Licorice as a Resource for Pharmacologically Active Phenolic Substances: Antioxidant and Antimicrobial Effects

The findings from our studies on licorice phenolics are summarized here. The following types of flavonoids, i.e., flavones, flavonols, flavanones, chalcones, isoflavones, isoflavanones, isoflavans, 3-arylcoumarins, coumestans, pterocarpans, 2-benzyldihydrobenzofuran-3-ones, benzyl phenyl ketones, 2-arylbenzofurans, and others, were identified by the structural studies. Among them, licochalcone A (chalcone), isolicoflavonol (flavonol), glycycoumarin (3-arylcoumarin), and glycyrrhisoflavone (isoflavone) displayed antihuman immunodeficiency virus effects, and also 8-(γ,γ-dimethylallyl)-wighteone (isoflavone) and 3′-(γ,γ-dimethylallyl)-kievitone (isoflavanone) showed potent antibacterial effects on methicillin-resistant Staphylococcus aureus (MRSA) strains. Licoricidin (isoflavan) suppressed the oxacillin resistance of the MRSA strains noticeably. Effects of phenolics with related structures isolated from Psoralea corylifolia were also examined, and bakuchiol (meroterpene), isobavachalcone, and corylifol B (chalcones) also showed potent effects on MRSA strains. Some licorice phenolics such as licoricidin (isoflavan), 8-(γ,γ-dimethylallyl)-wighteone (isoflavone), and gancaonin I (2-arylbenzofuran) also showed potent antibacterial effects on vancomycin-resistant Enterococcus (VRE) strains. The potency of the effects largely depended on their structures including the lipophilic prenyl or related substituents and also phenolic hydroxyl groups. Inhibitory effects of licorice phenolics on oxidative enzymes, in addition to their radical-scavenging effects, are also shown. The methods used in the structural studies and high-performance liquid chromatographic analysis of licorice extracts are described shortly, too

Obesity in a model of haploinsufficiency uncovers a causal role for lipid-derived aldehydes in human metabolic disease and cardiomyopathy

Lipid peroxides and their reactive aldehyde derivatives (LPPs) have been linked to obesity-related pathologies, but whether they have a causal role has remained unclear. Glutathione peroxidase 4 (GPx4) is a selenoenzyme that selectively neutralizes lipid hydroperoxides, and human gpx4 gene variants have been associated with obesity and cardiovascular disease in epidemiological studies. This study tested the hypothesis that LPPs underlie cardio-metabolic derangements in obesity using a high fat, high sucrose (HFHS) diet in gpx4 haploinsufficient mice (GPx4(+/-)) and in samples of human myocardium. METHODS: Wild-type (WT) and GPx4(+/-) mice were fed either a standard chow (CNTL) or HFHS diet for 24 weeks, with metabolic and cardiovascular parameters measured throughout. Biochemical and immuno-histological analysis was performed in heart and liver at termination of study, and mitochondrial function was analyzed in heart. Biochemical analysis was also performed on samples of human atrial myocardium from a cohort of 103 patients undergoing elective heart surgery. RESULTS: Following HFHS diet, WT mice displayed moderate increases in 4-hydroxynonenal (HNE)-adducts and carbonyl stress, and a 1.5-fold increase in GPx4 enzyme in both liver and heart, while gpx4 haploinsufficient (GPx4(+/-)) mice had marked carbonyl stress in these organs accompanied by exacerbated glucose intolerance, dyslipidemia, and liver steatosis. Although normotensive, cardiac hypertrophy was evident with obesity, and cardiac fibrosis more pronounced in obese GPx4(+/-) mice. Mitochondrial dysfunction manifesting as decreased fat oxidation capacity and increased reactive oxygen species was also present in obese GPx4(+/-) but not WT hearts, along with up-regulation of pro-inflammatory and pro-fibrotic genes. Patients with diabetes and hyperglycemia exhibited significantly less GPx4 enzyme and greater HNE-adducts in their hearts, compared with age-matched non-diabetic patients. CONCLUSION: These findings suggest LPPs are key factors underlying cardio-metabolic derangements that occur with obesity and that GPx4 serves a critical role as an adaptive countermeasure

Structures and Antibacterial Properties of Isorugosins H–J, Oligomeric Ellagitannins from <i>Liquidambar formosana</i> with Characteristic Bridging Groups between Sugar Moieties

Three new ellagitannin oligomers, isorugosins H (<b>1</b>), I (<b>2</b>), and J (<b>3</b>), together with 11 known hydrolyzable tannins were isolated from an aqueous acetone extract of the fresh leaves of <i>Liquidambar formosana</i>. Their chemical structures were elucidated based on spectroscopic data and chemical conversion into known hydrolyzable tannins. The bridging mode of the valoneoyl groups between their sugar moieties has been identified only in this plant species. Additionally, the effects of the isorugosins isolated from this species on drug-resistant bacteria were evaluated and showed that isorugosin A (<b>4</b>) exhibited the most potent antibacterial activity against methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). The isorugosins also had a suppressing effect on pigment formation in <i>Pseudomonas aeruginosa</i>. The isorugosin–protein complexes were analyzed using size-exclusion chromatography and polyacrylamide gel electrophoresis to clarify the relationship of their antibacterial properties with their protein interaction potency as hydrolyzable tannins. The results suggested that the antibacterial properties of hydrolyzable tannins are not simply a result of their binding activity to proteins, but are due to other factors such as the accessibility of polyphenolic acyl groups to bacterial membranes

Ellagitannins of Davidia involucrata. I. Structure of Davicratinic Acid A and Effects of Davidia Tannins on Drug-Resistant Bacteria and Human Oral Squamous Cell Carcinomas

We isolated a new ellagitannin, davicratinic acid A (5), together with four known ellagitannins, davidiin (1), granatin A (2), pedunculagin (3), and 3-O-galloylgranatin A (4), from an aqueous acetone extract of dried Davidia involucrata leaves. The known ellagitannins were identified based on spectroscopic data. The structure of davicratinic acid A (5), a monomeric ellagitannin possessing a unique, skew-boat glucopyranose core, was established based on spectroscopic data. Additionally, we examined the effects of several tannins with good yields from this plant on drug-resistant bacteria and human oral squamous cell carcinomas, and found that davidiin (1) exhibited the most potent antibacterial and antitumor properties among the tannins examined