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Introduction: Background: stevia and D-tagatose have shown a reduction in total calorie and carbohydrate intake as a substitute for sucrose, demonstrating a stabilizing effect on pH and bacterial proliferation. Objective: to evaluate the effect of D-tagatose, stevia and sucrose on salivary pH and bacterial activity in odontology students. Methodology: a controlled study of parallel and randomized groups with a single blind, whose sample considered three groups subjected to a mouthwash of D-tagatose (n = 10), stevia (n = 10) and sucrose (n = 10). These solutions were administered over 1 minute in a single 6.4 % concentrated dose. Data collection and analysis considered the recording of salivary pH 5 min before exposure to the sweetener, immediately after expulsion of the mouthwash and 15 min later, 30 min, 45 min and 48 hours. The counting of the final number of colony-forming units per mL (CFU/mL) was counted using the salivary samples obtained immediately after exposure of the sweetener together with the sample obtained 30 minutes later, with the cultures performed on agar plates. Results: D-tagatose, stevia and sucrose presented significant differences in total CFU/mL at 30 minutes (p < 0.001), while salivary pH showed significant differences at 48 hours after administration (p < 0.001). Conclusion: D-tagatose, stevia and sucrose present significant differences in total CFU/mL and salivary pH, these findings being a possible indication of a partial inhibitory effect on bacterial metabolism.

Nanoparticles have become versatile assets in the medical field, providing notable benefits across diverse medical arenas including controlled drug delivery, imaging, and immunological assays. Among these, non-lamellar lipid nanoparticles, notably cubosomes and hexosomes, showcase remarkable biocompatibility and stability, rendering them as optimal choices for theranostic applications. Particularly, incorporating edge activators like sodium taurocholate enhances the potential of these nanoparticles for dermal and transdermal drug delivery, overcoming the stratum corneum, a first line of defense in our skin. This study reports on the formulation of monoolein-based cubosomes and hexosomes incorporating taurocholate and stabilized by Span 80 and co-encapsulating Chlorin e6 and coenzyme QH for photodynamic therapy in skin metastatic melanoma. The formulations were optimized using small-angle X-ray scattering, and cryo-transmission electron microscopy confirmed the presence of cubosomes or hexosomes, depending on the ratio between taurocholate and Span 80. Furthermore, the co-loaded nanoparticles exhibited high encapsulation efficiencies for both Ce6 and the coenzyme QH. In vitro studies on human melanoma cells (Me45) demonstrated the biocompatibility and photodynamic activity of the loaded formulations. These findings show the possibility of formulating more biocompatible cubosomes and hexosomes for photodynamic therapy in skin cancer treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Carbohydrates have a dietary role, but excessive consumption of high-calorie sugars can contribute to an increased incidence of metabolic diseases and dental caries. Recently, carbohydrates with sweetening properties and low caloric value, such as D-tagatose, have been investigated as alternative sugars. D-tagatose is a rare sugar that has nutritional and functional properties of great interest for health. This literature review presents an approach to the biological effects of D-tagatose, emphasizing its benefits for oral health. Studies report that D-tagatose has antioxidant and prebiotic effects, low digestibility, reduced glycemic and insulinemic responses, and the potential to improve the lipid profile, constituting an alternative for diabetes mellitus and obesity. It can also be observed that D-tagatose has an antioxidant action, favoring the elimination of free radicals and, consequently, causing a reduction in cellular oxidative stress. Furthermore, it also has antibacterial potential against oral species. Regarding oral health, studies have shown that D-tagatose efficiently reversed bacterial coaggregations, including periodontopathogenic species, and impaired the activity and growth of cariogenic bacteria, such as S. mutans . D-tagatose significantly inhibited biofilm formation, pH decrease and insoluble glucan synthesis in S. mutans cultures. Salivary S. mutans counts were also significantly reduced by the consumption of chewing gum containing D-tagatose and xylitol. In addition, there is evidence that tagatose is effective as an air-polishing powder for biofilm decontamination. The literature indicates that D-tagatose can contribute to the prevention of systemic diseases, also constituting a promising agent to improve oral health.

Chronic lymphocytic leukemia (CLL) is a disease characterized by the accumulation of mature CD19 + CD5 + CD23 + B cells in the bloodstream and in lymphoid organs. It usually affects people over 70 years of age, which limits the options for treatments. The disease is typically well-managed, but to date is still incurable. Hence, the need for novel therapeutic strategies remains. Nurse-like cells (NLCs) are major components of the microenvironment for CLL, supporting tumor cell survival, proliferation, and even drug resistance. They are of myeloid lineage, guided toward differentiating into their tumor-supportive role by the CLL cells themselves. As such, they are analogous to tumor-associated macrophages and represent a major therapeutic target. Previously, it was found that a mushroom extract, Active Hexose-Correlated Compound (AHCC), promoted the death of acute myeloid leukemia cells while preserving normal monocytes. Given these findings, it was asked whether AHCC might have a similar effect on the abnormally differentiated myeloid-lineage NLCs in CLL. CLL-patient PBMCs were treated with AHCC, and it was found that AHCC treatment showed a direct toxic effect against isolated CLL cells. In addition, it significantly reduced the number of tumor-supportive NLCs and altered their phenotype. The effects of AHCC were then tested in the Eµ-TCL1 mouse model of CLL and the Mll PTD/WT Flt3 ITD/WT model of AML. Results showed that AHCC not only reduced tumor load and increased survival in the CLL and AML models, but it also enhanced antitumor antibody treatment in the CLL model. These results suggest that AHCC has direct and indirect effects against CLL and that it may be of benefit when combined with existing treatments.

1,4-Anhydro-4-seleno-D-talitol (SeTal) is a highly water-soluble selenosugar with interesting antioxidant and skin-tissue-repair properties; it is highly stable in simulated gastric and gastrointestinal fluids and is a potential pharmaceutical ingredient that may be administered orally. Hepatic toxicity is often a major problem with novel drugs and can result in drug withdrawal from the market. Predicting hepatotoxicity is therefore essential to minimize late failure in the drug-discovery process. Herein, we report in vitro studies to evaluate the cytotoxic and genotoxic potential of SeTal in HepG2 and hepatocyte-like differentiated HepaRG cells. Except for extremely high concentrations (10 mM, 68 h-treatment in HepG2), SeTal did not affect the viability of each cell type. While the highest examined concentrations (0.75 and 1 mM in HepG2; 1 mM in HepaRG) were observed to induce primary DNA damage, SeTal did not exhibit clastogenic or aneugenic activity toward either HepG2 or HepaRG cells. Moreover, no significant cytostasis variations were observed in any experiment. The clearly negative results observed in the CBMN test suggest that SeTal might be used as a potential active pharmaceutical ingredient. The present study will be useful for the selection of non-toxic concentrations of SeTal in future investigations., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Carl H. Schiesser reports a relationship with Seleno Therapeutics that includes: board membership. Michael J. Davies reports a relationship with Seleno Therapeutics that includes: board membership. Michael J. Davies and Carl H. Schiesser are major shareholders and Directors of Seleno Therapeutics, and are named as co-inventors on several patents of relevance to the work presented in this article. Michael J. Davies also declares commercial consultancy contracts with Novo Nordisk A/S. These funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish these results. The other authors declare no conflicts of interest with regard to the data presented., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Benzylamine is a natural molecule present in food and edible plants, capable of activating hexose uptake and inhibiting lipolysis in human fat cells. These effects are dependent on its oxidation by amine oxidases present in adipocytes, and on the subsequent hydrogen peroxide production, known to exhibit insulin-like actions. Virtually, other substrates interacting with such hydrogen peroxide-releasing enzymes potentially can modulate lipid accumulation in adipose tissue. Inhibition of such enzymes has also been reported to influence lipid deposition. We have therefore studied in human adipocytes the lipolytic and lipogenic activities of pharmacological entities designed to interact with amine oxidases highly expressed in this cell type: the semicarbazide-sensitive amine oxidase (SSAO also known as PrAO or VAP-1) and the monoamine oxidases (MAO). The results showed that SZV-2016 and SZV-2017 behaved as better substrates than benzylamine, releasing hydrogen peroxide once oxidized, and reproduced or even exceeded its insulin-like metabolic effects in fat cells. Additionally, several novel SSAO inhibitors, such as SZV-2007 and SZV-1398, have been evidenced and shown to inhibit benzylamine metabolic actions. Taken as a whole, our findings reinforce the list of molecules that influence the regulation of triacylglycerol assembly/breakdown, at least in vitro in human adipocytes. The novel compounds deserve deeper investigation of their mechanisms of interaction with SSAO or MAO, and constitute potential candidates for therapeutic use in obesity and diabetes.

Background: Surface functionalization enhances the properties and characteristics of polymeric nanocapsules (NCs) mainly due to the surface charge, surfactants, and polymer coating type. Curcumin (CUR) is a bioactive compound with several proven pharmacological properties and low bioavailability. This study aimed to develop anionic (poly-ɛ-caprolactone; PCL) and cationic (Eudragit ® RS100 (EUD)) NCs prepared with sorbitan monostearate (Span 60 ® ) or sorbitan monooleate (Span 80 ® ), coated with d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and optimized using 2 3 factorial analysis. Subsequently, the biological activity was evaluated., Methods: A two-level, three-factor design (polymer, Span type, and TPGS concentration) was used. The biological effects of CUR-loaded TPGS-coated cationic and anionic NCs were assessed in apomorphine-induced stereotyped behavior in rats., Results: The type of polymer (anionic or cationic) and Span ® had a factorial influence on the physical and chemical characteristics of NCs according to the changes in TPGS concentrations. Both cationic and anionic CUR-NCs could block apomorphine-induced behavioral changes., Conclusions: The CUR-loaded TPGS-coated NCs proved to be a promising brain delivery system., (© 2021. Maj Institute of Pharmacology Polish Academy of Sciences.)

Eight mono- or disaccharide analogues derived from BLM disaccharide, along with the corresponding carbohydate-dye conjugates have been designed and synthesized in this study, aiming at exploring the effect of a gulose residue on the cellular binding/uptake of BLM disaccharide and it possible uptake mechanism. Our evidence is presented indicating that, for the cellular binding/uptake of BLM disaccharide, a gulose residue is an essential subunit but unrelated to its chemical nature. Interestingly, d-gulose-dye conjugate is able to selectively target A549 cancer cells, but l-gulose-dye conjugate fails. Further uptake mechanism studies demonstrate d-gulose-dye derivatives similar to BLM disaccharide-dye ones behave in a temperature- and ATP-dependent manner, and are partly directed by the GLUT1 receptor. Moreover, d-gulose modifying gemcitabine 53a exhibits more potent antitumor activity compared to derivatives 53b-c in which gemcitabine is decorated with other monosaccharides. Taken together, the monosacharide d-gulose conjugate offers a new strategy for solving cytotoxic drugs via the increased tumor targeting in the therapy of lung cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Tagatose is a rare sugar metabolised by a limited number of microorganisms that inhibits a large spectrum of phytopathogens. In particular, tagatose inhibited Phytophthora infestans growth and negatively affected mitochondrial processes. However, the possible effects of tagatose on P. infestans metabolism have not yet been investigated. The aim of this study was to analyse the impact of this rare sugar on the sugar metabolism in P. infestans, in order to better understand its mode of action. Tagatose inhibited the growth of P. infestans with a precise reprogramming of the carbohydrate metabolism that involved a decrease of glucose, glucose-1-phosphate and mannose content and β-glucosidase activity. The combination of tagatose with common sugars led to three different responses and highlighted antagonistic interactions. In particular, glucose partially attenuated the inhibitory effects of tagatose, while fructose fully impaired tagatose-mediated growth inhibition and metabolite changes. Moreover, sucrose did not attenuate tagatose effects, suggesting that the inhibition of sucrose catabolism and the alteration of glucose-related pathways contributed to the growth inhibition caused by tagatose to P. infestans. The interactions of tagatose with the common sugar metabolism were found to be a key mode of action against P. infestans growth, which may represent the basis for the further development of tagatose as an eco-friendly fungicide., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Chlamydia trachomatis genital infection is the most common bacterial sexually transmitted disease worldwide. Previously, we reported that cold-induced stress results in immune suppression of mice that subsequently leads to increased intensity of Chlamydia muridarum genital infection. Furthermore, we demonstrated that stressed mice orally fed with active hexose-correlated compound (AHCC) have reduced shedding of C. muridarum from the genital tract. However, the mechanism of AHCC in reducing the organ load and changing the immune response in the stress model is not well known. This study evaluated infection and changes in immunological parameters of stressed AHCC-fed mice with or without C. muridarum genital infection. We hypothesized that AHCC feeding to stressed mice restores protective immune function and reduces susceptibility to C. muridarum genital infection. The results show that oral feeding of stressed mice with AHCC resulted in decreased shedding of C. muridarum from the genital tract, reduced production of plasma catecholamines, increased expression of T-bet and reduced GATA-3 in CD4 + T cells, increased production of interleukin-12 (IL-12) and interferon gamma (IFN-γ) and reduced production of IL-4 in CD4 + T cells, and enhanced expression of surface markers and costimulatory molecules of CD4 + T cells, bone marrow-derived dendritic cells (BMDCs), and natural killer cells. Coculturing of mature BMDCs with splenic CD4 + T cells led to the increased and decreased production of T helper 1 and T helper 2 cytokines, respectively. Overall, our results show that AHCC fosters the restoration of Th1 cytokine production while reducing Th2 cytokine production, which would promote C. muridarum clearance in the murine stress model., (Copyright © 2021 American Society for Microbiology.)

Dental implants are one of the most frequently used treatment options for tooth replacement, and titanium is the metal of choice due to its demonstrated superiority in resisting corrosion, lack of allergic reactions and mechanical strength. Surface roughness of titanium implants favors the osseointegration process; nevertheless, its topography may provide a suitable substrate for bacterial biofilm deposition, causing peri-implantitis and leading to implant failure. Subgingival prophylaxis treatments with cleansing powders aimed to remove the bacterial accumulation are under investigation. Two different air-polishing powders-glycine and tagatose-were assayed for their cleaning and antimicrobial potential against a Pseudomonas biofilm and for their effects on human dental pulp stem cells (hDPSCs), seeded on sandblasted titanium disks. Immunofluorescence analyses were carried out to evaluate cell adhesion, proliferation, stemness and osteogenic differentiation. The results demonstrate that both the powders have a great in vitro cleaning potential in the early period and do not show any negative effects during hDPSCs osteogenic differentiation process, suggesting their suitability for enhancing the biocompatibility of titanium implants. Our data suggest that the evaluated cleansing systems reduce microbial contamination and allow us to propose tagatose as an adequate alternative to the gold standard glycine for the air-polishing prophylaxis treatment.

Understanding the mechanism by which the exogenous biomolecule modulates the GLUT-4 signalling cascade along with the information on glucose metabolism is essential for finding solutions to increasing cases of diabetes and metabolic disease. This study aimed at investigating the effect of hamamelitannin on glycogen synthesis in an insulin resistance model using L6 myotubes. Glucose uptake was determined using 2-deoxy-D-[1- 3 H] glucose and glycogen synthesis were also estimated in L6 myotubes. The expression levels of key genes and proteins involved in the insulin-signaling pathway were determined using real-time PCR and western blot techniques. The cells treated with various concentrations of hamamelitannin (20 µM to 100 µM) for 24 h showed that, the exposure of hamamelitannin was not cytotoxic to L6 myotubes. Further the 2-deoxy-D-[1- 3 H] glucose uptake assay was carried out in the presence of wortmannin and Genistein inhibitor for studying the GLUT-4 dependent cell surface recruitment. Hamamelitannin exhibited anti-diabetic activity by displaying a significant increase in glucose uptake (125.1%) and glycogen storage (8.7 mM) in a dose-dependent manner. The optimum concentration evincing maximum activity was found to be 100 µm. In addition, the expression of key genes and proteins involved in the insulin signaling pathway was studied to be upregulated by hamamelitannin treatment. Western blot analysis confirmed the translocation of GLUT-4 protein from an intracellular pool to the plasma membrane. Therefore, it can be conceived that hamamelitannin exhibited an insulinomimetic effect by enhancing the glucose uptake and its further conversion into glycogen by regulating glucose metabolism.

The rare sugar D-tagatose is a safe natural product used as a commercial food ingredient. Here, we show that D-tagatose controls a wide range of plant diseases and focus on downy mildews to analyze its mode of action. It likely acts directly on the pathogen, rather than as a plant defense activator. Synthesis of mannan and related products of D-mannose metabolism are essential for development of fungi and oomycetes; D-tagatose inhibits the first step of mannose metabolism, the phosphorylation of D-fructose to D-fructose 6-phosphate by fructokinase, and also produces D-tagatose 6-phosphate. D-Tagatose 6-phosphate sequentially inhibits phosphomannose isomerase, causing a reduction in D-glucose 6-phosphate and D-fructose 6-phosphate, common substrates for glycolysis, and in D-mannose 6-phosphate, needed to synthesize mannan and related products. These chain-inhibitory effects on metabolic steps are significant enough to block initial infection and structural development needed for reproduction such as conidiophore and conidiospore formation of downy mildew.

We investigated new development in photodynamic therapy (PDT), aiming at enhanced tumor selectivity and biocompatibility, which included application of a third-generation photosensitizing agent, i.e. xanthene-origin Rose Bengal (RB) co-encapsulated with up-converting NaYF 4 nanoparticles (NPs) co-doped with lanthanide ions: Er 3+ (2%) and Yb 3+ (20%). The hybrid fluorophores were applied as components of double core nanocarriers (NCs) obtained by double (multiple) emulsion solvent evaporation process. Next, to improve the biocompatibility and photodynamic activity, biodegradable polymer: poly(lactide-co-glycolide) - PLGA and non-ionic surfactants with different hydrophobicity: Span 80 and Cremophor A25, were used. After the engineering process, controlled by dynamic light scattering (DLS) measurements, ζ-potential evaluation, transmission electron and atomic force microscopy (TEM and AFM) imaging, as well as optical analysis provided by measurements of the up-conversion emission spectra and luminescence kinetics for encapsulated only NaYF 4 :Er 3+ ,Yb 3+ NPs and co-encapsulated RB + NaYF 4 :Er 3+ ,Yb 3+ molecules, spherical polyester NCs with average size <200 nm, were tested on human melanoma (Me-45 and MeWo) cells and a control human keratinocyte (HaCaT) cell line. The photodynamic action of the investigated NCs was assessed by oxidoreductive potential measurements with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, that corresponds to percentage of the viable cells. Immunofluorescence and the NCs internalization studies were visualized by confocal laser scanning microscopy (CLSM studies). Our results indicated effective photosensitizer delivery into the cancer cells and significant photodynamic efficiency enhanced by the near infrared (NIR)-activation of the encapsulated hybrid cargo in the skin melanoma cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: This study investigates the effectiveness of self-nanoemulsifying drug delivery system (SNEDDS) in improving voriconazole transcorneal permeability., Methods: Voriconazole-SNEDDS was prepared with isopropyl myristate, PEG 400, Tween 80 ® and Span 80 ® and was subjected for physicochemical characterization after reconstitution with NaCl 0.9% (1/9; v/v). In-vitro antifungal activity was assessed and compared with the marketed formulation. In-vivo studies, namely ocular irritation test via modified Draize test and pharmacokinetic study, were investigated using rabbit as animal model., Key Findings: Voriconazole-SNEDDS presented a droplet size of 21.353 ± 0.065 nm, a polydispersity index of 0.123 ± 0.003, a pH of 7.205 ± 0.006 and an osmolarity of 342.667 ± 2.517 mOsmol/l after reconstitution with NaCl 0.9%. Voriconazole-SNEDDS minimum inhibitory concentration (MIC 90 ) was similar to the one of marketed formulation for Candida species while it was significantly lower (P < 0.001) for Aspergillus fumigatus. Draize test revealed that Voriconazole-SNEDDS was safe for ocular administration. Voriconazole maximum concentration (5.577 ± 0.852 µg/ml) from SNEDDS was higher than marketed formulation (C max  = 4.307 ± 0.623 µg/ml), and the T max was delayed to 2 h. The area under the concentration-time curve value of Voriconazole-SNEDDS was improved by 2.419-fold., Conclusion: Our results suggest that SNEDDS is a promising carrier for voriconazole ocular delivery and this encourages further clinical studies., (© 2020 Royal Pharmaceutical Society.)

Background: Metastasis causes the most breast cancer-related deaths in women. Here, we investigated the antitumor effect of solid lipid nanoparticles (SLN-DTX) when used in the treatment of metastatic breast tumors using 4T1-bearing BALB/c mice., Results: Solid lipid nanoparticles (SLNs) were produced using the high-energy method. Compritol 888 ATO was selected as the lipid matrix, and Pluronic F127 and Span 80 as the surfactants to stabilize nanoparticle dispersion. The particles had high stability for at least 120 days. The SLNs' dispersion size was 128 nm, their polydispersity index (PDI) was 0.2, and they showed a negative zeta potential. SLNs had high docetaxel (DTX) entrapment efficiency (86%), 2% of drug loading and showed a controlled drug-release profile. The half-maximal inhibitory concentration (IC 50 ) of SLN-DTX against 4T1 cells was more than 100 times lower than that of free DTX after 24 h treatment. In the cellular uptake test, SLN-DTX was taken into the cells significantly more than free DTX. The accumulation in the G2-M phase was significantly higher in cells treated with SLN-DTX (73.7%) than in cells treated with free DTX (23.0%), which induced subsequent apoptosis. TEM analysis revealed that SLN-DTX internalization is mediated by endocytosis, and fluorescence microscopy showed DTX induced microtubule damage. In vivo studies showed that SLN-DTX compared to free docetaxel exhibited higher antitumor efficacy by reducing tumor volume (p < 0.0001) and also prevented spontaneous lung metastasis in 4T1 tumor-bearing mice. Histological studies of lungs confirmed that treatment with SLN-DTX was able to prevent tumor. IL-6 serum levels, ki-67 and BCL-2 expression were analyzed and showed a remarkably strong reduction when used in a combined treatment., Conclusions: These results indicate that DTX-loaded SLNs may be a promising carrier to treat breast cancer and in metastasis prevention.

Chronic low-grade inflammation and oxidative damage are strongly associated with pathologies including cardiovascular disease. As a consequence, there is considerable interest in agents that mitigate damage. Selenium compounds can act as potent protective agents against oxidation due to the high reactivity and nucleophilicity of the selenium atom. 1,4-Anhydro-4-seleno-d-talitol (SeTal, a novel water-soluble selenium-based sugar) is a potent oxidant scavenger in vitro and in human plasma. Here we show that SeTal is highly stable in solutions that mimic biological fluids and the gastrointestinal tract, and is not rapidly degraded or metabolized unlike some other selenium-containing compounds. SeTal remains intact during extended storage, and it rapidly penetrates into, and effluxes from, primary human coronary artery endothelial and smooth muscle cells, but does not induce loss of metabolic activity, or modulate cell survival and growth rates at concentrations ≤2 mM. Steady-state intracellular concentrations can reach 2-10 μM. SeTal affords protection against H 2 O 2 - and HOCl-mediated oxidative damage, with this being independent of the concentration or activities of the selenium-dependent protective enzymes TrxR and GPx. Protection was observed with both concurrent drug and oxidant administration and also (to a lesser extent) with cellular pre-loading. SeTal also affords protection to isolated arterial segments, with the compound decreasing HOCl (50 μΜ) mediated effects on aortic ring relaxation, consistent with the preservation of NO bioavailability. The stability, bioavailability and protective actions of this compound, suggest that it is worthy of further investigation as a protective agent, particularly in the area of cardiovascular disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Plants host a complex microbiota inside or outside their tissues, and phyllosphere microorganisms can be influenced by environmental, nutritional and agronomic factors. Rare sugars are defined as monosaccharides with limited availability in nature and they are metabolised by only few certain microbial taxa. Among rare sugars, tagatose (TAG) is a low-calories sweetener that stimulates and inhibits beneficial and pathogenic bacteria in the human gut microbiota, respectively. Based on this differential effect on human-associated microorganisms, we investigated the effect of TAG treatments on the grapevine phyllosphere microorganisms to evaluate whether it can engineer the microbiota and modify the ratio between beneficial and pathogenic plant-associated microorganisms. TAG treatments changed the structure of the leaf microbiota and they successfully reduced leaf infections of downy mildew (caused by Plasmopara viticola) and powdery mildew (caused by Erysiphe necator) under field conditions. TAG increased the relative abundance of indigenous beneficial microorganisms, such as some potential biocontrol agents, which could partially contribute to disease control. The taxonomic composition of fungal and bacterial leaf populations differed according to grapevine locations, therefore TAG effects on the microbial structure were influenced by the composition of the originally residing microbiota. TAG is a promising biopesticide that could shift the balance of pathogenic and beneficial plant-associated microorganisms, suggesting selective nutritional/anti-nutritional properties for some specific taxa. More specifically, TAG displayed possible plant prebiotic effects on the phyllosphere microbiota and this mechanism of action could represent a novel strategy that can be further developed for sustainable plant protection., (Copyright © 2019 The Authors. Published by Elsevier GmbH.. All rights reserved.)

d-tagatose, a monosaccharide as well as a dietary supplement, has been reported as having a wide range of applicability in the food industry, however, the prebiotic activity, anticonstipation effects, and related mechanisms are still unclear. In this study, using the loperamide-induced constipation Kunming mice as the animal model, the effects of d-tagatose for the prevention of constipation were evaluated by gastrointestinal transit experiment and defecation experiment. Furthermore, the underlying mechanism was clarified by evaluating the change of the biochemical indicators and analyzing 16S rRNA amplicon of gut microbiota among the different mice groups. The results showed that the gastrointestinal transit rate, fecal number, and weight in six hours were significantly enhanced after the administration of d-tagatose. In addition, d-tagatose significantly increased the serum levels of acetylcholine (Ach) and substance P (SP), whereas the serum levels of nitric oxide (NO) were significantly decreased. Moreover, the 16S rRNA sequencing analysis revealed that the changes in the gut microbiota caused by constipation were restored by d-tagatose treatment. In conclusion, this study indicated that the administration of d-tagatose as a dietary supplement can effectively prevent and relieve constipation in Kunming mice, and it is a promising prebiotic candidate with constipation-relieving properties., Competing Interests: The authors declare no conflict of interest.

A set of three mannopyranoside possessing identical 1,1'-biphenyl glycosidic pharmacophore but different aglyconic atoms were synthesized using either a palladium-catalyzed Heck cross coupling reaction or a metathesis reaction between their corresponding allylic glycoside derivatives. Their X-ray structures, together with their calculated 3D structures, showed strong indicators to explain the observed relative binding abilities against E. coli FimH as measured by a improved surface plasmon resonance (SPR) method. Amongst the O -, C -, and S -linked analogs, the C -linked analog showed the best ability to become a lead candidate as antagonist against uropathogenic E. coli with a Kd of 11.45 nM.

Calorie restriction (CR) can prolong the human lifespan, but enforcing long-term CR is difficult. Therefore, a compound that reproduces the effect of CR without CR is needed. In this review, we summarize the current knowledge on compounds with CR mimetic (CRM) effects. More than 10 compounds have been listed as CRMs, some of which are conventionally categorized as upstream-type CRMs showing glycolytic inhibition, while the others are categorized as downstream-type CRMs that regulate or genetically modulate intracellular signaling proteins. Among these, we focus on upstream-type CRMs and propose their classification as compounds with energy metabolism inhibition effects, particularly glucose metabolism modulation effects. The upstream-type CRMs reviewed include chitosan, acarbose, sodium-glucose cotransporter 2 inhibitors, and hexose analogs such as 2-deoxy-d-glucose, d-glucosamine, and d-allulose, which show antiaging and longevity effects. Finally, we discuss the molecular definition of upstream-type CRMs.

Nutraceuticals are gaining importance owing to their potential applications in numerous sectors including food and feed industries. Among the emerging nutraceuticals, d-tagatose occupies a significant niche because of its low calorific value, antidiabetic property and growth promoting effects on beneficial gut bacteria. As d-tagatose is present in minute quantities in naturally occurring food substances, it is produced mainly by chemical or biological means. Recently, attempts were made for bio-production of d-tagatose using l-arabinose isomerase enzyme to overcome the challenges of chemical process of production. Applications of d-tagatose for maintaining health and wellbeing are increasing due to growing consumer awareness and apprehension against modern therapeutic agents. This review outlines the current status on d-tagatose, particularly its production, properties, biological role, applications, and the future perspectives., (© 2018 Institute of Food Technologists®.)

Background: D-tagatose is an isomer of fructose and is ~90% as sweet as sucrose with less caloric value. Nowadays, D-tagatose is used as a nutritive or low-calorie sweetener. Despite clinical findings suggesting that D-tagatose could be beneficial in subjects with type 2 diabetes, there are no experimental data comparing D-tagatose with fructose, in terms of metabolic derangements and related molecular mechanisms evoked by chronic exposure to these two monosaccharides., Materials and Methods: C57Bl/6j mice were fed with a control diet plus water (CD), a control diet plus 30% fructose syrup (L-Fr), a 30% fructose solid diet plus water (S-Fr), a control diet plus 30% D-tagatose syrup (L-Tg), or a 30% D-tagatose solid diet plus water (S-Tg), during 24 weeks., Results: Both solid and liquid fructose feeding led to increased body weight, abnormal systemic glucose homeostasis, and an altered lipid profile. These effects were associated with vigorous increase in oxidative markers. None of these metabolic abnormalities were detected when mice were fed with both the solid and liquid D-tagatose diets, either at the systemic or at the local level. Interestingly, both fructose formulations led to significant Advanced Glycation End Products (AGEs) accumulation in mouse hearts, as well as a robust increase in both myocardial AGE receptor (RAGE) expression and NF- κ B activation. In contrast, no toxicological effects were shown in hearts of mice chronically exposed to liquid or solid D-tagatose., Conclusion: Our results clearly suggest that chronic overconsumption of D-tagatose in both formulations, liquid or solid, does not exert the same deleterious metabolic derangements evoked by fructose administration, due to differences in carbohydrate interference with selective proinflammatory and oxidative stress cascades.

In the current study, we have tested the nonenzymatic glycation activities of ketohexoses, such as tagatose and psicose. Although tagatose-treated apoA-I (t-A-I) and psicose-treated apoA-I (p-A-I) exerted more inhibitory activity you cupric ion-mediated low-density lipoprotein (LDL) oxidation and oxidized LDL (oxLDL) phagocytosis into macrophage than fructose-treated apoA-I (f-A-I). In the lipid-free state, t-A-I and f-A-I showed more multimerized band without crosslinking. Since t-A-I lost its phospholipid binding ability, the rHDL formation was not as successful as f-A-I. However, injecting t-A-I showed more antioxidant activities in zebrafish embryo under the presence of oxLDL. Three weeks of consumption of fructose (50% of wt in Tetrabit/4% cholesterol) showed a 14% elevation of serum triacylglycerol (TG), while tagatose-administered group showed 30% reduction in serum TG compared to high cholesterol control. Fructose-fed group showed the biggest area of Oil Red O staining with the intensity as strong as the HCD control. However, tagatose-consumed group showed much lesser Oil Red O-stained area with the reduction of lipid accumulation. In conclusion, although tagatose treatment caused modification of apoA-I, the functional loss was not as much severe as the fructose treatment in macrophage cell model, zebrafish embryo, and hypercholesterolemic zebrafish model.

At present, only little is known about the enzymatic machinery required for N -glycosylation in Chlamydomonas reinhardtii , leading to the formation of N -glycans harboring Xyl and methylated Man. This machinery possesses new enzymatic features, as C. reinhardtii N -glycans are independent of β1,2- N -acetylglucosaminyltransferase I. Here we have performed comparative N -glycoproteomic analyses of insertional mutants of mannosidase 1A (IM Man1A ) and xylosyltransferase 1A (IM XylT1A ). The disruption of man1A affected methylation of Man and the addition of terminal Xyl. The absence of XylT1A led to shorter N -glycans compared to the wild type. The use of a IM Man1A xIM XylT1A double mutant revealed that the absence of Man1A suppressed the IM XylT1A phenotype, indicating that the increased N -glycan trimming is regulated by core β1,2-Xyl and is dependent on Man1A activity. These data point toward an enzymatic cascade in the N -glycosylation pathway of C. reinhardtii with interlinked roles of Man1A and XylT1A. The results described herein represent the first step toward a functional characterization of the enzymatic N -glycosylation machinery in C. reinhardtii ., (© 2018 American Society of Plant Biologists. All Rights Reserved.)

Objective: It was the aim of this study to evaluate the impact of nonionic and ionic surfactants on skin penetration of dexpanthenol., Methods: The relative potency of three surfactants (two nonionic and one ionic) as enhancers in the permeability of a series of compounds was investigated. The influence of the enhancers was also studied. For this purpose, porcine abdominal skin was prepared and mounted on Franz diffusion cells, while different mixtures of Dexpanthenol containing Tween®85, SDS and Span®80 in concentrations of 0.5%, 1%, 2%, 5% (m/V) were evaluated in terms of their permeation enhancing effect. The amount of permeated drug was determined via HPLC analysis. Moreover, the cytotoxicity and skin irritating effect of the compounds were tested on Caco-2 cells., Results: The cytotoxicity profile of Dexpanthenol showed no toxicity to the cells over 1 and 3 h of incubation. The permeation was evaluated over a time period of 180 min, whereas a ranking of SDS> Span>Tween could be determined as permeation enhancer., Conclusion: Taking these findings into consideration, concentration of 1% (w/w) surfactant showed the most promising results. The increase in flux based on low concentrations of enhancer was ascribed to their ability to reduce skin´s barrier and improve drug permeation. The results showed that the nature of enhancer greatly impacts cutaneous barrier impairment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Dental caries is an important global health concern and Streptococcus mutans has been established as a major cariogenic bacterial species. Reports indicate that a rare sugar, D‑tagatose, is not easily catabolized by pathogenic bacteria. In the present study, the inhibitory effects of D‑tagatose on the growth and biofilm formation of S. mutans GS‑5 were examined. Monitoring S. mutans growth over a 24 h period revealed that D‑tagatose prolonged the lag phase without interfering with the final cell yield. This growth retardation was also observed in the presence of 1% sucrose, although it was abolished by the addition of D‑fructose. S. mutans biofilm formation was significantly inhibited by growth in sucrose media supplemented with 1 and 4% D‑tagatose compared with that in a culture containing sucrose alone, while S. mutans formed granular biofilms in the presence of this rare sugar. The inhibitory effect of D‑tagatose on S. mutans biofilm formation was significantly more evident than that of xylitol. Growth in sucrose media supplemented with D‑tagatose significantly decreased the expression of glucosyltransferase, exo‑β‑fructosidase and D‑fructose‑specific phosphotransferase genes but not the expression of fructosyltransferase compared with the culture containing sucrose only. The activity of cell‑associated glucosyltransferase in S. mutans was inhibited by 4% D‑tagatose. These results indicate that D‑tagatose reduces water‑insoluble glucan production from sucrose by inhibiting glucosyltransferase activities, which limits access to the free D‑fructose released during this process and retards the growth of S. mutans. Therefore, foods and oral care products containing D‑tagatose are anticipated to reduce the risk of caries by inhibiting S. mutans biofilm formation.

The effect of surfactant type and concentration on a bland soap formulation's ability to remove bacteria from hands remains largely unstudied. Several combinations of surfactants and water were combined to test bacterial removal efficacy using a hand-washing device (two pieces of pig skin and a mechanical motor) to simulate a hand wash. A nalidixic acid-resistant, nonpathogenic strain of Escherichia coli (ATCC 11229) was used. Two anionic surfactants, sodium lauryl sulphate and sodium stearoyl lactylate, and two nonionic surfactants, poloxamer 407 and sorbitan monostearate, each in concentrations of 2, 5 and 10% were studied. A slight positive (r 2  = 0·17) but significant (P = 0·03) correlation was observed between hydrophile-lipophile balance value and mean log reduction. No correlation was observed between pH of the treatment solution and the mean log reduction (r 2  = 0·05, P = 0·25). A 10% sodium lauryl sulphate mixture showed the highest log reduction (x¯ = 1·1 log CFU reduction, SD = 0·54), and was the only treatment significantly different from washing with water (P = 0·0005). There was a correlation between increasing surfactant concentrations above the critical micelle concentration, and mean microbial reduction (r 2  = 0·62, P = 0·001)., Significance and Impact of the Study: This study characterizes the role of surfactants in removing microbes during a hand wash. Numerous studies address how surfactants support antimicrobial effect in soap, or cause irritation of skin, but no published studies show which surfactants are best for removing microbes. We used pig skin as a model for human skin and a lathering device to simulate a hand wash. A 10% sodium lauryl sulphate mixture was the only treatment significantly different from a water wash. There was a strong correlation between increasing surfactant concentrations above the critical micelle concentration and mean microbial reduction., (© 2017 The Society for Applied Microbiology.)

Bacillus natto is commonly used in industrial production of menaquinone-7, an important vitamin which plays a crucial role for blood clotting and may contribute to prevention of cardiovascular disease and osteoporosis. This study determined the optimal combination of key nutrients and established an effective use of surfactant in a coupling medium to enhance the yield of extracellular MK-7. MK-7 yield of 31.18 mg/L was achieved under optimal conditions containing 53.6 g/L glycerol, 100 g/L soy peptone, and 10 g/L K 2 HPO 4 . A maximal yield of 40.96 mg/L MK-7 and a secretion ratio of 61.1% were obtained when 20 g/L soybean oil was supplemented at the logarithmic phase. The non-ionic surfactant span 20 was the second most promising surfactant in improving product yield, whereas addition of 2 g/L betaine exerted a minimal effect on secretion ratio of MK-7 at 19.1%. The results collectively showed that the supplementation of surfactants was an effective strategy to regulate cytomembrane permeability. Graphical abstract ᅟ.

In this study, the feasibility of ultrasonic processing (UP) technique as green preparation method for production of poorly soluble model drug substance, diacerein, loaded niosomes was demonstrated. Also, the effects of different surfactant systems on niosomes' characteristics were analyzed. Niosomes were prepared using both the green UP technique and traditional thin-film hydration (TFH) technique, which requires the use of environmentally hazardous organic solvents. The studied surfactant systems were Span 20, Pluronic L64, and their mixture (Span 20 and Pluronic L64). Both the production techniques produced well-defined spherical vesicles, but the UP technique produced smaller and more monodisperse niosomes than TFH. The entrapment efficiencies with the UP method were lower than with TFH, but still at a feasible level. All the niosomal formulations released diacerein faster than pure drug, and the drug release rates from the niosomes produced by the UP method were higher than those from the TFH-produced niosomes. With UP technique, the optimum process conditions for small niosomal products with low PDI values and high entrapment efficiencies were obtained when 70% amplitude and 45-min sonication time were used. The overall results demonstrated the potency of UP technique as an alternative fast, cost-effective, and green preparation approach for production of niosomes, which can be utilized as drug carrier systems for poorly soluble drug materials.

Pollen germination as a crucial process in plant development strongly depends on the accessibility of carbon as energy source. Carbohydrates, however, function not only as a primary energy source, but also as important signaling components. In a comprehensive study, we analyzed various aspects of the impact of 32 different sugars on in vitro germination of Arabidopsis pollen comprising about 150 variations of individual sugars and combinations. Twenty-six structurally different mono-, di- and oligosaccharides, and sugar analogs were initially tested for their ability to support pollen germination. Whereas several di- and oligosaccharides supported pollen germination, hexoses such as glucose, fructose and mannose did not support and even considerably inhibited pollen germination when added to germination-supporting medium. Complementary experiments using glucose analogs with varying functional features, the hexokinase inhibitor mannoheptulose and the glucose-insensitive hexokinase-deficient Arabidopsis mutant gin2-1 suggested that mannose- and glucose-mediated inhibition of sucrose-supported pollen germination depends partially on hexokinase signaling. The results suggest that, in addition to their role as energy source, sugars act as signaling molecules differentially regulating the complex process of pollen germination depending on their structural properties. Thus, a sugar-dependent multilayer regulation of Arabidopsis pollen germination is supported, which makes this approach a valuable experimental system for future studies addressing sugar sensing and signaling., (© The Author 2017. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Hyperglycaemia increases the generation of reactive oxidants in blood vessels and is a major cause of endothelial dysfunction. A water-soluble selenium-containing sugar (1,4-Anhydro-4-seleno-d-talitol, SeTal) has potent antioxidant activity in vitro and is a promising treatment to accelerate wound healing in diabetic mice. One possible mechanism of SeTal action is a direct effect on blood vessels. Therefore, we tested the hypothesis that SeTal prevents endothelial dysfunction by scavenging reactive oxidants in isolated mouse aorta under conditions of acute oxidative stress induced by hyperglycaemia. Aortae were isolated from C57BL/6 male mice and mounted on a wire-myograph to assess vascular function. In the presence of a superoxide radical generator, pyrogallol, 300μM and 1mM of SeTal effectively prevented endothelial dysfunction compared to other selenium-containing compounds. In a second set of ex vivo experiments, mouse aortae were incubated for three days with either normal or high glucose, and co-incubated with SeTal at 37°C in 5% CO 2 . High glucose significantly reduced the sensitivity to the endothelium-dependent agonist, acetylcholine (ACh), increased superoxide production and decreased basal nitric oxide (NO) availability. SeTal (1mM) co-treatment prevented high glucose-induced endothelial dysfunction and oxidative stress in the mouse aorta. The presence of a cyclooxygenase inhibitor, indomethacin significantly improved the sensitivity to ACh in high glucose-treated aortae, but had no effect in SeTal-treated aortae. Our data show that SeTal has potent antioxidant activity in isolated mouse aortae and prevents high glucose-induced endothelial dysfunction by decreasing superoxide levels, increasing basal NO availability and normalising the contribution of vasoconstrictor prostanoids., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Skin permeation/penetration enhancers are substances that enable drug delivery through or into the skin., Methods: To search for new enhancers with high but reversible activity and acceptable toxicity, we synthesized a series of D-glucose derivatives, both hydrophilic and amphiphilic., Results: Initial evaluation of the ability of these sugar derivatives to increase permeation and penetration of theophylline through/into human skin compared with a control (no enhancer) or sorbitan monolaurate (Span 20; positive control) revealed dodecyl 6-amino-6-deoxy-α-D-glucopyranoside 5 as a promising enhancer. Furthermore, this amino sugar 5 increased epidermal concentration of a highly hydrophilic antiviral cidofovir by a factor of 7. The effect of compound 5 on skin electrical impedance suggested its direct interaction with the skin barrier. Infrared spectroscopy of isolated stratum corneum revealed no effect of enhancer 5 on the stratum corneum proteins but an overall decrease in the lipid chain order. The enhancer showed acceptable toxicity on HaCaT keratinocyte and 3T3 fibroblast cell lines. Finally, transepidermal water loss returned to baseline values after enhancer 5 had been removed from the skin., Conclusions: Compound 5, a dodecyl amino glucoside, is a promising enhancer that acts through a reversible interaction with the stratum corneum lipids.

Antimicrobial research is increasingly being focused on the problem of resistance and biofilm formation. Hamamelitannin (HAM) was recently identified as an antimicrobial potentiator for conventional antibiotics towards Staphylococcus aureus. This paper describes the synthesis and biological evaluation of novel hamamelitannin analogues with alternative central scaffolds. Via a ligand-based approach, several interesting compounds with improved synthetic accessibility were identified as potentiators for vancomycin in the treatment of MRSA infections., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

The optimal foraging strategy in a given environment depends on the number of competing individuals and their behavioural strategies. Little is known about the genes and neural circuits that integrate social information into foraging decisions. Here we show that ascaroside pheromones, small glycolipids that signal population density, suppress exploratory foraging in Caenorhabditis elegans, and that heritable variation in this behaviour generates alternative foraging strategies. We find that natural C. elegans isolates differ in their sensitivity to the potent ascaroside icas#9 (IC-asc-C5). A quantitative trait locus (QTL) regulating icas#9 sensitivity includes srx-43, a G-protein-coupled icas#9 receptor that acts in the ASI class of sensory neurons to suppress exploration. Two ancient haplotypes associated with this QTL confer competitive growth advantages that depend on ascaroside secretion, its detection by srx-43 and the distribution of food. These results suggest that balancing selection at the srx-43 locus generates alternative density-dependent behaviours, fulfilling a prediction of foraging game theory.

Obesity has reached pandemic proportions, and there is mounting evidence that environmental exposures to endocrine disrupting chemicals known as "obesogens" may contribute to obesity and associated medical conditions. The Deepwater Horizon (DWH) oil spill resulted in a massive environmental release of crude oil and remediation efforts applied large quantities of Corexit dispersants to the oil spill. The Corexit-enhanced Water Accommodated Fraction (CWAF) of DWH crude oil contains PPARγ transactivation activity, which is attributed to dioctyl sodium sulfosuccinate (DOSS), a probable obesogen. In addition to its use in oil dispersants, DOSS is commonly used as a stool softener and food additive. Because PPARγ functions as a heterodimer with RXRα to transcriptionally regulate adipogenesis we investigated the potential of CWAF to transactivate RXRα and herein demonstrated that the Corexit component Span 80 has RXRα transactivation activity. Span 80 bound to RXRα in the low micromolar range and promoted adipocyte differentiation of 3T3-L1 preadipocytes. Further, the combination of DOSS and Span 80 increased 3T3-L1 adipocyte differentiation substantially more than treatment with either chemical individually, likely increasing the obesogenic potential of Corexit dispersants. From a public health standpoint, the use of DOSS and Span 80 as food additives heightens concerns regarding their use and mandates further investigations., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Staphylococcus aureus is a frequent cause of biofilm-related infections. Bacterial cells within a biofilm are protected from attack by the immune system and conventional antibiotics often fail to penetrate the biofilm matrix. The discovery of hamamelitannin as a potentiator for antibiotics, recently led to the design of a more drug-like lead. In the present study, we want to gain further insight into the structure-activity relationship (S.A.R.) of the 5-position of the molecule, by preparing a library of 21 hamamelitannin analogues., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The crude polysaccharide (KPV-0) isolated from Korean persimmon vinegar was fractionated using gel filtration chromatography to enhance the immunostimulatory activity and to identify the structural features of active fraction. Among three fractions, KPV-I obtained in a void volume, demonstrated the potent production of macrophage-stimulating mediators, including tumor necrosis factor-α, interleukin (IL)-6, IL-12, and nitric oxide. KPV-I showed a combined single peak with high molecular weight of 55,000Da by high performance size exclusion chromatography. Component sugar analysis revealed that KPV-I contained mainly of arabinose, mannose, galactose, rhamnose and galacturonic acid. Single radial gel diffusion assay using β-glucosyl Yariv reagent showed that KPV-I contained arabinogalactan protein with 13.7%. Methylation analysis indicated that KPV-I contained 21 kinds of neutral glycosidic linkages, which seemed to be composed three kinds of polysaccharide; that is a rhamnogalacturonan-I (65-70%) derived from persimmon as a raw material, a mannan (20-25%) derived from fermentation-associated microorganisms, and a linear glucans (less than 10%). In conclusion, polysaccharide isolated from persimmon vinegar could augment the macrophage stimulation, and a large amounts of RG-I polysaccharide derived from persimmon is likely a crucial role in expression of the activity in persimmon vinegar., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Sugar-sweetened beverage (SSB) consumption and low-grade chronic inflammation are both independently associated with type 2 diabetes and cardiovascular disease. Fructose, a major component of SSBs, may acutely trigger inflammation, which may be one link between SSB consumption and cardiometabolic disease., Objective: We sought to determine whether beverages sweetened with fructose, high-fructose corn syrup (HFCS), and glucose differentially influence systemic inflammation [fasting plasma C-reactive protein and interleukin-6 (IL-6) as primary endpoints] acutely and before major changes in body weight. Secondary endpoints included adipose tissue inflammation, intestinal permeability, and plasma fetuin-A as potential mechanistic links between fructose intake and low-grade inflammation., Design: We conducted a randomized, controlled, double-blind, crossover design dietary intervention (the Diet and Systemic Inflammation Study) in 24 normal-weight to obese adults without fructose malabsorption. Participants drank 4 servings/d of fructose-, glucose-, or HFCS-sweetened beverages accounting for 25% of estimated calorie requirements while consuming a standardized diet ad libitum for three 8-d periods., Results: Subjects consumed 116% of their estimated calorie requirement while drinking the beverages with no difference in total energy intake or body weight between groups as reported previously. Fasting plasma concentrations of C-reactive protein and IL-6 did not differ significantly at the end of the 3 diet periods. We did not detect a consistent differential effect of the diets on measures of adipose tissue inflammation except for adiponectin gene expression in adipose tissue (P = 0.005), which was lowest after the glucose phase. We also did not detect consistent evidence of a differential impact of these sugars on measures of intestinal permeability (lactulose:mannitol test, plasma zonulin, and plasma lipopolysaccharide-binding protein)., Conclusion: Excessive amounts of fructose, HFCS, and glucose from SSBs consumed over 8 d did not differentially affect low-grade chronic systemic inflammation in normal-weight to obese adults. This trial was registered at clinicaltrials.gov as NCT01424306., (© 2016 American Society for Nutrition.)

We compared the growth inhibitory effects of all aldohexose stereoisomers against the model animal Caenorhabditis elegans. Among the tested compounds, the rare sugars d-allose (d-All), d-talose (d-Tal), and l-idose (l-Ido) showed considerable growth inhibition under both monoxenic and axenic culture conditions. 6-Deoxy-d-All had no effect on growth, which suggests that C6-phosphorylation by hexokinase is essential for inhibition by d-All.

The modulation of bacterial communication to potentiate the effect of existing antimicrobial drugs is a promising alternative to the development of novel antibiotics. In the present study, we synthesized 58 analogues of hamamelitannin (HAM), a quorum sensing inhibitor and antimicrobial potentiator. These efforts resulted in the identification of an analogue that increases the susceptibility of Staphylococcus aureus towards antibiotics in vitro, in Caenorhabditis elegans, and in a mouse mammary gland infection model, without showing cytotoxicity., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Carbohydrate-based infusion solutions are widely used in the clinic. Here we show that co-administration of phosphorodiamidate morpholino oligomers (PMOs) with glucose enhances exon-skipping activity in Duchenne muscular dystrophy (DMD) mdx mice. We identify a glucose-fructose (GF) formulation that potentiates PMO activity, completely corrects aberrant Dmd transcripts, restores dystrophin levels in skeletal muscles and achieves functional rescue without detectable toxicity. This activity is attributed to enhancement of GF-mediated PMO uptake in the muscle. We demonstrate that PMO cellular uptake is energy dependent, and that ATP from GF metabolism contributes to enhanced cellular uptake of PMO in the muscle. Collectively, we show that GF potentiates PMO activity by replenishing cellular energy stores under energy-deficient conditions in mdx mice. Our findings provide mechanistic insight into hexose-mediated oligonucleotide delivery and have important implications for the development of DMD exon-skipping therapy.

Despite significant advances in the understanding of lung cancer biology, the prognosis of cancer patients remains poor. Part of the failure of anticancer therapy is due to intratumoral heterogeneity in these patients that limits the efficacy of single agents. Therefore, there is an urgent need for new anticancer drugs or drug combination regimens that possess increased activity against all cellular subtypes found within the tumor. In this study, we evaluated the in vitro antiproliferative activity of the cardiac glycosides (CGs) digitoxin and its synthetic analog MonoD on H460 lung cancer cells grown under different culture conditions. The CGs were tested alone in H460 cells under routine culture as well as in cells growing under short (24-72 h) and prolonged serum starvation (7 days) in order to evaluate the activity of drugs on cancer cells under varied degrees of proliferation. Our results showed that both CGs, and MonoD in particular, have potent antiproliferative activity at clinically relevant concentrations against cells in all the tested culture conditions. In contrast, paclitaxel, hydroxyurea and colchicine were only active in cells growing in routine culture conditions, and relatively inactive in serum-starved conditions. Importantly, both CGs were able to potentiate the effect of clinically relevant concentrations of hydroxyurea or paclitaxel in serum-starved conditions. When paclitaxel was used in combination with CGs, the highest antiproliferative effect was obtained when paclitaxel was administered first, followed by either digitoxin or MonoD. Our results indicate that CGs have potential clinical applications in translational oncology especially in combination with other drugs, and warrants further investigation of CGs in more advanced preclinical models of lung cancer.

Treatment of Staphylococcus aureus infections has become increasingly challenging due to the rapid emergence and dissemination of methicillin-resistant strains. In addition, S. aureus reside within biofilms at the site of infection. Few novel antibacterial agents have been developed in recent years and their bacteriostatic or bactericidal activity results in selective pressure, inevitably inducing antimicrobial resistance. Consequently, innovative antimicrobials with other modes of action are urgently needed. One alternative approach is targeting the bacterial quorum sensing (QS) system. Hamamelitannin (2',5-di-O-galloyl-d-hamamelose; HAM) was previously suggested to block QS through the TraP QS system and was shown to increase S. aureus biofilm susceptibility towards vancomycin (VAN) although mechanistic insights are still lacking. In the present study we provide evidence that HAM specifically affects S. aureus biofilm susceptibility through the TraP receptor by affecting cell wall synthesis and extracellular DNA release of S. aureus. We further provide evidence that HAM can increase the susceptibility of S. aureus biofilms towards different classes of antibiotics in vitro. Finally, we show that HAM increases the susceptibility of S. aureus to antibiotic treatment in in vivo Caenorhabditis elegans and mouse mammary gland infection models.

There is evidence that many plant secondary metabolites may act as signal molecules to trigger the bacterial ability to metabolize polychlorinated biphenyls (PCBs) during the rhizoremediation process. However, the bases for the PCB rhizoremediation process are still largely unknown. The rhizobacterium Rhodococcus erythropolis U23A is unable to use flavanone as a growth substrate. However, on the basis of an assay that monitors the amount of 4-chlorobenzoate produced from 4-chlorobiphenyl by cells grown co-metabolically on flavanone plus sodium acetate, this flavonoid was previously found to be a potential inducer of the U23A biphenyl catabolic pathway. In this work, and using the same assay, we identified ten other flavonoids that did not support growth, but that acted as inducers of the U23A biphenyl pathway, and we confirmed flavonoid induction of the biphenyl catabolic pathway using quantitative real-time polymerase chain reaction (RT-qPCR) on the bphA gene. We also examined the effect of the growth co-substrate on flavonoid induction. Sodium acetate was replaced by glucose, mannose, sucrose, or mannitol, which are sugars found in plant root exudates. The data showed that the level of induction of strain U23A biphenyl-degrading enzymes was significantly influenced by the nature and concentration of the flavonoid in the growth medium, as well as by the substrate used for growth. Sucrose allowed for an optimal induction response for most flavonoids. Some flavonoids, such as flavone and isoflavone, were better inducers of the biphenyl catabolic enzymes than biphenyl itself. We also found that all flavonoids tested in this work were metabolized by strain U23A during co-metabolic growth, but that the metabolite profiles, as well as the level of efficiency of degradation, differed for each flavonoid. To obtain insight into how flavonoids interact with strain U23A to promote polychlorinated biphenyl (PCB) degradation, we determined the concentration of flavanone at which optimal PCB-degrading performance of strain U23A was achieved. We showed that it corresponded to the concentration required to fully induce the biphenyl catabolic pathway of the strain. Together, our data demonstrate that optimal PCB degradation during the rhizoremediation process will require the adjustment of several parameters, including the presence of the appropriate flavonoids at the proper concentrations and the presence of proper growth substrates that positively influence the ability of flavonoids to induce the pathway.

Introduction: Early detection and/or prediction of metastasis provide more prognostic relevance than local recurrence. Direct spread into the peritoneum is frequently found in pancreatic cancer patients, but positron emission tomography (PET) with 2-deoxy-2-fluoro-d-glucose (FDG) is not useful for identifying such metastasis. We investigated a method to enhance FDG accumulation using AsPC-1 human ascites tumor cells., Methods: (14)C-FDG accumulation was assessed under the following conditions: 1) characteristics of (14)C-FDG transport were examined using phloridzin, a Na(+)-free buffer, and various hexoses, and 2) accumulation of (14)C-FDG was measured in cells that were pretreated with hexose for various time periods, and activity of 6-phosphofructo-1-kinase (PFK-1) was assayed., Results: (14)C-FDG transport into AsPC-1 cells was mediated primarily by a Na(+)-independent transport mechanism. Aldohexoses such as d-glucose, D-mannose, and D-galactose inhibited (14)C-FDG transport. Cells pretreated with d-glucose, D-mannose, or D-fructose exhibited augmented (14)C-FDG accumulation. Pretreatment with higher concentrations of D-glucose or D-fructose tended to increase PFK-1 activity., Conclusions: Very little information has been published about the association between PFK-1 and FDG accumulation, and we confirmed the impacts of various hexoses on the activity of PFK-1 and FDG accumulation in AsPC-1 cells. Clarifying the relevance of PFK-1 in FDG accumulation will contribute to developing new features of FDG-PET, because PFK-1 is the main regulator of glycolysis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The current study explains the development of sorbitan monostearate and sesame oil-based organogels for topical drug delivery. The organogels were prepared by dissolving sorbitan monostearate in sesame oil (70°C). Metronidazole was used as a model antimicrobial. The formulations were characterized using phase contrast microscopy, infrared spectroscopy, viscosity, mechanical test, and differential scanning calorimetry. Phase contrast microscopy showed the presence of needle-shaped crystals in the organogel matrix. The length of the crystals increased with the increase in the sorbitan monostearate concentration. XRD studies confirmed the amorphous nature of the organogels. Viscosity study demonstrated shear thinning behavior of the organogels. The viscosity and the mechanical properties of the organogels increased linearly with the increase in the sorbitan monostearate concentration. Stress relaxation study confirmed the viscoelastic nature of the organogels. The organogels were biocompatible. Metronidazole-loaded organogels were examined for their controlled release applications. The release of the drug followed zero-order release kinetics. The drug-loaded organogels showed almost similar antimicrobial activity against Escherichia coli when compared to the commercially available Metrogyl® gel. In gist, it can be proposed that the developed organogels had sufficient properties to be used for controlled delivery of drugs.

We examined and compared the inhibitory effects of D-tagatose on the growth, acid production, and water-insoluble glucan synthesis of GS5, a bacterial strain of Streptococcus mutans, with those of xylitol, D-psicose, L-psicose and L-tagatose. GS5 was cultured for 12h in a medium containing 10% (w/v) of xylitol, D-psicose, L-psicose, D-tagatose or L-tagatose, and the inhibitory effect of GS5 growth was assessed. Each sugar showed different inhibitory effects on GS5. Both D-tagatose and xylitol significantly inhibited the acid production and water-insoluble glucan synthesis of GS5 in the presence of 1% (w/v) sucrose. However, the inhibitory effect of acid production by D-tagatose was significantly stronger than that of xylitol in presence of sucrose.

Background: The aim of this study was to develop and characterize a babassu oil microemulsion system and determine the effect of this microemulsion on the functional activity of phagocytes., Methods: The microemulsion was formulated using distilled water, babassu as the oil phase component, Sorbitan monooleate-Span 80(®) (SP), Polysorbate 80-Tween 80(®) (TW), and 1-butanol (BT). Pseudoternary diagrams were prepared, and microemulsion diagram regions were preselected. Rheological characterization and preliminary and accelerated stability tests were performed. The effect of the microemulsion on the interactions between leukocytes and bacteria was determined by superoxide release, phagocytosis, and microbicidal activity., Results: The developed formulation SP/TW/BT (4.2/4.8/1.0) was classified as oil/water, showed a Newtonian profile, and had linear viscosity. When we assessed the interaction of the microemulsion or babassu oil with phagocytes, we observed an increase in superoxide, phagocytosis, and microbicidal activity., Conclusion: The babassu oil microemulsion system is an option for future applications, including for vaccine delivery systems. Babassu oil is a natural product, so is an alternative for future immunotherapy strategies, in particular for infectious diseases.

In an attempt to develop D-sorbose as a new sweetener that could help in preventing lifestyle-related diseases, we investigated the inhibitory effect of D-sorbose on disaccharidase activity, using the brush border membrane vesicles of rat small intestines. The inhibitory effect was compared with that of L-sorbose and other rare sugars, and the small intestinal disaccharidases in rats was compared with that of humans as well. In humans and the small intestines of rats, d-sorbose strongly inhibited sucrase activity and weakly inhibited maltase activity. Inhibition by D-sorbose of sucrase activity was similar to that of L-arabinose, and the K(i) of D-sorbose was 7.5 mM. Inhibition by D-sorbose was very strong in comparison with that of L-sorbose (K(i), 60.8 mM), whereas inhibition of d-tagatose was between that of D-sorbose and L-sorbose. The inhibitory mode of D-sorbose for sucrose and maltase was uncompetitive, and that of L-sorbose was competitive. To determine a suppressive effect on postprandial blood levels of glucose and insulin via inhibition of sucrase activity, sucrose solution with or without D-sorbose was administered to rats. Increments in the blood levels of glucose and insulin were suppressed significantly after administration of sucrose solution with D-sorbose to rats, in comparison to administration of sucrose solution without D-sorbose. In contrast, the suppressive effect of L-sorbose on postprandial blood levels of glucose and insulin was very weak. These results suggest that D-sorbose may have an inhibitory effect on disaccharidase activity and could be used as a sweetener to suppress the postprandial elevation of blood levels of glucose and insulin. The use of D-sorbose as a sweetener may contribute to the prevention of lifestyle-related diseases, such as type 2 diabetes mellitus., (Copyright © 2014 Elsevier Inc. All rights reserved.)