Chemical Composition of Volatile Extracts from Black Raspberries, Blueberries, and Blackberries and Their Antiproliferative Effect on A549 Non-Small-Cell Lung Cancer Cells.

Berry volatiles are responsible for the berry aroma but there is limited information available on the health-promoting activities of berry volatiles. The objectives of this study were to evaluate the chemical composition of volatile extracts from black raspberries, blueberries, and blackberries and investigate their antiproliferative effect and apoptotic mechanisms on A549 lung cancer cells. The chemical composition of three berry volatile extracts (BVEs) was identified by using gas chromatography-mass spectrometry. Cells were treated with different dilutions of three BVEs for 48 h and determined for cell proliferation and apoptosis. Total volatiles in BVEs were 1.6−3.2 mg/L. Two-fold diluted BVEs significantly inhibited cell proliferation after 48 h, inducing apoptosis (p < 0.05). Blackberry volatile extract significantly reduced the inactive form of apoptotic proteins, including poly adenosine diphosphate-ribose polymerase (PARP), procaspase-9, and procaspase-3 compared to the control (p < 0.05). Blueberry volatile extract showed higher apoptotic cell death (p < 0.05) with a slightly higher cell population in G0/G1 phase than other berries. These results showed that volatile extracts from three berries have the antiproliferative effect on human lung adenocarcinoma cells partially via apoptosis, suggesting that volatiles from three berries may have potential anti-cancer activity through apoptosis in lung cancer.

Exploring the Role of Metabolites in Cancer and the Associated Nerve Crosstalk.

Since Otto Warburg's first report on the increased uptake of glucose and lactate release by cancer cells, dysregulated metabolism has been acknowledged as a hallmark of cancer that promotes proliferation and metastasis. Over the last century, studies have shown that cancer metabolism is complex, and by-products of glucose and glutamine catabolism induce a cascade of both pro- and antitumorigenic processes. Some vitamins, which have traditionally been praised for preventing and inhibiting the proliferation of cancer cells, have also been proven to cause cancer progression in a dose-dependent manner. Importantly, recent findings have shown that the nervous system is a key player in tumor growth and metastasis via perineural invasion and tumor innervation. However, the link between cancer-nerve crosstalk and tumor metabolism remains unclear. Here, we discuss the roles of relatively underappreciated metabolites in cancer-nerve crosstalk, including lactate, vitamins, and amino acids, and propose the investigation of nutrients in cancer-nerve crosstalk based on their tumorigenicity and neuroregulatory capabilities. Continued research into the metabolic regulation of cancer-nerve crosstalk will provide a more comprehensive understanding of tumor mechanisms and may lead to the identification of potential targets for future cancer therapies.

In Vitro Fecal Fermentation Patterns of Arabinoxylan from Rice Bran on Fecal Microbiota from Normal-Weight and Overweight/Obese Subjects.

Arabinoxylan (AX) is a structural polysaccharide found in wheat, rice and other cereal grains. Diets high in AX-containing fiber may promote gut health in obesity through prebiotic function. Thus, the impact of soluble AX isolated from rice bran fiber on human gut microbiota phylogenetic composition and short-chain fatty acid (SCFA) production patterns from normal-weight and overweight/obese subjects was investigated through in vitro fecal fermentation. Results showed that rice bran arabinoxylan modified the microbiota in fecal samples from both weight classes compared to control, significantly increasing Collinsella, Blautia and Bifidobacterium, and decreasing Sutterella, Bilophila and Parabacteroides. Rice bran AX also significantly increased total and individual SCFA contents (p < 0.05). This study suggests that rice bran AX may beneficially impact gut health in obesity through prebiotic activities.

Effect of quercetin on nonshivering thermogenesis of brown adipose tissue in high-fat diet-induced obese mice.

Activating nonshivering thermogenesis in brown adipose tissue (BAT) is a promising strategy to prevent obesity. This study investigated whether quercetin supplementation improves obesity in mice by increasing nonshivering thermogenesis in BAT and white adipose tissue (WAT) browning. Compared to high-fat diet (HFD)-fed mice, mice fed a HFD supplemented with 1% quercetin (HFDQ) had reduced body weight and total plasma cholesterol. In HFDQ-fed mice, retroperitoneal WAT (RWAT) weight was decreased, and browning effect and lipolysis were increased. HFDQ-fed mice had increased expression of nonshivering thermogenesis genes in BAT, including uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC1α), cell death-inducing DFFA-like effector A (CIDEA), and mitochondrial transcriptional factor A (mtTFA). Quercetin supplementation increased genes and proteins in ß3-adrenergic receptor (ADRB3), p38 mitogen-activated protein kinase (MAPK), and AMP-activated protein kinase (AMPK) pathways in HFD-fed mice, which were suppressed by an AMPK inhibitor or an ADRB3 antagonist. Energy expenditure and core body temperature were not changed by quercetin, but physical activity was increased in HFDQ mice during dark periods at room and cold temperatures. Quercetin also decreased the Firmicutes to Bacteroidetes ratio and increased short-chain fatty acid production in the feces of HFD-fed mice. In summary, quercetin supplementation in HFD-fed mice may attenuate obesity. Although the study did not show consistency in data at molecular and pathophysiological levels between BAT function and obesity, it also shows promising health effects of quercetin, accompanied by improved physical activity and gut microbiota dysbiosis.

Berry Phenolic and Volatile Extracts Inhibit Pro-Inflammatory Cytokine Secretion in LPS-Stimulated RAW264.7 Cells through Suppression of NF-κB Signaling Pathway.

Berries are a rich source of phytochemicals, especially phenolics well known for protective activity against many chronic diseases. Berries also contain a complex mixture of volatile compounds that are responsible for the unique aromas of berries. However, there is very limited information on the composition and potential health benefits of berry volatiles. In this study, we isolated phenolic and volatile fractions from six common berries and characterized them by HPLC/HPLC-MS and GC/GC-MS, respectively. Berry phenolic and volatile fractions were evaluated for an anti-inflammatory effect using lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells by measuring levels of pro-inflammatory cytokines and the nuclear factor-kappa B (NF-κB) signaling pathway. Results showed that LPS-induced excessive production of nitric oxide (NO), prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), which were inhibited by berry phenolic and volatile extracts. Moreover, berry phenolic and volatile extracts reduced the nuclear translocation of NF-κB by blocking the phosphorylation of p65 and degradation of IκBα. These findings showed that berry volatiles from six berries had comparable anti-inflammatory effects to berry phenolics through the suppression of pro-inflammatory mediators and cytokines expression via NF-κB down-regulation, despite being present in the fruit at a lower concentration.

Inhibitory effects of cranberry polyphenol and volatile extracts on nitric oxide production in LPS activated RAW 264.7 macrophages.

Cranberry volatiles have received little attention for health-promoting properties. In this study, we compared the inhibitory effects of cranberry polyphenol and volatile extracts and volatile standards on nitric oxide (NO) production in lipopolysaccharide (LPS) activated RAW 264.7 macrophages. Polyphenols were analyzed by HPLC/HPLC-MS and volatiles were analyzed by GC/GC-MS. The inhibition of NO production of the fresh cranberry polyphenol and volatile extracts and α-terpineol, linalool, linalool oxide, and eucalyptol standards at 2, 4, and 8-fold dilutions of their original concentrations in fresh cranberries was evaluated by treating these extracts/standards for 1 h before or after LPS application for 24 h. After inducing inflammation with LPS, the polyphenol treatments (317.8 and 635.7 µg g-1) and 1.8 µg g-1 volatile treatment lowered NO levels 46-62% compared to the positive control (P < 0.05). When the cells were treated with polyphenol and volatile extracts before inducing inflammation, the 635.7 µg g-1 and 317.8 µg g-1 polyphenol treatments and 1.8 µg g-1 and 0.9 µg g-1 volatile treatments lowered NO levels (13-52%) compared to the positive control (P < 0.05). Polyphenol and volatile extracts from cranberry were effective in reducing NO production whether applied before or after the application of LPS. α-Terpineol at a concentration found in fresh cranberries (1.16 µg mL-1) was also found to be effective in reducing NO production whether cells were treated before or after application of LPS. Future studies are needed to reveal the mechanisms by which volatile compounds, especially α-terpineol act to mitigate inflammation and to determine the bioavailability of terpenes.

Auriculasin sensitizes primary prostate cancer cells to TRAIL-mediated apoptosis through up-regulation of the DR5-dependent pathway.

Primary prostate cancer cells frequently develop resistance toward chemotherapy as well as most chemotherapeutics have been reported to induce undesirable cytotoxicity in normal cells. In this study, we performed sensitizing activity analysis of auriculasin (AC) to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in RC-58T/h/SA#4 primary prostate cancer cells without significant cytotoxicity in RWPE-1 prostate epithelial cells. Combined treatment with AC and TRAIL at optimal concentrations resulted in tumor-specific apoptotic cell death in RC-58T/h/SA#4 cells, characterized by DNA fragmentation, accumulation of apoptotic cell population, and nuclear condensation. Compared to single treatment with AC or TRAIL, co-treatment with AC and TRAIL significantly increased expression of Bax, cleaved PARP, AIF, endo G, and cytochrome c but decreased expression of phosphorylation of AKT and mammalian target of rapamycin (mTOR), phosphoinositide 3-kinase (PI3K), Bcl-2 and caspases-9, -8, -3, and -10. The sensitizing effect of AC to TRAIL was well correlated with inhibition of death receptor 5 (DR5) CHOP, and p53 expression. Moreover, pre-treatment with a chimeric blocking antibody for DR5 effectively reduced AC-TRAIL-induced cell death and apoptosis-related protein expression. These results suggest that non-toxic concentrations of AC sensitize TRAIL-resistant primary prostate cancer cells to TRAIL-mediated apoptosis via up-regulation of DR5 and downstream signaling pathways.