plants Review Pharmacological Exploration of Phenolic Compound: Raspberry Ketone—Update 2020 Shailaja Rao 1,†, Mallesh Kurakula 2,*,† , Nagarjuna Mamidipalli 3, Papireddy Tiyyagura 4, Bhaumik Patel 5 and Ravi Manne 6 1 Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA; [email protected] 2 Department of Biomedical Engineering, The University of Memphis, Memphis, TN 38152, USA 3 Analytical R&D, Akron Inc., Lake Forest, IL 60045, USA; [email protected] 4 Analytical R&D, BioDuro LLC, San Diego, CA 92121, USA; [email protected] 5 Product Development Department, Cure Pharmaceutical Corporation, Los Angeles, CA 90025, USA; [email protected] 6 Chemtex Environmental Laboratory, Quality Control and Assurance Department, Port Arthur, TX 77642, USA; [email protected] * Correspondence: [email protected] † Authors have contributed equally. Abstract: Raspberry ketone (RK) is an aromatic phenolic compound naturally occurring in red raspberries, kiwifruit, peaches, and apples and reported for its potential therapeutic and nutraceu- tical properties. Studies in cells and rodents have suggested an important role for RK in hep- atic/cardio/gastric protection and as an anti-hyperlipidemic, anti-obesity, depigmentation, and sexual maturation agent. Raspberry ketone-mediated activation of peroxisome proliferator-activated receptor-α (PPAR-α) stands out as one of its main modes of action. Although rodent studies have demonstrated the efficacious effects of RK, its mechanism remains largely unknown. In spite of a Citation: Rao, S.; Kurakula, M.; lack of reliable human research, RK is marketed as a health supplement, at very high doses. In this Mamidipalli, N.; Tiyyagura, P.; Patel, review, we provide a compilation of scientific research that has been conducted so far, assessing B.; Manne, R. Pharmacological the therapeutic properties of RK in several disease conditions as well as inspiring future research Exploration of Phenolic Compound: before RK can be considered safe and efficacious with limited side effects as an alternative to modern Raspberry Ketone—Update 2020. medicines in the treatment of major lifestyle-based diseases. Plants 2021, 10, 1323. https:// doi.org/10.3390/plants10071323 Keywords: raspberry ketone; hepatoprotection; cardioprotection; gastroprotection; obesity; depig- mentation; bone regeneration Academic Editor: Francesca Pintus Received: 17 May 2021 Accepted: 25 June 2021 Published: 29 June 2021 1. Introduction to Raspberry Ketone Raspberry ketone (RK; 4-(4-hydroxyphenyl) butan-2-one), one of the major aromatic Publisher’s Note: MDPI stays neutral compounds found in European red raspberry (Rubus idaeus), defines the characteristic with regard to jurisdictional claims in fragrance and taste of raspberry. Raspberry ketone may also be found in other fruits such published maps and institutional affil- as peaches, grapes, apples, various berries, vegetables, and in the bark of yew, maple, iations. and pine. Raspberry ketone is widely used in perfumes, cosmetics, and as a flavoring agent in food and beverages [1–3]. Although chemically synthesized, RK can be produced via the condensation of p-hydroxybenzaldehyde with acetone; it is only considered as a nature-identical flavoring substance according to the EU and US regulations [4] and Copyright: © 2021 by the authors. cannot be marketed as a “natural” flavoring compound according to food laws [5]. The Licensee MDPI, Basel, Switzerland. biosynthesis of RK is a two-step process. The first step begins with the phenylpropanoid This article is an open access article subsequently hydrolyzed into p-coumaric acid in the raspberry fruit. Coumaroyl-CoA distributed under the terms and (an intermediate of the lignin synthesis pathway) condensed with one malonyl-CoA to conditions of the Creative Commons form p-hydroxybenzalacetone [4-(4-hydroxyphenyl)-but-3-ene-2-one] by an enzyme called Attribution (CC BY) license (https:// benzalacetone synthases (BAS), a type III polyketide synthase (PKS). The second step is creativecommons.org/licenses/by/ the double bonds of the p-hydroxybenzalacetone are reduced by an NADPH-dependent 4.0/). Plants 2021, 10, 1323. https://doi.org/10.3390/plants10071323 https://www.mdpi.com/journal/plants Plants 2021, 10, x FOR PEER REVIEW 2 of 17 Plants 2021, 10, 1323 2 of 17 NADPH-dependent benzalacetone reductase (BAR) and the expense of NADPH to form benzalacetoneRK [1,4] reductase. Extraction (BAR) of raspberry and the expense ketone offrom NADPH raspberries to form or RKfruits [1, 4containing]. Extraction RK is very of raspberryexpensive. ketone The from main raspberries limitations or fruits are due containing to the seasonal RK is very availability expensive. of fruits The main as well as the limitationssmall are concentrations due to the seasonal of RK availability naturally ofoccurring fruits as in well these as thefruits. small To concentrationsovercome these limita- of RK naturallytions, occurringRK is incurrently these fruits. synthesized To overcome chemically these limitations, via RKthe iscondensation currently of synthesizedp-hydroxybenzaldehyde chemically via the condensation with acetone of p-hydroxybenzaldehydeor biosynthesized in genetically with acetone modified or micro- biosynthesizedorganisms in genetically such as bacteria modified or yeast. microorganisms such as bacteria or yeast. The physicochemicalThe physicochemical properties properties of RK are of givenRK are in given Table 1in. OneTable group 1. One produced group produced natural raspberrynatural raspberry compounds compounds by cloning by thecloning genes the involved genes involved in the natural in the synthesis natural synthesis of of RK, in micro-organismsRK, in micro-organisms [1]. Alternatively, [1]. Alternatively, another groupanother described group described a method a tomethod produce to produce biosyntheticbiosynthetic RK by converting RK by converting the precursor, the precursor betuloside,, betuloside in a secondary, in a alcoholsecondary dehydro- alcohol dehy- genase (ADH)drogenase producing (ADH) micro-organisms producing micro [6-].organisms A recent report[6]. A suggestsrecent report that introducingsuggests that intro- four heterologousducing four genes, heterologous encoding phenylalanine/tyrosinegenes, encoding phenylalanine/tyrosine ammonia-lyase, cinnamate-4- ammonia-lyase, cin- hydroxylase,namate coumarate-CoA-4-hydroxylase, ligase, coumarate and benzalacetone-CoA ligase, synthases and benzalacetone in an industrial synthases strain in of an indus- S. cerevisiaetrialincreased strain of theS. cerevisiae yields of increased RK compared the yields to traditional of RK compared methods to [7 ].traditional methods [7]. Table 1. PhysiochemicalTable 1. Physiochemical properties of properties raspberry of ketone raspberry (RK). ketone (RK). Chemical StructureChemical Structure Chemical Formula C10 H12 O2 Chemical Formula C10 H12 O2 Molecular Weight 164.204 g·mol−1 Molecular Weight 164.204 g·mol−1 ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, acetic acid, methyl acetate, Solubility ethylethanol, acetate, 1-propanol, acetone, and 2-propanol, binary 1-butanol,mixtures 2-butanol,of ethanol acetic + acetone acid, [8] Solubility methyl acetate, ethyl acetate, acetone, and binary mixtures of Melting Point ethanol81–85 + acetone°C (lit.) [8] Boiling Point Melting Point 292.2 ± 15.081–85 °C◦ Cat (lit.) 760 mmHg Lambda Max 280 nm Boiling Point 292.2 ± 15.0 ◦C at 760 mmHg LogP 1.48 Lambda Max 280 nm LogPRaspberry ketone has been qualified as 1.48a “Generally Reconized As Safe” (GRAS) flavoring agent and has been widely used. Raspberry ketone has also gained a lot of at- Raspberrytention ketoneas a nutraceutical has been qualified that owes as potential a “Generally health Reconized benefits. Numerous As Safe” (GRAS)research studies flavoringhave agent indicated and has its been anti widely-obesity, used. anti Raspberry-androgenic ketone activity, has cardio/ also gainedhepatoprotective, a lot of and attentionanti as a-inflammatory nutraceutical thatproperties owes potential [8]. health benefits. Numerous research studies have indicatedA itsstudy anti-obesity, assessing anti-androgenicthe metabolism activity,of RK in cardio/hepatoprotective, male rats, rabbits, and andguinea pigs anti-inflammatoryshowed that properties RK was [rapidly8]. absorbed from the gastrointestinal tract after administration A studyof 1 mmol/ assessingkg by the oral metabolism gavage. More of than RK in90% male of ingested rats, rabbits, RK was and excreted guinea in pigs urine within showed24 that h, RKprimarily was rapidly reduced absorbed to raspberry from alcohol the gastrointestinal [9]. Raspberry tract ketone after and administra- its metabolites are tion of 1bioavailable mmol/kg by oralin both gavage. plasma More thanand 90%the ofbrain. ingested Raspberry RK was excretedketone catabolism in urine is a within 24well h, primarily-coordinated reduced process to raspberry involving alcohol intracellular [9]. Raspberry ketone reduction ketone and and its methylation metabo- into lites aremetabolites bioavailable including in both plasma methylated and the raspberry brain. Raspberry ketone (RK ketone-Me) catabolismand raspberry is a alcohol well-coordinated(ROH). Of process the many involving health intracellularbenefits reported, ketone the reduction anti-obesity and property methylation of RK into has gained metabolitesthe includingmost popularity. methylated Adding raspberry RK as ketone a supplement (RK-Me) andto a raspberryweight loss alcohol plan