponential regression. Increasing dose levels of PhyG resulted in an exponential increase (P < 0.01) in the apparent ileal digestibility (AID) of P, ileal digestible P content of the diet, ileal IP6 content, and IP6 disappearance in birds fed either HSL or LSL diets, but AID Ca and ileal digestible Ca were exponentially increased by the phytase only in HSL diets (P < 0.01). Relative to HSL, the LSL increased AID P, ileal digestible P, and IP6 disappearance (P < 0.05) but reduced AID Ca, ileal digestible Ca, and retainable Ca (P < 0.05), resulting in reduced retainable P and tibia ash. Phytase exponentially increased the apparent total tract digestibility of P, retainable P, and tibia ash in HSL and LSL diets, but at or above 500 FTU/kg values were higher in HSL than LSL (interaction P < 0.05). The findings highlight that phytase dose–response effects on mineral digestibility and utilization are different for high- and low-solubility limestones, and it is therefore recommended to use digestible rather than total Ca content during diet formulation to ensure an optimal balance of Ca and P, especially in low-Ca diets. In diets containing HSL, higher phytase dose levels may be needed to compensate for the low digestible P content of the basal diet. [ABSTRACT FROM AUTHOR]

A novel chlorophyte algae strain with outstanding resilience to high inorganic phosphate (Pi) concentrations in the medium was isolated from a phosphorus-polluted site near a rock phosphate mine. According to the morphological, ultrastructural and genetic criteria the strain was assigned to the species Micractinium simplicissimum H.Chae, H.-G. Choi & J.H.Kim. This strain retained cell viability and growth capacity in the presence of Pi concentrations up to 14 g L–1. The uptake of Pi by the cells was moderate (equal to ca. 0.7% increase in cell dry weight P percentage) regardless of the amount of the exogenic Pi added to the culture. At the same time, approximately a half of the Pi removed by the M. simplicissimum from the culture was reversely adsorbed by the cell surface and/or the intercellular matrix and cell debris. The ultrastructural studies indicated the metabolically active status of the cells together with the presence of phosphorus-rich (likely, polyphosphate) inclusions outside and inside the cells (mainly in vacuoles). We hypothesized that the Pi resilience of the studied strain stems from its high Pi adsorption capacity together with its ability to throttle the Pi influx into the cell preventing the rapid buildup of intracellular Pi and potentially toxic short-chain polyphosphate. [ABSTRACT FROM AUTHOR]

Background: Limited phosphate (Pi) reserves and the economic and adverse environmental impacts of excessive application of mineral fertilizers in soils are alarming. Therefore, the use of organic phosphorus (Porg) is suggested to reduce reliance on chemical fertilizers. Aims: There is currently little information regarding the accessibility of Porg to N2 fixation plants. Therefore, the present study aims to address the question of to what extent Porg substrates can serve as reliable sources of phosphorus (P) for faba bean in its nodulated phase. Specifically, we intended to explore whether N2‐fixing plants employ intrinsic mechanisms to facilitate Porg availability. Methods: A pot experiment was conducted to assess the inherent capacity of two faba bean varieties (Tiffany vs. Mallory) to utilize Porg supplied as phytic acid and Ca‐glycerophosphate. Plants were inoculated with Rhizobium leguminosarum bv. viciae 3841 strain and cultivated on sterilized loamy sand under greenhouse conditions. Results: Phytic acid was relatively less efficient than Ca‐glycerophosphate in sustaining plant growth. Compared to Mallory, the variety Tiffany displayed a higher capability to use Porg, as evidenced by the relatively higher biomass production, nodulation, phosphorus use efficiency, and P‐ and N‐accumulations in plant tissues. Porg exploitation was intimately linked to the efficient utilization of the host's carbohydrate budget into nutrient‐acquiring structures (roots and nodules). In addition, the preferential allocation of Pi to prolific nodules is essential for plants to thrive best under these circumstances. Conclusions: Together with N profitability, these findings suggested that N2‐fixing plants (e.g., faba bean) can promote the sustainable exploitation of Porg, thereby diminishing the sizeable environmental footprint. [ABSTRACT FROM AUTHOR]

Acinetobacter baumannii is considered as a gram-negative, ubiquitous nonmotile organism, it's growth is limited by many conditions such as phosphate abundance. Phosphorus is the most essential element contributes too many biological processes like energy metabolism, the inheritance of genetic materials, intracellular signalling, and membrane integrity. In this study, different phosphorus sources and concentrations were used to detect the best source and the best concentration for bacterial growth. Serial concentrations (5,10.15,20,25,30,35 mg ml-1) of KH2PO4 and K2HPO4 were used as inorganic phosphate source in nutrient broth to culture A. baumannii ATCC 17904 and A.baumannii HHR 1 The results showed that 5 mg ml-1of KH2PO4 is the best source and best concentration for both isolates, where the bacterial growth was increased to OD600 of 1.596 for A. baumannii ATCC 17904 and 1.580 for A. baumannii HHR1 after 20 h, whereas, bacterial growth was slightly decreased when 35 mg ml-1 of KH2PO4 was added to both isolates in comparison to the control. As for using of K2HPO4, it was noticed that the growth of A. baumannii ATCC 17904 and A. baumannii HHR1 in the presence of 5 mg ml-1 (K2HPO4) increased the growth to approximately OD600 of 1.580 and 1.541 for both isolates respectively, compared to the control and other concentrations where the growth of both isolates slightly less than that of 5 mg ml-1. [ABSTRACT FROM AUTHOR]

The mechanisms controlling Mycobacterium tuberculosis (Mtb) replication and survival inside its human host remain ill-defined. Phagosome acidification and nutrient deprivation are common mechanisms used by macrophages to restrict the replication of intracellular bacteria. Mtb stops replicating at mildly acidic pH (

Myelosuppression is a common and intractable side effect of cancer therapies including radiotherapy and chemotherapy, while the underlying mechanism remains incompletely understood. Here, using a mouse model of radiotherapy-induced myelosuppression, we show that inorganic phosphate (Pi) metabolism is acutely inhibited in hematopoietic stem cells (HSCs) during irradiation-induced myelosuppression, and closely correlated with the severity and prognosis of myelosuppression. Mechanistically, the acute Pi metabolic inhibition in HSCs results from extrinsic Pi loss in the bone marrow niche and the intrinsic transcriptional suppression of soluble carrier family 20 member 1 (SLC20A1)-mediated Pi uptake by p53. Meanwhile, Pi metabolic inhibition blunts irradiation-induced Akt hyperactivation in HSCs, thereby weakening its ability to counteract p53-mediated Pi metabolic inhibition and the apoptosis of HSCs and consequently contributing to myelosuppression progression. Conversely, the modulation of the Pi metabolism in HSCs via a high Pi diet or renal Klotho deficiency protects against irradiation-induced myelosuppression. These findings reveal that Pi metabolism and HSC survival are causally linked by the Akt/p53–SLC20A1 axis during myelosuppression and provide valuable insights into the pathogenesis and management of myelosuppression. [ABSTRACT FROM AUTHOR]

Acanthamoeba castellanii is the etiological agent of amoebic keratitis and is present in the environment in trophozoite or cyst forms. Both forms can infect the vertebrate host and colonize different tissues. The high resistance of cysts to standard drugs used in clinics contributes to the lack of effective treatments. Therefore, in this context, studies have emerged to understand cyst physiology and metabolism. Phosphate transporters are proteins responsible for the uptake of extracellular inorganic phosphate and transport to the cytosol. This work aims to verify the relationship between Pi transport and energetic metabolism in cysts of A. castellanii. The phosphate uptake ratio was higher in cysts compared with trophozoites. Recently, three sequences related to phosphate transporters have been identified in the A. castellanii genome (AcPHS1, AcPHS2, and AcPHS3); the messenger RNA expression levels of which differ depending on the amoeba life form. Pi uptake in cysts displayed peak activity at alkaline pH, whereas Pi transport in trophozoites was not affected in the same pH ranges. Cysts harbor a low‐affinity Pi transport system (K0,5 and Vmax values of 1.76 ± 0.26 mM and 104.6 ± 6.3 nmol Pi × h−1 × 106 cells) compared to the trophozoite phosphate transport system. Pi transport seems important for anaerobic adenosine triphosphate synthesis in cysts, which initially occurs through the glycolytic pathway and subsequently through the pyruvate ferredoxin oxidoreductase pathway. Altogether, these results suggest that contrary to that previously postulated, cysts are active metabolic forms, and, as noted in trophozoites, phosphate uptake is important for energetic metabolism. [ABSTRACT FROM AUTHOR]

Background Context: 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.Purpose: To investigate bone strength measured by QCT/FEA in symptomatic patients with OPLL.Study Design/setting: A single-center prospective observational study.Patient Sample: A total of 157 patients with cervical or thoracic compressive myelopathy were included in the study.Outcome Measures: 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.Methods: 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.Results: 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.Conclusions: Hyperostosis of the posterior longitudinal ligament in OPLL was associated with higher bone strength by QCT/FEA, especially in female OPLL patients. [ABSTRACT FROM AUTHOR]

Tissue-nonspecific alkaline phosphatase (TNAP) is one of four isozymes, which include germ cell, placental and intestinal alkaline phosphatases. The TNAP isozyme has 3 isoforms (liver, bone and kidney) which differ by tissue expression and glycosylation pattern. Despite a long history of investigation, the exact function of TNAP in many tissues is largely unknown. Only the bone isoform has been well characterised during mineralization where the enzyme hydrolyses pyrophosphate to inorganic phosphate, which combines with calcium to form hydroxyapatite crystals deposited as new bone. The inorganic phosphate also increases gene expression of proteins that support tissue mineralization. Recent studies have shown that TNAP is expressed in preadipocytes from several species, and that inhibition of TNAP activity causes attenuation of intracellular lipid accumulation in these and other lipid-storing cells. The mechanism by which TNAP stimulates lipid accumulation is not known; however, proteins that are important for controlling phosphate levels in bone are also expressed in adipocytes. This review examines the evidence that inorganic phosphate generated by TNAP promotes transcription that enhances the expression of the regulators of lipid storage and consequently, that TNAP has a major function of lipid metabolism. [ABSTRACT FROM AUTHOR]

One of the most common assays for nucleoside triphosphatase (NTPase) activity entails the quantification of inorganic phosphate (Pi) as a colored phosphomolybdate complex at low pH. While this assay is very sensitive, it is not selective for Pi in the presence of labile organic phosphate compounds (OPCs). Since NTPase activity assays typically require a large excess of OPCs, such as nucleotides, selectivity for Pi in the presence of OPCs is often critical in evaluating enzyme activity. Here we present an improved method for the measurement of enzymatic nucleotide hydrolysis as Pi released, which achieves selectivity for Pi in the presence of OPCs while also avoiding the costs and hazards inherent in other methods for measuring nucleotide hydrolysis. We apply this method to the measurement of ATP hydrolysis by nitrogenase and GTP hydrolysis by elongation factor G (EF-G) in order to demonstrate the broad applicability of our method for the determination of nucleotide hydrolysis in the presence of interfering OPCs.

Background: Metabolic bone disorder is a significant endocrine system disorder that encompasses any disorder that alters the natural skeleton's mineralization process. Epilepsy is a prevalent central nervous system disorder that can cause biochemical abnormalities involving bone metabolism in the epileptic patients. The present study aimed to investigate the effects of chronic use of older compared to the newer generations of antiepileptic drugs on bone metabolism-related biomarkers. Methods: The study included fifty-one epileptic outpatients who attended the Consultation Clinic of Baghdad Teaching Hospital at the Medical City Complex from October/2021 to December/2021. The selected patients were on antiepileptic drugs for more than 2 years, hence were grouped according to their antiepileptic therapy into: Group-1: 24 epileptic patients on old antiepileptic drugs (Carbamazepine or Valproate). Group-2: 27 epileptic patients on new antiepileptic drugs (Levetiracetam), compared with Group-3: 28 healthy control subjects. Serum was obtained from their blood specimens to measure: calcium and inorganic phosphate by colorimetric assays, parathyroid hormone, and level of bone alkaline phosphatase activity. Results: Data analysis revealed that the median value of serum parathyroid hormone levels was significantly elevated in the epileptic patients' groups compared to the healthy control group. However, group-2 (new generation antiepileptic drugs) presented higher values. Whereas serum calcium and inorganic phosphate levels showed non-significant variation for all the studied groups. Furthermore, serum bone alkaline phosphatase activity exhibited significantly higher values in the patients compared to the healthy subjects group, with more significant elevation among those on old generation antiepileptic drugs (Carbamazepine or Valproate). Conclusion: Epileptic individuals who had been on AEDs for more than two years had increased parathyroid hormone levels, which were boosted by the newer antiepileptic drug Levetiracetam. Furthermore, BAP serum levels were considerably greater in epileptic patients than in healthy control participants, with larger values generated by older antiepileptic medications.

Fast, simple, and low-cost on-site visualized detection of inorganic phosphate (Pi) is in great demand since phosphate is the major reason of eutrophication. In this work, a ratiometric fluorescent probe composed by green carbon dots (GCDs) and red carbon dots (RCDs) has been established for high-sensitivity and selective sensing of Pi. A trend of color change from red to green is observed for the detection of Pi under ultraviolet light and the detection limit is 0.09 μM in the range of 0 to 55 μM. Fluorescent test paper prepared from the probe solution was successfully applied to semi-quantitative visual detection of Pi in real-world water and soil samples, which shows great real-world application potentials. [ABSTRACT FROM AUTHOR]

Biofertilizers are a key component of organic agriculture. Bacterial biofertilizers enhance plant growth through a variety of mechanisms, including soil compound mobilization and phosphate solubilizing bacteria (PSB), which convert insoluble phosphorus to plant-available forms. This specificity of PSB allows them to be used as biofertilizers in order to increase P availability, which is an immobile element in the soil. The objective of our study is to assess the capacity of PSB strains isolated from phosphate solid sludge to solubilize three forms of inorganic phosphates: tricalcium phosphate (Ca3(PO4)2), aluminum phosphate (AlPO4), and iron phosphate (FePO4), in order to select efficient solubilization strains and use them as biofertilizers in any type of soil, either acidic or calcareous soil. Nine strains were selected and they were evaluated for their ability to dissolve phosphate in the National Botanical Research Institute's Phosphate (NBRIP) medium with each form of phosphate (Ca3(PO4)2, AlPO4, and FePO4) as the sole source of phosphorus. The phosphate solubilizing activity was assessed by the vanadate-molybdate method. All the strains tested showed significantly (p ≤ 0.05) the ability to solubilize the three different forms of phosphates, with a variation between strains, and all strains solubilized Ca3(PO4)2 more than FePO4 and AlPO4. [ABSTRACT FROM AUTHOR]

Both ectomycorrhizal fungi (ECMF) and inorganic phosphate (Pi) can improve plant growth. However, the relationship between Pi levels and mycorrhizal colonization rate is divergent, and information on the differential and interactive effects of Pi levels and ECMF on nutrient uptake and seedling quality is lacking. We conducted a study on 4-week-old Castanea henryi 'You Zhen' seedlings by inoculating with Scleroderma sp. (+ECM) to compare with uninoculated (-ECM), under low Pi level (-Pi) and high Pi level (+Pi). The mycorrhizal colonization rate, seedlings morphological and physiological parameters, nutrient uptake content, and the rhizosphere soil enzymatic activities and chemical properties were investigated. Results indicated that the mycorrhizal colonization rate at low Pi level (84 ± 2%) was higher than that at high Pi level (71 ± 2.52%). No matter the Pi level, inoculating with ECMF significantly improved seedling dry weight, height, diameter, and seedling quality index (SQI). The +ECM+Pi and +ECM-Pi treatments significantly increased SQI by 282.76% and 232.76% in comparison to the -ECM-Pi treatment, respectively. Applied Pi had no significant effect on SQI. ECMF inoculation significantly increased nitrogen (N), phosphorus (P), and potassium (K) uptake in roots, stems, and leaves, while Pi application increased the P uptake in roots only. There was no significant interaction between ECMF and Pi levels on seedling quality and nutrient uptake (except P uptake in leaf). Results indicated that ECMF is a suitable alternative to the use of phosphorus fertilizer in nursery production of C. henryi seedlings in terms of protecting the environment, saving resources, and reducing production costs. [ABSTRACT FROM AUTHOR]

Context: Type 1 diabetes mellitus (T1DM) accounts for over 90% of diabetic cases with a prevalence of 0.33/1000 children in the African subregion. Hyperglycemia which is the major characteristic of T1DM may have a direct toxicity on osteoblasts and could lead to increased bone fragility and fractures in patients with T1DM. However, long-term glucose control can be monitored effectively with the measurement of glycated hemoglobin (HbA1c), while alkaline phosphatase (ALP), serum calcium, and inorganic phosphate are simple ways of assessing bone mineral density. Aim: This study aimed to evaluate the association between HbA1c and serum calcium, inorganic phosphate, and ALP. Subjects and Methods: This was a prospective cross-sectional study with a total of 26 T1DM patients and 20 apparently well children within the age range of 1-18 years. Blood samples were collected from the patients for measurement of HbAIc, serum ALP, serum calcium, and inorganic phosphate at the beginning of the study and after 3 months of insulin therapy. Results: The baseline mean HbA1c was significantly higher in the T1DM patients than in the controls (P = 0.00) and there was no significant decrease in HbA1c after 3 months of insulin therapy (P = 0.13) although HbA1c tended to be lower (12.57 ± 0.86% [baseline], 10.12 ± 0.74% [3 months postinsulin therapy]). There was a statistically significant reduction in ALP (P = 0.00). There was also a statistically significant correlation between ALP and mean HbA1c (r = 0.79, P = 0.00). Conclusion: Patients with T1DM often exhibit disorders related to calcium, inorganic phosphate, and ALP homeostasis with associated poor bone metabolism which may improve with adequate glycemic control and the addition of calcium supplements to their therapy. [ABSTRACT FROM AUTHOR]

Platelet-derived extracellular polyphosphate (PolyP) is a major mediator of thrombosis. PolyP is a linear chain of inorganic phosphate (Pi) and is stored in platelet dense granules. Pi enters cells from the extracellular fluid through phosphate transporters and may be stored as PolyP. Here we show that high extracellular Pi concentration in vitro increases platelet PolyP content, in a manner dependent on phosphate transporters, IP6K and V-type ATPases. The increased PolyP also enhanced PolyP-dependent coagulation in platelet-rich plasma. These data suggest a mechanistic link between hyperphosphatemia, PolyP and enhanced coagulation, which may be important in pathologies such as chronic kidney disease.

Cerium oxide based nanozymes are intensively studied due to their catalytic activity and structural flexibility. Such nanozymes have a great future potential in human therapeutics and antimicrobial activity. The structural complexity of their surfaces enables a great variety of enzyme mimetic activities. However, selection of a specific activity remains challenging, as such activities are sensitive to morphological and compositional changes as well as the physicochemical and biological environments. When delivered into biological systems, many processes occur at the surface, redefining the biological identity and activity of the nanozyme. Inorganic phosphates and phosphate-bearing molecules are some critical examples of items that can interact with cerium oxide nanozymes. Inorganic phosphates can interact directly with cerium oxide and even have a scavenging activity converting the material into cerium phosphate. Phosphate-bearing molecules can absorb on the surface of the nanozyme where phosphatase activity may occur. Given the abundance of phosphates in biological environments, cerium oxide nanozymes are strongly affected by their local concentration. Here, we discuss the interaction of cerium oxide with phosphates and phosphate-bearing molecules, providing a focussed review of the computational and experimental literature, with a focus on the surface morphology and chemistry of the nanozyme and their impact on the phosphate adsorption and phosphatase activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

SUMMARY: Removal of inorganic phosphate (Pi) from broiler diets could improve sustainability in poultry production. Small-scale studies of total Pi replacement by a novel consensus bacterial 6-phytase variant have been promising but larger scale studies are needed. In this study, effects of 4 diets on growth performance and bone quality were evaluated: PC1, nutritionally adequate and containing Pi without enzyme supplementation; PC2, as PC1 but containing xylanase (2,000 units [XU]/kg) and 75 kcal/kg reduction in ME; IPF1 and IPF2, as PC1 and PC2, respectively, formulated without Pi and 1.5 g/kg reduction in Ca, containing phytase at 3,000, 2,000, and 1,000 phytase units (FTU)/kg during starter (1–10 d), grower (10–22 d), and finisher (22–37 d) phases. A randomized complete block design used 820 Ross 308 mixed-sex birds/pen and 8 pens/diet. The phytase in IPF diets maintained all growth performance parameters, per phase and cumulatively, equivalent to the respective PC. Contrast analysis of pooled PC vs. pooled IPF data showed that phytase in IPF diets reduced or maintained FCR during all phases and cumulatively (−5.0 points during 22–37 d and −3.0 points during 1–37 d; P < 0.05). Tibia ash at d 21 and 36 was not different in birds fed IPF and PC diets, but tibia breaking strength was higher in birds fed IPF diets (+6.6% and +1.3%, respectively; P < 0.05). Overall (0–37 d), total feed costs per kilogram BW gain were reduced (P < 0.05) in the phytase supplemented IPF diets vs. PC diets under commercial broiler production conditions.

Inorganic phosphate (Pi) is an essential nutrient for the human body which exerts adverse health effects in excess and deficit. High Pi-mediated cytotoxicity has been shown to induce systemic organ damage, though the underlying molecular mechanisms are poorly understood. In this study, we employed proteomics and phosphoproteomics to analyze Pi-mediated changes in protein abundance and phosphorylation. Bioinformatic analyses and literature review revealed that the altered proteins and phosphorylation were enriched in signaling pathways and diverse biological processes. Western blot analysis confirms the extensive change in protein level and phosphorylation in key effectors that modulate pre-mRNA alternative splicing. Global proteome and phospho-profiling provide a bird-eye view of excessive Pi-rewired cell signaling networks, which deepens our understanding of the molecular mechanisms of phosphate toxicity.