molecules Review The Promising Ability of Humulus lupulus L. Iso-α-acids vs. Diabetes, Inflammation, and Metabolic Syndrome: A Systematic Review Maria Ponticelli 1,* , Daniela Russo 1,2 , Immacolata Faraone 1,2 , Chiara Sinisgalli 1,2, Fabiana Labanca 1 , Ludovica Lela 1 and Luigi Milella 1,* 1 Department of Science, University of Basilicata, Viale dell’Ateneo Lucano 10, 85100 Potenza, Italy; [email protected] (D.R.); [email protected] (I.F.); [email protected] (C.S.); [email protected] (F.L.); [email protected] (L.L.) 2 Spinoff BioActiPlant s.r.l., Viale dell’Ateneo Lucano 10, 85100 Potenza, Italy * Correspondence: [email protected] (M.P.); [email protected] (L.M.); Tel.: +39-0971-205-525 (L.M.) Abstract: For centuries, natural medicines have represented the only option for treating human diseases and, nowadays, plant phytochemicals are considered as promising compounds to treat or prevent chronic conditions. Among them, hop flowers (Humulus lupulus L.), typically used in brewing industries to give the typical aroma and flavor to beer, have attracted particular attention for their health promoting properties. Several in vivo/vitro studies and human interventional trials have demonstrated the beneficial effects of these molecules on weight gain, lipid metabolism, glu- cose homeostasis, insulin sensitivities, and inflammation by acting on different targets. All these activities suggest a possible role of bitter hop acid in preventing metabolic syndrome and its re- Citation: Ponticelli, M.; Russo, D.; lated diseases. A systematic quest on PubMed and Scopus databases was performed to identify Faraone, I.; Sinisgalli, C.; Labanca, F.; pre-clinical and clinical studies focusing on this topic. This systematic review summarizes the results Lela, L.; Milella, L. The Promising obtained by different cell lines, animal models, and human interventional trials to propose iso-α- Ability of Humulus lupulus L. acids as medical nutrition therapy to treat or prevent metabolic syndrome and its related disorders Iso-α-acids vs. Diabetes, as diabetes, dislipidemia inflammation, etc. Inflammation, and Metabolic Syndrome: A Systematic Review. Keywords: Humulus lupulus L.; iso-α-acids; reduced iso-α-acids; metabolic syndrome; PPAR receptors Molecules 2021, 26, 954. https:// doi.org/10.3390/molecules26040954 Academic Editor: Gilles Comte Received: 31 December 2020 1. Introduction Accepted: 4 February 2021 Metabolic Syndrome (MetS) is a condition characterized by a complex mosaic of Published: 11 February 2021 metabolic abnormalities, including visceral obesity, impaired glucose tolerance, insulin re- sistance leading to type II diabetes, dyslipidemia, and atherosclerotic cardiovascular dis- Publisher’s Note: MDPI stays neutral eases. In the pathogenesis of MetS either acquired or genetic factors are involved, leading to with regard to jurisdictional claims in the rise of oxidative stress and a systemic inflammatory process. Indeed, systemic inflam- published maps and institutional affil- mation is a constant feature of metabolic syndrome since obesity is generally associated iations. with low-grade inflammation of white adipose tissue resulting in the chronic activation of the innate immune system. The excess in macronutrients results in a dysregulated secretion of pro-inflammatory adipokines and cytokines from adipose tissue such as leptin, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein- Copyright: © 2021 by the authors. 1 (MCP-1), and resistin [1]. These inflammatory mediators are not only limited to adipose Licensee MDPI, Basel, Switzerland. tissue but also reach the liver through the portal vein, and finally, other peripheral tissues, This article is an open access article like vascular tissues, where they can induce atherosclerosis, hypertension, and vascular distributed under the terms and insulin resistance [2]. According to the National Cholesterol Treatment Program Adult conditions of the Creative Commons Treatment Panel III (NCEP–ATP III), it is possible to diagnose MetS when three or more of Attribution (CC BY) license (https:// the following criteria fulfilled: waist circumference over 35 inches for women or 40 inches creativecommons.org/licenses/by/ for men, fasting triglycerides level over 150 mg/dL, fasting HDL-C level less than 50 mg/dL 4.0/). Molecules 2021, 26, 954. https://doi.org/10.3390/molecules26040954 https://www.mdpi.com/journal/molecules Molecules 2021, 26, 954 2 of 32 for women and 40 mg/dL for men, blood pressure over 130/85 mmHg, and fasting blood sugar over 100 mg/dL [3]. Due to the worldwide increase in obesity, MetS represent a serious public health prob- lem; thus, researchers have moved their attention to the study of this condition. Gener- ally, the common treatment of metabolic disorders consists of drastic dietary interventions based on the replacement of refined carbohydrates with proteins and fibers, the reduction of saturated fats, and the increment of poly-unsaturated oils. Diets are often associated with pharmacologic therapies leading to the decrease of obesity incidence, the treatment of dia- betes, and the reduction of heart disease by decreasing LDL cholesterol and reducing high blood pressure [4]. However, dietary interventions are difficult to implement in obese pa- tients, and different drugs have shown low efficacy and a high number of adverse reactions. For these reasons, new safe and effective therapeutic strategies are demanded. In particular, several studies have described the beneficial effects of various natural extracts and active principles and their potential role in the improvement of MetS related diseases, as diabetes, dislipidemia, oxidative stress, etc. [5–8]. Moreover an increasing attention has been paid to bitter compounds able to exert their activity interacting with specific gastrointestinal receptors [9]. To the best of our knowledge, the effectiveness of bitter compound present in Humulus lupulus L. using a systematic approach have not been reported yet. Hop (Hu- mulus lupulus L.) is globally known since it is the brewing industry’s raw material. Hop’s female inflorescences, also called hop cones, contain resin glands capable of secreting a yellow resinous powder known as lupulin. It is rich in different active compounds that contribute to beer aroma and stability, and that can be classified as volatile oils, bitter acids, and polyphenols [10]. Several of these molecules have been demonstrated to exert differ- ent biological activities. In particular, during the last years, hop bitter acids have been demonstrated to be possible candidates for treating and/or preventing several human dis- orders, including cancer, diabetes mellitus, and cardiovascular diseases [11,12]. Due to the described effects, our attention was focused on metabolic syndrome-related diseases. Several studies have recently described the ability of iso-α-acid and reduced iso-α-acid to improve metabolic disorders by affecting body weight, glucose tolerance, insulin resistance, lipid metabolism, and inflammatory mediators. This review analyzes, using a systematic approach, research papers available to date to make a comprehensive knowledge of the recent achievements in the field of hop bitter acid activity in preventing and treating obesity, hyperlipidemia, insulin resistance, sys- temic inflammation, and atherosclerosis, starting from the bioavailability and metabolism of these compounds. 2. Bitter Hop acid Chemistry Hop bitter acids (25% or even more of the dry weight of hop) are phloroglucinol derivatives consisting of two series of compounds: α-acids or humulones and β-acids or lupulones (Figure1). These two groups comprise three compounds whose chemical struc- ture differs in the side chains’ composition. In fact, the α-acids’ side chain may be derived from hydrophobic amino acids, leucine, valine, and isoleucine, for humulone/lupulone, cohumulone/colupulone, and adhumulone/adlupulone, respectively [13]. The amount of α-acids depends strongly on the hop variety and it reflects the quality of the raw ma- terial used in brewer industries. During beer production, α-acids are susceptible to an isomerization process, via an acyloin-type ring contraction, by boiling hops or hop ex- tract in aqueous wort medium at high pH. As a result, the most hydrophilic and bitter iso-α-acids are produced. Depending on the spatial arrangement of the tertiary alcohol function at C(4) and the prenyl side chain at C(5) it is possible to distinguish two di- astereomeric pairs of iso-α-acids: cis-iso-α-acids and trans-iso-α-acids. It is also possible to obtain these compounds in laboratory practices by boiling α-acids in the presence of a catalyst as divalent cations, in alkaline media or by irradiation, with UV light of an α-acids methanolic solution (photoisomerization acts in a stereoselective ways and exclusively forms trans-isomers) [14,15]. Molecules 2021, 26, 954 3 of 32 Figure 1. Representation of α-acids or humulones and β-acids or lupulones. With the isomerization process from the three main α-acids analogs, six stereoisomers of iso-α-acids are produced: cis-isohumulone and trans-isohumulone, cis-isocohumulone and trans-isocohumulone, cis-isoadhumulone and trans-isoadhumulone. The ratio between the two isomers is 68:32 in favor of the cis isomers, which are more stable (half-life ≈ 5 years) than trans-isomers (half-life ≈ 1 year) due to the lower steric impedance which exists be- tween the two large vicinal side chains. However, both isomers in the