Rutinosides-derived from Sarocladium strictum 6-O-α-rhamnosyl-ß-glucosidase show enhanced anti-tumoral activity in pancreatic cancer cells.

BACKGROUND: Low targeting efficacy and high toxicity continue to be challenges in Oncology. A promising strategy is the glycosylation of chemotherapeutic agents to improve their pharmacodynamics and anti-tumoral activity. Herein, we provide evidence of a novel approach using diglycosidases from fungi of the Hypocreales order to obtain novel rutinose-conjugates therapeutic agents with enhanced anti-tumoral capacity. RESULTS: Screening for diglycosidase activity in twenty-eight strains of the genetically related genera Acremonium and Sarocladium identified 6-O-α-rhamnosyl-ß-glucosidase (αRßG) of Sarocladium strictum DMic 093557 as candidate enzyme for our studies. Biochemically characterization shows that αRßG has the ability to transglycosylate bulky OH-acceptors, including bioactive compounds. Interestingly, rutinoside-derivatives of phloroglucinol (PR) resorcinol (RR) and 4-methylumbelliferone (4MUR) displayed higher growth inhibitory activity on pancreatic cancer cells than the respective aglycones without significant affecting normal pancreatic epithelial cells. PR exhibited the highest efficacy with an IC50 of 0.89 mM, followed by RR with an IC50 of 1.67 mM, and 4MUR with an IC50 of 2.4 mM, whereas the respective aglycones displayed higher IC50 values: 4.69 mM for phloroglucinol, 5.90 mM for resorcinol, and 4.8 mM for 4-methylumbelliferone. Further, glycoconjugates significantly sensitized pancreatic cancer cells to the standard of care chemotherapy agent gemcitabine. CONCLUSIONS: αRßG from S. strictum transglycosylate-based approach to synthesize rutinosides represents a suitable option to enhance the anti-proliferative effect of bioactive compounds. This finding opens up new possibilities for developing more effective therapies for pancreatic cancer and other solid malignancies.

Evaluation of antimicrobial and non-steroidal anti-inflammatory treatments for BRD on health and welfare in fattening bulls: a cross-sectional study.

Our study aimed to evaluate the effect of different treatments for BRD on health and welfare in fattening bulls. A total of 264 bulls were enrolled. Welfare was assessed on day 2 (T0) and day 15 (T1) after arrival. A decrease in the welfare level was observed from T0 to T1. All bulls were inspected clinically at T0 and T1 revealing an increase of skin lesions and lameness in T1. In both periods, a high incidence of respiratory disease was observed. A prevalence of 79.55% and 95.45% of Mycoplasma bovis using RT-PCR and culture at T0 and T1 respectively was observed. Blood samples were collected for haematology at T0 and T1. At T0, 36 animals were individually treated for BRD with an antimicrobial (IT), 54 received a metaphylactic treatment with tulathromycin (M), 150 received a metaphylactic treatment with tulathromycin plus a second antimicrobial (M + IT) whereas 24 were considered healthy and therefore not treated (NT). Additionally, 128 were treated with a non-steroid anti-inflammatory (NSAID). Neutrophils of M + IT were significantly higher than groups NT and M and the lymphocytes of M + IT were significantly lower than that of IT. White blood cells, neutrophils and N/L ratio of animals treated with an NSAID was significantly higher than that not treated. Lung inspection of 172 bulls at the abattoir indicated that 92.43% presented at least one lung lesion. A statistically significant effect of the NSAID treatment on the lung lesions was observed. Our findings indicate that BRD was a major welfare and health concern and evidence the difficulties of antimicrobial treatment of M. bovis.

Modified minimal-size fragments of heparan sulfate as inhibitors of endosulfatase-2 (Sulf-2).

Sulf-2 has been identified as a putative target for anticancer therapies. Here we report the design and synthesis of sulfated disaccharide inhibitors based on IdoA(2S)-GlcNS(6S). Trisulfated disaccharide inhibitor IdoA(2S)-GlcNS(6Sulfamate) demonstrated potent Sulf-2 inhibition. The IC50 value was determined to be 39.8 µM ± 18.3, which is comparable to a tetrasaccharide inhibitor of HSulf-1 reported in the literature. We propose that the disaccharide IdoA(2S)-GlcNS(6S) is the shortest fragment size required for effective inhibition of the Sulfs.

Xylobiose treatment strengthens intestinal barrier function by regulating claudin 2 and heat shock protein 27 expression in human Caco-2 cells.

BACKGROUND: Xylobiose, a non-digestible disaccharide, largely contributes to the beneficial physiological effects of xylooligosaccharides. However, there is insufficient evidence to assess the direct effect of xylobiose on intestinal barrier function. Here, we investigated the intestinal barrier function in human intestinal Caco-2 cells treated with xylobiose. RESULTS: In total, 283 genes were upregulated and 256 genes were downregulated in xylobiose-treated Caco-2 cells relative to the controls. We focused on genes related to intestinal barrier function, such as tight junction (TJ) and heat shock protein (HSP). Xylobiose decreased the expression of the TJ gene Claudin 2 (CLDN2) and increased the expression of the cytoprotective HSP genes HSPB1 and HSPA1A, which encode HSP27 and HSP70, respectively. Immunoblot analysis confirmed that xylobiose suppressed CLDN2 expression and enhanced HSP27 and HSP70 expression. A quantitative reverse transcription-PCR and promoter assays indicated that xylobiose post-transcriptionally regulated CLDN2 and HSPB1 levels. Additionally, selective inhibition of phosphatidyl-3-inositol kinase (PI3K) inhibited xylobiose-mediated CLDN2 expression, whereas HSP27 expression induced by xylobiose was sensitive to the inhibition of PI3K, mitogen-activated protein kinase kinase and Src. CONCLUSION: The results of the present study reveal that xylobiose suppresses CLDN2 and increases HSP27 expression in intestinal Caco-2 cells via post-transcriptional regulation, potentially strengthening intestinal barrier integrity; however, these effects seem to occur via different signaling pathways. Our findings may help to assess the physiological role of xylobiose. © 2023 Society of Chemical Industry.

Rosavin: Research Advances in Extraction and Synthesis, Pharmacological Activities and Therapeutic Effects on Diseases of the Characteristic Active Ingredients of Rhodiola rosea L.

Rhodiola rosea L. (RRL) is a popular plant in traditional medicine, and Rosavin, a characteristic ingredient of RRL, is considered one of the most important active ingredients in it. In recent years, with deepening research on its pharmacological actions, the clinical application value and demand for Rosavin have been steadily increasing. Various routes for the extraction and all-chemical or biological synthesis of Rosavin have been gradually developed for the large-scale production and broad application of Rosavin. Pharmacological studies have demonstrated that Rosavin has a variety of biological activities, including antioxidant, lipid-lowering, analgesic, antiradiation, antitumor and immunomodulation effects. Rosavin showed significant therapeutic effects on a range of chronic diseases, including neurological, digestive, respiratory and bone-related disorders during in vitro and vivo experiments, demonstrating the great potential of Rosavin as a therapeutic drug for diseases. This paper gives a comprehensive and insightful overview of Rosavin, focusing on its extraction and synthesis, pharmacological activities, progress in disease-treatment research and formulation studies, providing a reference for the production and preparation, further clinical research and applications of Rosavin in the future.

Biological properties of (1-4)-thio disaccharides.

Thio sugars are carbohydrate derivatives in which one or more oxygen atoms have been replaced with sulfur. Thio sugars are effective inhibitors of glycosylases, have considerable therapeutic potential, and are used as drugs in the treatment of diabetes and infectious diseases. The development of this branch of carbohydrate chemistry would not be possible without the development of novel methods for its synthesis and the analysis of their biochemical properties. In this Review Article, we summarize our findings on the biological properties of a collection of thio sugars and their derivatives synthesized by the Witczak and Bielski team using their original methods based on the Michael addition of sugar thiols to levoglucosenone.

Involvement of langerin in the protective function of a keratan sulfate-based disaccharide in an emphysema mouse model.

Chronic obstructive pulmonary disease (COPD), which includes emphysema and chronic bronchitis, is now the third cause of death worldwide, and COVID-19 infection has been reported as an exacerbation factor of them. In this study, we report that the intratracheal administration of the keratan sulfate-based disaccharide L4 mitigates the symptoms of elastase-induced emphysema in a mouse model. To know the molecular mechanisms, we performed a functional analysis of a C-type lectin receptor, langerin, a molecule that binds L4. Using mouse BMDCs (bone marrow-derived dendritic cells) as langerin-expressing cells, we observed the downregulation of IL-6 and TNFa and the upregulation of IL-10 after incubation with L4. We also identified CapG (a macrophage-capping protein) as a possible molecule that binds langerin by immunoprecipitation combined with a mass spectrometry analysis. We identified a portion of the CapG that was localized in the nucleus and binds to the promoter region of IL-6 and the TNFa gene in BMDCs, suggesting that CapG suppresses the gene expression of IL-6 and TNFa as an inhibitory transcriptional factor. To examine the effects of L4 in vivo, we also generated langerin-knockout mice by means of genome editing technology. In an emphysema mouse model, the administration of L4 did not mitigate the symptoms of emphysema as well as the inflammatory state of the lung in the langerin-knockout mice. These data suggest that the anti-inflammatory effect of L4 through the langerin-CapG axis represents a potential therapeutic target for the treatment of emphysema and COPD.

Rare Sugar Metabolism and Impact on Insulin Sensitivity along the Gut-Liver-Muscle Axis In Vitro.

Rare sugars have recently attracted attention as potential sugar replacers. Understanding the biochemical and biological behavior of these sugars is of importance in (novel) food formulations and prevention of type 2 diabetes. In this study, we investigated whether rare sugars may positively affect intestinal and liver metabolism, as well as muscle insulin sensitivity, compared to conventional sugars. Rare disaccharide digestibility, hepatic metabolism of monosaccharides (respirometry) and the effects of sugars on skeletal muscle insulin sensitivity (impaired glucose uptake) were investigated in, respectively, Caco-2, HepG2 and L6 cells or a triple coculture model with these cells. Glucose and fructose, but not l-arabinose, acutely increased extracellular acidification rate (ECAR) responses in HepG2 cells and impaired glucose uptake in L6 cells following a 24 h exposure at 28 mM. Cellular bioenergetics and digestion experiments with Caco-2 cells indicate that especially trehalose (α1-1α), D-Glc-α1,2-D-Gal, D-Glc-α1,2-D-Rib and D-Glc-α1,3-L-Ara experience delayed digestion and reduced cellular impact compared to maltose (α1-4), without differences on insulin-stimulated glucose uptake in a short-term setup with a Caco-2/HepG2/L6 triple coculture. These results suggest a potential for l-arabinose and specific rare disaccharides to improve metabolic health; however, additional in vivo research with longer sugar exposures should confirm their beneficial impact on insulin sensitivity in humans.

Structure, anti-SARS-CoV-2, and anticoagulant effects of two sulfated galactans from the red alga Botryocladia occidentalis.

The structure of the sulfated galactan from the red alga Botryocladia occidentalis (BoSG) was originally proposed as a simple repeating disaccharide of alternating 4-linked α-galactopyranose (Galp) and 3-linked ß-Galp units with variable sulfation pattern. Abundance was estimated only for the α-Galp units: one-third of 2,3-disulfation and one-third of 2-monosulfation. Here, we isolated again the same BoSG fractions from the anion-exchange chromatography, obtaining the same NMR profile of the first report. More careful NMR analysis led us to revise the structure. A more complex sulfation pattern was noted along with the occurrence of 4-linked α-3,6-anhydro-Galp (AnGalp) units. Interestingly, the more sulfated BoSG fraction showed slightly reduced in vitro anti-SARS-CoV-2 activities against both wild-type and delta variants, and significantly reduced anticoagulant activity. The BoSG fractions showed no cytotoxic effects. The reduction in both bioactivities is attributed to the presence of the AnGalp unit. Docking scores from computational simulations using BoSG disaccharide constructs on wild-type and delta S-proteins, and binding analysis through competitive SPR assays using blood (co)-factors (antithrombin, heparin cofactor II and thrombin) and four S-proteins (wild-type, delta, gamma, and omicron) strongly support the conclusion about the deleterious impact of the AnGalp unit.

Trehalose counteracts the dissociation of tetrameric rabbit lactate dehydrogenase induced by acidic pH conditions.

The lactate dehydrogenase from rabbit skeletal muscle (rbLDH) is a tetrameric enzyme, known to undergo dissociation when exposed to acidic pH conditions. Moreover, it should be mentioned that this dissociation translates into a pronounced loss of enzyme activity. Notably, among the compounds able to stabilize proteins and enzymes, the disaccharide trehalose represents an outperformer. In particular, trehalose was shown to efficiently counteract quite a number of physical and chemical agents inducing protein denaturation. However, no information is available on the effect, if any, exerted by trehalose against the dissociation of protein oligomers. Accordingly, we thought it of interest to investigate whether this disaccharide is competent in preventing the dissociation of rbLDH induced by acidic pH conditions. Further, we compared the action of trehalose with the effects triggered by maltose and cellobiose. Surprisingly, both these disaccharides enhanced the dissociation of rbLDH, with maltose being responsible for a major effect when compared to cellobiose. On the contrary, trehalose was effective in preventing enzyme dissociation, as revealed by activity assays and by Dynamic Light Scattering (DLS) experiments. Moreover, we detected a significant decrease of both K0.5 and Vmax when the rbLDH activity was tested (at pH 7.5 and 6.5) as a function of pyruvate concentration in the presence of trehalose. Further, we found that trehalose induces a remarkable increase of Vmax when the enzyme is exposed to pH 5. Overall, our observations suggest that trehalose triggers conformational rearrangements of tetrameric rbLDH mirrored by resistance to dissociation and peculiar catalytic features.

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

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

Glycosidic linkage of rare and new-to-nature disaccharides reshapes gut microbiota in vitro.

The impact of glycosidic linkage of seven rare and new-to-nature disaccharides on gut bacteria was assessed in vitro. The community shift of the inocula from four donors in response to 1 % (w/v) disaccharide supplementation was captured by sequencing the 16S rRNA gene. A significant loss of bacterial alpha diversity, short lag time, low pH, and high total short-chain fatty acid displayed a faster fermentation of trehalose(Glc-α1,1α-Glc) and fibrulose(fructan, DP2-10). Bacteroides reduced in relative abundance under disaccharide supplementation suggesting a loss in complex carbohydrates metabolizing capacity. Fibrulose and l-arabinose glucoside(Glc-α1,3-l-Ara) significantly stimulated bifidobacteria but was suppressed with trehalose, ribose glucoside(Glc-α1,2-Rib), and 4'-epitrehalose(Glc-α1,1α-Gal) supplementation. Albeit insignificant, bifidobacteria increased with 4'-epikojibiose(Glc-α1,2-Gal), nigerose(Glc-α1,3-Glc), and kojibiose(Glc-α1,2-Glc). Prior conditioning of inoculum in kojibiose medium profoundly induced bifidobacteria by 44 % and 55 % upon reinoculation into kojibiose and fibrulose-supplemented media respectively. This study has demonstrated the importance of the disaccharide structure-function relationship in driving the gut bacterial community.

Antiviral Disaccharide Lead Compounds against SARS-CoV-2 through Computer-Aided High-Throughput Screen.

SARS-CoV-2 infects human epithelial cells through specific interaction with angiotensin-converting enzyme 2 (ACE2). In addition, heparan sulfate proteoglycans act as the attachment factor to promote the binding of viral spike protein receptor binding domain (RBD) to ACE2 on host cells. Though the rapid development of vaccines has contributed significantly to preventing severe disease, mutated SARS-CoV-2 strains, especially the SARS-CoV-2 Omicron variant, show increased affinity of RBD binding to ACE2, leading to immune escape. Thus, there is still an unmet need for new antiviral drugs. In this study, we constructed pharmacophore models based on the spike RBD of SARS-CoV-2 and SARS-CoV-2 Omicron variant and performed virtual screen for best-hit compounds from our disaccharide library. Screening of 96 disaccharide structures identified two disaccharides that displayed higher binding affinity to RBD in comparison to reported small molecule antiviral drugs. Further, screening PharmMapper demonstrated interactions of the disaccharides with a number of inflammatory cytokines, suggesting a potential for disaccharides with multiple-protein targets.

Ketogenic and Low FODMAP Diet in Therapeutic Management of a Young Autistic Patient with Epilepsy and Dysmetabolism Poorly Responsive to Therapies: Clinical Response and Effects of Intestinal Microbiota.

Autism spectrum disorder (ASD) is often associated with several intestinal and/or metabolic disorders as well as neurological manifestations such as epilepsy (ASD-E). Those presenting these neuropathological conditions share common aspects in terms of gut microbiota composition. The use of microbiota intervention strategies may be an approach to consider in the management of these cases. We describe the case of a 17-year-old girl affected by ASD, reduced growth, neurological development delay, mutations in the PGM1 and EEF1A2 genes (in the absence of clinically manifested disease) and, intestinal disorders such as abdominal pain and diarrhea associated with weight loss. As she demonstrated poor responsiveness to the therapies provided, we attempted two specific dietary patterns: a ketogenic diet, followed by a low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet, with the aim of improving her neurological, metabolic, and intestinal symptoms through modulation of the gut microbiota's composition. The ketogenic diet (KD) provided a reduction in Firmicutes, Bacteroidetes, and Proteobacteria. Although her intestinal symptoms improved, KD was poorly tolerated. On the other hand, the passage to a low FODMAPs diet produced a significant improvement in all neurological, intestinal, and metabolic symptoms and was well-tolerated. The following gut microbiota analysis showed reductions in Actinobacteria, Firmicutes, Lactobacilli, and Bifidobacteria. The alpha biodiversity was consistently increased and the Firmicutes/Bacteroidetes ratio decreased, reducing the extent of fermentative dysbiosis. Gut microbiota could be a therapeutic target to improve ASD-related symptoms. Further studies are needed to better understand the correlation between gut microbiota composition and ASD, and its possible involvement in the physiopathology of ASD.

Disaccharide trehalose in experimental therapies for neurodegenerative disorders: Molecular targets and translational potential.

Induction of autophagy is a prospective approach to the treatment of neurodegeneration. In the recent decade, trehalose attracted special attention. It is an autophagy inducer with negligible adverse effects and is approved for use in humans according to FDA requirements. Trehalose has a therapeutic effect in various experimental models of diseases. This glucose disaccharide with a flexible α-1-1'-glycosidic bond has unique properties: induction of mTOR-independent autophagy (with kinase AMPK as the main target) and a chaperone-like effect on proteins imparting them natural spatial structure. Thus, it can reduce the accumulation of neurotoxic aberrant/misfolded proteins. Trehalose has an anti-inflammatory effect and inhibits detrimental oxidative stress partially owing to the enhancement of endogenous antioxidant defense represented by the Nrf2 protein. The disaccharide activates lysosome and autophagosome biogenesis pathways through the protein factors TFEB and FOXO1. Here we review various mechanisms of the neuroprotective action of trehalose and touch on the possibility of pleiotropic effects. Current knowledge about specific features of trehalose pharmacodynamics is discussed. The neuroprotective effects of trehalose in animal models of major neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases are examined too. Attention is given to translational transition to clinical trials of this drug, especially oral and parenteral routes of administration. Besides, the possibility of enhancing the therapeutic benefit via a combination of mTOR-dependent and mTOR-independent autophagy inducers is analyzed. In general, trehalose appears to be a promising multitarget tool for the inhibition of experimental neurodegeneration and requires thorough investigation of its clinical capabilities.

Investigating the stabilisation of IFN-α2a by replica exchange molecular dynamics simulation.

Current biopharmaceutical drugs are mainly a class of peptides or proteins that play an essential role in the treatment of many diseases. Such peptides/proteins are usually thermally unstable and may lose their bioactivity when exposed to ambient conditions. Therefore, they are not suitable for long-term storage. Lyophilisation is the most common method to prolong shelf life of solid peptide/protein drugs; however, the freeze-drying process can lead to irreversible damage. In the present study, human interferon-alpha 2a (IFN-α2a) was selected as a model protein drug; four disaccharides (ß-lactose, ß-maltose, sucrose, and trehalose) were selected as bioactive protectants. We investigated the effects of different protectants on IFN-α2a under various ambient conditions (vacuum, dry state, and aqueous solution) using replica exchange molecular dynamics simulation. The protective effect of ß-maltose on IFN-α2a was the highest in aqueous solution and dry state, ß-lactose showed a poor protective effect in all three conditions, the performance of sucrose was good in all conditions, and trehalose showed a better protective effect under vacuum conditions and in aqueous solution. Disaccharides form H-bonds with water, thereby preventing water from the tertiary structure of proteins. Trehalose forms strong H-bonds with water which explains its extraordinary stability.

Increased intake of mono- and disaccharides by Reeves's muntjac (Muntiacus reevesi). Effect on gastrointestinal tract structure and function and blood parameters.

The aim of this study was to determine the effect of an increased mono- and disaccharide (MD) intake on selected functions and structure of the gastrointestinal tract (GIT), and selected blood parameters in Reeves's muntjac (Muntiacus reevesi), a small browsing ruminant. Eighteen male muntjacs were fed diets consisting of lucerne (ad libitum), a high fibre pellet (100 g/day) and wheat bran (30 g/day) without (MD0) or with addition of 10 or 20 g of glucose, fructose and sucrose mixture/day (MD10 and MD20, respectively) for 14 days. MD dosages were set to increase intake of these saccharides by 25% and 50% relative to MD0, which resulted in a range of water-soluble carbohydrate content in the consumed dry matter from 7% to 12%. Compared to MD0 animals, MD20 animals had a lower dry matter intake, a higher MD concentrations in the reticulorumen (RR), abomasal and small intestinal digesta, higher ruminal butyrate concentration, higher SGLT1 expression in the epithelium of proximal jejunum, higher plasma glucose, lower RR tissue weight but greater caecal tissue weight (p ≤ 0.05), and had or tended to have shorter papillae and lower mucosa surface area in the Atrium ruminis (by 44%; p = 0.02 and p = 0.10, respectively); MD10 animals tended to have higher MD concentrations in the abomasal and small intestinal digesta (p ≤ 0.10), and a higher amylolytic activity (p = 0.02) as well as a tendency to lower xylanolytic activity in the RR digesta (p = 0.06). MD supplementation did not affect ruminal pH. In conclusion, low to moderate increase of MD intake increased MD concentrations in the RR, abomasal and intestinal digesta, and SGLT1 expression in intestinal epithelium, suggesting incomplete fermentation of those saccharides in the RR. MD supplementation dose-dependently affects structure of GIT in Reeves's muntjac.

Prospective multifunctional roles and pharmacological potential of dietary flavonoid narirutin.

Plant-based phytochemicals are now being used to treat plenty of physiological diseases. Herbal drugs have gained popularity in recent years because of their strength, purity, and cheap cost-effectiveness. Citrus fruits contain significant amounts of flavanones, which falls to the category of polyphenols. Flavanones occupy a major fraction of the total polyphenols present in the plasma when orange juice is taken highly or in moderate states. Narirutin is a disaccharide derivative available in citrus fruits, primarily dihydroxy flavanone. From a pharmacological viewpoint, narirutin is a bioactive phytochemical with therapeutic efficacy. Many experimental researches were published on the use of narirutin. Anticancer activity, neuroprotection, stress relief, hepatoprotection, anti-allergic activity, antidiabetic activity, anti-adipogenic activity, anti-obesity action, and immunomodulation are a couple of the primary pharmacological properties. Narirutin also has antioxidant, and anti-inflammatory activities. The ultimate goal of this review is to provide the current scenario of pharmacological research with narirutin; to make a better understanding for therapeutic potential of narirutin, as well as its biosynthesis strategies and side effects. Extensive literature searches and studies were undertaken to determine the pharmacological properties of narirutin.

Molecular dynamics simulations of the secondary-binding site in disaccharide-modified glycopeptide antibiotics.

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.

Synthesis of novel S- and O-disaccharide analogs of heparan sulfate for heparanase inhibition.

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.