[Inhibition of TRPV2 Channel Activation by NK-4, a Cryptocyanine Dye].

Transient receptor potential vanilloid 2 (TRPV2) channels are expressed and play functional roles in various immune cells. Physical stimuli leading to TRPV2 activation causes mast cell degranulation. Besides their roles in immune cells, it has been shown that TRPV2 channels are pathophysiologically relevant to degenerative muscular diseases such as dilated cardiomyopathy and muscular dystrophy.

Ingredients such as trehalose and hesperidin taken as supplements or foods reverse alterations in human T cells, reducing asbestos exposure-induced antitumor immunity.

Exposure of human immune cells to asbestos causes a reduction in antitumor immunity. The present study aimed to investigate the recovery of reduced antitumor immunity by several ingredients taken as supplements or foods, including trehalose (Treh) and glycosylated hesperidin (gHesp). Peripheral blood CD4 cells were stimulated with IL‑2, anti‑CD3 and anti‑CD28 antibodies for 3 days, followed by further stimulation with IL‑2 for 7 days.

Inflammatory M1-like macrophages polarized by NK-4 undergo enhanced phenotypic switching to an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells.

Background: NK-4 has been used to promote wound healing since the early-1950s; however, the mechanism of action of NK-4 is unknown. In this study, we examined whether NK-4 exerts a regulatory effect on macrophages, which play multiple roles during wound healing from the initial inflammatory phase until the tissue regeneration phase.

Results: NK-4 treatment of THP-1 macrophages induced morphological features characteristic of classically-activated M1 macrophages, an inflammatory cytokine profile, and increased expression of the M1 macrophage-associated molecules CD38 and CD86.

Trehalose alleviates oxidative stress-mediated liver injury and Mallor-Denk body formation via activating autophagy in mice.

Autophagy is a degradation pathway for long-lived cytoplasmic proteins or damaged organelles and also for many aggregate-prone and disease-causing proteins. Endoplasmic reticulum (ER) stress and oxidative stress are associated with the pathophysiology of various liver diseases. These stresses induce the accumulation of abnormal proteins, Mallory-Denk body (MDB) formation and apoptosis in hepatocytes.

Trehalose itself plays a critical role on lipid metabolism: Trehalose increases jejunum cytoplasmic lipid droplets which negatively correlated with mesenteric adipocyte size in both HFD-fed trehalase KO and WT mice.

Background: Trehalose is a functional disaccharide that has anti-metabolic activities such as suppression of adipocyte hypertrophy in mice and alleviation of impaired glucose tolerance in humans. Trehalase hydrolyzes trehalose in the small intestine into two glucose molecules. In this study, we investigated whether trehalose can suppress adipocyte hypertrophy in mice in the presence or absence of trehalase.

Continuous intake of Trehalose induces white adipose tissue Browning and Enhances energy metabolism.

Background: Trehalose is well known as a functional disaccharide with anti-metabolic activities such as suppression of adipocyte hypertrophy in mice and alleviation of impaired glucose tolerance in humans. Recently, a new type of adipocyte beige cells, involved in so-called white adipocyte tissue (WAT) browning, has received much attention as a target for adaptive thermogenesis. To clarify the relationship between adipocyte hypertrophy suppression and beige cells involved in thermogenesis, we examined the effect of trehalose on the changes in beige adipocytes in mice under normal dietary conditions.

Adenosine N1-Oxide Exerts Anti-inflammatory Effects through the PI3K/Akt/GSK-3β Signaling Pathway and Promotes Osteogenic and Adipocyte Differentiation.

Previously, we reported that adenosine N1-oxide (ANO), which is found in royal jelly, inhibited the secretion of inflammatory mediators by activated macrophages and reduced lethality in lipopolysaccharide (LPS)-induced endotoxin shock. Here, we examined the regulatory mechanisms of ANO on the release of pro-inflammatory cytokines, with a focus on the signaling pathways activated by toll-like receptor (TLR)4 in response to LPS. ANO inhibited both tumor necrosis factor (TNF)-α and interleukin (IL)-6 secretion from LPS-stimulated RAW264.

NK-4 exerts selective regulatory effects on the activation and function of allergy-related Th2 cells.

NK-4 is the main component of the antiallergic drug Lumin, which has been in popular usage since the early 1950s. In this study, we examined whether NK-4 exerts a regulatory effect on the activation and effector function of Th2 cells. NK-4 inhibited IL-4 production by anti-CD3ε mAb-stimulated BALB/c mouse spleen cells, whereas NK-4 had little effect on IFN-γ production.

Daily Intake of Trehalose Is Effective in the Prevention of Lifestyle-Related Diseases in Individuals with Risk Factors for Metabolic Syndrome.

We previously performed animal studies that suggested that trehalose potentially prevents the development of metabolic syndrome in humans. To evaluate this possibility, we examined whether trehalose suppressed the progression of insulin resistance in a placebo-controlled, double-blind trial in 34 subjects with a body mass index (BMI) ≥23. The subjects were divided into two groups and were assigned to ingest either 10 g/d of trehalose or sucrose with meals for 12 wk.

Glycemic, insulinemic and incretin responses after oral trehalose ingestion in healthy subjects.

Background: Trehalose is hydrolyzed by a specific intestinal brush-border disaccharidase (trehalase) into two glucose molecules. In animal studies, trehalose has been shown to prevent adipocyte hypertrophy and mitigate insulin resistance in mice fed a high-fat diet. Recently, we found that trehalose improved glucose tolerance in human subjects.

Cholesteryl Pullulan Encapsulated TNF-α Nanoparticles Are an Effective Mucosal Vaccine Adjuvant against Influenza Virus.

We encapsulated tumor necrosis factor-α (TNF-α), a major proinflammatory cytokine, into cholesteryl pullulan (CHP) to prepare TNF/CHP nanoparticles. In this report, we describe the immune-enhancing capability of the nanoparticles to act as a vaccine adjuvant. TNF/CHP nanoparticles showed excellent storage stability and enhanced host immune responses to external immunogens.

Suppressive effects of a cyanine dye against herpes simplex virus (HSV)-1 infection.

In this study, we demonstrate that a cyanine dye, lumin, significantly suppressed cytopathic effect by herpes simplex virus (HSV)-1 toward human amnionic FL cell and also it reduced replication of HSV-1 in a dose-dependent manner. In addition, lumin additively augmented the antiviral effect of interferon (IFN)-alpha. Furthermore, fluorescence microscopic study showed that lumin (not IFN-alpha) itself remarkably induced alkalinization of intracellular organelle, suggesting the inhibition of virus invasion into the cells.

Creation of interferon-alpha8 mutants with amino acid substitutions against interferon-alpha receptor-2 binding sites using phage display system and evaluation of their biologic properties.

In this study, we describe the creation of three interferon-alpha (IFN-alpha)8 mutants with markedly higher antiviral and antiproliferative activities in comparison with those of the wild-type (wt)IFN-alpha8, wtIFN-alpha2, and IFN-con1 using a phage display system. Sequence analysis showed that three out of the six hot-spot amino acid residues of wtIFN-alpha8 known to be important for the interaction with the IFN-alpha receptor-2 (IFNAR-2)-binding sites were substituted to other amino acids and the others remained. Although affinity analysis revealed that the dissociation constant (K(D)) of IFN-alpha8 mutants was almost the same with that of wtIFN-alpha8, furthermore, the rates of association (k(a)) and dissociation (k(d)) were relatively lower.

Establishment of antihuman IFN-alpha8-specific monoclonal antibodies and their application in the enzyme-linked immunosorbent assay (ELISA).

In the present study, we describe the generation of a series of anti-interferon-alpha8 (IFN-alpha8)-specific monoclonal antibodies (mAbs), their characterization, and the establishment of a sandwich enzyme-linked immunosorbent assay (ELISA) system for human IFN-alpha8. The sandwich ELISA system is highly sensitive to human natural IFN-alpha8 (nIFN-alpha8), with a minimum detection limit of 50 pg/mL, which did not cross-react with the other IFN preparations and several cytokines tested. Using this ELISA system, pharmacokinetic properties of an IFN-alpha preparation administered in mice were examined.

The combination of IFN-alpha2 and IFN-alpha8 exhibits synergistic antiproliferative activity on renal cell carcinoma (RCC) cell lines through increased binding affinity for IFNAR-2.

Although there are at least 13 interferon-alpha (IFN-alpha) subtypes in humans, interactions between the subtypes remain unknown. To understand IFN-alpha interactions, we examined the antiproliferative activities and the receptor binding affinities of different combinations of IFN-alpha2 and IFN-alpha8 using six renal cell carcinoma (RCC) cell lines. Although IFN-alpha8 was the more potent subtype, synergistic and antagonistic antiproliferative effects were also observed in certain combinations of IFN-alpha2 and IFN-alpha8.

Regulation of Candida albicans morphogenesis by tumor necrosis factor-alpha and potential for treatment of oral candidiasis.

Background: Endogenous tumor necrosis factor-alpha (TNF-alpha) has a beneficial effect as an activation mediator of host defense against infection by the fungus Candida albicans (C. albicans). However, it is unclear whether exogenous TNF-alpha has a beneficial or detrimental effect against Candida.

Role of p53 in the inhibitory effects of interferon-alpha subtypes on proliferation of hepatocellular carcinoma cells.

While interferon-alpha (IFN-alpha) subtypes share a common specific receptor composed of two subunits, interferon-alpha receptor (IFNAR)-1 and IFNAR-2, their subtype activities are exhibited via several intracellular signaling pathways and thus subsequently show different biological effects. Anti-proliferative effects of single treatment with IFN-alpha subtypes or 5-fluorouracil (FU), and of combined treatment with each IFN-alpha subtype and 5-FU were examined on three hepatocellular carcinoma cell lines, HepG2, HLE and PLC/PRF/5. HepG2 and PLC/PRF/5 cells were susceptible to the combination treatment, but HLE cells were not.

Effects of interferon-alpha subtypes on the TH1/TH2 balance in peripheral blood mononuclear cells from patients with hepatitis virus infection-associated liver disorders.

Interferon-alpha (IFN-alpha) has recently been shown to modulate in vitro T helper (Th) 1-driven responses in the peripheral blood mononuclear cells (PBMC) of patients with hepatitis B virus or C virus infection. In this study, we examined the in vitro effects of IFN-alpha subtypes (IFN-alpha1, -alpha2, -alpha5, -alpha8, and -alpha10) on the Th1/Th2 balance in PBMC obtained from patients with hepatitis virus infection-associated liver disorders and chronic hepatitis (CH), in comparison with the effect on healthy control volunteer PBMC. The Th1-type cell percentages and Th1/Th2 ratios were significantly higher in the PBMC of patients when compared with controls both before and after cultivation in vitro, with the IFN-alpha subtypes.

Correlation Between Interferon Alpha Receptor Protein Expression and Sensitivity to Interferon Alpha Subtypes in Human Renal Carcinoma Cell Lines.

Background: We have previously characterized the antitumor activities and immunological properties of interferon-alpha (IFN-α) subtypes on renal cell carcinoma (RCC). However, the mechanism responsible for the different biologic activities among the IFN-α subtypes is still unclear. To explain the different cellular sensitivities to IFN-α subtypes, detailed expression of the interferon-alpha receptor (IFNAR)-1 and IFNAR-2 subunits on different RCC cell lines was examined and compared with sensitivity of the cell lines to the IFN-α subtypes.

Taste receptor T1R3 is an essential molecule for the cellular recognition of the disaccharide trehalose.

Recently, a sweet taste receptor family, the T1R family, that recognizes some carbohydrates including sucrose was identified. Although the T1R3 molecule is known to participate in heterodimers that are used as sweet- and umami-tasting receptors, there is no evidence that T1R3 alone recognizes similar ligands. We demonstrate for the first time that the candidate sweet taste receptor T1R3 is essential for the recognition and response to the disaccharide trehalose.

Trehalose augments osteoprotegerin production in the FHs74Int human intestinal epithelial cell line.

The disaccharide trehalose has been shown to inhibit both bone loss in ovariectomized mice and excessive osteoclastogenesis in lipopolysaccharide-injected mice. However, the mechanism of osteoclastogenesis inhibition by oral administration of trehalose is still unclear. We report here for the first time that a human intestinal epithelial cell line, FHs74Int, also produces osteoprotegerin (OPG) and that trehalose augments OPG production by this cell line.