D-galactose Intake Alleviates Atopic Dermatitis in Mice by Modulating Intestinal Microbiota.

Atopic dermatitis (AD) is one of the most prevalent, chronic and persistent inflammatory skin diseases closely associated with intestinal microbiota. To evaluate the effect of D-galactose intake on AD, we orally administered D-galactose to BALB/c mice whose ears and skin were treated with 2,4-dinitrochlorobenzene (DNCB). D-galactose alleviated DNCB-induced AD-like phenotypes such as redness, scaling/dryness and excoriation. Ear thickness was also decreased by D-galactose administration. Histopathological analysis revealed decreased epidermal thickening, infiltration of immune cells, especially mast cells, in the dermis. Total levels of serum IgE representing the immunological response of AD were decreased by D-galactose administration. Microbiota analysis showed that D-galactose administration restored gut microbiota profiles, which were altered in AD mice, characterized by increased abundance of Bacteroidetes and decreased abundance of Firmicutes. The increased abundance of Bacteroides and the decreased abundance of Prevotella and Ruminococcus were reversed by D-galactose treatment, following improvement of AD. Our results suggest the possible use of D-galactose as a prebiotic to alleviate AD by altering gut microbiota.

Use of d-galactose to regulate biofilm growth of oral streptococci.

In the oral microbial community, commensals can compete with pathogens and reduce their colonization in the oral cavity. A substance that can inhibit harmful bacteria and enrich beneficial bacteria is required to maintain oral health. The purpose of this study was to examine the effect of d-galactose on the biofilm formation of the cariogenic bacteria Streptococcus mutans and oral commensal streptococci and to evaluate their use in solution and in paste form. Biofilms of S. mutans, Streptococcus oralis, and Streptococcus mitis were formed on saliva-coated glass slips in the absence or presence of d-galactose and evaluated by staining with 1 % crystal violet. d-Galactose significantly inhibited the biofilm formation of S. mutans at concentrations ranging from 2 µM to 200 mM but increased the biofilm formation of S. oralis and S. mitis at concentrations of 2-200 mM. d-Galactose significantly inhibited three glucosyltransferase genes, gtfB, gtfC, and gtfD. The effect of d-galactose in the form of solution and paste was evaluated using bovine teeth. Pretreatment with 100 mM d-galactose on bovine teeth resulted in significantly reduced S. mutans biofilm formation. Our results suggest that d-galactose can be a candidate substance for the development of oral hygiene products to prevent caries by inhibiting the biofilm formation of S. mutans and simultaneously increasing the biofilm formation of commensal oral streptococci.

New bicyclic brominated furanones as potent autoinducer-2 quorum-sensing inhibitors against bacterial biofilm formation.

Bacterial behaviors such as virulence factor secretion and biofilm formation are critical for survival, and are effectively regulated through quorum sensing, a mechanism of intra- and interspecies communication in response to changes in cell density and species complexity. Many bacterial species colonize host tissues and form a defensive structure called a biofilm, which can be the basis of inflammatory diseases. Periodontitis, a chronic inflammatory disease affecting the periodontium, is caused by subgingival biofilms related to periodontopathogens. In particular, Fusobacterium nucleatum is a major co-aggregation bridge organism in the formation and growth of subgingival biofilms, linking the early and late colonizers in periodontal biofilms. According to our previous study, the intergeneric quorum-sensing signal molecule autoinducer-2 (AI-2) of F. nucleatum plays a key role in intra- and interspecies interactions of periodontopathogens, and may be a good target for periodontal biofilm inhibition. Recently, brominated furanones produced by the macroalga Delisea pulchra were shown to inhibit biofilm formation via AI-2, and have been investigated toward the goal of increasing the inhibition effect. In this study, we describe the synthesis of new bromofuranone analogs, i.e., 3-(dibromomethylene)isobenzofuran-1(3H)-one derivatives, and demonstrate their inhibitory activities against biofilm formation by periodontopathogens, including F. nucleatum, Porphyromonas gingivalis, and Tannerella forsythia.

D-Galactose as an autoinducer 2 inhibitor to control the biofilm formation of periodontopathogens.

Autoinducer 2 (AI-2) is a quorum sensing molecule to which bacteria respond to regulate various phenotypes, including virulence and biofilm formation. AI-2 plays an important role in the formation of a subgingival biofilm composed mostly of Gram-negative anaerobes, by which periodontitis is initiated. The aim of this study was to evaluate D-galactose as an inhibitor of AI-2 activity and thus of the biofilm formation of periodontopathogens. In a search for an AI-2 receptor of Fusobacterium nucleatum, D-galactose binding protein (Gbp, Gene ID FN1165) showed high sequence similarity with the ribose binding protein (RbsB), a known AI-2 receptor of Aggregatibacter actinomycetemcomitans. D-Galactose was evaluated for its inhibitory effect on the AI-2 activity of Vibrio harveyi BB152 and F. nucleatum, the major coaggregation bridge organism, which connects early colonizing commensals and late pathogenic colonizers in dental biofilms. The inhibitory effect of D-galactose on the biofilm formation of periodontopathogens was assessed by crystal violet staining and confocal laser scanning microscopy in the absence or presence of AI-2 and secreted molecules of F. nucleatum. D-Galactose significantly inhibited the AI-2 activity of V. harveyi and F. nucleatum. In addition, D-galactose markedly inhibited the biofilm formation of F. nucleatum, Porphyromonas gingivalis, and Tannerella forsythia induced by the AI-2 of F. nucleatum without affecting bacterial growth. Our results demonstrate that the Gbp may function as an AI-2 receptor and that galactose may be used for prevention of the biofilm formation of periodontopathogens by targeting AI-2 activity.

Discovery of biological evaluation of pyrazole/imidazole amides as mGlu5 receptor negative allosteric modulators.

Development of SAR in a 5-aryl-3-acylpyridinyl-pyrazoles and 1-aryl-4-acylpyridinyl imidazoles series of mGlu5 receptor negative allosteric modulators (mGluR5 NAMs) using a functional cell-based assay is described in this Letter. Analysis of the Ligand-lipophilic efficiency (LipE) of compounds provided new insight for the design of potent mGluR5 negative allosteric modulators with anti-depressant activities.

Synthesis and pharmacological evaluation of 3-aryl-3-azolylpropan-1-amines as selective triple serotonin/norepinephrine/dopamine reuptake inhibitors.

A series of 3-aryl-3-azolylpropan-1-amines was prepared and screened for its capability of inhibiting monoamine reuptake. Analogs with nanomolar potency, good human in vitro microsomal stability, and low drug-drug interaction potential were described. In vivo models were used to evaluate the compound 19r for antidepressive, anxiolytic, and analgesic activity.