Crystalline materials are crucial to the function of living organisms, in the shells of molluscs, the matrix of bone, the teeth of sea urchins, and the exoskeletons of coccoliths. However, ...pathological biomineralization can be an undesirable crystallization process associated with human diseases. The crystal growth of biogenic, natural and synthetic materials may be regulated by the action of modifiers, most commonly inhibitors, which range from small ions and molecules to large macromolecules. Inhibitors adsorb on crystal surfaces and impede the addition of solute, thereby reducing the rate of growth. Complex inhibitor-crystal interactions in biomineralization are often not well elucidated. Here we show that two molecular inhibitors of calcium oxalate monohydrate crystallization--citrate and hydroxycitrate--exhibit a mechanism that differs from classical theory in that inhibitor adsorption on crystal surfaces induces dissolution of the crystal under specific conditions rather than a reduced rate of crystal growth. This phenomenon occurs even in supersaturated solutions where inhibitor concentration is three orders of magnitude less than that of the solute. The results of bulk crystallization, in situ atomic force microscopy, and density functional theory studies are qualitatively consistent with a hypothesis that inhibitor-crystal interactions impart localized strain to the crystal lattice and that oxalate and calcium ions are released into solution to alleviate this strain. Calcium oxalate monohydrate is the principal component of human kidney stones and citrate is an often-used therapy, but hydroxycitrate is not. For hydroxycitrate to function as a kidney stone treatment, it must be excreted in urine. We report that hydroxycitrate ingested by non-stone-forming humans at an often-recommended dose leads to substantial urinary excretion. In vitro assays using human urine reveal that the molecular modifier hydroxycitrate is as effective an inhibitor of nucleation of calcium oxalate monohydrate nucleation as is citrate. Our findings support exploration of the clinical potential of hydroxycitrate as an alternative treatment to citrate for kidney stones.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
Sr sub(1-x)Ce sub(x)MnO sub(3) (SCM, 0.1 less than or equal to x less than or equal to 0.4) powders were synthesised by an ethylenediaminetetraacetic acid citrate complexing process, and their ...properties were investigated. The synthesised Sr sub(1-x)Ce sub(x)MnO sub(3) powders showed a pure perovskite phase, whereas the composition with x = 0.4 had second phases. The unit cell volumes increased with increasing Ce content because substituted Ce ions formed some Mn super(3+) ions, which have a larger ionic radius than Mn super(4+). The electrical conductivity improved with increasing Ce content up to x = 0.3 (291 S cm super(-1) at 750 degree C), revealing a double exchange interaction. Although the electrical conductivity was increased by doping Ce ions, the polarisation resistance increased due to the increase in lattice distortion with doping Ce content. The substitution of Ce ions for Sr in SrMnO sub(3) led to the formation of larger Mn super(3+) ions than Mn super(4+) ions and lattice distortion, which would affect the electrical and oxygen ion conductivity.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Kidney stones affect people worldwide and have a high rate of recurrence even with treatment. Recurrences are particularly prevalent in people with low urinary citrate levels. These people ...have a higher incidence of calcium phosphate and calcium oxalate stones. Oral citrate therapy increases the urinary citrate levels, which in turn binds with calcium and inhibits the crystallisation thus reduces stone formation. Despite the widespread use of oral citrate therapy for prevention and treatment of calcium oxalate stones, the evidence to support its clinical efficacy remains uncertain.
Objectives
The objective of this review was to determine the efficacy and adverse events associated with citrate salts for the treatment and prevention of calcium containing kidney stones.
Search methods
We searched the Cochrane Kidney and Transplant Specialised Register to 29 July 2015 through contact with the Trials' Search Co‐ordinator using search terms relevant to this review.
Selection criteria
We included randomised controlled trials (RCTs) that assessed the efficacy and adverse events associated with citrate salts for the treatment and prevention of calcium containing kidney stones in adults treated for a minimum of six months.
Data collection and analysis
Two authors assessed studies for inclusion in this review. Data were extracted according to predetermined criteria. Summary estimates of effect were obtained using a random‐effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes.
Main results
We included seven studies that included a total of 477 participants, most of whom had oxalate stones. Of these, three studies (247 participants) compared potassium citrate with placebo or no intervention; three (166 participants) compared potassium‐sodium citrate with no intervention; and one (64 participants) compared potassium‐magnesium citrate with placebo. Overall, quality of the reporting of the included studies was considered moderate to poor, and there was a high risk of attrition bias in two studies.
Compared with placebo or no intervention, citrate therapy significantly reduced the stone size (4 studies, 160 participants: RR 2.35, 95% CI 1.36 to 4.05). New stone formation was significantly lower with citrate therapy compared to control (7 studies, 324 participants: RR 0.26, 95% CI 0.10 to 0.68). The beneficial effect on stone size stability was also evident (4 studies, 160 participants: RR 1.97, 95% CI 1.19 to 3.26). Adverse events were reported in four studies, with the main side effects being upper gastrointestinal disturbance and one patient reported a rash. There were more gastrointestinal adverse events in the citrate group; however this was not significant (4 studies, 271 participants: RR 2.55, 95% CI 0.71 to 9.16). There were significantly more dropouts due to adverse events with citrate therapy compared to control (4 studies, 271 participants: RR 4.45, 95% CI 1.28 to 15.50). The need for retreatment was significantly less with citrate therapy compared to control (2 studies, 157 participants: RR 0.22, 95% CI 0.06 to 0.89).
Authors' conclusions
Citrate salts prevent new stone formation and reduce further stone growth in patients with residual stones that predominantly contain oxalate. The quality of reported literature remains moderate to poor; hence a well‐designed statistically powered multi‐centre RCT is needed in order to answer relevant questions concerning the efficacy of citrate salts.
Hemorrhagic complications have been reported in up to 30% of critically ill patients with AKI undergoing RRT with systemic anticoagulation. Because bleeding is associated with significantly increased ...mortality risk, strategies aimed at reducing hemorrhagic complications while maintaining extracorporeal circulation should be implemented. Among the alternatives to systemic anticoagulation, regional citrate anticoagulation has been shown to prolong circuit life while reducing the incidence of hemorrhagic complications and lowering transfusion needs. For these reasons, the recently published Kidney Disease Improving Global Outcomes Clinical Practice Guidelines for Acute Kidney Injury have recommended regional citrate anticoagulation as the preferred anticoagulation modality for continuous RRT in critically ill patients in whom it is not contraindicated. However, the use of regional citrate anticoagulation is still limited because of concerns related to the risk of metabolic complications, the complexity of the proposed protocols, and the need for customized solutions. The introduction of simplified anticoagulation protocols based on citrate and the development of dialysis monitors with integrated infusion systems and dedicated software could lead to the wider use of regional citrate anticoagulation in upcoming years.
This work reports two new diketoprrrolopyrrole-based fluorescent chemosensors (DPP-Py1 and DPP-Py2) using symmetrical diamides as recognition groups for selective and fast detection of citrate in the ...near-infrared region. To our delight, DPP-Py1 is a ratiometric sensor, whereas DPP-Py2 is a turn-on fluorescent sensor. It is worth noting that DPP-Py1 has higher accuracy and sensitivity with a relatively lower detection limit (1.8 × 10–7 M) and better stability in different pH buffers than DPP-Py2. Scanning electron microscopy, dynamic light scattering analyses, 1H NMR titration, and 2D-NOESY NMR suggested that the fluorescence increment of the probes DPP-Py1 and DPP-Py2 for citrate could probably originate from aggregation-induced emission (AIE) on the basis of the complexation of the pyridinium-based symmetrical diamides, DPPs, with carboxyl anions of citrate. Our work may provide a simpler and faster means for qualitative and quantitative analysis of citrate through an AIE mechanism.
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IJS, KILJ, NUK, PNG, UL, UM
Nanocrystals of apatitic calcium phosphate impart the organic-inorganic nanocomposite in bone with favorable mechanical properties. So far, the factors preventing crystal growth beyond the favorable ...thickness of ca. 3 nm have not been identified. Here we show that the apatite surfaces are studded with strongly bound citrate molecules, whose signals have been identified unambiguously by multinuclear magnetic resonance (NMR) analysis. NMR reveals that bound citrate accounts for 5.5 wt% of the organic matter in bone and covers apatite at a density of about 1 molecule per (2 nm)², with its three carboxylate groups at distances of 0.3 to 0.45 nm from the apatite surface. Bound citrate is highly conserved, being found in fish, avian, and mammalian bone, which indicates its critical role in interfering with crystal thickening and stabilizing the apatite nanocrystals in bone.
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An easily prepared platinum nanoparticle (PtNP) probe for the sensitive and selective detection of Hg2+ ions is developed here. The PtNPs with an average size of approximately 2.5 nm were prepared by ...a reduction method with sodium borohydride and trisodium citrate serving as reductant and stabilizer, respectively. The resulting PtNPs could catalyze the reduction of Hg2+ by surface-capping citrate. The effect of Hg2+ uptake implies amalgam formation, which leads to remarkable inhibition of the peroxidase-like activity of citrate-capped PtNPs. On the basis of this effect, a colorimetric mercury sensor was established through the use of citrate-capped PtNPs to catalyze the colorimetric system of 3,3′,5,5′-tetramethylbenzidine (TMB) and H2O2. The high specificity of the Hg–Pt interaction provides the excellent selectivity for Hg2+ over interfering metal ions. The sensitivity of this smart probe to Hg2+ is extremely excellent with a limit of detection (LOD) as low as 8.5 pM. In view of these advantages, as well as the cost-effectiveness, minimized working steps, and naked-eye observation, we expect that this colorimetric sensor will be a promising candidate for the field detection of toxic Hg2+ ions in environmental, biological, and food samples.
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IJS, KILJ, NUK, PNG, UL, UM
Eucalyptus camaldulensis can detoxify Al by forming Al–citrate complexes, and this is achieved through citrate accumulation via suppression of the citrate decomposition pathway.
•The citrate content ...in the roots was increased with Al treatments.•The activities of aconitase and NADP+-ICDH were decreased with Al treatments.•The activity of citrate synthase was not affected by Al.•Al–citrate complexes were a major chemical form in the cell sap of root tips.
Eucalyptus (Eucalyptus camaldulensis) has relatively high resistance to aluminum (Al) toxicity than the various herbaceous plants and model plant species. To investigate Al-tolerance mechanism, the metabolism of organic acids and the chemical forms of Al in the target site (root tips) in Eucalyptus was investigated. To do this, 2-year old rooted cuttings of E. camaldulensis were cultivated in half-strength Hoagland solution (pH 4.0) containing Al (0, 0.25, 0.5, 1.0, 2.5 and 5.0mM) salts for 5weeks; growth was not affected at concentrations up to 2.5mM even with Al concentration reaching 6000μgg−1 DW. In roots, the citrate content also increased with increasing Al application. Concurrently, the activities of aconitase and NADP+-isocitrate dehydrogenase, which catalyze the decomposition of citrate, decreased. On the other hand, the activity of citrate synthase was not affected at concentrations up to 2.5mM Al. 27Al-NMR spectroscopic analyses were carried out where it was found that Al–citrate complexes were a major chemical form present in cell sap of root tips. These findings suggested that E. camaldulensis detoxifies Al by forming Al–citrate complexes, and that this is achieved through Al-induced citrate accumulation in root tips via suppression of the citrate decomposition pathway.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Plant mitochondria have a fully operational tricarboxylic acid (TCA) cycle that plays a central role in generating ATP and providing carbon skeletons for a range of biosynthetic processes in both ...heterotrophic and photosynthetic tissues. The cycle enzyme-encoding genes have been well characterized in terms of transcriptional and effector-mediated regulation and have also been subjected to reverse genetic analysis. However, despite this wealth of attention, a central question remains unanswered: “What regulates flux through this pathway in vivo?” Previous proteomic experiments with Arabidopsis discussed below have revealed that a number of mitochondrial enzymes, including members of the TCA cycle and affiliated pathways, harbor thioredoxin (TRX)-binding sites and are potentially redox-regulated. We have followed up on this possibility and found TRX to be a redox-sensitive mediator of TCA cycle flux. In this investigation, we first characterized, at the enzyme and metabolite levels, mutants of the mitochondrial TRX pathway in Arabidopsis : the NADP-TRX reductase a and b double mutant ( ntra ntrb ) and the mitochondrially located thioredoxin o1 ( trxo1 ) mutant. These studies were followed by a comparative evaluation of the redistribution of isotopes when ¹³C-glucose, ¹³C-malate, or ¹³C-pyruvate was provided as a substrate to leaves of mutant or WT plants. In a complementary approach, we evaluated the in vitro activities of a range of TCA cycle and associated enzymes under varying redox states. The combined dataset suggests that TRX may deactivate both mitochondrial succinate dehydrogenase and fumarase and activate the cytosolic ATP-citrate lyase in vivo, acting as a direct regulator of carbon flow through the TCA cycle and providing a mechanism for the coordination of cellular function.
Significance The present work extends redox-based change in enzyme activity to the TCA cycle of plant mitochondria. Thioredoxin (TRX) was found to regulate the activity of enzymes of the mitochondrial cycle (succinate dehydrogenase and fumarase) and of an enzyme associated with it (ATP-citrate lyase) by modulating thiol redox status. A combination of experiments based on mutant and carbon isotope labeling analyses provides evidence that flux through this pathway is coordinately modulated by TRX at the enzyme level of both mitochondria and cytosol. The results provide in vivo confirmation of earlier in vitro results and further show that mitochondria resemble plastids in using TRX and redox status to regulate the main carbon flux pathway of the organelle.
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Starmerella bombicola
is a non-conventional yeast commercially used as a microbial cell factory for sophorolipid production. Sophorolipids are glycolipid biosurfactants composed of a glucose ...disaccharide sophorose and a fatty acid. In de novo sophorolipid synthesis, the fatty acid moiety is derived from the fatty acid synthesis (FAS) complex; therefore, the yeast’s lipid metabolism plays a crucial role in sophorolipid biosynthesis. As a fatty acid precursor, citric acid is a key primary metabolite that connects carbohydrate and lipid metabolism, and in
S. bombicola
, it also has a regulatory effect on sophorolipid composition and productivity. We aimed to identify the mitochondrial transporters involved in citrate shuttling and the ATP citrate lyase (Acl), the enzyme that converts citric acid into acetyl-CoA. Subsequently, we studied their role in the citric acid shuttle and glycolipid synthesis and the potential of citrate metabolism as a genetic manipulation target for increased glycolipid synthesis. Bioinformatics analyses predicted 32 mitochondrial carriers of which two were identified as citrate transporters, named SbCtp1 and SbYhm2. Deletion of these mitochondrial carriers led to a lesser sophorolipid yield and a shift in the lactonic/acidic sophorolipid ratio. However, only the knockout of SbYhm2 caused a decrease of citric and an increase of malic acid extracellular concentrations. Additionally, deletion of SbAcl1 had a negative effect on
S. bombicola’
s specific growth rate and sophorolipid synthesis and contributed to extra- and intracellular citric acid accumulation. Unexpectedly, SbAcl1 overexpression also decreased glycolipid production.
Key Points
• Starmerella bombicola is an industrially relevant microbial cell factory for biosurfactant production.
• There are 32 predicted mitochondrial carriers in S. bombicola.
• Citrate mitochondrial carriers SbYhm2 and SbCtp1 are essential for glycolipid synthesis in S. bombicola.
• Deletion of SbAcl1 negatively affects growth and sophorolipid production in S. bombicola.
Graphical abstract
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CEKLJ, DOBA, EMUNI, FZAB, GEOZS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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