Gas Chromatography Coupled to Atmospheric Pressure Chemical Ionization High-Resolution Mass Spectrometry for Metabolite Fingerprinting of Grape (Vitis vinifera L) Berry.

This chapter describes the application of atmospheric pressure chemical ionization in conjunction with gas chromatography (APGC) coupled to high-resolution mass spectrometry for profiling metabolites in plant and fruit extracts. The APGC technique yields molecular ions and limited fragmentation of volatile or derivatized compounds. The data-independent acquisition mode, MSE, was used for measuring precursor and fragment ions with high resolution using a quadrupole ion mobility time-of-flight mass spectrometry system. We demonstrate the importance of acquiring accurate mass information in conjunction with accurate mass fragment ions for efficient database searching and compound assignments with high confidence. We demonstrate the application of APGC-MSE for obtaining metabolite data for grape berry extracts after derivatization.

KLF10 integrates circadian timing and sugar signaling to coordinate hepatic metabolism.

The mammalian circadian timing system and metabolism are highly interconnected, and disruption of this coupling is associated with negative health outcomes. Krüppel-like factors (KLFs) are transcription factors that govern metabolic homeostasis in various organs. Many KLFs show a circadian expression in the liver. Here, we show that the loss of the clock-controlled KLF10 in hepatocytes results in extensive reprogramming of the mouse liver circadian transcriptome, which in turn alters the temporal coordination of pathways associated with energy metabolism. We also show that glucose and fructose induce Klf10, which helps mitigate glucose intolerance and hepatic steatosis in mice challenged with a sugar beverage. Functional genomics further reveal that KLF10 target genes are primarily involved in central carbon metabolism. Together, these findings show that in the liver KLF10 integrates circadian timing and sugar metabolism-related signaling, and serves as a transcriptional brake that protects against the deleterious effects of increased sugar consumption.

Potential use of polyphenols in the battle against COVID-19.

The coronavirus disease 2019 (COVID-19) is a public health emergency of international concern. The rising number of cases of this highly transmissible infection has stressed the urgent need to find a potent drug. Although repurposing of known drugs currently provides an accelerated route to approval, there is no satisfactory treatment. Polyphenols, a major class of bioactive compounds in nature, are known for their antiviral activity and pleiotropic effects. The aim of this review is to assess the effects of polyphenols on COVID-19 drug targets as well as to provide a perspective on the possibility to use polyphenols in the development of natural approaches against this viral disease.

Targeting the Liver-Brain Axis with Hop-Derived Flavonoids Improves Lipid Metabolism and Cognitive Performance in Mice.

SCOPE: Sphingolipids including ceramides are implicated in the pathogenesis of obesity and insulin resistance. Correspondingly, inhibition of pro-inflammatory and neurotoxic ceramide accumulation prevents obesity-mediated insulin resistance and cognitive impairment. Increasing evidence suggests the farnesoid X receptor (FXR) is involved in ceramide metabolism, as bile acid-FXR crosstalk controls ceramide levels along the gut-liver axis. The authors previously reported that FXR agonist xanthohumol (XN), the principal prenylated flavonoid in hops (Humulus lupulus), and its hydrogenated derivatives, α,ß-dihydroxanthohumol (DXN), and tetrahydroxanthohumol (TXN), ameliorated obesity-mediated insulin resistance, and cognitive impairment in mice fed a high-fat diet. METHODS AND RESULTS: To better understand how the flavonoids improve both, lipid and bile acid profiles in the liver are analyzed, sphingolipid relative abundance in the hippocampus is measured, and linked them to metabolic and neurocognitive performance. XN, DXN, and TXN (30 mg kg-1 BW per day) decrease ceramide content in liver and hippocampus; the latter is linked to improvements in spatial learning and memory. In addition, XN, DXN, and TXN decrease hepatic cholesterol content by enhancing de novo synthesis of bile acids. CONCLUSION: These observations suggest that XN, DXN, and TXN may alleviate obesity-induced metabolic and neurocognitive impairments by targeting the liver-brain axis.

Improvements in Metabolic Syndrome by Xanthohumol Derivatives Are Linked to Altered Gut Microbiota and Bile Acid Metabolism.

SCOPE: Two hydrogenated xanthohumol (XN) derivatives, α,ß-dihydro-XN (DXN) and tetrahydro-XN (TXN), improved parameters of metabolic syndrome (MetS), a critical risk factor of cardiovascular disease (CVD) and type 2 diabetes, in a diet-induced obese murine model. It is hypothesized that improvements in obesity and MetS are linked to changes in composition of the gut microbiota, bile acid metabolism, intestinal barrier function, and inflammation. METHODS AND RESULTS: To test this hypothesis, 16S rRNA genes were sequenced and bile acids were measured in fecal samples from C57BL/6J mice fed a high-fat diet (HFD) or HFD containing XN, DXN or TXN. Expression of genes associated with epithelial barrier function, inflammation, and bile acid metabolism were measured in the colon, white adipose tissue (WAT), and liver, respectively. Administration of XN derivatives decreases intestinal microbiota diversity and abundance-specifically Bacteroidetes and Tenericutes-alters bile acid metabolism, and reduces inflammation. In WAT, TXN supplementation decreases pro-inflammatory gene expression by suppressing macrophage infiltration. Transkingdom network analysis connects changes in the microbiota to improvements in MetS in the host. CONCLUSION: Changes in the gut microbiota and bile acid metabolism may explain, in part, the improvements in obesity and MetS associated with administration of XN and its derivatives.

Non-estrogenic Xanthohumol Derivatives Mitigate Insulin Resistance and Cognitive Impairment in High-Fat Diet-induced Obese Mice.

Xanthohumol (XN), a prenylated flavonoid from hops, improves dysfunctional glucose and lipid metabolism in animal models of metabolic syndrome (MetS). However, its metabolic transformation into the estrogenic metabolite, 8-prenylnaringenin (8-PN), poses a potential health concern for its use in humans. To address this concern, we evaluated two hydrogenated derivatives, α,ß-dihydro-XN (DXN) and tetrahydro-XN (TXN), which showed negligible affinity for estrogen receptors α and ß, and which cannot be metabolically converted into 8-PN. We compared their effects to those of XN by feeding C57BL/6J mice a high-fat diet (HFD) containing XN, DXN, or TXN for 13 weeks. DXN and TXN were present at higher concentrations than XN in plasma, liver and muscle. Mice administered XN, DXN or TXN showed improvements of impaired glucose tolerance compared to the controls. DXN and TXN treatment resulted in a decrease of HOMA-IR and plasma leptin. C2C12 embryonic muscle cells treated with DXN or TXN exhibited higher rates of uncoupled mitochondrial respiration compared to XN and the control. Finally, XN, DXN, or TXN treatment ameliorated HFD-induced deficits in spatial learning and memory. Taken together, DXN and TXN could ameliorate the neurocognitive-metabolic impairments associated with HFD-induced obesity without risk of liver injury and adverse estrogenic effects.

Mitochondria-Centric Review of Polyphenol Bioactivity in Cancer Models.

SIGNIFICANCE: Humans are exposed daily to polyphenols in milligram-to-gram amounts through dietary consumption of fruits and vegetables. Polyphenols are also available as components of dietary supplements for improving general health. Although polyphenols are often advertised as antioxidants to explain health benefits, experimental evidence shows that their beneficial cancer preventing and controlling properties are more likely due to stimulation of pro-oxidant and proapoptotic pathways. Recent Advances: The understanding of the biological differences between cancer and normal cell, and especially the role that mitochondria play in carcinogenesis, has greatly advanced in recent years. These advances have resulted in a wealth of new information on polyphenol bioactivity in cell culture and animal models of cancer. Polyphenols appear to target oxidative phosphorylation and regulation of the mitochondrial membrane potential (MMP), glycolysis, pro-oxidant pathways, and antioxidant (adaptive) stress responses with greater selectivity in tumorigenic cells. CRITICAL ISSUES: The ability of polyphenols to dissipate the MMP (Δψm) by a protonophore mechanism has been known for more than 50 years. However, researchers focus primarily on the downstream molecular effects of Δψm dissipation and mitochondrial uncoupling. We argue that the physicochemical properties of polyphenols are responsible for their anticancer properties by virtue of their protonophoric and pro-oxidant properties rather than their specific effects on downstream molecular targets. FUTURE DIRECTIONS: Polyphenol-induced dissipation of Δψm is a physicochemical process that cancer cells cannot develop resistance against by gene mutation. Therefore, polyphenols should receive more attention as agents for cotherapy with cancer drugs to gain synergistic activity. Antioxid. Redox Signal.