-
BMC Nephrology Feb 2024Intravenous iron is commonly used in patients with non-dialysis-dependent chronic kidney disease (CKD). Modern intravenous iron compounds (e.g. ferric derisomaltose... (Randomized Controlled Trial)
Randomized Controlled Trial
The differential effect of modern intravenous iron on fibroblast growth factor 23 and phosphate in non-dialysis dependent CKD - the exploratory randomized controlled double-blind ExplorIRON-CKD study.
BACKGROUND
Intravenous iron is commonly used in patients with non-dialysis-dependent chronic kidney disease (CKD). Modern intravenous iron compounds (e.g. ferric derisomaltose (FDI), ferric carboxymaltose (FCM)) are increasingly utilized with similar efficacy. A differential effect in terms of hypophosphatemia has been noted following administration of FCM, which may be related to fibroblast growth factor 23 (FGF23). This study was designed to examine the comparative effects of FDI and FCM on FGF23, phosphate and other markers of bone turnover.
METHODS
The single-center double-blind randomized controlled trial "Iron and Phosphaturia - ExplorIRON-CKD" primarily assessed the effects of FCM and FDI on intact FGF23 and phosphate, whilst also studying the impact on vitamin D, parathyroid hormone and phosphaturia. Bone markers including alkaline phosphatase, bone-specific alkaline phosphatase, procollagen type 1 N-terminal propeptide and carboxy-terminal collagen cross-linked telopeptide were monitored. Non-dialysis-dependent CKD patients (stage 3a-5) with iron deficiency with/without anemia (serum ferritin < 200 µg/L or transferrin saturation = 20% and serum ferritin 200-299 µg/L) were randomized to receive FDI or FCM in a 1:1 ratio. At baseline 1000 mg of intravenous iron was administered followed by 500-1000 mg at 1 month to achieve replenishment. Measurements were performed at baseline, 1-2 days following iron administration, 2 weeks, 1 month (second iron administration), 1-2 days following second administration, 2 months and 3 months following initial infusion.
RESULTS
Twenty-six patients participated in the trial; 14 randomized to FDI and 12 to FCM. Intact FGF23 increased following administration of iron, and the increase was significantly higher with FCM compared to FDI (Baseline to 1-2 days following 1st administration: FDI: 3.0 (IQR: - 15.1 - 13.8) % vs. FCM: 146.1 (IQR: 108.1-203.1) %; p < 0.001 and Baseline to 1-2 days following 2nd administration: FDI: 3.2 (IQR: - 3.5 - 25.4) % vs. FCM: 235.1 (138.5-434.6) %; p = 0.001). Phosphate levels decreased in the FCM group, causing a significant difference versus FDI 2 weeks following administration of the first dose. A significantly greater decrease in 1,25 (OH) Vitamin D was noted with FCM. Several markers of bone turnover significantly changed following administration of FCM but not FDI.
CONCLUSIONS
The study suggests a differential effect on FGF23 following administration of FCM compared to FDI in non-dialysis-dependent CKD patients, similar to other patient groups. This may lead to changes consistent with hypovitaminosis D and alterations in bone turnover with potential clinical consequences. Further definitive studies are required to understand these differences of intravenous iron compounds.
TRIAL REGISTRATION
European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) number: 2019-004370-26 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004370-26/GB ) (First date of trial registration: 03/12/2019).
Topics: Humans; Alkaline Phosphatase; Anemia, Iron-Deficiency; Ferric Compounds; Ferritins; Fibroblast Growth Factor-23; Hypophosphatemia, Familial; Iron; Maltose; Phosphates; Renal Insufficiency, Chronic; Double-Blind Method
PubMed: 38347520
DOI: 10.1186/s12882-023-03440-7 -
Gates Open Research 2023Anemia affects 40% of pregnant women globally, leading to maternal mortality, premature birth, low birth weight, and poor baby development. Iron deficiency causes over...
Protocol and statistical analysis plan for a randomized controlled trial of the effect of intravenous iron on anemia in Malawian pregnant women in their third trimester (REVAMP - TT).
BACKGROUND
Anemia affects 40% of pregnant women globally, leading to maternal mortality, premature birth, low birth weight, and poor baby development. Iron deficiency causes over 40% of anemia cases in Africa. Oral iron supplementation is insufficient for Low-and-Middle-Income-Countries (LMICs) to meet current WHO targets. We hypothesized that a single intravenous dose of Ferric Carboxymaltose (FCM) may be more effective than oral iron treatment for anemia recovery, particularly in these settings where women present late for antenatal care.
METHODS
This is a two-arm parallel open-label individual-randomized controlled trial in third trimester, in malaria Rapid Diagnostic Test-negative pregnant women with moderate or severe anemia - capillary hemoglobin <10 g/dL - who are randomized to receive either parenteral iron - with FCM - or standard-of-care oral iron for the remainder of pregnancy. This is the sister trial to the second-trimester trial, funded by the Bill and Melinda Gates Foundation (trial registration ACTRN12618001268235, Gates Grant number INV-010612). In REVAMP-TT, recruitment and treatment are performed within primary health centers. The trial will recruit 590 women across Zomba district, Malawi. The primary outcome is the proportion of anemic women - venous hemoglobin <11 g/dL - at 36 weeks' gestation or delivery (whichever occurs first). Other pre-specified key secondary clinical and safety outcomes include maternal iron-status and hypophosphatemia, neonate birth weight, infant growth and infant iron and hematological parameters.
DISCUSSION
This study will determine whether FCM, delivered within primary health centers, is effective, safe and feasible for treating moderate to severe anemia in third-trimester pregnant Malawian women. This intervention could have long-term benefits for maternal and child health, resulting in improved survival and child development.
Topics: Infant, Newborn; Child; Female; Humans; Pregnancy; Iron; Pregnancy Trimester, Third; Pregnant Women; Anemia, Iron-Deficiency; Anemia; Hemoglobins; Malawi; Randomized Controlled Trials as Topic; Ferric Compounds; Maltose
PubMed: 38343768
DOI: 10.12688/gatesopenres.14710.2 -
Protein Expression and Purification May 2024A novel tandem affinity tag is presented that enables the use of cation exchange resins for initial affinity purification, followed by an additional column step for...
A novel tandem affinity tag is presented that enables the use of cation exchange resins for initial affinity purification, followed by an additional column step for enhanced purity and affinity tag self-removal. In this method, the highly charged heparin-binding tag binds strongly and selectively to either a strong or weak cation exchange resin based on electrostatic interactions, effectively acting as an initial affinity tag. Combining the heparin-binding tag (HB-tag) with the self-removing iCapTag™ provides a means for removing both tags in a subsequent self-cleaving step. The result is a convenient platform for the purification of diverse tagless proteins with a range of isoelectric points and molecular weights. In this work, we demonstrate a dual column process in which the tagged protein of interest is first captured from an E. coli cell lysate using a cation exchange column via a fused heparin-binding affinity tag. The partially purified protein is then diluted and loaded onto an iCapTag™ split-intein column, washed, and then incubated overnight to release the tagless target protein from the bound tag. Case studies are provided for enhanced green fluorescent protein (eGFP), beta galactosidase (βgal), maltose binding protein (MBP) and beta lactamase (βlac), where overall purity and host cell DNA clearance is provided. Overall, the proposed dual column process is shown to be a scalable platform technology capable of accessing both the high dynamic binding capacity of ion exchange resins and the high selectivity of affinity tags for the purification of recombinant proteins.
Topics: Recombinant Fusion Proteins; Escherichia coli; Recombinant Proteins; Chromatography, Affinity; Heparin
PubMed: 38336119
DOI: 10.1016/j.pep.2024.106442 -
Water content, transition temperature and fragility influence protection and anhydrobiotic capacity.BBA Advances 2024Water is essential for metabolism and all life processes. Despite this, many organisms distributed across the kingdoms of life survive near-complete desiccation or...
UNLABELLED
Water is essential for metabolism and all life processes. Despite this, many organisms distributed across the kingdoms of life survive near-complete desiccation or anhydrobiosis. Increased intracellular viscosity, leading to the formation of a vitrified state is necessary, but not sufficient, for survival while dry. What properties of a vitrified system make it desiccation-tolerant or -sensitive are unknown. We have analyzed 18 different vitrified systems, composed of one of three protective disaccharides (trehalose, sucrose, or maltose) and glycerol, quantifying their enzyme-protective capacity and their material properties in a dry state. Protection conferred by mixtures containing maltose correlates strongly with increased water content, increased glass-transition temperature, and reduced glass former fragility, while the protection of glasses formed with sucrose correlates with increased glass transition temperature and the protection conferred by trehalose glasses correlates with reduced glass former fragility. Thus, different vitrified sugars confer protection through distinct material properties. Next, we examined the material properties of a dry desiccation tolerant and intolerant life stage from three different organisms. The dried desiccation tolerant life stage of all organisms had an increased glass transition temperature and reduced glass former fragility relative to its dried desiccation intolerant life stage. These results suggest in nature organismal desiccation tolerance relies on a combination of various material properties. This study advances our understanding of how protective and non-protective glasses differ in terms of material properties that promote anhydrobiosis. This knowledge presents avenues to develop novel stabilization technologies for pharmaceuticals that currently rely on the cold-chain.
STATEMENT OF SIGNIFICANCE
For the past three decades the anhydrobiosis field has lived with a paradox, while vitrification is necessary for survival in the dry state, it is not sufficient. Understanding what property(s) distinguishes a desiccation tolerant from an intolerant vitrified system and how anhydrobiotic organisms survive drying is one of the enduring mysteries of organismal physiology. Here we show the enzyme-protective capacity of different vitrifying sugars can be correlated with distinct material properties. However, diverse desiccation tolerant organisms appear to combine these material properties to promote their survival in a dry state.
PubMed: 38318251
DOI: 10.1016/j.bbadva.2024.100115 -
BioRxiv : the Preprint Server For... Jan 2024Biomolecular condensates are broadly implicated in both normal cellular regulation and disease. Consequently, several chemical biology and optogenetic approaches have...
Biomolecular condensates are broadly implicated in both normal cellular regulation and disease. Consequently, several chemical biology and optogenetic approaches have been developed to induce phase separation of a protein of interest. However, few tools are available to perform the converse function-dissolving a condensate of interest on demand. Such a tool would aid in testing whether the condensate plays specific functional roles, a major question in cell biology and drug development. Here we report an optogenetic approach to selectively dissolve a condensate of interest in a reversible and spatially controlled manner. We show that light-gated recruitment of maltose-binding protein (MBP), a commonly used solubilizing domain in protein purification, results in rapid and controlled dissolution of condensates formed from proteins of interest. Our optogenetic MBP-based dissolution strategy (OptoMBP) is rapid, reversible, and can be spatially controlled with subcellular precision. We also provide a proof-of-principle application of OptoMBP, showing that disrupting condensation of the oncogenic fusion protein FUS-CHOP results in reversion of FUS-CHOP driven transcriptional changes. We envision that the OptoMBP system could be broadly useful for disrupting constitutive protein condensates to probe their biological functions.
PubMed: 38293146
DOI: 10.1101/2024.01.16.575860 -
Frontiers in Nutrition 2023There is a huge gap between food production and the exploding population demands in various parts of the world, especially developing countries. This increases the...
There is a huge gap between food production and the exploding population demands in various parts of the world, especially developing countries. This increases the chances of malnutrition, leading to increased disease incidence and the need for functional foods to reduce mortality. are edible mushrooms that are cheaply sourced and rich in nutrient with the potential to be harnessed toward addressing the present and future food crisis while serving as functional foods for disease prevention and treatment. This study evaluated the nutritional, proximate, vitamins and amino acids contents of . The proximate composition of in this study revealed that it contains 43.42% carbohydrate, 23.63% crude fiber, 17.06% crude protein, 8.22% ash, 1.21% lipid and a moisture content of 91.01 and 6.46% for fresh and dry samples of . The monosaccharide and disaccharide profile of revealed the presence of glucose (55.08 g/100 g), xylose (7.19 g/100 g), fructose (19.70 g/100 g), galactose (17.47 g/100 g), trehalose (7.37 g/100 g), chitobiose (11.79 g/100 g), maltose (29.21 g/100 g), sucrose (51.60 g/100 g) and lower amounts of cellobiose (0.01 g/100 g), erythrose (0.48 g/100 g) and other unidentified sugars. Potassium, Iron and Magnesium were the highest minerals present with 12.25 mg, 9.66 mg and 7.00 mg amounts, respectively. The vitamin profile revealed the presence of vitamin A (2.93 IU/100 g), C (16.46 mg/100 g), E (21.50 mg/100 g) and B vitamins with vitamin B2 having the highest concentration of 92.97 mg/kg. The amino acid scores showed that had more non-essential amino acids (564.17 mg/100 g) than essential amino acids (67.83 mg/100 g) with a ratio of 0.11. Lysine (23.18 mg/100 g) was the highest essential amino acid while aspartic acid (492.12 mg/kg) was the highest non-essential amino acid present in . It had a higher concentration of acidic amino acids, 492.12 mg/100 g (77.87%), followed by neutral amino acids, 106.66 mg/100 g (16.88%) and least were the basic amino acids, 23.18 mg/100 g (3.67%). Based on the nutritional assessment of the analyzed in this study, it can be concluded that it can serve as an important functional food source that can be exploited to meet the increasing food demands and reduce micronutrient deficiencies in many parts of the world, especially developing countries.
PubMed: 38292699
DOI: 10.3389/fnut.2023.1279208 -
Cureus Dec 2023Intravenous immunoglobulin (IVIG) is a common therapeutic modality used in immune-mediated neuropathy. While the therapeutic benefits are well known, adverse reactions...
Intravenous immunoglobulin (IVIG) is a common therapeutic modality used in immune-mediated neuropathy. While the therapeutic benefits are well known, adverse reactions have been reported. One such adverse event, though rare, is transaminitis, which appears to be a transient and a self-limiting adverse reaction. Though most of the cases implicate the stabilizing agent to be the culprit, the exact mechanism is unknown. Thus far, it has been speculated that maltose, which has been commonly used as a stabilizer, is the cause of IVIG transaminitis. We present a unique case of a patient who developed transaminitis post-IVIG in which glycine was used as a stabilizing agent. We aim to draw a potential association between IVIG therapy and the development of transaminitis, thereby providing insight into the underlying mechanisms, as well as clinical features, and possibly encouraging further research on this topic.
PubMed: 38288188
DOI: 10.7759/cureus.51347 -
Nature Communications Jan 2024It is estimated that two-thirds of all proteins in higher organisms are composed of multiple domains, many of them containing discontinuous folds. However, to date, most...
It is estimated that two-thirds of all proteins in higher organisms are composed of multiple domains, many of them containing discontinuous folds. However, to date, most in vitro protein folding studies have focused on small, single-domain proteins. As a model system for a two-domain discontinuous protein, we study the unfolding/refolding of a slow-folding double mutant of the maltose binding protein (DM-MBP) using single-molecule two- and three-color Förster Resonance Energy Transfer experiments. We observe a dynamic folding intermediate population in the N-terminal domain (NTD), C-terminal domain (CTD), and at the domain interface. The dynamic intermediate fluctuates rapidly between unfolded states and compact states, which have a similar FRET efficiency to the folded conformation. Our data reveals that the delayed folding of the NTD in DM-MBP is imposed by an entropic barrier with subsequent folding of the highly dynamic CTD. Notably, accelerated DM-MBP folding is routed through the same dynamic intermediate within the cavity of the GroEL/ES chaperone system, suggesting that the chaperonin limits the conformational space to overcome the entropic folding barrier. Our study highlights the subtle tuning and co-dependency in the folding of a discontinuous multi-domain protein.
Topics: Maltose-Binding Proteins; Entropy; Fluorescence Resonance Energy Transfer; Protein Folding; Research Design
PubMed: 38263337
DOI: 10.1038/s41467-024-44901-3 -
Microorganisms Jan 2024Lignocellulosic materials are composed of cellulose, hemicellulose and lignin and are one of the most abundant biopolymers in marine environments. The extent of the...
Lignocellulosic materials are composed of cellulose, hemicellulose and lignin and are one of the most abundant biopolymers in marine environments. The extent of the involvement of marine microorganisms in lignin degradation and their contribution to the oceanic carbon cycle remains elusive. In this study, a novel lignin-degrading bacterial strain, LCG003, was isolated from intertidal seawater in Lu Chao Harbor, East China Sea. Phylogenetically, strain LCG003 was affiliated with the genus within the family . Metabolically, strain LCG003 contains various extracellular (signal-fused) glycoside hydrolase genes and carbohydrate transporter genes and can grow with various carbohydrates as the sole carbon source, including glucose, fructose, sucrose, rhamnose, maltose, stachyose and cellulose. Moreover, strain LCG003 contains many genes of amino acid and oligopeptide transporters and extracellular peptidases and can grow with peptone as the sole carbon and nitrogen source, indicating a proteolytic lifestyle. Notably, strain LCG003 contains a gene of dyp-type peroxidase and strain-specific genes involved in the degradation of 4-hydroxy-benzoate and vanillate. We further confirmed that it can decolorize aniline blue and grow with lignin as the sole carbon source. Our results indicate that the species can depolymerize and mineralize lignocellulosic materials and potentially play an important role in the marine carbon cycle.
PubMed: 38257972
DOI: 10.3390/microorganisms12010144 -
Metabolites Jan 2024Black ginseng (BG) is processed ginseng traditionally made in Korea via the steaming and drying of ginseng root through three or more cycles, leading to changes in its...
Black ginseng (BG) is processed ginseng traditionally made in Korea via the steaming and drying of ginseng root through three or more cycles, leading to changes in its appearance due to the Maillard reaction on its surface, resulting in a dark coloration. In this study, we explored markers for differentiating processed ginseng by analyzing the chemical characteristics of BG. We elucidated a new method for the structural identification of ginsenoside metabolites and described the features of processed ginseng using UPLC-QTOF-MS in the positive ion mode. We confirmed that maltose, glucose, and fructose, along with L-arginine, L-histidine, and L-lysine, were the key compounds responsible for the changes in the external quality of BG. These compounds can serve as important metabolic markers for distinguishing BG from conventionally processed ginseng. The major characteristics of white ginseng, red ginseng, and BG can be distinguished based on their high-polarity and low-polarity ginsenosides, and a precise method for the structural elucidation of ginsenosides in the positive ion mode is presented.
PubMed: 38248865
DOI: 10.3390/metabo14010062