Whiskey Congeners Suppress LPS/IFNγ-Induced NO Production in Murine Macrophage RAW 264 Cells by Inducing Heme Oxygenase‑1 Expression

Whiskey includes many nonvolatile substances (whiskey congeners; Whc) that seep from the oak cask during the maturation process. To date, many functions of Whc have reported, such as antiallergy and antimelanogenesis. This study examined the effect of Whc on LPS/IFNγ-induced nitric oxide (NO) production in murine macrophage RAW 264 cells. Whc suppressed LPS/IFNγ-induced NO production in a concentration-dependent manner. To determine the active compounds in Whc, the effect of 10 major compounds isolated from Whc on LPS/IFNγ-induced NO production was examined. Coniferylaldehyde (CA) and sinapylaldehyde (SiA) strongly suppressed LPS/IFNγ-induced NO production. Pretreatment with Whc, CA, and SiA induced heme oxygenase-1 (HO-1) expression. The expression of HO-1 by Whc, CA, and SiA pretreatment was due to activation of Nrf2/ARE signaling via the elevation of intracellular reactive oxygen species. To investigate the in vivo effects of Whc, Whc was administered to mice with antitype II collagen antibody-induced arthritis, and we the arthritis score and hind paw volume were measured. Administration of Whc remarkably suppressed the arthritis score and hind paw volume. Taken together, these findings suggest that Whc is beneficial for the treatment of inflammatory disease

Prognostic significance for survival of the immunohistochemistry profile and other parameters by Cox univariate and multivariate analyses.

<p>HR, hazard ratio; CI, confidence interval; PS, performance status.</p

Overall survival curve by the Kaplan-Meier method for the groups with each primary site as classified by the immunohistochemistry profiles.

<p>Overall survival curve by the Kaplan-Meier method for the groups with each primary site as classified by the immunohistochemistry profiles.</p

Progression-free survival curve by the Kaplan-Meier method for the groups with each primary site as classified by the immunohistochemistry profiles.

<p>Progression-free survival curve by the Kaplan-Meier method for the groups with each primary site as classified by the immunohistochemistry profiles.</p

An adenocarcinoma showing typical presentation of the breast profile by immunohistochemistry.

<p>Hematoxylin-eosin stain (left upper), cytokeratin (CK)7 (right upper), CK20 (left lower), and mammaglobin (right lower). CK7 and mammaglobin are positive in the cytoplasm of tumor cells (original magnification ×200).</p

Primary tumor site of unfavorable subsets of adenocarcinoma of unknown primary determined by a immunohistochemistry profile of 15 markers and the relationship to response rate to platinum doublet regimens.

<p>Primary tumor site of unfavorable subsets of adenocarcinoma of unknown primary determined by a immunohistochemistry profile of 15 markers and the relationship to response rate to platinum doublet regimens.</p

Prognostic significance for progression-free survival of the immunohistochemistry profile and other parameters by Cox univariate and multivariate analyses.

<p>HR, hazard ratio; CI, confidence interval; PS, performance status.</p

Patient characteristics at diagnosis.

<p>FOLFOX: 5FU, oxaliplatin, and <i>l</i>-leukovorin.</p

Identification of the primary tumor site by immunohistochemistry and gene analysis.

<p>Thirteen patients were not sorted to specific profiles and an additional 8 patients were not classified into the profiles in the manner defined by the algorithm. Two patients presenting with both CK7− and CK20-positive were classified into an unclassified profile. Ten patients with CK7-positive and CK20-negative were classified into an unclassified profile. Three patients with CK7-positive and CK20-negative were classified into the digestive (<i>n</i> = 1) and urothelial (<i>n</i> = 2) profiles. One patient with both CK7− and CK20-negative was classified into the unclassified profile. Four patients with both CK7− and CK20-negative were classified into the digestive (<i>n</i> = 3) and lung (<i>n</i> = 1) profiles. Footnote: * Estrogen receptor- or progesterone receptor-positive with CK19-positive.</p

Information provided in advertisements for trial registration by year.

<p>Information provided in advertisements for trial registration by year.</p