MA'AT analysis has been applied to two biologically‐important O‐glycosidic linkages in two disaccharides, α‐D‐Galp‐(1→3)‐β‐D‐GalpOMe (3) and β‐D‐Galp‐(1→3)‐β‐D‐GalpOMe (4). Using density functional ...theory (DFT) to obtain parameterized equations relating a group of trans‐O‐glycosidic NMR spin‐couplings to either phi (ϕ') or psi (ψ'), and experimental 3JCOCH, 2JCOC, and 3JCOCC spin‐couplings measured in aqueous solution in 13C‐labeled isotopomers, probability distributions of ϕ' and ψ' in each linkage were determined and compared to those determined by aqueous 1‐μs molecular dynamics (MD) simulation. Good agreement was found between the MA'AT and single‐state MD conformational models of these linkages for the most part, with modest (approximately <15°) differences in the mean values of ϕ' and ψ', although the envelope of allowed angles (encoded in circular standard deviations or CSDs) is consistently larger for ϕ' determined from MA'AT analysis than from MD for both linkages. The MA'AT model of the α‐Galp‐(1→3)‐β‐Galp linkage agrees well with those determined previously using conventional NMR methods (3JCOCH values and/or 1H‐1H NOEs), but some discrepancy was observed for the β‐Galp‐(1→3)‐β‐Galp linkage, which may arise from errors in the conventions used to describe the linkage torsion angles. Statistical analyses of X‐ray crystal structures show ranges of ϕ' and ψ' for both linkages that include the mean angles determined from MA'AT analyses, although both angles adopt a wide range of values in the crystalline state, with ϕ' in β‐Galp‐(1→3)‐β‐Galp linkages showing greater‐than‐expected conformational variability.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Activation of glycosyl methylpropiolates by TfOH was investigated. Armed and superarmed glycosyl donors can be activated by use of 0.2 equivalent TfOH whereas 1.0 equivalent of TfOH was required for ...the activation of the disarmed glycosyl donors. All the glycosidations gave very good yields. The method is suitable for synthesis of glycosides and disaccharides and it may result in the hydrolysis of the interglycosidic bond if the sugar at the non-reducing end is armed or superarmed. These problems are not seen when gold-catalyzed activation procedures are invoked for the activation of glycosyl alkynoates.
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•Methylpropiolate glycosides are explored as glycosyl donors.•Sub-stoichiometric quantity (0.2 equivalents) of Brønsted acid (TfOH) was sufficient to activate armed and super armed glycosyl donors.•TfOH (1.0 equivalents) is required for disarmed glycosyl donors.•The glycosyl donor chemistry is suitable for the synthesis of glycosides and disaccharides.•Attempts to synthesize higher oligosaccharides led to the hydrolysis of the interglycosidic bond.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Carrageenans are sulfated galactans found in certain red seaweeds with proven biological activities. In this work, we have prepared purified native and degraded κ-, ι-; and λ-carrageenans, including ...the disaccharides (carrabioses) and disaccharide-alditols (carrabiitols) from seaweed extracts as potential antitumor compounds and identified the active principle of the cytotoxic and potential antitumor properties of these compounds. Both κ and ι-carrageenan, as well as carrageenan oligosaccharides showed cytotoxic effect over LM2 tumor cells. Characterized disaccharides (carrabioses) and the reduced product carrabiitols, were also tested. Only carrabioses were cytotoxic, and among them, κ-carrabiose was the most effective, showing high cytotoxic properties, killing the cells through an apoptotic pathway. In addition, the cells surviving treatment with κ-carrabiose, showed a decreased metastatic ability in vitro, together with a decreased cell-cell and cell-matrix interactions, thus suggesting possible antitumor potential. Overall, our results indicate that most cytotoxic compounds derived from carrageenans have lower molecular weights and sulfate content. Potential applications of the results emerging from the present work include the use of disaccharide units such as carrabioses coupled to antineoplasics in order to improve its cytotoxicity and antimetastatic properties, and the use of ι-carrageenan as adjuvant or carrier in anticancer treatments.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The identification of general and efficient methods for the construction of oligosaccharides stands as one of the great challenges for the field of synthetic chemistry
. Selective glycosylation of ...unprotected sugars and other polyhydroxylated nucleophiles is a particularly significant goal, requiring not only control over the stereochemistry of the forming bond but also differentiation between similarly reactive nucleophilic sites in stereochemically complex contexts
. Chemists have generally relied on multi-step protecting-group strategies to achieve site control in glycosylations, but practical inefficiencies arise directly from the application of such approaches
. Here we describe a strategy for small-molecule-catalyst-controlled, highly stereo- and site-selective glycosylations of unprotected or minimally protected mono- and disaccharides using precisely designed bis-thiourea small-molecule catalysts. Stereo- and site-selective galactosylations and mannosylations of a wide assortment of polyfunctional nucleophiles is thereby achieved. Kinetic and computational studies provide evidence that site-selectivity arises from stabilizing C-H/π interactions between the catalyst and the nucleophile, analogous to those documented in sugar-binding proteins. This work demonstrates that highly selective glycosylation reactions can be achieved through control of stabilizing non-covalent interactions, a potentially general strategy for selective functionalization of carbohydrates.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Non‐absorbable disaccharides (lactulose and lactitol) are recommended as first‐line treatment for hepatic encephalopathy. The previous (second) version of this review included 10 ...randomised clinical trials (RCTs) evaluating non‐absorbable disaccharides versus placebo/no intervention and eight RCTs evaluating lactulose versus lactitol for people with cirrhosis and hepatic encephalopathy. The review found no evidence to either support or refute the use of the non‐absorbable disaccharides and no differences between lactulose versus lactitol.
Objectives
To assess the beneficial and harmful effects of i) non‐absorbable disaccharides versus placebo/no intervention and ii) lactulose versus lactitol in people with cirrhosis and hepatic encephalopathy.
Search methods
We carried out electronic searches of the Cochrane Hepato‐Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 10), MEDLINE, EMBASE, and Science Citation Index Expanded to 19 October 2015; manual searches of meetings and conference proceedings; checks of bibliographies; and correspondence with investigators and pharmaceutical companies.
Selection criteria
We included RCTs, irrespective of publication status, language, or blinding.
Data collection and analysis
Two review authors, working independently, retrieved data from published reports and correspondence with investigators. The primary outcomes were mortality, hepatic encephalopathy, and serious adverse events. We presented the results of meta‐analyses as risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI). We assessed the quality of the evidence using 'Grading of Recommendations Assessment Development and Evaluation' (GRADE) and bias control using the Cochrane Hepato‐Biliary Group domains. Our analyses included regression analyses of publication bias and other small study effects, Trial Sequential Analyses to detect type 1 and type 2 errors, and subgroup and sensitivity analyses.
Main results
We included 38 RCTs with a total of 1828 participants. Eight RCTs had a low risk of bias in the assessment of mortality. All trials had a high risk of bias in the assessment of the remaining outcomes. Random‐effects meta‐analysis showed a beneficial effect of non‐absorbable disaccharides versus placebo/no intervention on mortality when including all RCTs with extractable data (RR 0.59, 95% CI 0.40 to 0.87; 1487 participants; 24 RCTs; I2 = 0%; moderate quality evidence) and in the eight RCTs with a low risk of bias (RR 0.63, 95% CI 0.41 to 0.97; 705 participants). The Trial Sequential Analysis with the relative risk reduction (RRR) reduced to 30% confirmed the findings when including all RCTs, but not when including only RCTs with a low risk of bias or when we reduced the RRR to 22%. Compared with placebo/no intervention, the non‐absorbable disaccharides were associated with beneficial effects on hepatic encephalopathy (RR 0.58, 95% CI 0.50 to 0.69; 1415 participants; 22 RCTs; I2 = 32%; moderate quality evidence). Additional analyses showed that non‐absorbable disaccharides can help to reduce serious adverse events associated with the underlying liver disease including liver failure, hepatorenal syndrome, and variceal bleeding (RR 0.47, 95% CI 0.36 to 0.60; 1487 participants; 24 RCTs; I2 = 0%; moderate quality evidence). We confirmed the results in Trial Sequential Analysis. Tests for subgroup differences showed no statistical differences between RCTs evaluating prevention, overt, or minimal hepatic encephalopathy. The evaluation of secondary outcomes showed a potential beneficial effect of the non‐absorbable disaccharides on quality of life, but we were not able to include the data in an overall meta‐analysis (very low quality evidence). Non‐absorbable disaccharides were associated with non‐serious (mainly gastrointestinal) adverse events (very low quality evidence). None of the RCTs comparing lactulose versus lactitol evaluated quality of life. The review found no differences between lactulose and lactitol for the remaining outcomes (very low quality evidence).
Authors' conclusions
This review includes a large number of RCTs evaluating the prevention or treatment of hepatic encephalopathy. The analyses found evidence that non‐absorbable disaccharides may be associated with a beneficial effect on clinically relevant outcomes compared with placebo/no intervention.
Transmission electron microscopic image of iron isomaltoside 1000.
The treatment of iron deficiency anemia with polynuclear iron formulations is an established therapy in patients with chronic kidney ...disease but also in other disease areas like gastroenterology, cardiology, oncology, pre/post operatively and obstetrics’ and gynecology. Parenteral iron formulations represent colloidal systems in the lower nanometer size range which have traditionally been shown to consist of an iron core surrounded by a carbohydrate shell. In this publication, we for the first time describe the novel matrix structure of iron isomaltoside 1000 which differs from the traditional picture of an iron core surrounded by a carbohydrate. Despite some structural similarities between the different iron formulations, the products differ significantly in their physicochemical properties such as particle size, zeta potential, free and labile iron content, and release of iron in serum. This study compares the physiochemical properties of iron isomaltoside 1000 (Monofer®) with the currently available intravenous iron preparations and relates them to their biopharmaceutical properties and their approved clinical applications. The investigated products encompass low molecular weight iron dextran (CosmoFer®), sodium ferric gluconate (Ferrlecit®), iron sucrose (Venofer®), iron carboxymaltose (Ferinject®/Injectafer®), and ferumoxytol (Feraheme®) which are compared to iron isomaltoside 1000 (Monofer®). It is shown that significant and clinically relevant differences exist between sodium ferric gluconate and iron sucrose as labile iron formulations and iron dextran, iron carboxymaltose, ferumoxytol, and iron isomaltoside 1000 as stable polynuclear formulations. The differences exist in terms of their immunogenic potential, safety, and convenience of use, the latter being expressed by the opportunity for high single-dose administration and short infusion times. Monofer is a new parenteral iron product with a very low immunogenic potential and a very low content of labile and free iron. This enables Monofer, as the only IV iron formulation, to be administered as a rapid high dose infusion in doses exceeding 1000
mg without the application of a test dose. This offers considerable dose flexibility, including the possibility of providing full iron repletion in a single infusion (one-dose iron repletion).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Stingless bee (Meliponini) honey has long been considered a high-value functional food, but the perceived therapeutic value has lacked attribution to specific bioactive components. Examination of ...honey from five different stingless bee species across Neotropical and Indo-Australian regions has enabled for the first time the identification of the unusual disaccharide trehalulose as a major component representing between 13 and 44 g per 100 g of each of these honeys. Trehalulose is an isomer of sucrose with an unusual α-(1 → 1) glucose-fructose glycosidic linkage and known acariogenic and low glycemic index properties. NMR and UPLC-MS/MS analysis unambiguously confirmed the identity of trehalulose isolated from stingless bee honeys sourced across three continents, from Tetragonula carbonaria and Tetragonula hockingsi species in Australia, from Geniotrigona thoracica and Heterotrigona itama in Malaysia and from Tetragonisca angustula in Brazil. The previously unrecognised abundance of trehalulose in stingless bee honeys is concrete evidence that supports some of the reported health attributes of this product. This is the first identification of trehalulose as a major component within a food commodity. This study allows the exploration of the expanded use of stingless bee honey in foods and identifies a bioactive marker for authentication of this honey in associated food standards.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
A diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) is recommended for irritable bowel syndrome (IBS), if general lifestyle and dietary advice fails. ...However, although the impact of a low FODMAP diet on individual IBS symptoms has been examined in some randomised controlled trials (RCTs), there has been no recent systematic assessment, and individual trials have studied numerous alternative or control interventions, meaning the best comparator is unclear. We performed a network meta-analysis addressing these uncertainties.
We searched the medical literature through to 2 April 2021 to identify RCTs of a low FODMAP diet in IBS. Efficacy was judged using dichotomous assessment of improvement in global IBS symptoms or improvement in individual IBS symptoms, including abdominal pain, abdominal bloating or distension, and bowel habit. Data were pooled using a random effects model, with efficacy reported as pooled relative risks (RRs) with 95% CIs, and interventions ranked according to their P-score.
We identified 13 eligible RCTs (944 patients). Based on failure to achieve an improvement in global IBS symptoms, a low FODMAP diet ranked first vs habitual diet (RR of symptoms not improving=0.67; 95% CI 0.48 to 0.91, P-score=0.99), and was superior to all other interventions. Low FODMAP diet ranked first for abdominal pain severity, abdominal bloating or distension severity and bowel habit, although for the latter it was not superior to any other intervention. A low FODMAP diet was superior to British Dietetic Association (BDA)/National Institute for Health and Care Excellence (NICE) dietary advice for abdominal bloating or distension (RR=0.72; 95% CI 0.55 to 0.94). BDA/NICE dietary advice was not superior to any other intervention in any analysis.
In a network analysis, low FODMAP diet ranked first for all endpoints studied. However, most trials were based in secondary or tertiary care and did not study effects of FODMAP reintroduction and personalisation on symptoms.
The low‐FODMAP diet is a new dietary therapy for the management of irritable bowel syndrome that is gaining in popularity around the world. Developing the low‐FODMAP diet required not only extensive ...food composition data but also the establishment of “cutoff values” to classify foods as low‐FODMAP. These cutoff values relate to each particular FODMAP present in a food, including oligosaccharides (fructans and galacto‐oligosaccharides), sugar polyols (mannitol and sorbitol), lactose, and fructose in excess of glucose. Cutoff values were derived by considering the FODMAP levels in typical serving sizes of foods that commonly trigger symptoms in individuals with irritable bowel syndrome, as well as foods that were generally well tolerated. The reliability of these FODMAP cutoff values has been tested in a number of dietary studies. The development of the techniques to quantify the FODMAP content of foods has greatly advanced our understanding of food composition. FODMAP composition is affected by food processing techniques and ingredient selection. In the USA, the use of high‐fructose corn syrups may contribute to the higher FODMAP levels detected (via excess fructose) in some processed foods. Because food processing techniques and ingredients can vary between countries, more comprehensive food composition data are needed for this diet to be more easily implemented internationally.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Chondroitin sulfate proteoglycans (CSPGs) are polyanionic extra/pericellular matrix macromolecules that surround almost all cell types and create microenvironmental niches to support miscellaneous ...cellular events. In general, the multifunctional properties of CSPGs are attributable to the structural divergence of the CS glycosaminoglycan (GAG) moieties. Because the expression profiles of the GAG chains of CSPGs change with developmental stage, aging, and disease progression, characterization of the GAG chains is essential to understand the functional roles of CSPGs. This chapter describes the basic protocols for GAG moiety-based immunochemical detection of CSPGs in biological samples in conjunction with CS disaccharide composition analysis.
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