Design, Synthesis, and Anti-Osteoporotic Characterization of Arginine N-Glycosylated Teriparatide Analogs via the Silver-catalyzed Solid-Phase Glycosylation Strategy.

In spite of effective antiosteoporosis potency, teriparatide, a bone-building agent approved by the FDA (Food and Drug Administration), was proven to exhibit various side effects. In our previous work, we developed a universal strategy for synthesizing arginine N-glycosylated peptides termed silver-promoted solid-phase glycosylation (SSG) strategy. However, it is unknown whether the SSG strategy can be applied in the peptide drug design. Herein, we first reported the optimization of teriparatide via SSG strategy. Using Arg20 and/or Arg25 as the modifying positions, three series of arginine N-glycosylated teriparatide analogs were successfully synthesized, of which the introduced sugar groups included glucose, galactose, mannose, rhamnose, ribose, 2-acetamino-2-deoxy-glucose, xylose, lactose, and maltose. Among the 27 arginine N-glycosylated derivatives, Arg20-xylose and Arg25-maltose teriparatide analogs, termed PTH-1g and PTH-2i, respectively, indicated enhanced serum stability and significantly improved antiosteoporotic activities in vitro and in vivo compared with the native counterpart. They may serve as effective therapeutic candidates for treating osteoporosis.

Cellular signaling in the hypoxic cancer microenvironment: Implications for drug resistance and therapeutic targeting.

The rewiring of cellular metabolism is a defining characteristic of cancer, as tumor cells adapt to acquire essential nutrients from a nutrient-poor environment to sustain their viability and biomass. While hypoxia has been identified as a major factor depriving cancer cells of nutrients, recent studies have revealed that cancer cells distant from supporting blood vessels also face nutrient limitations. To overcome this challenge, hypoxic cancer cells, which heavily rely on glucose as an energy source, employ alternative pathways such as glycogen metabolism and reductive carboxylation of glutamine to meet their energy requirements for survival. Our preliminary studies, alongside others in the field, have shown that under glucose-deficient conditions, hypoxic cells can utilize mannose and maltose as alternative energy sources. This review aims to comprehensively examine the hypoxic cancer microenvironment, its association with drug resistance, and potential therapeutic strategies for targeting this unique niche. Furthermore, we will critically evaluate the current literature on hypoxic cancer microenvironments and explore state-of-the-art techniques used to analyze alternate carbohydrates, specifically mannose and maltose, in complex biological fluids. We will also propose the most effective analytical methods for quantifying mannose and maltose in such biological samples. By gaining a deeper understanding of the hypoxic cancer cell microenvironment and its role in drug resistance, novel therapeutic approaches can be developed to exploit this knowledge.

The Biostimulant, Potassium Humate Ameliorates Abiotic Stress in Arabidopsis thaliana by Increasing Starch Availability.

Potassium humate is a widely used biostimulant known for its ability to enhance growth and improve tolerance to abiotic stress. However, the molecular mechanisms explaining its effects remain poorly understood. In this study, we investigated the mechanism of action of potassium humate using the model plant Arabidopsis thaliana. We demonstrated that a formulation of potassium humate effectively increased the fresh weight accumulation of Arabidopsis plants under normal conditions, salt stress (sodium or lithium chloride), and particularly under osmotic stress (mannitol). Interestingly, plants treated with potassium humate exhibited a reduced antioxidant response and lower proline accumulation, while maintaining photosynthetic activity under stress conditions. The observed sodium and osmotic tolerance induced by humate was not accompanied by increased potassium accumulation. Additionally, metabolomic analysis revealed that potassium humate increased maltose levels under control conditions but decreased levels of fructose. However, under stress, both maltose and glucose levels decreased, suggesting changes in starch utilization and an increase in glycolysis. Starch concentration measurements in leaves showed that plants treated with potassium humate accumulated less starch under control conditions, while under stress, they accumulated starch to levels similar to or higher than control plants. Taken together, our findings suggest that the molecular mechanism underlying the abiotic stress tolerance conferred by potassium humate involves its ability to alter starch content under normal growth conditions and under salt or osmotic stress.

Glucose- and disaccharide-containing baits impede secondary mortality in glucose-averse German cockroaches.

Glucose aversion in the German cockroach, Blattella germanica (L.), results in behavioral resistance to insecticidal baits. Glucose-averse (GA) cockroaches reject foods containing glucose, even in relatively low concentrations, which protects the cockroaches from ingesting lethal amounts of toxic baits. Horizontal transfer of baits and the resulting secondary mortality have been documented in German cockroaches, including in insecticide resistant strains. However, the effects of the GA trait on secondary mortality have not been investigated. We hypothesized that ingestion of insecticide baits that contain glucose or glucose-containing disaccharides would result in behaviorally relevant glucose levels in the feces, possibly deterring coprophagy by GA nymphs. We fed adult female cockroaches hydramethylnon baits rich in either glucose, fructose, sucrose, or maltose and compared secondary mortality of GA and wild-type (WT) nymphs via coprophagy. When adult females were fed baits containing glucose, sucrose, or maltose and their feces offered to nymphs, secondary mortality was significantly lower in GA nymphs than in WT nymphs. However, survival of GA and WT nymphs was similar on feces generated by adult females fed fructose bait. Analysis of feces indicated that disaccharides in baits were hydrolyzed into glucose, some of which was excreted in the feces of females that ingested the bait. Based on these results, we caution that baits containing glucose or glucose-containing oligosaccharides may impede cockroach interventions; while GA adults and large nymphs avoid ingesting such baits, first instars reject the glucose-containing feces of any WT cockroaches that consumed the bait.

Direct liquid transmission of sound has little impact on fermentation performance in Saccharomyces cerevisiae.

Sound is a physical stimulus that has the potential to affect various growth parameters of microorganisms. However, the effects of audible sound on microbes reported in the literature are inconsistent. Most published studies involve transmitting sound from external speakers through air toward liquid cultures of the microorganisms. However, the density differential between air and liquid culture could greatly alter the sound characteristics to which the microorganisms are exposed. In this study we apply white noise sound in a highly controlled experimental system that we previously established for transmitting sound underwater directly into liquid cultures to examine the effects of two key sound parameters, frequency and intensity, on the fermentation performance of a commercial Saccharomyces cerevisiae ale yeast growing in a maltose minimal medium. We performed these experiments in an anechoic chamber to minimise extraneous sound, and find little consistent effect of either sound frequency or intensity on the growth rate, maltose consumption, or ethanol production of this yeast strain. These results, while in contrast to those reported in most published studies, are consistent with our previous study showing that direct underwater exposure to white noise sound has little impact on S. cerevisiae volatile production and sugar utilization in beer medium. Thus, our results suggest the possibility that reported microorganism responses to sound may be an artefact associated with applying sound to cultures externally via transmission through air.

Synthesis and biological and physico-chemical characterization of glycodendrimers and oligopeptides for the treatment of systemic lupus erythematosus.

Anti-(ds)-DNA antibodies are the serological hallmark of Systemic Lupus Erythematosus (SLE). They assemble in the bloodstream with (ds)-DNA, forming immunocomplexes, which spread all over the body causing, among the other symptoms, lupic glomerulonephritis. Pathological manifestations of the disease may be reduced by destabilizing or inhibiting the formation of the immunocomplexes. In this respect, glycodendrimers showed peculiar interacting abilities towards this kind of biomolecule. Various generations of open-shell maltose-decorated poly(amidoamine) (PAMAM) and poly(propyleneimine) (PPI) dendrimers and two oligopeptides with different polyethylene glycol units were synthesized and characterized, and then tested for their anti-SLE activity. The activity of glycodendrimers and oligopeptides was evaluated in human plasma from patients with SLE, compared to healthy plasma, by means of an enzyme-linked immunosorbent assay (ELISA), and electron paramagnetic resonance (EPR) characterization using spin-label and spin-probe techniques. Different strategies for the immunocomplex formation were tested. The results show that both kinds of glycodendrimers and oligopeptides inhibited the formation of immunocomplexes. Also, a partial breakdown of preformed immunocomplexes was observed. Both ELISA and EPR analyses indicated a better activity of glycodendrimers compared to oligopeptides, the 3rd generation PPI dendrimer being the most promising against SLE. This study highlights the possibility to develop a new class of dendritic therapeutics for the treatment of Lupus in pre-clinical studies.

An operator-based expression toolkit for Bacillus subtilis enables fine-tuning of gene expression and biosynthetic pathway regulation.

SignificanceA gene regulatory system is an important tool for the engineering of biosynthetic pathways of organisms. Here, we report the development of an inducible-ON/OFF regulatory system using a malO operator as a key element. We identified and modulated sequence, position, numbers, and spacing distance of malO operators, generating a series of activating or repressive promoters with tunable strength. The stringency and robustness are both guaranteed in this system, a maximal induction factor of 790-fold was achieved, and nine proteins from different organisms were expressed with high yields. This system can be utilized as a gene switch, promoter enhancer, or metabolic valve in synthetic biology applications. This operator-based engineering strategy can be employed for developing similar regulatory systems in different microorganisms.

Enzymatic Synthesis of Maltitol and Its Inhibitory Effect on the Growth of Streptococcus mutans DMST 18777.

This study aimed to synthesize maltitol using recombinant CGTase from Bacillus circulans A11 with ß-cyclodextrin (ß-CD) and sorbitol as a glucosyl donor and acceptor, respectively, and assess its antibacterial activity. Optimal conditions for producing the highest yield, 25.0% (w/w), were incubation of 1% (w/v) ß-CD and sorbitol with 400 U/mL of CGTase in 20 mM phosphate buffer at pH 6.0 and 50 °C for 72 h. Subsequently, maltitol underwent large-scale production and was purified by HPLC. By mass spectrometry, the molecular weight of the synthesized maltitol was 379.08 daltons, corresponding exactly to that of standard maltitol. The relative sweetness of synthesized and standard maltitol was ~90% of that of sucrose. Spot assay on the agar plate showed that maltitol inhibited the growth of Streptococcus mutans DMST 18777 cells. In addition, the MIC and MBC values of synthesized and standard maltitol against S. mutans were also determined as 20 and 40 mg/mL, respectively. These results show that the synthesized maltitol can be produced at high yields and has the potential to be used as an anticariogenic agent in products such as toothpaste.

Diverse prebiotic effects of isomaltodextrins with different glycosidic linkages and molecular weights on human gut bacteria in vitro.

Isomaltodextrin (IMD) is a novel dietary fiber enzymatically produced by reconstructing the molecular chain structure of starch using glycosyltransferases. In this study, the specific prebiotic effects of α-1,6 linear and α-1,2 or α-1,3 branched IMDs with different molecular weights (Mw) on human intestinal bacteria were investigated by pure culture of single strains and mixed fermentation of human fecal microflora in vitro. The results showed that α-1,6 linear IMDs markedly promoted beneficial Bifidobacterium and Lactobacillus in both pure culture and mixed fermentation. α-1,3 branching exhibited similar selectivity with α-1,6 linkage but yielded more butyrate in pure cultures. In contrast, IMDs containing α-1,2 branches were utilized efficiently only during mixed fermentation, which was speculated to result from metabolic cross-feeding. Regarding Mw, IMDs with lower Mw showed better prebiotic effects in pure cultures but no differences in mixed culture. These findings provide a theoretical basis for their application as functional foods.

Kinetically modelled approach of xanthan production using different carbon sources: A study on molecular weight and rheological properties of xanthan.

The present study emphasizes improving the overall yield, productivity and quality of xanthan by Xanthomonas campestris using different carbon sources via optimizing the fermentation media and kinetic modelling work. After optimization, six carbon sources and one nitrogen source were selected for xanthan production in 5 L bioreactor. Kinetic modelling was applied to assess the experimental fermentation data and to check its influence on scale-up production. In this work, xanthan production reached 40.65 g/L with a growth-associated rate constant (α) of 2.831, and highest specific growth rate (µm) of 0.37/h while using maltose as the sole carbon source. Furthermore, rheological properties were determined, and Herschel-Bulkley model was employed to assess the experimental data. Interestingly, xanthan obtained from sucrose and glucose showed the highest yield stress (τ0) of 12.50 ± 0.31 and 7.17 ± 0.21. Moreover, the highest xanthan molecular weight of 3.53 × 107 and 3.25 × 107 g/mol were also found with sucrose and glucose. At last, the proposed mechanism of sugar metabolism and xanthan biosynthesis pathway were described. Conclusively, maltose appeared as the best carbon source for maximum xanthan production: while sucrose and glucose gave qualitatively best results. In short, this systematically modelled approach maximizes the potential output and provides a solid base for continuous cultivation of xanthan at large-scale production.

Randomized Placebo-Controlled Trial of Ferric Carboxymaltose in Heart Failure With Iron Deficiency: Rationale and Design.

BACKGROUND: Iron deficiency (ID) has a prevalence of ≈40% to 50% among patients in heart failure (HF) with reduced ejection fraction and is associated with worse prognosis. Several trials demonstrated that intravenous ferric carboxymaltose leads to early and sustained improvement in patient-reported outcomes and functional capacity in patients with HF with reduced ejection fraction with ID, yet morbidity and mortality data are limited. METHODS: The objective of the HEART-FID trial (Ferric Carboxymaltose in Heart Failure With Iron Deficiency) is to assess efficacy and safety of ferric carboxymaltose compared with placebo as treatment for symptomatic HF with reduced ejection fraction with ID. HEART-FID is a multicenter, randomized, double-blind, placebo-controlled trial enrolling ≈3014 patients at ≈300 international centers. Eligible patients are aged ≥18 years in stable chronic HF with New York Heart Association functional class II to IV symptoms, ejection fraction ≤40%, ID (ferritin <100 ng/mL or ferritin 100-300 ng/mL with a transferrin saturation <20%), and documented HF hospitalization or elevated N-terminal pro-brain natriuretic peptide. Consented patients are assigned to ferric carboxymaltose or placebo at baseline, with repeated visits/assessments every 6 months for additional study drug based on hemoglobin and iron indices for the trial duration. The primary end point is a hierarchical composite of death and HF hospitalization at 12 months and change from baseline to 6 months in the 6-minute walk test distance. CONCLUSIONS: The HEART-FID trial will inform clinical practice by clarifying the role of long-term treatment with intravenous ferric carboxymaltose, added to usual care, in ambulatory patients with symptomatic HF with reduced ejection fraction with ID. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037931.

Trehalose Recycling Promotes Energy-Efficient Biosynthesis of the Mycobacterial Cell Envelope.

The mycomembrane layer of the mycobacterial cell envelope is a barrier to environmental, immune, and antibiotic insults. There is considerable evidence of mycomembrane plasticity during infection and in response to host-mimicking stresses. Since mycobacteria are resource and energy limited under these conditions, it is likely that remodeling has distinct requirements from those of the well-characterized biosynthetic program that operates during unrestricted growth. Unexpectedly, we found that mycomembrane remodeling in nutrient-starved, nonreplicating mycobacteria includes synthesis in addition to turnover. Mycomembrane synthesis under these conditions occurs along the cell periphery, in contrast to the polar assembly of actively growing cells, and both liberates and relies on the nonmammalian disaccharide trehalose. In the absence of trehalose recycling, de novo trehalose synthesis fuels mycomembrane remodeling. However, mycobacteria experience ATP depletion, enhanced respiration, and redox stress, hallmarks of futile cycling and the collateral dysfunction elicited by some bactericidal antibiotics. Inefficient energy metabolism compromises the survival of trehalose recycling mutants in macrophages. Our data suggest that trehalose recycling alleviates the energetic burden of mycomembrane remodeling under stress. Cell envelope recycling pathways are emerging targets for sensitizing resource-limited bacterial pathogens to host and antibiotic pressure.IMPORTANCE The glucose-based disaccharide trehalose is a stress protectant and carbon source in many nonmammalian cells. Mycobacteria are relatively unique in that they use trehalose for an additional, extracytoplasmic purpose: to build their outer "myco" membrane. In these organisms, trehalose connects mycomembrane biosynthesis and turnover to central carbon metabolism. Key to this connection is the retrograde transporter LpqY-SugABC. Unexpectedly, we found that nongrowing mycobacteria synthesize mycomembrane under carbon limitation but do not require LpqY-SugABC. In the absence of trehalose recycling, compensatory anabolism allows mycomembrane biosynthesis to continue. However, this workaround comes at a cost, namely, ATP consumption, increased respiration, and oxidative stress. Strikingly, these phenotypes resemble those elicited by futile cycles and some bactericidal antibiotics. We demonstrate that inefficient energy metabolism attenuates trehalose recycling mutant Mycobacterium tuberculosis in macrophages. Energy-expensive macromolecule biosynthesis triggered in the absence of recycling may be a new paradigm for boosting host activity against bacterial pathogens.

Parenteral iron therapy and phosphorus homeostasis: A review.

Phosphorus has an essential role in cellular and extracellular metabolism; maintenance of normal phosphorus homeostasis is critical. Phosphorus homeostasis can be affected by diet and certain medications; some intravenous iron formulations can induce renal phosphate excretion and hypophosphatemia, likely through increasing serum concentrations of intact fibroblast growth factor 23. Case studies provide insights into two types of hypophosphatemia: acute symptomatic and chronic hypophosphatemia, while considering the role of pre-existing conditions and comorbidities, medications, and intravenous iron. This review examines phosphorus homeostasis and hypophosphatemia, with emphasis on effects of iron deficiency and iron replacement using intravenous iron formulations.

Diastereomeric Cyclopentane-Based Maltosides (CPMs) as Tools for Membrane Protein Study.

Amphiphilic agents, called detergents, are invaluable tools for studying membrane proteins. However, membrane proteins encapsulated by conventional head-to-tail detergents tend to denature or aggregate, necessitating the development of structurally distinct molecules with improved efficacy. Here, a novel class of diastereomeric detergents with a cyclopentane core unit, designated cyclopentane-based maltosides (CPMs), were prepared and evaluated for their ability to solubilize and stabilize several model membrane proteins. A couple of CPMs displayed enhanced behavior compared with the benchmark conventional detergent, n-dodecyl-ß-d-maltoside (DDM), for all the tested membrane proteins including two G-protein-coupled receptors (GPCRs). Furthermore, CPM-C12 was notable for its ability to confer enhanced membrane protein stability compared with the previously developed conformationally rigid NBMs [J. Am. Chem. Soc. 2017, 139, 3072] and LMNG. The effect of the individual CPMs on protein stability varied depending on both the detergent configuration (cis/trans) and alkyl chain length, allowing us draw conclusions on the detergent structure-property-efficacy relationship. Thus, this study not only provides novel detergent tools useful for membrane protein research but also reports on structural features of the detergents critical for detergent efficacy in stabilizing membrane proteins.

Maltose Induced Expression of Cecropin AD by SUMO Technology in Bacillus subtilis WB800N.

Cecropin AD (CAD) is a hybrid peptide composed of 37 amino acids with the characters of strong antibacterial, antitumor properties and no hemolytic activity, which was regarded as a promising antibiotic candidate. Thus, a safe method to produce Cecropin AD is necessary to be found. In the study, Bacillus subtilis WB800N was employed as host strain. The CAD coding sequence fused with the signal peptide of SPsacB, the 6 × His gene and the gene of small ubiquitin-like modifier were cloned into the maltose-inducible vector pGJ148. Under the induction by 6% maltose, the recombinant fusion protein was successfully expressed and detected in culture substrate. An optimized amount (26.4 mg/L) of the recombinant CAD was purified of culture supernatant. After purification and digestion, the recombinant CAD was harvested about 4.5 mg/L with a purity of 93%. Recombinant CAD exhibited similar antimicrobial activity with synthetic CAD. This shows that the production of CAD in maltose-induced Bacillus subtilis expression system is a relatively safe method, which is vital for the application of CAD in animal husbandry production.

Assessing the individual microbial inhibitory capacity of different sugars against pathogens commonly found in food systems.

Highly concentrated sugar solutions are known to be effective antimicrobial agents. However, it is unknown whether this effect is solely the result of the collective osmotic effect imparted by a mixture of sugars or whether the type of carbohydrate used also has an individual chemical effect on bacterial responses, that is, inhibition/growth. In view of this, in this work, the antimicrobial properties of four sugars, namely, glucose, fructose, sucrose and maltose against three common food pathogens; Staphylococcus aureus, Escherichia coli and Salmonella enterica, were investigated using a turbidimetric approach. The results obtained indicate that the type of sugar used has a significant effect on the extent of bacterial inhibition which is not solely dependent on the water activity of the individual sugar solution. In addition, while it was shown that high sugar concentrations inhibit bacterial growth, very low concentrations show the opposite effect, that is, they stimulate bacterial growth, indicating that there is a threshold concentration upon which sugars cease to act as antimicrobial agents and become media instead. SIGNIFICANCE AND IMPACT OF THE STUDY: In this work, an analysis on the antimicrobial properties of glucose, fructose, sucrose and maltose in solution was conducted using a turbidimetric approach. Our findings indicate that while, as expected, all of these sugars exhibit significant antimicrobial effects at high concentrations, at low concentrations they appear to act as substrates for the bacteria which results in enhanced microbial growth instead of inhibition. In addition, the results obtained also suggest that the resultant osmotic stress imparted by the sugar solutions is not the only factor which determines their antimicrobial activity and that other chemical factors may be playing a significant role.

Pharmacokinetic, Pharmacodynamic, and Safety Profiles of Ferric Carboxymaltose in Chinese Patients with Iron-deficiency Anemia.

PURPOSE: Iron deficiency (ID) is one of the most commonly known nutritional deficiencies and is considered the primary cause of anemia (iron-deficiency anemia). Ferric carboxymaltose (FCM), an intravenous iron preparation, has been widely used for >10 years for iron-deficiency anemia treatment worldwide because of its many advantages. METHODS: This single-center, open-label, single dose escalation study in Chinese subjects was designed to assess the pharmacokinetic/pharmacodynamic parameters and safety of FCM in this population. The first 12 subjects received a 500-mg dose; after assessing safety data from the first 6 subjects in this cohort, another 12 subjects were assigned to the 1000-mg dose cohort. FINDINGS: After an infusion of FCM over 15 min, a rapid dose-dependent increase in total serum iron levels was observed with a median Tmax of 30 min following the start of the infusion for both cohorts. The Cmax and AUC for the 1000-mg dose were ~1.8-fold (p = 0.2929) and 2.3-fold (p = 0.0318) those associated with the 500-mg dose, respectively. Mean terminal t1/2 values were 12.3 and 10.5 h for the 2 cohorts. The renal elimination of FCM was negligible (<0.1%). Increase in mean serum iron levels and ferritin concentrations showed dose dependency. Iron-binding capacity was transiently well utilized after dosing, as indicated by transferrin saturation >88% with 500-mg FCM and >90% with 1000-mg FCM. Hemoglobin levels did not show significant changes during the 7-day observation period, whereas mean reticulocyte counts significantly increased in both cohorts, suggesting activation of the hematopoietic system. FCM was well tolerated in these Chinese subjects. No new or unexpected treatment-emergent adverse events were attributable to FCM. IMPLICATIONS: The pharmacokinetic/pharmacodynamic and safety profiles in Chinese subjects seemed comparable to those in white and Japanese populations. ChinaDrugTrials.org.cn identifier: CTR20160863.

Iron Infusion and Induced Hypophosphatemia: The Role of Fibroblast Growth Factor-23.

The mechanism of action of fibroblast growth factor-23 (FGF23) is becoming increasingly clearer as a result of studies that have defined its structure and pleiotropic effects. Furthermore, data are emerging on the effects exerted on this hormone by iron administration. Ten main iron formulations are recognized (with clear differences in composition and possible reactions of intolerance and anaphylaxis), which are indicated for iron deficiency anemia, including nephropathic subjects, as suggested by medical guidelines. With some types of iron formulation (especially iron carboxymaltose) a particular side effect has been observed: hypophosphatemia, mediated by FGF23. This review aims to draw attention to this correlation and the contradiction represented by the presence of both positive and negative modulation by FGF23, with the effects induced by its increase even after long-term treatment with iron formulation. However, more evidence is needed to understand the reasons for this differential stimulation.

High-dose intravenous versus oral iron in blood donors with iron deficiency: The IronWoMan randomized, controlled clinical trial.

INTRODUCTION: Frequent blood donation often leads to iron deficiency and even anemia but appropriate strategies for detection and prevention are currently not mandatory. At the Medical University of Graz, we conducted a single-center prospective clinical trial to compare oral and IV iron supplementation in iron deficient blood donors including Austrian regular whole blood and platelet apheresis donors. We aimed to determine the difference of transferrin saturation between the treatment groups 8-12 weeks iron administration besides other parameters of iron status and blood count. METHODS: 176 healthy male and female blood donors with iron deficiency (ferritin ≤30 ng/mL) were randomized to either a single dose of IV ferric carboxymaltose (1000 mg, n = 86) or oral iron (II)fumarate (100 tablets of 100 mg [10 per week], n = 90). RESULTS: Between 2014 and 2016, 172 donors (137 women) completed the study; 4 in the oral group were lost to follow-up. At follow-up, median (IQR) transferrin saturation and ferritin were significantly higher in the intravenous group (27 [23-35]%, vs 21.0 [16-32]%; p < 0.001 and 105 [75-145] ng/mL vs 25 [17-34] ng/mL; p < 0.001, respectively) while median (IQR) hemoglobin levels were comparable (IV, 13.6 [13.0-14.4] g/dL vs oral, 13.6 [13.0-14.2] g/dL). The frequency of adverse effects was comparable (38% in both groups) and no serious adverse events occurred. CONCLUSIONS: A single dose of 1000 mg of intravenous iron is highly effective to counteract iatrogenic iron deficiency in blood donors. Oral iron appears to be an acceptable alternative. The assessment of body iron stores should play a key role in maintaining blood donors' health. This trial was registered at www.clinicaltrials.gov as NCT01787526 on February 8, 2013 and at www.clinicaltrialsregister.eu (EudraCT identifier: 2013-000327-14) on September 24, 2013.

Oral intake of slowly digestible α-glucan, isomaltodextrin, stimulates glucagon-like peptide-1 secretion in the small intestine of rats.

To investigate whether oral intake of highly branched α-glucan isomaltodextrin (IMD) could stimulate ileal glucagon-like peptide-1 (GLP-1) secretion, we examined (1) the digestibility of IMD, (2) the digestion and absorption rates of IMD, in rat small intestine and (3) portal GLP-1 concentration in rats given IMD. In Expt 1, ileorectostomised rats were given a 3 % IMD diet for 10 d. Separately, a 16-h in vitro digestion of IMD, using porcine pancreatic α-amylase and brush-border membrane vesicles from rat small intestine, was conducted. In Expt 2, upon 24-h fasting, rats were given any of glucose, IMD and high-amylose maize starch (HAMS) (1 g/kg of body weight). In Expt 3, caecectomised rats were given 0·2 % neomycin sulphate and a 5 % IMD diet for 10 d. The in vivo and in vitro digestibility of IMD was 70-80 %. The fraction of IMD digested in vitro for the first 120 min was 67 % of that in maize starch. The AUC for 0-120 min of plasma glucose concentration was significantly lower in HAMS group and tended to be lower in IMD group than in the glucose group. Finally, we also observed that, when compared with control rats, glucose of IMD significantly stimulated and improved the concentration of portal active GLP-1 in antibiotic-administered, caecectomised rats. We concluded that IMD was slowly digested and the resulting glucose stimulated GLP-1 secretion in rat small intestine. Oral delivery of slowly released IMD glucose to the small intestine probably exerts important, yet unknown, physiological effects on the recipient.