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1.
Sci Rep ; 12(1): 6853, 2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35477731

RESUMO

Iron deficiency commonly affects patients with chronic kidney disease and has an important burden in disease trajectory and quality of life; nonetheless current guidelines do not advocate treatment of iron-deficiency without anemia in this patient group. Concerns exist regarding the potential effects of intravenous iron on oxidative stress, inflammation, and endothelial function. As part of a multicenter double-blinded randomized controlled clinical trial, we examined the effects of a single dose of intravenous iron vs. placebo on biomarkers of oxidative stress, inflammation and endothelial function in non-anemic iron deficient patients (serum ferritin < 100 µg/L and/or transferrin saturation < 20%) with chronic kidney disease (stage 3b-5). Fifty-four individuals were randomized to receive ferric derisomaltose (n = 26) or placebo (n = 28). Ferric derisomaltose was associated with a non-significant decrease in mean F2-isoprostane and no effect on thiobarbituric acid reactive substances when compared to placebo throughout follow up. No effect on inflammatory markers was observed. A modest but statistically significant rise in E-selectin was noted in the intravenous iron group at 1 month and 3 month follow-up (p = 0.030 and p = 0.002 respectively). These results suggest ferric derisomaltose administration in non-dialysis dependent chronic kidney disease patients who are iron deficient does not induce prolonged oxidative stress or inflammation. Larger trials are required to quantify the benefit of intravenous iron administration in this patient group.


Assuntos
Ferro , Insuficiência Renal Crônica , Biomarcadores , Dissacarídeos , Feminino , Compostos Férricos , Humanos , Inflamação/tratamento farmacológico , Ferro/farmacologia , Masculino , Estresse Oxidativo , Qualidade de Vida , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico
2.
Sci Rep ; 12(1): 7087, 2022 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-35490171

RESUMO

Oritavancin is a semisynthetic glycopeptide antibiotic used to treat severe infections by multidrug-resistant Gram-positive pathogens. Oritavancin is known to be a thousand times more potent than vancomycin against Gram-positive bacteria due to the additional interactions with bacterial peptidoglycan (PG) facilitated by a secondary-binding site. The presence of this secondary-binding site is evident in desleucyl-oritavancin, an Edman degradation product of oritavancin, still retaining its potency against Gram-positive bacteria, whereas desleucyl-vancomycin is devoid of any antimicrobial activities. Herein, using explicit solvent molecular dynamics (MD) simulations, steered MD simulations, and umbrella sampling, we show evidence of a secondary-binding site mediated by the disaccharide-modified hydrophobic sidechain of oritavancin interactions with the pentaglycyl-bridge segment of the PG. The interactions were characterized through comparison to the interaction of PG with chloroeremomycin, vancomycin, and the desleucyl analogs of the glycopeptides. Our results show that the enhanced binding of oritavancin to PG over the binding of the other complexes studied is due to an increase in the hydrophobic effect, electrostatic and van der Waals interactions, and not the average number of hydrogen bonds. Our ranking of the binding interactions of the biomolecular complexes directly correlates with the order based on their experimental minimum inhibitory concentrations. The results of our simulations provide insight into the modification of glycopeptides to increase their antimicrobial activities or the design of novel antibiotics against pathogenic Gram-positive bacteria.


Assuntos
Simulação de Dinâmica Molecular , Vancomicina , Antibacterianos/química , Sítios de Ligação , Dissacarídeos/farmacologia , Glicopeptídeos/química , Bactérias Gram-Positivas , Peptidoglicano/metabolismo , Vancomicina/química
3.
J Med Econ ; 25(1): 561-570, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35403540

RESUMO

OBJECTIVES: Two intravenous (IV) iron formulations, ferric derisomaltose (FDI) and iron sucrose (IS), are currently available for the treatment of iron deficiency anemia (IDA) in China. Clinical studies have demonstrated that FDI has an improved efficacy and safety profile versus IS, while requiring fewer infusions to correct iron deficits. Based on these findings, the present study evaluated the costs and benefits of FDI and IS for the treatment of IDA, from a healthcare system and societal perspective in China. METHODS: A patient-level model was developed to project time to hematological response and incidence of cardiovascular adverse events and hypersensitivity reactions (HSRs) associated with FDI and IS over 5 years. Costs included iron acquisition, administration, and adverse event/HSR treatment costs, based on published studies, fee schedules, and a physician survey. Health state utilities associated with adverse events, HSRs, and the number of infusions were obtained from the literature and a time trade-off survey. RESULTS: From a healthcare system perspective, FDI was associated with incremental costs of RMB 1,934 (purchasing power parity USD 462) and incremental quality-adjusted life expectancy of 0.078 quality-adjusted life-years (QALYs) versus IS, yielding an incremental cost-utility ratio of RMB 24,901 (USD 5,949) in the base case scenario. From a societal perspective, FDI was associated with reduced total costs and therefore dominant versus IS. LIMITATIONS: Limitations included the absence of clinical data specific to China and insufficient data to model persistence with treatment. CONCLUSIONS: This was the first cost-utility analysis comparing FDI and IS for the treatment of IDA in China. Based on a patient-level model, FDI was found to improve quality of life and reduce administration and adverse events costs relative to IS. Using the 2020 Chinese gross domestic product per capita of RMB 72,447 (USD 17,307) as a cost-effectiveness threshold, FDI would be considered cost-effective in China.


Ferric derisomaltose (FDI) was approved in February 2021 for the treatment of iron deficiency anemia (IDA) in China and allows for fast iron correction in one visit with a good safety profile. The current standard of care in China is iron sucrose (IS). Clinical and economic decision-making can benefit from having longer-term projections on the benefits and costs of new medications relative to the current standard of care, which is why we conducted the first cost-utility analysis of FDI and IS for China. We developed a patient-level model that captured the effects of the iron formulations on IDA, in addition to incidences of adverse events and hypersensitivity reactions (HSRs) associated with either formulation. Costs of the iron formulations, their administration, and of treatments for adverse events and HSR were modeled alongside the quality of life effects of IDA, adverse events, HSRs, and iron infusions. We used published clinical data and Chinese cost data to inform our model. Our results show that FDI was associated with higher quality-adjusted life expectancy than IS, regardless of the perspective of the analysis, and higher total costs from the healthcare system perspective. From a societal perspective, FDI was associated with lower costs due to reduced travel and waiting time and smaller productivity losses given there were fewer appointments. These results imply that FDI is likely good value for money for the healthcare system and indeed cost-saving for society relative to IS, which has so far been the most widely used IV iron treatment in China.


Assuntos
Anemia Ferropriva , Anemia Ferropriva/tratamento farmacológico , Análise Custo-Benefício , Dissacarídeos , Compostos Férricos/uso terapêutico , Óxido de Ferro Sacarado/efeitos adversos , Humanos , Ferro/uso terapêutico , Qualidade de Vida
4.
J Am Soc Mass Spectrom ; 33(5): 859-864, 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35437995

RESUMO

Determining the primary structure of glycans remains challenging due to their isomeric complexity. While high-resolution ion mobility spectrometry (IMS) has recently allowed distinguishing between many glycan isomers, the arrival-time distributions (ATDs) frequently exhibit multiple peaks, which can arise from positional isomers, reducing-end anomers, or different conformations. Here, we present the combination of ultrahigh-resolution ion mobility, collision-induced dissociation (CID), and cryogenic infrared (IR) spectroscopy as a systematic method to identify reducing-end anomers of glycans. Previous studies have suggested that high-resolution ion mobility of sodiated glycans is able to separate the two reducing-end anomers. In this case, Y-fragments generated from mobility-separated precursor species should also contain a single anomer at their reducing end. We confirm that this is the case by comparing the IR spectra of selected Y-fragments to those of anomerically pure mono- and disaccharides, allowing the assignment of the mobility-separated precursor and its IR spectrum to a single reducing-end anomer. The anomerically pure precursor glycans can henceforth be rapidly identified on the basis of their IR spectrum alone, allowing them to be distinguished from other isomeric forms.


Assuntos
Espectrometria de Mobilidade Iônica , Polissacarídeos , Dissacarídeos , Espectrometria de Mobilidade Iônica/métodos , Isomerismo , Polissacarídeos/análise , Espectrofotometria Infravermelho
5.
World J Microbiol Biotechnol ; 38(6): 95, 2022 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-35441950

RESUMO

Galacto-oligosaccharides (GOS) are used as prebiotic ingredients in various food and pharmaceutical formulations. Currently, production of GOS involves the enzymatic conversion of lactose by transgalactosylation using ß-galactosidase. The purity of the resulting product is low, typically limited to up to 55% GOS on total carbohydrate basis due to the presence of non-reacted lactose, and the formation of by-products glucose and galactose. In industrial practice high-purity GOS is manufactured by removing the unwanted mono- and disaccharides from raw GOS with simulated moving bed (SMB) chromatography. This purification step is associated with high processing cost that increases the price of pure GOS and limits its marketability. The last decades have witnessed a growing interest in developing competitive biotechnological processes that could replace chromatography. This paper presents a comprehensive review on the recent advancements of microbial GOS purification, a process commonly referred to as selective fermentation or selective metabolism. Purification strategies include: (i) removal of glucose alone or together with galactose by lactose negative yeast species, that typically results in purity values below 60% due to remaining lactose; (ii) removal of both mono- and disaccharides by combining the fast monosaccharide metabolizing capacity of some yeast species with efficient lactose consumption by certain lactose positive microbes, reaching GOS purity in the range of 60-95%; and (iii) the application of selected strains of Kluyveromyces species with high lactose metabolizing activity to achieve high-purity GOS that is practically free from lactose and monosaccharides.


Assuntos
Galactose , Lactose , Dissacarídeos , Glucose/metabolismo , Lactose/metabolismo , Monossacarídeos , Oligossacarídeos/metabolismo , Prebióticos , beta-Galactosidase/metabolismo
6.
Org Biomol Chem ; 20(17): 3528-3534, 2022 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-35388870

RESUMO

Heparan sulfate (HS), a glycosaminoglycan related to heparin, is a linear polysaccharide, consisting of repeating disaccharide units. This compound is involved in multiple biological processes such as inflammation, coagulation, angiogenesis and viral infections. Our work focuses on the synthesis of simple HS analogs for the study of structure-activity relationships, with the aim of modulating these biological activities. Thioglycoside analogs, in which the interglycosidic oxygen is replaced by a sulfur atom, are very interesting compounds in terms of therapeutic applications. Indeed, the thioglycosidic bond leads to an improvement of their stability and can allow the inhibition of enzymes involved in physiological and pathological processes. In our previous work, we developed a synthetic sequence which led to a non-sulfated thiodisaccharide analog of HS. In this paper, we report our results of the development of a new synthetic method allowing access to the novel sulfated S-disaccharide, as well as to their oxygenated analogues (O-disaccharide and sulfated O-disaccharide). These 4 compounds were also tested for the inhibition of heparanase, an enzyme involved in biological processes like tumor growth and inflammation. The obtained IC50 values in the micromolar range showed the impact of the interglycosidic sulfur atom and the 6-sulfate group.


Assuntos
Dissacarídeos , Heparitina Sulfato , Dissacarídeos/química , Dissacarídeos/farmacologia , Glucuronidase , Heparitina Sulfato/química , Heparitina Sulfato/farmacologia , Humanos , Inflamação , Enxofre
7.
Nutrients ; 14(8)2022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35458106

RESUMO

The dietary approach low in oligosaccharides, disaccharides, monosaccharides, and fermentable polyols (FODMAPs-LFD) is a good strategy for treating irritable bowel syndrome (IBS). Beyond the LFD, other dietary approaches with beneficial effects may be hypothesized. Among them, consumption of Tritordeum-based foods (TBD, bread, bakery products, and pasta) in substitution of other cereals seem to achieve promising results. In a randomized controlled trial, we compared the effects of 12 weeks of LFD to TBD in improving the symptom profile of IBS-diarrhea (IBS-D) patients. The two diets equally improved gastrointestinal symptoms and QoL, measured by the IBS Severity Scoring System (IBS-SSS) questionnaire, reducing the total score after four weeks and maintaining this range until the end of treatment (IBS-SSS total score change: -132.1; 95% CI: -74.9 to -189.4 and -130.5; 95% CI: -73.2 to -187.7; p < 0.0001 after LFD and TBD, respectively). The two diets did not modify the micronutrients content when extended for 12 weeks. LFD could be regarded as a first-line dietary approach for IBS-D patients. However, TBD may represent a valid alternative, with high palatability, especially among Italian patients, for whom pasta is considered one of the main assets of dietetic culture, and would be easier to manage in their daily habits.


Assuntos
Síndrome do Intestino Irritável , Diarreia/etiologia , Dieta , Dieta com Restrição de Carboidratos , Dissacarídeos , Fermentação , Humanos , Monossacarídeos , Oligossacarídeos , Qualidade de Vida
8.
Elife ; 112022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35394422

RESUMO

Protein N-glycosylation is a post-translational modification found in organisms of all domains of life. The crenarchaeal N-glycosylation begins with the synthesis of a lipid-linked chitobiose core structure, identical to that in Eukaryotes, although the enzyme catalyzing this reaction remains unknown. Here, we report the identification of a thermostable archaeal ß-1,4-N-acetylglucosaminyltransferase, named archaeal glycosylation enzyme 24 (Agl24), responsible for the synthesis of the N-glycan chitobiose core. Biochemical characterization confirmed its function as an inverting ß-D-GlcNAc-(1→4)-α-D-GlcNAc-diphosphodolichol glycosyltransferase. Substitution of a conserved histidine residue, found also in the eukaryotic and bacterial homologs, demonstrated its functional importance for Agl24. Furthermore, bioinformatics and structural modeling revealed similarities of Agl24 to the eukaryotic Alg14/13 and a distant relation to the bacterial MurG, which are catalyzing the same or a similar reaction, respectively. Phylogenetic analysis of Alg14/13 homologs indicates that they are ancient in Eukaryotes, either as a lateral transfer or inherited through eukaryogenesis.


Assuntos
Archaea , Eucariotos , Archaea/genética , Dissacarídeos , Filogenia , Polissacarídeos
9.
Sci Rep ; 12(1): 5654, 2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35383226

RESUMO

This study aimed to evaluate the anti-pancreatic cancer effects of flavonoids in Plumula Nelumbinis. High-performance liquid chromatography/quadrupole time-of-flight mass spectrometry showed that apiin, rhoifolin, and vitexin were three principal components in total flavonoids derived from Plumula Nelumbinis, with vitexin being the most abundant component. Cell viability assay revealed that apiin, rhoifolin, and vitexin could inhibit proliferation of PANC-1 and ASPC-1, with rhoifolin showing the maximum inhibitory effect. Rhoifolin inhibited cell proliferation and promoted apoptosis of pancreatic cancer cells, which was associated with up-regulated JNK and p-JNK as well as down-regulated p-AKT. Rhoifolin also inhibited cell migration and invasion, and increased the antioxidant capacity in PANC-1 and ASPC-1. Besides, AKT activator (SC79) or JNK inhibitor (SP600125) effectively reversed the anticancer effects of rhoifolin in pancreatic cancer. Quantitative proteomics analysis showed that rhoifolin altered proteomic profiles in pancreatic cancer cells. Western blot analysis showed that rhoifolin down-regulated transforming growth factor beta 2 (TGF-ß2), the regulator of proteoglycan synthesis, with the concomitant down-regulation of phosphorylated SMAD family member 2 (SMAD2), the downstream effector of TGF-ß2. In conclusion, rhoifolin regulates the AKT/JNK/caspase-3 and TGF-ß2/SMAD2 signaling pathways, which may contribute to its anti-pancreatic cancer effects.


Assuntos
Sistema de Sinalização das MAP Quinases , Neoplasias Pancreáticas , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Dissacarídeos , Flavonoides , Glicosídeos , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Proteômica , Proteínas Proto-Oncogênicas c-akt
10.
J Med Life ; 15(2): 174-179, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35419092

RESUMO

Many aspects make irritable bowel syndrome (IBS) challenging for both patients and physicians. The unclear pathogenesis with many pathways to be explored, bothering symptoms that affect the quality of life, and many subtypes of the condition are only a few reasons that make IBS difficult to control and obtain satisfactory results. Treatment options start with general advice for lifestyle, continue with non-pharmaceutical treatments, and finally touch classic treatments. In this review, pharmaceutical treatment options are not accounted for. Consensus groups and meta-analyses have concluded guidelines that overall are the same, with variations in the strength of recommendations and some cultural and geographical particularities. Dietary interventions, probiotics, and fibers can be seen as non-pharmaceutical treatments that coexist in various protocols because of the relevant evidence regarding their efficacy in treating IBS symptoms.


Assuntos
Síndrome do Intestino Irritável , Probióticos , Dieta , Dissacarídeos , Fermentação , Humanos , Síndrome do Intestino Irritável/complicações , Síndrome do Intestino Irritável/terapia , Monossacarídeos , Probióticos/uso terapêutico , Qualidade de Vida
11.
Enzyme Microb Technol ; 158: 110038, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35453037

RESUMO

Heparosan as an acidic polysaccharide is mainly applied for heparin biosynthesis and drug delivery. Escherichia coli Nissle 1917 (EcN) naturally synthesizes and secrets heparosan as its capsular polysaccharides. In this study, we described the metabolic engineering of EcN to enhance heparosan production by optimizing the biosynthesis of precursors UDP-GlcA and UDP-GlcNAc and the expression of heparosan synthase. The orthologs of heparosan synthetic pathway enzymes from five species were expressed and comparatively investigated. bsGalU and ecKfiD for UDP-GlcA and ecGlmM for UDP-GlcNAc were introduced into EcN and the production of heparosan was increased from 0.15 g/L to 0.34 g/L, 0.39 g/L and 0.37 g/L, respectively. Combinational overexpression of bsGalU, ecKfiD and ecGlmM improved heparosan production to 0.80 g/L in flask cultures. After further upregulation of the endogenous heparosan synthases KfiAC, the titer of heparosan was improved to 1.29 g/L. Meanwhile, pathway engineering also led to the fluctuation of molecular weights between 312.39 and 410.84 kDa. Eventually, the engineered strain EC048 with overexpression of bsGalU, ecKfiD, ecGlmM and KfiAC produced 11.50 g/L heparosan in 3-L fed-batch fermentor, demonstrating EcN as a good microbial chassis is applicable for engineering an efficient heparosan cell factory.


Assuntos
Escherichia coli , Probióticos , Dissacarídeos/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Engenharia Metabólica , Difosfato de Uridina/metabolismo
12.
Anal Chim Acta ; 1206: 339783, 2022 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-35473855

RESUMO

Glycans are ubiquitous, structurally diverse molecules that have specific and general roles involving metabolism, structure, and cell-to-cell signaling. Functional specificity depends strongly on the complexity of structures that polysaccharides can adopt based on their subunit composition, length, extent of branching, glycosidic bond connectivity and anomeric configuration. However, a rapid and comprehensive characterization of glycan isomers can be challenging owing to limitations associated with their separation. Here, ten composition, anomeric and connectivity disaccharide isomers were separated and detected using high-resolution differential ion mobility-mass spectrometry (DMS-MS, also known as FAIMS). Focus was primarily directed to compositional isomers corresponding to epimers that differ by the axial or equatorial position of a single hydroxyl group. DMS resolving power was enhanced 14-fold primarily by increasing the fraction of helium in the ion carrier gas and lowering the flow rate. At relatively high disaccharide concentrations, DMS-MS of each disaccharide resulted in complex and unique multi-peak spectra with up to ten fully and partially resolved peaks for ß-1,4-mannobiose (Man-1,4ß-Man), which can be attributed to the DMS separation and subsequent dissociation of ionic non-covalently bound oligomers into monomer ions. Each DMS spectrum has at least one differentiating peak that is not in the other spectra, indicating that DMS can be used to fully or partially resolve composition, configuration and connectivity isomers. At relatively low disaccharide concentrations, mixtures of disaccharide epimers can also be readily separated by DMS. The integration of high-resolution, ambient pressure DMS with complementary reduced-pressure ion mobility and MS-based glycomics and glycoproteomics workflows may be useful for improving the characterization of glycans and glycosylated biomolecules.


Assuntos
Dissacarídeos , Dissacarídeos/análise , Humanos , Íons/química , Isomerismo , Espectrometria de Massas/métodos
13.
Org Biomol Chem ; 20(14): 2964-2980, 2022 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-35333269

RESUMO

Many children suffering from autism spectrum disorder (ASD) experience gastrointestinal (GI) conditions. Enterocloster bolteae has been regularly detected in the stool of individuals suffering from GI symptoms and autism. Literature has suggested that E. bolteae strains WAL 16351 and WAL 14578 produce an immunogenic capsular polysaccharide (CPS) comprised of disaccharide repeating units: α-D-Man-(1 → 4)-ß-Rha-(1 → 3) that could be used for the development of an immunotherapeutic vaccine. Ambiguity in the configuration of rhamnose led to the synthesis of tri- and disaccharide analogues containing D-rhamnose and L-rhamnose, respectively. ROESY-NMR spectra showed that CH3-6 of rhamnose and H-2 of mannose in the L-Rha containing disaccharide gave correlation. No such correlation was seen between the CH3-6 of rhamnose and the H-2 of mannose in the D-Rha containing trisaccharide. Molecular dynamics studies on hexasaccharide containing L-Rha or D-Rha confirmed that these structures adopt conformations resulting in different distances between the C6-rhamnose and the H-2 mannose of the preceding residue. We also demonstrate that assignment of the absolute configuration of the rhamnosyl residue in the ß-Rhap-(1 → 3)-D-Man linkage can be determined using the 13C chemical shift of C-2 in of D-Mannose. While ß-D-Rha will lead to an upfield shift of C-2 due to γ-gauche interaction between H-1 Rha and H-2 Man, ß-L-Rha will not. Our results provide insights to distinguish between D- and L-rhamnose in the α-D-Manp-(1 → 4)-ß-Rhap-(1 → 3) repeating motif.


Assuntos
Transtorno do Espectro Autista , Ramnose , Criança , Dissacarídeos , Humanos , Espectroscopia de Ressonância Magnética , Manose/química , Ramnose/química
14.
Phytomedicine ; 100: 154058, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35349834

RESUMO

BACKGROUND: Skeletal muscle atrophy is caused by aging, disuse, malnutrition, and several diseases. However, there are still no effective drugs or treatments for muscle atrophy. Codonopsis lanceolata (CL), a traditional medicinal plant and food, has been reported to have anti-oxidative, anti-inflammatory, anti-tumor, and anti-obesity effects. PURPOSE: This study aimed to investigate the efficacy and active component of CL on muscle atrophy in vitro and to confirm the effect of CL and its active component on muscle atrophy and the underlying molecular mechanisms in vivo. STUDY: design/Methods This study used the dexamethasone (Dex)-induced muscle atrophy C2C12 myotube model and immobilization (IM)-induced muscle atrophy C57BL/6 mice model. In vitro study, the myotube diameter was measured. In vivo study, the grip strength, muscle mass (quadriceps, gastrocnemius, and soleus) and muscle fiber cross-sectional area (CSA) was measured. Western blot analysis and qRT-PCR were performed to confirm the underlying molecular mechanisms Results:In vitro study, CL and its main component, Tangshenoside I (TSI), effectively restored C2C12 myotube diameters decreased by Dex. Surprisingly, TSI was identified as the active component responsible for the overall efficacy of CL on muscle atrophy. In vivo study, CL and TSI, dose-dependently increased grip strength, mass muscle, and muscle fiber CSA reduced by IM. In the molecular mechanism studies, CL and TSI increased muscle protein synthesis via activating the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin complex 1 (mTORC1) pathway and decreased muscle protein degradation via inhibiting the muscle ring finger-1 (MuRF1) and muscle atrophy F-box protein (Atrogin-1) expressions. It also upregulated mitochondrial biogenesis via the silent information regulator 1 (SIRT1)/ peroxisome proliferator-activated receptor gamma and coactivator-1 alpha (PGC-1α) pathway. CONCLUSION: This study suggests that CL and its active component, TSI, can be potential drug candidates for the prevention and treatment of muscle atrophy.


Assuntos
Codonopsis , Proteínas Proto-Oncogênicas c-akt , Animais , Dissacarídeos , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/etiologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sirtuína 1/metabolismo
15.
J Nat Prod ; 85(3): 530-539, 2022 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-35263115

RESUMO

A chemical reinvestigation of the Indonesian strain Streptomyces sp. SHP 22-7 led to the isolation of three new pyrimidine nucleosides, along with six known analogues and zincphyrin. The structures of the new compounds (6, 7, 10) were elucidated by employing spectroscopic techniques (NMR, MS, CD, and IR) as well as enantioselective analyses of methyl branched side chain configurations. Application of the precursor-directed feeding approach led to the production and partial isolation of nine further pyrimidine analogues. The new compounds 6, 7, and 11 and three of the known compounds (2-4) were found to possess antimycobacterial and cytotoxic properties.


Assuntos
Nucleosídeos de Pirimidina , Streptomyces , Vias Biossintéticas , Dissacarídeos , Estrutura Molecular , Nucleosídeos , Nucleosídeos de Pirimidina/química , Streptomyces/química
16.
J Org Chem ; 87(8): 5125-5135, 2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35357132

RESUMO

Orthogonally protected N-substituted ß-aminooxy sugars can be stereoselectively synthesized from sugar epoxides and nitrones derived from aromatic aldehydes. Both the ether- and ester-protected sugar epoxides can be employed. The synthesized aminooxy sugars could be reacted with aldehyde bearing/free reducing sugars under the heating condition to afford N-O-linked 1,1-/1,5/1,6-disaccharide mimetics in a good yield.


Assuntos
Aldeídos , Dissacarídeos , Biomimética , Compostos de Epóxi
17.
Sci Rep ; 12(1): 4960, 2022 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-35322144

RESUMO

Non-celiac gluten sensitivity (NCGS) and irritable bowel syndrome (IBS) frequently overlap. Although, gluten-free diet (GFD) and low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) improve the IBS clinical picture, many aspects remain unclear. Therefore, we designed a study to evaluate gluten tolerance, anxiety and quality of life in a specific study population. Fifty IBS patients were asked to follow a low FODMAP strict GFD for 6 weeks and were then randomly allocated to the following groups for a further 6 weeks: (A) receiving 8 g/day of gluten for 2 weeks; gluten-tolerating subjects received 16 g/day for 2 weeks and then 32 g/day for a further 2 weeks; (B) continuing to follow a low FODMAP strict GFD; and (C) receiving a gluten-containing diet. After the first 6 weeks, symptom scores significantly improved. Pain severity, bloating and total score were significantly decreased in the GFD and in the high-gluten groups, while the satiety score significantly increased in group C. Between-group analysis revealed significant differences for pain severity (p = 0.02), pain frequency (p = 0.04) and impact on community function (p = 0.02) at the end of the study. Our findings suggest that low FODMAP strict GFD could be prescribed in IBS patients and would reduce anxiety and improve the quality of life.


Assuntos
Glutens , Síndrome do Intestino Irritável , Dieta Livre de Glúten , Dissacarídeos , Fermentação , Glutens/efeitos adversos , Humanos , Monossacarídeos , Oligossacarídeos , Qualidade de Vida , Método Simples-Cego
18.
Gastroenterology ; 162(6): 1737-1745.e5, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35337654

RESUMO

DESCRIPTION: Irritable bowel syndrome (IBS) is a commonly diagnosed gastrointestinal disorder that can have a substantial impact on quality of life. Most patients with IBS associate their gastrointestinal symptoms with eating food. Mounting evidence supports dietary modifications, such as the low-fermentable oligo-, di-, and monosaccharides and polyols (FODMAP) diet, as a primary treatment for IBS symptoms. The aim of this American Gastroenterological Association (AGA) Clinical Practice Update (CPU) is to provide best practice advice statements, primarily to clinical gastroenterologists, covering the role of diet in IBS treatment. METHODS: This expert review was commissioned and approved by the AGA CPU Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPU Committee and external peer review through standard procedures of Gastroenterology. The best practice advice statements were drawn from reviewing existing literature combined with expert opinion to provide practical advice on the role of diet in treating patients with IBS. Because this was not a systematic review, formal rating of the quality of evidence or strength of the presented considerations was not performed. Best Practice Advice Statements BEST PRACTICE ADVICE 1: Dietary advice is ideally prescribed to patients with IBS who have insight into their meal-related gastrointestinal symptoms and are motivated to make the necessary changes. To optimize the quality of teaching and clinical response, referral to a registered dietitian nutritionist (RDN) should be made to patients who are willing to collaborate with a RDN and patients who are not able to implement beneficial dietary changes on their own. If a gastrointestinal RDN is not available, other resources can assist with implementation of diet interventions. BEST PRACTICE ADVICE 2: Patients with IBS who are poor candidates for restrictive diet interventions include those consuming few culprit foods, those at risk for malnutrition, those who are food insecure, and those with an eating disorder or uncontrolled psychiatric disorder. Routine screening for disordered eating or eating disorders by careful dietary history is critical because they are common and often overlooked in gastrointestinal conditions. BEST PRACTICE ADVICE 3: Specific diet interventions should be attempted for a predetermined length of time. If there is no clinical response, the diet intervention should be abandoned for another treatment alternative, for example, a different diet, medication, or other form of therapy. BEST PRACTICE ADVICE 4: In preparation for a visit with a RDN, patients should provide dietary information that will assist in developing an individualized nutrition care plan. BEST PRACTICE ADVICE 5: Soluble fiber is efficacious in treating global symptoms of IBS. BEST PRACTICE ADVICE 6: The low-FODMAP diet is currently the most evidence-based diet intervention for IBS. Healthy eating advice as described by the National Institute of Health and Care Excellence Guidelines, among others, also offers benefit to a subset of patients with IBS. BEST PRACTICE ADVICE 7: The low-FODMAP diet consists of the following 3 phases: 1) restriction (lasting no more than 4-6 weeks), 2) reintroduction of FODMAP foods, and 3) personalization based on results from reintroduction. BEST PRACTICE ADVICE 8: Although observational studies found that most patients with IBS improve with a gluten-free diet, randomized controlled trials have yielded mixed results. BEST PRACTICE ADVICE 9: There are limited data showing that selected biomarkers can predict response to diet interventions in patients with IBS, but there is insufficient evidence to support their routine use in clinical practice.


Assuntos
Síndrome do Intestino Irritável , Dieta , Dieta com Restrição de Carboidratos/métodos , Dieta Livre de Glúten , Dissacarídeos , Fermentação , Humanos , Síndrome do Intestino Irritável/diagnóstico , Síndrome do Intestino Irritável/terapia , Monossacarídeos , Oligossacarídeos , Qualidade de Vida
19.
Int J Biol Macromol ; 207: 683-699, 2022 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-35248606

RESUMO

Targeted-drug administration to liver reduces side effects by minimising drug distribution to non-target organs and increases therapeutic efficacy by boosting drug concentration in target cells. In this study, arabinogalactan-(AG), pullulan-(PL) and lactobionic acid-(LA) were selected as natural ligands to target asialoglycoprotein receptor-(ASGPR-1) present on hepatocytes. In silico docking studies were performed and binding affinities of novel ligands viz. palmitoylated AG-(PAG), lauroylated AG-(LAG), palmitoylated PL-(PPL), lauroylated PL-(LPL) and lactobionic acid-adipic acid dihydrazide conjugate-(LAD) were compared with AG, PL and LA. These novel ligands were successfully synthesized and characterized. The ligands were incorporated into drug loaded nanostructured lipid carriers-(NLCs) for surface functionalization. HepG2 cellular internalization of hepatocyte-targeted NLCs was studied using fluorescence microscopy and LAD-decorated-drug loaded NLCs giving maximum cellular uptake were studied using confocal microscopy. Toxicity potential of LAD-decorated NLCs was assessed in vivo. Molecular docking results suggested that among the ligands, order of binding affinity was found to be LAD>PAG > PPL > LPL > LAG. Acute toxicity studies revealed hemocompatibility and absence of organ toxicity for ligand LAD. Additionally, the results establish proof-of-concept of enhanced targeting efficacy of novel ASGPR targeting ligands. These ligands can be used for surface modification of nanocarriers for future targeted delivery in treating various liver disorders.


Assuntos
Portadores de Fármacos , Receptor de Asialoglicoproteína/metabolismo , Dissacarídeos , Galactanos , Glucanos , Ligantes , Simulação de Acoplamento Molecular
20.
Br J Anaesth ; 128(5): 796-805, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35256150

RESUMO

BACKGROUND: Preoperative anaemia is a risk factor for adverse postoperative outcomes after cardiac surgery. Iron deficiency is a frequent cause of low preoperative haemoglobin. An effective treatment for preoperative anaemia associated with iron deficiency has not been determined. METHODS: We conducted a single-centre, open-label, pragmatic randomised trial, enrolling 156 elective cardiac surgery patients who had low preoperative haemoglobin (100-130 g L-1) with iron deficiency (serum ferritin <100 µg L-1 or transferrin saturation <30%) to compare intravenous ferric derisomaltose 1000 mg and darbepoetin 200 µg subcutaneously (intervention group) with oral ferrous sulphate 600 mg daily (control group). The primary outcome was transfusion of at least one unit of allogeneic red cells during surgery and within the following 5 days. Secondary outcomes included the change in haemoglobin concentration between randomisation and surgery, red cell transfusion volume, postoperative blood loss, pre-specified postoperative complications, length of hospital stay, and in-hospital death. RESULTS: The odds of red cell transfusion were lower in the intervention group compared with the control group (adjusted odds ratio=0.33; 95% confidence interval [CI], 0.15-0.75; P=0.008). Of the secondary outcomes, the only significant difference was the increase in haemoglobin between randomisation and surgery, intervention vs control 9.5 g L-1 (95% CI, 6.8-12.2; P<0.001). CONCLUSIONS: In patients with a low preoperative haemoglobin and iron deficiency, preoperative treatment with a single dose of ferric derisomaltose and darbepoetin decreased the proportion of participants who received a perioperative blood transfusion as a consequence of a greater increase in haemoglobin compared with treatment with oral ferrous sulphate. CLINICAL TRIAL REGISTRATION: ISRCTN Number: 41421863; EUDRACT number: 2011-003695-36.


Assuntos
Anemia Ferropriva , Anemia , Procedimentos Cirúrgicos Cardíacos , Hematínicos , Anemia/tratamento farmacológico , Anemia/etiologia , Anemia Ferropriva/tratamento farmacológico , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Dissacarídeos , Eritropoese , Compostos Férricos , Hematínicos/uso terapêutico , Hemoglobinas , Mortalidade Hospitalar , Humanos , Ferro/uso terapêutico
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