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Anti-Inflammatory, Anti-Glycation, Anti-Tyrosinase and CDK4 Inhibitory Activities of Alaternin (=7-Hydroxyemodin)

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Anti-Inflammatory, Anti-Glycation, Anti-Tyrosinase and CDK4 Inhibitory Activities of Alaternin (=7-Hydroxyemodin) Natural Product Sciences 27(1) : 28-35 (2021) https://doi.org/10.20307/nps.2021.27.1.28 Anti-inflammatory, Anti-glycation, Anti-tyrosinase and CDK4 Inhibitory Activities of Alaternin (=7-Hydroxyemodin) Grishma Bhatarrai1,#, Jeong-Wook Choi1,#, Su Hui Seong1,#, Taek-Jeong Nam1, Hyun Ah Jung2,*, and Jae Sue Choi1,* 1Department of Food and Life Sciences, Pukyoung National University, Busan 48513, Republic of Korea 2Department of Food Science and Human Nutrition, Jeonbuk National University, Jeonju 54896, Republic of Korea Abstract The aim of this study was to anatomize the therapeutic potential of alaternin (=7-hydroxyemodin) against inflammation, advanced glycation end products (AGEs) formation, tyrosinase, and two cyclin-dependent kinases (CDKs), CDK2 and CDK4, and compare its potency with emodin. Alaternin showed lower cytotoxicity and higher dose-dependent inhibition against lipopolysaccharide (LPS) induced nitric oxide (NO) production with half maximal inhibitory concentration (IC50) of 18.68 µM. Similarly, alaternin efficaciously inhibited biotransformation of fluorescent AGEs and amyloid cross-β structure on the bovine serum albumin (BSA)- glucose-fructose system, five times more than emodin. Interestingly, alaternin also showed selective activity against CDK4 at 170 µM, whereas emodin inhibited both CDK2 and CDK4 at a concentration of 17 and 380 µM respectively. In addition, alaternin showed dose-dependent inhibitory activity against mushroom tyrosinase with inhibition percentage of 35.84 % at 400 µM. Altogether, alaternin with pronounced inhibition against inflammatory mediator (NO), glycated products formation, and targeted inhibition towards CDK4 receptor can be taken as an important candidate to target multiple diseases. Keywords Alaternin, inflammation, tyrosinase, AGEs, CDK4, RAW 264.7 Introduction oxidative,11 neuroprotective,12 hepatoprotective,13 and selective monoamine oxidase (MAO) inhibitory activities14 Anthraquinone comprises a large group of aromatic whereas emodin is testified to have anti-bacterial,15 anti- compounds nucleated with 9, 10-dioxoanthracene. A wide inflammatory,16,17 anti-purgative, vasorelaxant, anti-fibrotic, range of anthraquinones has been shown to exhibit and immunosuppressive effects.18 numerous biological properties like hepatoprotective,1,2 Inflammation occurs as a host defense mechanism in anti-Alzheimer’s,3 anti-inflammatory,4 lung anti-inflam- response to harmful stimuli (pathogen) and is accom- matory,5 mucin production inhibiting,6 anti-microbial,7,8 panied by inflammatory mediators. Dysregulation of and anti-cancer effects.9 Among the derivatives of inflammatory response is related to neurodegenerative anthraquinone family, alaternin and emodin are two disorders, cancer, atherosclerosis, and type 1 diabetes.19 important compounds that differ by the number and Lipopolysaccharide (LPS), a bacterial endotoxin, when position of functional group, chemically named as 1,2,3,8- presented to macrophage produces a proinflammatory tetrahydroxy-6-methyl-9,10-anthraquinone and 1,3,8-trihydroxy- signals and inflammatory mediators like cyclooxygenase 6-methyl-9,10-anthraquinone, respectively. Alaternin has been (COX)-2, NO, and ROS. Three isoforms of NO: neuronal reported with anti-diabetic,10 anti-Alzheimer’s,3 anti- NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS) are the enzymes responsible for catalyzing 20 #These authors contributed equally to this work. the production of NO from L-arginine substrate . The stimulation of iNOS in response to immunological stimuli *Author for correspondence produces NO in nanomolar concentration. Excessive Hyun Ah Jung, Department of Food Science and Human Nutrition, Jeonbuk National University, Jeonju 54896, Republic of Korea. productions of NO leads to oxidation of various cellular Tel: +82-63-270-4882; E-mail: [email protected] contents like proteins, lipids, and DNA.21,11 ROS is Jae Sue Choi, Department of Food and Life Sciences, Pukyoung produced by cells like polymorphonuclear neutrophils National University, Busan 48513, Republic of Korea. (PMNs) that are involved in host-defense mechanism are Tel: +51-629-7547; E-mail: [email protected] 28 Vol. 27, No. 1, 2021 29 well-known effectors of inflammation. The action of diseases involving oxidative stress; anti-inflammatory, ROS, superoxide, for instance, reacts with NO to form anti-AGE, anti-tyrosinase and, anti-CDK activities. The reactive nitrogen species such as peroxynitrite (ONOO) influence of structure on activities of alaternin has not that induces nitrosative stress and pro-inflammatory been fully established. Therefore, we applied a versatile burden to the cell.22 approach to explore and compare and relate the biological The formation of advanced glycation end products properties of alaternin and emodin. (AGEs) occurs via nucleophilic addition of amino group of protein or nucleic acid to the carbonyl group of a Experimental reducing sugar called Maillard reaction. In this reaction, nonenzymatic glycation of proteins or amino acids with Chemicals and reagents – Alaternin and emodin were reducing sugars results in production of a large number of isolated from Cassia obtusifolia Linn. through a column free radicals, carbonyl species, and reactive dicarbonyl chromatographic technique as mentioned by Jung et al. species.23 Several studies have highlighted anti-glycation (2016)3. CellTiter 96 Aqueous Non-Radioactive Cell activity of Cassia species.24-26 Some studies have linked Proliferation Assay Kit was purchased from Promega AGEs with chronic diseases, oxidative stress, and, Corporation (Madison, WI, USA). The bovine serum inflammatory reaction.27-29 Therefore, the discovery of albumin (BSA), LPS, D-(−)-fructose, D-(+)-glucose, glycation inhibitor can provide a therapeutic aspect to aminoguanidine hydrochloride (AG), thioflavin T, L- other related diseases like diabetes.24 DOPA, kojic acid, and mushroom tyrosinase were bought Cyclin-dependent kinases (CDKs) are one of the most from Sigma-Aldrich (St. Louis, MO, USA). Dulbecco’s studied anti-cancer targets that play a vital role in cell modified essential medium (DMEM), penicillin–strep- cycle events. CDK binds to a family of regulatory tomycin, fetal bovine serum (FBS), were procured from proteins called cyclins that phosphorylates specific serine/ Gibco-BRL Life Technologies (Grand Island, NY, USA). threonine residue and forms activated heterodimer Primary and secondary antibodies were obtained from complex, thereby regulating cell cycle progression.30 Cell Signaling Technology Inc. (Beverly, MA, USA) and Inhibition of such kinase can be used as an effective Santa Cruz Biotechnology Inc. (Santa Cruz, CA, USA). strategy to halt uncontrolled cellular proliferation in Sodium azide and K2HPO4, were acquired from Junsei cancer.31 Some of the CDK inhibitors like palbociclib, Chemical Co. Ltd. (Tokyo, Japan) and, L-tyrosine, and ribociclib, and abemaciclib (CDK4/6 inhibitors) have KH2PO4 were purchased from Jannssen Chimica (Geel already been already identified.32 The toxicity profile of Belgium), and Yakuri Pure Chemicals Co. Ltd. (Osaka, individual inhibitory drug needs to be acceptable before Japan), respectively. Cell cycle kinases, Cdk4 (sc-23,896), proceeding into combination and monotherapies. The cyclin D1, Cdk2 (sc-6248), and cyclin A were supplied inhibition specificity at selective CDK like CDK4/6 and by Takara Bio, Inc. (Takara Bio, CA, USA). 96-Well CDK2 have shown to be associated with minimal side polyvinylidene fluoride (PVDF) filter and membrane effect when compared to the non-selective ones.33,30 The (Immobilon-P) was purchased from EMD Millipore presence of ROS has also shown to control cell cycle (Millipore, CA, USA). Ultra-pure grade water was used progression by influencing the activity of cyclins and through and all graded chemicals/solvents used all over CDKs.34-36 the experiment were purchased from the commercial Tyrosinase is a copper-containing metalloenzyme sources. Unless otherwise stated, all the solvents and capable of oxidizing tyrosine to L-DOPA or o-diphenol chemicals were acquired from Sigma-Aldrich (St. Louis, (3, 4-dihydroxyphenylalanine) and subsequently converting MO, USA). L-DOPA to dopaquinone (o-quinones).37 This transformed Cell culture – RAW 264.7 cell line was purchased dopaquinone leads to the formation of melanin which is from American Type Culture Collection (Rockville, MD, responsible for skin disorders like hyperpigmentation and USA) and cultured in Dulbecco’s modified essential enzymatic browning of foods. Along with the production medium (DMEM) that comprised of penicillin (100 units/ of melanin, highly reactive DOPA-quinones are also mL), streptomycin (100 μg/mL), and 10% heat- described to damage neurons and cause cell death.38 inactivated fetal bovine serum (FBS). Cells were grown to Our previous study demonstrated the anti-oxidant,39 70-80% confluency and then trypsinized and seeded for human monoamine oxidase inhibitory14 and hepato- experiments. Cells were maintained at 37 ºC in a 13 proprotective nature of alaternin. This study was humidified atmosphere of 5% CO2 at all times. undertaken to evaluate the potency of alaternin against Cell viability assay – The survival of LPS stimulated 30 Natural Product Sciences RAW 264.7 cell was determined using MTS assay CS analyzer. method as reported by Lee et al.40 Briefly, the formation Evaluation of glycated end products formation To of formazan product from tetrazolium compound was quantify the anti-glycation activity of alaternin,
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