New Bacterial Aryl Sulfotransferases: Effective Tools for Sulfation of Polyphenols.

The preparation of pure metabolites of bioactive compounds, particularly (poly)phenols, is essential for the accurate determination of their pharmacological profiles . Since the extraction of these metabolites from biological material is tedious and impractical, they can be synthesized enzymatically by bacterial PAPS-independent aryl sulfotransferases (ASTs). However, only a few ASTs have been studied and used for (poly)phenol sulfation.

Glycomimetic inhibitors of tandem-repeat galectins: Simple and efficient.

The binding of human galectins by glycomimetic inhibitors is a promising therapeutic approach. The structurally distinct group of tandem-repeat galectins has scarcely been studied so far, and there is hardly any knowledge on their ligand specificity or their inhibitory potential, particularly concerning non-natural carbohydrates. Here, we present the synthesis of a library of seven 3-O-disubstituted thiodigalactoside-derived glycomimetics and their affinity to two tandem-repeat galectins, Gal-8 and Gal-9.

Feeding High-Fat Diet Accelerates Development of Peripheral and Central Insulin Resistance and Inflammation and Worsens AD-like Pathology in APP/PS1 Mice.

Alzheimer's disease (AD) is a progressive brain disorder characterized by extracellular amyloid-β (Aβ) plaques, intracellular neurofibrillary tangles formed by hyperphosphorylated Tau protein and neuroinflammation. Previous research has shown that obesity and type 2 diabetes mellitus, underlined by insulin resistance (IR), are risk factors for neurodegenerative disorders. In this study, obesity-induced peripheral and central IR and inflammation were studied in relation to AD-like pathology in the brains and periphery of APP/PS1 mice, a model of Aβ pathology, fed a high-fat diet (HFD).

Galectin-targeting glycocalix[4]arenes can enter the cells.

Elevated levels of galectin-3 are associated with tumorigenesis. Its inhibition with high-affinity carbohydrate ligands opens new therapeutic routes. Targeting of intracellular galectin-3 is challenging for polar inhibitors like carbohydrates.

Metabolomic Study of Aging in / Rats: Multiplatform Urine and Serum Analysis.

Zucker fatty (/) rats represent a well-established and widely used model of genetic obesity. Because previous metabolomic studies have only been published for young / rats up to 20 weeks of age, which can be considered early maturity in male / rats, the aim of our work was to extend the metabolomic characterization to significantly older animals. Therefore, the urinary profiles of obese / rats and their lean controls were monitored using untargeted NMR metabolomics between 12 and 40 weeks of age.

Reduced phosphatidylcholine level in the intestinal mucus layer of prediabetic NOD mice.

Type 1 diabetes (T1D) is an autoimmune disease with rising incidence. Pre- and manifest T1D is associated with intestinal barrier dysfunction, skewed microbiota composition, and serum dyslipidemia. The intestinal mucus layer protects against pathogens and its structure and phosphatidylcholine (PC) lipid composition may be compromised in T1D, potentially contributing to barrier dysfunction.

Protective Effect of Vegan Microbiota on Liver Steatosis Is Conveyed by Dietary Fiber: Implications for Fecal Microbiota Transfer Therapy.

Fecal microbiota transfer may serve as a therapeutic tool for treating obesity and related disorders but currently, there is no consensus regarding the optimal donor characteristics. We studied how microbiota from vegan donors, who exhibit a low incidence of non-communicable diseases, impact on metabolic effects of an obesogenic diet and the potential role of dietary inulin in mediating these effects. Ex-germ-free animals were colonized with human vegan microbiota and fed a standard or Western-type diet (WD) with or without inulin supplementation.

Lipidized PrRP Analog Exhibits Strong Anti-Obesity and Antidiabetic Properties in Old WKY Rats with Obesity and Glucose Intolerance.

Prolactin-releasing peptide (PrRP) is an anorexigenic neuropeptide that has potential for the treatment of obesity and its complications. Recently, we designed a palmitoylated PrRP31 analog (palm-PrRP31) that is more stable than the natural peptide and able to act centrally after peripheral administration. This analog acted as an anti-obesity and glucose-lowering agent, attenuating lipogenesis in rats and mice with high-fat (HF) diet-induced obesity.

Glycocalix[4]arenes and their affinity to a library of galectins: the linker matters.

Galectins are lectins that bind β-galactosides. They are involved in important extra- and intracellular biological processes such as apoptosis, and regulation of the immune system or the cell cycle. High-affinity ligands of galectins may introduce new therapeutic approaches or become new tools for biomedical research.

Sulfation of Phenolic Acids: Chemoenzymatic vs. Chemical Synthesis.

Phenolic acids are known flavonoid metabolites, which typically undergo bioconjugation during phase II of biotransformation, forming sulfates, along with other conjugates. Sulfated derivatives of phenolic acids can be synthesized by two approaches: chemoenzymatically by 3'-phosphoadenosine-5'-phosphosulfate (PAPS)-dependent sulfotransferases or PAPS-independent aryl sulfotransferases such as those from , or chemically using SO complexes. Both approaches were tested with six selected phenolic acids (2-hydroxyphenylacetic acid (2-HPA), 3-hydroxyphenylacetic acid (3-HPA), 4-hydroxyphenylacetic acid (4-HPA), 3,4-dihydroxyphenylacetic acid (DHPA), 3-(4-hydroxyphenyl)propionic acid (4-HPP), and 3,4-dihydroxyphenylpropionic acid (DHPP)) to create a library of sulfated metabolites of phenolic acids.

Interaction of luteolin, naringenin, and their sulfate and glucuronide conjugates with human serum albumin, cytochrome P450 (CYP2C9, CYP2C19, and CYP3A4) enzymes and organic anion transporting polypeptide (OATP1B1 and OATP2B1) transporters.

Luteolin and naringenin are flavonoids found in various foods/beverages and present in certain dietary supplements. After a high intake of these flavonoids, their sulfate and glucuronide conjugates reach micromolar concentrations in the bloodstream. Some pharmacokinetic interactions of luteolin and naringenin have been investigated in previous studies; however, only limited data are available in regard to their metabolites.

Advanced high-affinity glycoconjugate ligands of galectins.

Galectins are proteins of the family of human lectins. By binding terminal galactose units of cell surface glycans, they moderate biological and pathological processes such as cell signaling, cell adhesion, apoptosis, fibrosis, carcinogenesis, and metabolic disorders. The binding of monovalent glycans to galectins is usually relatively weak.

Age-related metabolic and neurodegenerative changes in SAMP8 mice.

The most important risk factor for the development of sporadic Alzheimer's disease (AD) is ageing. Senescence accelerated mouse prone 8 (SAMP8) is a model of sporadic AD, with senescence accelerated resistant mouse (SAMR1) as a control. In this study, we aimed to determine the onset of senescence-induced neurodegeneration and the related potential therapeutic window using behavioral experiments, immunohistochemistry and western blotting in SAMP8 and SAMR1 mice at 3, 6 and 9 months of age.

Bacterial Aryl Sulfotransferases in Selective and Sustainable Sulfation of Biologically Active Compounds using Novel Sulfate Donors.

Regioselective sulfation of bioactive compounds is a vital and scarcely studied topic in enzyme-catalyzed transformations and metabolomics. The major bottleneck of enzymatic sulfation consists in finding suitable sulfate donors. In this regard, 3'-phosphoadenosine 5'-phosphosulfate (PAPS)-independent aryl sulfotransferases using aromatic sulfate donors are a favored choice due to their cost-effectiveness.

Sulfated Phenolic Substances: Preparation and Optimized HPLC Analysis.

Sulfation is an important reaction in nature, and sulfated phenolic compounds are of interest as standards of mammalian phase II metabolites or pro-drugs. Such standards can be prepared using chemoenzymatic methods with aryl sulfotransferases. The aim of the present work was to obtain a large library of sulfated phenols, phenolic acids, flavonoids, and flavonolignans and optimize their HPLC (high performance liquid chromatography) analysis.

Engineered Glycosidases for the Synthesis of Analogs of Human Milk Oligosaccharides.

Enzymatic synthesis is an elegant biocompatible approach to complex compounds such as human milk oligosaccharides (HMOs). These compounds are vital for healthy neonatal development with a positive impact on the immune system. Although HMOs may be prepared by glycosyltransferases, this pathway is often complicated by the high price of sugar nucleotides, stringent substrate specificity, and low enzyme stability.

Glycopolymers Decorated with 3--Substituted Thiodigalactosides as Potent Multivalent Inhibitors of Galectin-3.

Galectin-3 (Gal-3) participates in many cancer-related metabolic processes. The inhibition of overexpressed Gal-3 by, e.g.

Vegan Diet Is Associated With Favorable Effects on the Metabolic Performance of Intestinal Microbiota: A Cross-Sectional Multi-Omics Study.

Plant-based diets are associated with potential health benefits, but the contribution of gut microbiota remains to be clarified. We aimed to identify differences in key features of microbiome composition and function with relevance to metabolic health in individuals adhering to a vegan vs. omnivore diet.

Two fungal flavonoid-specific glucosidases/rutinosidases for rutin hydrolysis and rutinoside synthesis under homogeneous and heterogeneous reaction conditions.

The glycosidases within GH5-23 cleave the glycosidic bond of β-glucosylated or rutinosylated flavonoids. Moreover, by virtue of their transglycosylation activity, glycoconjugates with glucosyl and rutinosyl moieties are accessible. Here we report the biochemical characterization and biotechnological assessment of two heterologously expressed members of GH5-23-McGlc from Mucor circinelloides and PcGlc from Penicillium chrysogenum.

Complex Positive Effects of SGLT-2 Inhibitor Empagliflozin in the Liver, Kidney and Adipose Tissue of Hereditary Hypertriglyceridemic Rats: Possible Contribution of Attenuation of Cell Senescence and Oxidative Stress.

(1) Background: empagliflozin, sodium-glucose co-transporter 2 (SGLT-2) inhibitor, is an effective antidiabetic agent with strong cardio- and nephroprotective properties. The mechanisms behind its cardio- and nephroprotection are still not fully clarified. (2) Methods: we used male hereditary hypertriglyceridemic (hHTG) rats, a non-obese model of dyslipidaemia, insulin resistance, and endothelial dysfunction fed standard diet with or without empagliflozin for six weeks to explore the molecular mechanisms of empagliflozin effects.

NMR- and MS-Based Untargeted Metabolomic Study of Stool and Serum Samples from Patients with Anorexia Nervosa.

Anorexia nervosa (AN), a pathological restriction of food intake, leads to metabolic dysregulation. We conducted a metabolomics study to reveal changes caused by AN and the effect of hospital realimentation on metabolism. Both stool and serum from patients with AN and healthy controls were analyzed by NMR and MS.

Determination of Butyrate Synthesis Capacity in Gut Microbiota: Quantification of Gene Abundance by qPCR in Fecal Samples.

Butyrate is formed in the gut during bacterial fermentation of dietary fiber and is attributed numerous beneficial effects on the host metabolism. We aimed to develop a method for the assessment of functional capacity of gut microbiota butyrate synthesis based on the qPCR quantification of bacterial gene coding butyryl-CoA:acetate CoA-transferase, the key enzyme of butyrate synthesis. In silico, we identified bacteria possessing gene among human gut microbiota by searching coding sequences in available databases.

Exploration of GH94 Sequence Space for Enzyme Discovery Reveals a Novel Glucosylgalactose Phosphorylase Specificity.

The substantial increase in DNA sequencing efforts has led to a rapid expansion of available sequences in glycoside hydrolase families. The ever-increasing sequence space presents considerable opportunities for the search for enzymes with novel functionalities. In this work, the sequence-function space of glycoside hydrolase family 94 (GH94) was explored in detail, using a combined approach of phylogenetic analysis and sequence similarity networks.

Immunoprotective neo-glycoproteins: Chemoenzymatic synthesis of multivalent glycomimetics for inhibition of cancer-related galectin-3.

Galectin-3 plays a crucial role in cancerogenesis; its targeting is a prospective pathway in cancer diagnostics and therapy. Multivalent presentation of glycans was shown to strongly increase the affinity of glycoconjugates to galectin-3. Further strengthening of interaction with galectin-3 may be accomplished using artificial glycomimetics with apt aryl substitutions.

The intestinal microbiota and metabolites in patients with anorexia nervosa.

Brain-gut microbiota interactions are intensively studied in connection with various neurological and psychiatric diseases. While anorexia nervosa (AN) pathophysiology is not entirely clear, it is presumably linked to microbiome dysbiosis. We aimed to elucidate the gut microbiota contribution in AN disease pathophysiology.