Management of acute metabolic decompensation in maple syrup urine disease: guidance based on international clinical practice.

The hops plant ( L.) is primarily known for the use of the flowering inflorescence or strobile as one of the major components, along with malts, water and yeast, in the production of beer [,,,,]. Hops in brewing give desirable bitter and aroma flavors to the final product and have the added benefit of acting as a preservative, helping prevent infection by undesirable bacteria such as lactobacillus or pediococcus [,,]. Recently, hops have found use as a flavoring agent and desirable component of non-alcoholic beverages such as hop teas and relaxation drinks [,,]. Perhaps less known is the use of hop extracts for over-the-counter nutritional supplements purporting a wide range of potential benefits including treatment of anxiety, insomnia, symptoms of menopause, inflammation and an extended list of other maladies [,,]. Hops extracts have been evaluated for the alleviation of early menopausal symptoms in randomized placebo-controlled trials []. In a recent clinical trial, hop extracts have been shown to modulate gut peptide hormone secretion in healthy-weight men []. Hops have also proven to be an excellent source of isolated biologically active compounds [,,] (). The harvested strobiles of the hops plant contain between 2 and 15% by weight of humulones, a mixture of prenylated oxidized phloroglucinols []. The major homologs of humulone differ in the alkyl ketone substitution of the cyclohexadienone ring, with over 95% of the content represented by isobutyl (-), isopropyl (-) and sec-butyl (-) ketones. The homolog -humulone has been evaluated for sleep-promoting activity [] and shown to inhibit cell growth of lung and bone cancer cells []. Humulones can be isomerized to isohumulones by both thermal and photochemical methods []. Thermal isomerization is frequently employed and results primarily in six products consisting of a mixture of and isomers of each of the three most prominent homologs (-, - and -isohumulones). Following standard convention, the isomer indicates a arrangement between the C4 hydroxyl group and the C5 isoprenyl group. Isohumulone mixtures have been evaluated for medical nutrition therapy to treat or prevent metabolic syndrome and related disorders such as diabetes, inflammation and impaired glucose tolerance []. In a study with pre-diabetic patients, daily administration of capsules containing 48 mg of isohumulones over a 12-week period led to a significant reduction in body weight and BMI []. The brewing industry has developed reduced isohumulones for providing light-stable bittering agents for beer []. Unlike isohumulones, which are readily oxidized and sensitive to light, the reduced isohumulones have improved stability and provide bitter flavors that do not degrade in the final beverage []. META060 is a reduced tetrahydro-isohumulone product that consists of a mixture of the and isomers of the -, - and -homologs. Notably, a single oral dose of 940 mg of META060 in human trials was found to provide plasma levels sufficient to inhibit LPS-stimulation of TNFα and IL-6, suggesting its potential for treatment of chronic inflammatory disease []. Further development of reduced isohumulone derivatives led to the identification of KDT-501, which has been in phase 2 clinical trials for control of metabolic disease in insulin-resistant patients []. KDT-501 is also being considered for control of polycystic ovarian syndrome and non-fatty acid liver disease [,]. Our interest in the natural products obtained from hops began with the introduction of a special topics course on brewing science for non-science major undergraduate students []. During the development of this course, we explored analytical methods for the analysis of humulone and isohumulone in hops and beer [,]. Isotopically labeled isohumulones were prepared for use in stable isotope dilution assays and potential analysis of degradation products []. A continuous flow photochemical method was developed for stereoselective formation of gram quantities of -isohumulones in nearly quantitative yield []. A surprising result of the photochemical investigation was the impact of light-emitting diode (LED) wavelength on the product distribution of isohumulones obtained from -humulone. The advent of LEDs and monochromatic lasers in synthetic photochemistry has resulted in exquisite control of reaction conditions and has been termed ‘precision photochemistry’ [].