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ACS Infectious Diseases Apr 2024Tuberculosis (TB), caused by (Mtb), is the leading cause of death worldwide by infectious disease. Treatment of Mtb infection requires a six-month course of multiple...
Tuberculosis (TB), caused by (Mtb), is the leading cause of death worldwide by infectious disease. Treatment of Mtb infection requires a six-month course of multiple antibiotics, an extremely challenging regimen necessitated by Mtb's ability to form drug-tolerant persister cells. Mtb persister formation is dependent on the trehalose catalytic shift, a stress-responsive metabolic remodeling mechanism in which the disaccharide trehalose is liberated from cell surface glycolipids and repurposed as an internal carbon source to meet energy and redox demands. Here, using a biofilm-persister model, metabolomics, and cryo-electron microscopy (EM), we found that azidodeoxy- and aminodeoxy-d-trehalose analogues block the Mtb trehalose catalytic shift through inhibition of trehalose synthase TreS (Rv0126), which catalyzes the isomerization of trehalose to maltose. Out of a focused eight-member compound panel constructed by chemoenzymatic synthesis, the natural product 2-trehalosamine exhibited the highest potency and significantly potentiated first- and second-line TB drugs in broth culture and macrophage infection assays. We also report the first structure of TreS bound to a substrate analogue inhibitor, obtained via cryo-EM, which revealed conformational changes likely essential for catalysis and inhibitor binding that can potentially be exploited for future therapeutic development. Our results demonstrate that inhibition of the trehalose catalytic shift is a viable strategy to target Mtb persisters and advance trehalose analogues as tools and potential adjunctive therapeutics for investigating and targeting mycobacterial persistence.
Topics: Humans; Mycobacterium tuberculosis; Trehalose; Cryoelectron Microscopy; Tuberculosis; Catalysis
PubMed: 38485491
DOI: 10.1021/acsinfecdis.4c00138 -
Experimental Neurology Mar 2023In this study we investigated the effects of a neonatal handling protocol that mimics the handling of sham control pups in protocols of neonatal exposure to brain...
In this study we investigated the effects of a neonatal handling protocol that mimics the handling of sham control pups in protocols of neonatal exposure to brain insults on dendritic arborization and glycosaminoglycan (GAG) levels in the developing brain. GAGs are long, unbranched polysaccharides, consisting of repeating disaccharide units that can be modified by sulfation at specific sites and are involved in modulating neuronal plasticity during brain development. In this study, male and female Sprague-Dawley rats underwent neonatal handling daily between post-natal day (PD)4 and PD9, with brains analyzed on PD9. Neuronal morphology and morphometric analysis of the apical and basal dendritic trees of CA1 hippocampal pyramidal neurons were carried out by Golgi-Cox staining followed by neuron tracing and analysis with the software Neurolucida. Chondroitin sulfate (CS)-, Hyaluronic Acid (HA)-, and Heparan Sulfate (HS)-GAG disaccharide levels were quantified in the hippocampus by Liquid Chromatography/Mass Spectrometry analyses. We found sex by neonatal handling interactions on several parameters of CA1 pyramidal neuron morphology and in the levels of HS-GAGs, with females, but not males, showing an increase in both dendritic arborization and HS-GAG levels. We also observed increased expression of glucocorticoid receptor gene Nr3c1 in the hippocampus of both males and females following neonatal handling suggesting that both sexes experienced a similar stress during the handling procedure. This is the first study to show sex differences in two parameters of brain plasticity, CA1 neuron morphology and HS-GAG levels, following handling stress in neonatal rats.
Topics: Animals; Female; Rats; Male; Glycosaminoglycans; Sex Characteristics; Disaccharides; Rats, Sprague-Dawley; Hippocampus; Chondroitin Sulfates; Heparitin Sulfate
PubMed: 36572372
DOI: 10.1016/j.expneurol.2022.114313 -
Nutrients Jun 2022Background: The increased intake of FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyol) rich foods has been suggested as a possible trigger...
Background: The increased intake of FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyol) rich foods has been suggested as a possible trigger of functional gastrointestinal disorders (FGIDs). Despite the high FODMAP content, the Mediterranean diet (MD) appears to have beneficial effects on health. Our aim was to evaluate whether the prevalence of FGIDs in different Mediterranean countries may be influenced by FODMAP consumption and adherence to the MD. Methods: A school-based, cross-sectional, multicenter study was performed in six countries in the Mediterranean area: Croatia, Greece, Israel, Italy, Macedonia, and Serbia. Subjects 4-18 years were examined in relation to their eating habits and the presence of FGIDs, using Rome IV criteria, 3-day food diaries and Mediterranean Diet Quality Index in Children and Adolescents (KIDMED) questionnaires. Results: We enrolled 1972 subjects between 4 and 9 years old (Group A), and 2450 subjects between 10 and 18 years old (Group B). The overall prevalence of FGIDs was 16% in Group A and 26% in Group B. FODMAP intake was significantly different among countries for both age groups. In both groups, no significant association was found between FGIDs and FODMAPs. Adherence to the MD in all countries was intermediate, except for Serbia, where it was low. In both groups, we found a statistically significant association between FGIDs and the KIDMED score (Group A: OR = 0.83, p < 0.001; Group B: OR = 0.93, p = 0.005). Moreover, a significant association was found between the KIDMED score and functional constipation (Group A: OR = 0.89, p = 0.008; Group B: OR = 0.93, p = 0.010) and postprandial distress syndrome (Group A: OR = 0.86, p = 0.027; Group B: OR = 0.88, p = 0.004). Conclusions: Our data suggest that the prevalence of FGIDs in the Mediterranean area is not related to FODMAP consumption, whereas adherence to the MD seems to have a protective effect.
Topics: Adolescent; Child; Child, Preschool; Cross-Sectional Studies; Diet; Diet, Mediterranean; Disaccharides; Fermentation; Gastrointestinal Diseases; Humans; Irritable Bowel Syndrome; Monosaccharides; Oligosaccharides; Serbia
PubMed: 35684135
DOI: 10.3390/nu14112335 -
The Modification of the Gut Microbiota via Selected Specific Diets in Patients with Crohn's Disease.Nutrients Jun 2021Gastrointestinal symptoms in Crohn's disease (CD) are common and affect the quality of life of patients; consequently, a growing number of studies have been published on... (Review)
Review
Gastrointestinal symptoms in Crohn's disease (CD) are common and affect the quality of life of patients; consequently, a growing number of studies have been published on diet interventions in this group. The role of the gut microbiota in the pathogenesis and the progression of inflammatory bowel diseases (IBD), including CD, has been widely discussed. Mainly, a decreased abundance of Firmicutes, species of the genus, and the species as well as a reduced general diversity have been described. In this review article, we summarize available data on the influence of reduction diets on the microbiome of patients with CD. One of the most frequently used elimination diets in CD patients is the low-FODMAP (Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols) diet. Although many papers show it may reduce abdominal pain, diarrhea, or bloating, it also reduces the intake of prebiotic substances, which can negatively affect the gut microbiota composition, decreasing the abundance of species and . Other elimination diets used by IBD patients, such as lactose-free or gluten-free diets, have also been shown to disturb the microbial diversity. On the other hand, CDED (Crohn's disease exclusion diet) with partial enteral nutrition not only induces the remission of CD but also has a positive influence on the microbiota. The impact of diet interventions on the microbiota and, potentially, on the future course of the disease should be considered when nutritional guidelines for IBD patients are designed. Dietetic recommendations should be based not only on the regulation of the symptoms but also on the long-term development of the disease.
Topics: Crohn Disease; Diet; Diet, Carbohydrate-Restricted; Disaccharides; Fermentation; Gastrointestinal Microbiome; Humans; Monosaccharides; Oligosaccharides; Polymers
PubMed: 34206152
DOI: 10.3390/nu13072125 -
Advances in Therapy Oct 2022Intravenous (IV) iron is the preferred treatment for patients with iron deficiency anemia (IDA) who require rapid replenishment of iron stores or in whom oral iron is... (Meta-Analysis)
Meta-Analysis
A Systematic Review, Meta-Analysis, and Indirect Comparison of Blindly Adjudicated Cardiovascular Event Incidence with Ferric Derisomaltose, Ferric Carboxymaltose, and Iron Sucrose.
INTRODUCTION
Intravenous (IV) iron is the preferred treatment for patients with iron deficiency anemia (IDA) who require rapid replenishment of iron stores or in whom oral iron is not tolerated or effective. Data from two large-scale randomized controlled trials (RCTs) have recently been published reporting the incidence of adjudicated cardiovascular events after ferric derisomaltose (FDI) and iron sucrose (IS). The objective was to calculate the relative incidence of cardiovascular events with FDI and IS, and to conduct an indirect comparison with ferric carboxymaltose (FCM) based on previously published studies of cardiovascular risk.
METHODS
RCTs reporting the incidence of blindly adjudicated cardiovascular events in IDA patients treated with IV iron were identified by systematic literature review (SLR). Pairwise random effects meta-analyses of FDI versus IS, and FCM versus IS were conducted for the pre-specified adjudicated composite cardiovascular endpoint of: death due to any cause, nonfatal myocardial infarction, nonfatal stroke, unstable angina requiring hospitalization, congestive heart failure, arrhythmia, and protocol-defined hypertensive and hypotensive events. Analyses were also conducted for the composite endpoint excluding blood pressure events. Meta-analysis results were combined in an adjusted indirect comparison to provide an indirect estimate of cardiovascular risk with FDI versus FCM.
RESULTS
The SLR retrieved 694 unique articles, of which four were RCTs reporting the incidence of the composite cardiovascular endpoint; two studies comparing FCM (N = 1529) with IS (N = 1505), and two studies comparing FDI (N = 2008) with IS (N = 1000). The odds ratios of the composite CV endpoint were 0.59 (95% confidence interval: 0.39-0.90) for FDI versus IS, 1.12 (95% CI 0.90-1.40) for FCM versus IS, and the indirect OR for FDI versus FCM was 0.53 (95% CI 0.33-0.85).
CONCLUSIONS
Pooling data from four large-scale RCTs suggested that FDI was associated with significantly lower incidence of cardiovascular adverse events compared to both FCM and IS.
Topics: Anemia, Iron-Deficiency; Cardiovascular Diseases; Disaccharides; Ferric Compounds; Ferric Oxide, Saccharated; Heart Failure; Humans; Incidence; Iron; Maltose; Randomized Controlled Trials as Topic
PubMed: 35947351
DOI: 10.1007/s12325-022-02242-x -
Microbial Physiology 2021Escherichia coli is unable to grow on polymeric and oligomeric chitin, but grows on chitin disaccharide (GlcNAc-GlcNAc; N,N'-diacetylchitobiose) and chitin trisaccharide...
Escherichia coli is unable to grow on polymeric and oligomeric chitin, but grows on chitin disaccharide (GlcNAc-GlcNAc; N,N'-diacetylchitobiose) and chitin trisaccharide (GlcNAc-GlcNAc-GlcNAc; N,N',N''-triacetylchitotriose) via expression of the chb operon (chbBCARFG). The phosphotransferase system (PTS) transporter ChbBCA facilitates transport of both saccharides across the inner membrane and their concomitant phosphorylation at the non-reducing end, intracellularly yielding GlcNAc 6-phosphate-GlcNAc (GlcNAc6P-GlcNAc) and GlcNAc6P-GlcNAc-GlcNAc, respectively. We revisited the intracellular catabolism of the PTS products, thereby correcting the reported functions of the 6-phospho-glycosidase ChbF, the monodeacetylase ChbG, and the transcriptional regulator ChbR. Intracellular accumulation of glucosamine 6P-GlcNAc (GlcN6P-GlcNAc) and GlcN6P-GlcNAc-GlcNAc in a chbF mutant unraveled a role for ChbG as a monodeacetylase that removes the N-acetyl group at the non-reducing end. Consequently, GlcN6P- but not GlcNAc6P-containing saccharides likely function as coactivators of ChbR. Furthermore, ChbF removed the GlcN6P from the non-reducing terminus of the former saccharides, thereby degrading the inducers of the chb operon and facilitating growth on the saccharides. Consequently, ChbF was unable to hydrolyze GlcNAc6P-residues from the non-reducing end, contrary to previous assumptions but in agreement with structural modeling data and with the unusual catalytic mechanism of the family 4 of glycosidases, to which ChbF belongs. We also refuted the assumption that ChiA is a bifunctional endochitinase/lysozyme ChiA, and show that it is unable to degrade peptidoglycans but acts as a bona fide chitinase in vitro and in vivo, enabling growth of E. coli on chitin oligosaccharides when ectopically expressed. Overall, this study revises our understanding of the chitin, chitin oligosaccharide, and chitin disaccharide metabolism of E. coli.
Topics: Chitin; Disaccharides; Escherichia coli; Oligosaccharides; Operon
PubMed: 33794535
DOI: 10.1159/000515178 -
Clinical Nutrition (Edinburgh, Scotland) Jun 2024A diet low in fermentable oligo-, di-, monosaccharides, and polyols (LFD) has been shown to effectively reduce irritable bowel syndrome (IBS) symptoms. Effects resulting... (Meta-Analysis)
Meta-Analysis
The efficacy and real-world effectiveness of a diet low in fermentable oligo-, di-, monosaccharides and polyols in irritable bowel syndrome: A systematic review and meta-analysis.
BACKGROUND & AIMS
A diet low in fermentable oligo-, di-, monosaccharides, and polyols (LFD) has been shown to effectively reduce irritable bowel syndrome (IBS) symptoms. Effects resulting from real-world studies may differ from those seen in efficacy studies because of the diversity of patients in real-world settings. This systematic review and meta-analysis aimed to compare the effect of the LFD on reducing IBS symptoms and improving the quality of life (QoL) in efficacy trials and real-world studies.
METHODS
Major databases, trial registries, dissertations, and journals were systematically searched for studies on the LFD in adults with IBS. Meta-analysis was conducted using a random effects model with standardized mean differences (SMD) and 95% confidence intervals (CI). Outcomes of interest were all patient-reported: stool consistency, stool frequency, abdominal pain, overall symptoms, adequate symptom relief, IBS-specific QoL and adherence to the LFD.
RESULTS
Eleven efficacy and 19 real-world studies were reviewed. The meta-analysis results for abdominal pain (SMD 0.35, 95% CI 0.16 to 0.54) and QoL (SMD 0.23, 95% CI -0.05 to 0.50) showed the LFD was beneficial in efficacy studies with no statistically significant results for stool frequency (SMD 0.71, 95% CI 0.34 to 1.07). Real-world studies found improvements in abdominal pain and QoL. Due to heterogeneity, no meta-analysis was done for stool consistency and overall symptoms. In these outcomes, results were mostly supportive of the LFD, but they were not always statistically significant.
CONCLUSIONS
The results of this systematic review and meta-analysis suggest the LFD improves outcomes compared to a control diet (efficacy studies) or baseline data (real-world studies). Because of diverse study designs and heterogeneity of results, a clear superiority of the LFD over control diets could not be concluded. There are no indications of an efficacy-effectiveness gap for the LFD in adults with IBS.
Topics: Irritable Bowel Syndrome; Humans; Monosaccharides; Quality of Life; Fermentation; Polymers; Oligosaccharides; Disaccharides; Diet, Carbohydrate-Restricted; Treatment Outcome
PubMed: 38754307
DOI: 10.1016/j.clnu.2024.05.014 -
International Journal of Environmental... Jul 2020Bulk sweetener maltitol belongs to the polyols family and there have been several dietary applications in the past few years, during which the food industry has used it... (Review)
Review
Bulk sweetener maltitol belongs to the polyols family and there have been several dietary applications in the past few years, during which the food industry has used it in many food products: bakery and dairy products, chocolate, sweets. This review paper addresses and discusses in detail the most relevant aspects concerning the analytical methods employed to determine maltitol's food safety and industry applications, its metabolism and its impacts on human health. According to our main research outcome, we can assume that maltitol at lower doses poses little risk to humans and is a good alternative to using sucrose. However, it causes diarrhoea and foetus complications at high doses. Regarding its determination, high-performance liquid chromatography proved the primary method in various food matrices. The future role of maltitol in the food industry is likely to become more relevant as processors seek alternative sweeteners in product formulation without compromising health.
Topics: Food Industry; Humans; Maltose; Sugar Alcohols; Sweetening Agents
PubMed: 32698373
DOI: 10.3390/ijerph17145227 -
PloS One 2019Certain bacterial species target the polysaccharide glycosaminoglycans (GAGs) of animal extracellular matrices for colonization and/or infection. GAGs such as hyaluronan...
Certain bacterial species target the polysaccharide glycosaminoglycans (GAGs) of animal extracellular matrices for colonization and/or infection. GAGs such as hyaluronan and chondroitin sulfate consist of repeating disaccharide units of uronate and amino sugar residues, and are depolymerized to unsaturated disaccharides by bacterial extracellular or cell-surface polysaccharide lyase. The disaccharides are degraded and metabolized by cytoplasmic enzymes such as unsaturated glucuronyl hydrolase, isomerase, and reductase. The genes encoding these enzymes are assembled to form a GAG genetic cluster. Here, we demonstrate the Streptococcus agalactiae phosphotransferase system (PTS) for import of unsaturated hyaluronan disaccharide. S. agalactiae NEM316 was found to depolymerize and assimilate hyaluronan, whereas its mutant with a disruption in the PTS genes included in the GAG cluster was unable to grow on hyaluronan, while retaining the ability to depolymerize hyaluronan. Using toluene-treated wild-type cells, the PTS activity for import of unsaturated hyaluronan disaccharide was significantly higher than that observed in the absence of the substrate. In contrast, the PTS mutant was unable to import unsaturated hyaluronan disaccharide, indicating that the corresponding PTS is the only importer of fragmented hyaluronan, which is suitable for PTS to phosphorylate the substrate at the C-6 position. This is distinct from Streptobacillus moniliformis ATP-binding cassette transporter for import of sulfated and non-sulfated fragmented GAGs without substrate modification. The three-dimensional structure of streptococcal EIIA, one of the PTS components, was found to contain a Rossman-fold motif by X-ray crystallization. Docking of EIIA with another component EIIB by modeling provided structural insights into the phosphate transfer mechanism. This study is the first to identify the substrate (unsaturated hyaluronan disaccharide) recognized and imported by the streptococcal PTS. The PTS and ABC transporter for import of GAGs shed light on bacterial clever colonization/infection system targeting various animal polysaccharides.
Topics: Amino Acid Sequence; Disaccharides; Escherichia coli; Extracellular Matrix; Hyaluronic Acid; Models, Biological; Models, Molecular; Phosphotransferases; Streptococcus
PubMed: 31697725
DOI: 10.1371/journal.pone.0224753 -
International Journal of Molecular... Jan 2022Liver cancer is currently regarded as the second leading cause of cancer-related mortality globally and is the sixth most diagnosed malignancy. Selenium nanoparticles...
Liver cancer is currently regarded as the second leading cause of cancer-related mortality globally and is the sixth most diagnosed malignancy. Selenium nanoparticles (SeNPs) have attracted favorable attention as nanocarriers for gene therapy, as they possess beneficial antioxidant and anticancer properties. This study aimed to design, functionalize and characterize SeNPs to efficiently bind, protect and deliver pCMV- DNA to hepatocellular carcinoma (HepG2) cells. The SeNPs were synthesized by ascorbic acid reduction and functionalized with poly-L-lysine (PLL) to stabilize and confer positive charges to the nanoparticles. The SeNPs were further decorated with lactobionic acid (LA) to target the asialoglycoprotein receptors abundantly expressed on the surface of the hepatocytes. All SeNPs were spherical, in the nanoscale range (<130 nm) and were capable of successfully binding, compacting and protecting the pDNA against nuclease degradation. The functionalized SeNP nanocomplexes exhibited minimal cytotoxicity (<30%) with enhanced transfection efficiency in the cell lines tested. Furthermore, the targeted SeNP (LA-PLL-SeNP) nanocomplex showed significant (* < 0.05, ** < 0.01, **** < 0.0001) transgene expression in the HepG2 cells compared to the receptor-negative embryonic kidney (HEK293) cells, confirming receptor-mediated endocytosis. Overall, these functionalized SeNPs exhibit favorable features of suitable gene nanocarriers for the treatment of liver cancer.
Topics: Disaccharides; Gene Transfer Techniques; HEK293 Cells; HeLa Cells; Hep G2 Cells; Humans; Liver; Metal Nanoparticles; Polylysine; Selenium
PubMed: 35163414
DOI: 10.3390/ijms23031492