Several studies have suggested that flavan-3-ols/procyanidins are associated with a reduced risk of developing obesity and metabolic syndrome. However, the role of highly polymeric procyanidins (PP), which are major non-absorbable flavonoids, in the biological effects, is not completely understood. Here, we show that 0.5% PP administration for 20 weeks alleviated obesity and regulate expression of genes related to lipid metabolism in C57BL/6J mice fed a high-fat/high-sucrose diet. PP-treatment attenuated weight gain and inflammatory effects including lipopolysaccharide and gut permeability. Additionally, metabolic urine profiling using high-performance liquid chromatography–quadrupole time-of-flight/mass spectrometry demonstrated that PP-treatment decreased the levels of endogenous metabolites associated with insulin resistance. Furthermore, microbial 16S rRNA gene sequencing of the cecum demonstrated that PP administration markedly decreased the Firmicutes/Bacteroidetes ratio and increased eight times the proportion of Akkermansia. These data suggest that PPs influence the gut microbiota and the intestinal metabolome to produce beneficial effects on metabolic homeostasis.

Various epidemiologic and experimental in vivo and in vitro studies have suggested that polyphenols derived from fruits, vegetables and beverages might decrease the risk of developing lifestyle diseases, such as cardiovascular disorders and cancer. Apples are a major dietary source of polyphenols. Here we investigated the antitumor activity of apple polyphenols (APs) and procyanidins, namely condensed tannins, both in vitro and in vivo studies. APs and procyanidins inhibited the growth of transplanted B16 mouse melanoma cells and BALB-MC.E12 mouse mammary tumor cells, and increased the survival rate of the host mice-transplanted B16 cells. Among the APs, the apple procyanidins specifically, rather than other polyphenols such as chlorogenic acid, (-)-epicatechin, phloridzin and procyanidin B2, had a major effect on cell proliferation and induced apoptosis in vitro. The apple procyanidins increased mitochondrial membrane permeability and cytochrome c release from mitochondria and activated caspase-3 and caspase-9 within the tumor cells. In addition, we separated eight procyanidin fractions according to the degree of polymerization using normal-phase chromatography, and detected strong anti-tumor activity in the procyanidin pentamer and higher degree fractions. Our results indicate that the oral administration of apple procyanidins inhibits the proliferation of tumor cells by inducing apoptosis through the intrinsic mitochondrial pathway.

Our previous study showed that gamma interferon (IFN-␥), a T-helper 1 (Th1)-type cytokine, plays a detrimental role in

Exosome-like vesicles (ELV) are involved in mediating radiation-induced bystander effect (RIBE). Here, we used ELV from control cell conditioned medium (CCCM) and from 4 Gy of X-ray irradiated cell conditioned medium (ICCM), which has been used to culture normal human fibroblast cells to examine the possibility of ELV mediating RIBE signals. We investigated whether ELV from 4 Gy irradiated mouse serum mediate RIBE signals. Induction of DNA damage was observed in cells that were treated with ICCM ELV and ELV from 4 Gy irradiated mouse serum. In addition, we treated CCCM ELV and ICCM ELV with RNases, DNases, and proteinases to determine which component of ELV is responsible for RIBE. Induction of DNA damage by ICCM ELV was not observed after treatment with DNases. After treatment, DNA damages were not induced in CCCM ELV or ICCM ELV from mitochondria depleted (ρ0) normal human fibroblast cells. Further, we found significant increase in mitochondrial DNA (mtDNA) in ICCM ELV and ELV from 4 Gy irradiated mouse serum. ELV carrying amplified mtDNA (ND1, ND5) induced DNA damage in treated cells. These data suggest that the secretion of mtDNA through exosomes is involved in mediating RIBE signals.

The production and roles of endogenous interleukin-4 (IL-4) and IL-10 in a sublethal infection with Listeria monocytogenes were studied in normal mice and anti-gamma interferon (IFN-␥) monoclonal antibody (MAb)pretreated mice. In normal mice, the expression of mRNAs for IL-4 and IL-10, which was amplified by reverse transcription-PCR, was induced in the spleens and livers either early or late in infection, although the serum IL-4 and IL-10 were not detectable by enzyme-linked immunosorbent assays. In vivo administration of anti-IL-4 MAb showed no effect on antilisterial resistance, whereas anti-IL-10 MAb partially diminished the defense. In anti-IFN-␥ MAb-pretreated mice, a delay in the bacterial elimination from the spleens and livers was observed and high titers of serum IL-4 and IL-10 were induced late in infection. Production of endogenous IL-4 and IL-10 was suppressed in both CD4 ؉ cell-and CD8 ؉ cell-depleted mice. The suppression of antilisterial resistance in anti-IFN-␥ MAb-pretreated mice was canceled when anti-IL-4 MAb was injected late in infection, whereas anti-IL-10 MAb showed no effect. These results suggest that the host immune responses were polarized into the T-helper 2 phenotype in anti-IFN-␥ MAb-pretreated mice and that inhibition of host resistance against L. monocytogenes by depletion of IFN-␥ might be attributable to IL-4 produced by T cells polarized into the T-helper 2 phenotype as well as the inhibition of the IFN-␥ effects.