VIETNAM NATIONAL UNIVERSITY OF AGRICULTURE FACULTY OF BIOTECHNOLOGY -oOo - UNDERGRADUATE THESIS TYROSINASE INHIBITORY ACTIVITIES OF ZERUMBONE IN ZINGIBER ZERUMBET SMITH AND RUTIN IN SOPHORA JAPONICA HANOI, 02/2021 VIETNAM NATIONAL UNIVERSITY OF AGRICULTURE FACULTY OF BIOTECHNOLOGY -oOo - UNDERGRADUATE THESIS TYROSINASE INHIBITORY ACTIVITIES OF ZERUMBONE IN ZINGIBER ZERUMBET SMITH AND RUTIN IN SOPHORA JAPONICA Student name : Nguyen Thi Lan Student code : 610638 Department : Biotechnology Supervisor : Phi Thi Cam Mien, MSc HANOI, 02/2021 COMMITMENT I certainly assure that all results, images and research data were done by me, have not been previuosly submitted by any other undergraduate education institution All the information quoted in the thesis which is traced to the science sources and any help is appreciated I accept responsibility for my pledge to the Academy and the Council Hanoi, January 30th, 2021 Nguyen Thi Lan i ACKNOWLEDGEMENTS After a period of working and researching, I have finally completed a graduation thesis with the topic: “Tyrosinase inhibitory activities of ZER in Zingiber zerumbet Smith and Rutin in Sophora japonica” This project was conducted at Institute of Research and Development of Microalgae, Faculty of Agronomy in Vietnam National University of Agriculture (VNUA) and Vietnam Academy of Science and Technology (VAST) This graduation thesis is the last step to help me complete the training program of VNUA within 4.5 years To graduate on time is always the wish of me and other Advanced Biotechnology students VNUA not only gives students knowledge and skills to enter the life, herely we are forged in the enivironment with many different pressures It is these pressures that make Biotechnology students stronger, persistentand be able to endure Together overcoming such difficulties that are all my friends and relatives who have helped me in challenge time, I am very grateful to all of them during the past school years To be done this gradutation thesis, I have received enthusiastic help from you at the Institute of Research and Development of Microalage I sincerely thank Phi Thi Cam Mien and Ha Viet Cuong for directing guidance, enthusiastic guidance and giving motivation while I was doing experiments My deeply thanks come to all our friends during time we study in VNUA Their kindly help, care, motivation gave us strength and lift us up all the trouble for the rest of our life Hanoi, January 30th, 2021 Student Nguyen Thi Lan ii INDEX COMMITMENT i ACKNOWLEDGEMENTS ii INDEX iii LIST OF TABLES v LIST OF FIGURES vi LIST OF ABBREVIATIONS vii ABSTRACT CHAPTER I INTRODUCTION 1.1 Introduction 1.2 Objectives and requirements 1.2.1 Objectives .3 1.2.2 Requirements CHAPTER 2: LITERATURE OVERVIEW 2.1 Ginger- Zingiberaceae family and ZER in Z zerumbet Smith introduction 2.1.1 Ginger- Zingiberaceae family introduction 2.1.2 Zingiber zerumbet Smith introduction 2.1.3 ZER overview 10 2.2 Sophora japonica bud flowers and Rutin overview .14 2.2.1 Sophora japonica introduction 14 2.2.2 Rutin overview 15 2.4 The mechanism of melanin pigment production in skin color .18 2.4.1 Enzyme tyrosinase overview .18 2.4.2 The mechanism of tyrosinase activity in skin color 21 2.4.3 Tyrosinase inhibitor sources 23 2.4 Enzyme kinetic .26 2.5 Reseaches in tyrosinase inhibitory activities of Secondary natural products in Vietnam and the world 29 2.5.1 In Vietnam 29 2.5.2 In the world 30 CHAPTER 3: MATERIALS AND METHODS 31 3.1 Materials, reagents and equipments .31 iii 3.1.1 Matreials 31 3.1.2 Reagents .31 3.1.2 Equipments 31 3.1.3 Time and location 31 3.2 Contents 31 3.3 Methods 32 3.3.1 ZER isolation in the different sample states by Solvent extraction 32 3.3.2 Extracting of Rutin 36 3.3 Reagent preparation 37 3.3.1 Potassium phosphate buffer 0,1M, pH = 6,8 37 3.3.3 L-DOPA substrate ((3-(3,4-Dihydroxyphenyl)-L-alanine) 38 3.3.3 Arbutin disulting 38 3.3.4 DMSO solvent (Dimethyl sulfoxide) 39 3.3.5 Enzyme mushroom tyrosinase .40 3.4 The ZER and Rutin extracting solution 40 3.5 Tyrosinase inhibitory activities experiments from ZER and Rutin 41 CHAPTER 4: RESULTS AND DISCUSSION 44 4.1 Results 44 4.1.1 The effect of different samplesin the productivity of ZER 44 4.1.2 The effect of the extracting solvents in the productivity of Rutin from Sophora japonica bud flowers .45 4.1.3 Tyrosinase inhibitory activities of ZER and Rutin 45 4.1.5 Enyme kinetics of ZER and Rutin inhibitors 48 4.2 Discussion .49 CHAPTER CONCLUSION 51 REFERENCES 52 iv LIST OF TABLES Table 2.1: Some species and distribution in Zingiberaceae family Table 2.2: Chemical compounds in Zingiberaceae family[2] .5 Table 2.3: Characteristic features of zerumbone 11 Table 2.4: Different species of plants and their parts used for isolation of Rutin .16 Table 2.5: The physicochemical properties of Rutin 17 Table 3.1: The different concentrations of Arbutin .39 Table 3.6: The volume of components in each ELISA well 42 Table 3.7: The volume of components in each ELISA well 43 Table 4.1 The total of ZER isolated from fresh rhizomes, leaves and stems .44 Table 4.2: The different solvents efficiency in the productivity of Rutin .45 Table 4.3 The absorbtiontion of ZER inhibitor in anti-tyrosinase activity assay at 492nm 47 Table 4.4 The absorbtion of Rutin inhibitor in anti-tyrosinase activity assay at 492nm .47 Table 4.5: The percent of Tyrosianse inhibitory from ZER and Rutin 47 v LIST OF FIGURES Figure 2.1 (a) Zingiber zerumbet (L.) Roscoe ex Sm tree, (b) rhizome Figure 2.2: The terpenes compounds isolating from the Z zerumbet Smith Figure 2.3: The polyphenols compounds isolating from Z zerumbet Smith Figure 2.4: The structure of Zerumbone 10 Figure 2.5: Saphora japonica bud flowers .15 Figure 2.6: Rutin chemical structure .15 Figure 2.7: Soxhlet apparatus 18 Figure 2.8: Structure of tyrosinase 19 Figure 2.9: Production of different pigments by melanosomes 22 Figure 2.10: Structure or melanosome distribution for different racil groups 23 Figure 2.11: The effects of substrate concentration on a reaction initial velocity 28 Figure 2.12: Different types of enzyme inhibition show on a Lineweaver- Burk plot 29 Figure 3.1: Rhizome (a), stem (b) and leaves soaking (c) and n-hexan solvent (d) 33 Figure 3.3: Column for the isolation of dichloromethane .35 Figure 3.5: S Japonica bud flowers extracting in ethyl acetate (a), ethanol 96o and pure water (c) by Soxhlet apparatus 37 Figure 3.6: L-DOPA (3-(3,4-Dihydroxyphenyl)-L-alanine) 38 Figure 3.7: Arbutin 39 Figure 3.8: DMSO solvent (Dimethyl sulfoxide) 39 Figure 3.9: Enzyme mushroom tyrosinase 40 Figure 3.10: ELISA MR-96A Mindray Reader (96 wells) 41 Figure 4.1 ZER extract 44 Figure 4.2 The determination of tyrosinase concentrations 46 Figure 4.3 The percent inhibition of tyrosinase activity from ZER and Rutin 48 Figure 4.4 Linewear- Burk plot for tyrosinase enzyme inhibition of by ZER and Rutin (a), (b) Tyrosinase inhibition was analyzed in the presence of different sample concentration as follow 50, 400, 800 and 1000 µg/mL The effect of ZER and Rutin in the presence of different concentration of substrate L- DOPA 1, 2, 3, 5mM 49 vi LIST OF ABBREVIATIONS Zerumbone : ZER Ultraviolet : UV Reactive oxygen species : ROS Lactic acid bacteria : LAB Substrate complex : ES AND : Deoxyribonucleic acid L-DOPA : 3-(3,4-Dihydroxyphenyl)-L-alanine) HQ : Hydroquinone DMSO : Dimethylsulfoside Km : Michenlis Menten constant IC50 : The percent of tyrosinase at 50% vii ABSTRACT The aims of this study were to determine the ZER chemical structure, the ZER productivity in different sample from Z zerumbet Smith and the Rutin yied from S japonica bud flowers in different solvents, then develop the whitening cream from the extract and finally evaluate the satisfaction by users The results showed the Solvents extraction technique has given the productivity of ZER in different samples rhizomes (0.35%), leaves (0.1%) and stem (0.034%) in the fresh material In this review paper showed that the content of Rutin increased with the increase of processing temperature, but if the processing time is too long Rutin content will gradually decrease Under certain processing conditions, different solvents also have effected to the productivity of Rutin, then the Rutin content in water 3.3 %, Ethanol 96° (23.8%) and Ethyl acetate (15.4%) Following the calculation of tyrosinase inhibition percentage from ZER and Rutin, the ZER and Rutin concentrations were lowest at 50 ug/mL, reaching 13.38%, 4.55%, when at the highest concentration 1000 ug/mL reaching 86.46% and 70.03% Futhermore, the ZER and Rutin extracts were examined for anti-tyrosinase activity compared with Arbutin IC50 of Arbutin was 100.80 µg/mL (217.8 mM) whereas IC 50 of ZER and Rutin extract were 265.8 µg/mL and 512.7 µg/mL In addition, The Km values of ZER and Rutin were 1.843 mM and 2.195 mM, for L-DOPA substrates and both are competitive inhibitos ZER has been lower Km that mean is greater than Rutin in tyrosinase inhibitory activities It can be concluded that ZER and Rutin extracts can be applied in cosmetic industry to increase the value of ZER and Rutin wast substrates L-DOPA different concentrations 1, 2, and 5mM is added each well Incubation commenced for 30 minutes at room temperature Optical densities of the wells are determined at 492nm with ELISA reader Experiment 3: Tyrosianse inhibitory activity of ZERat different concentration In 96 well plates,70 µL of different ZERextract concentrations is combined with 30 µL of tyrosinase (1000U/mL in potassium phosphate) in triplicate After incubation at room temperature for min, 110µl of substrates L-DOPA 5mM is added each well Incubation commenced for 30 minutes at room temperature Optical densities of the wells are determined at 492nm with ELISA reader The percent inhibition of tyrosinase activity is calculated as follow: % inhibition= (A-B)/A× 100 Where A= absorbtionance at 492nm without test sample, and B= absorbtionance at 492 nm with test sample Table 3.6: The volume of components in each ELISA well No Components Volume (µL) ZERextract concentrations/buffer/arbutin 70 Enzyme tyrosinase 30 L-DOPA subtrate 110 Total volume 210 Experimental design: Column 1: blank, negative control, positive control Column 2: ZERconcentration at 50 µg/mL Column 3: ZERconcentration at 400 µg/mL Column 4: ZERconcentration at 800 µg/mL Column 5: ZERconcentration at 1000 µg/mL Experiment 4: Tyrosianse inhibitory activity of Rutin at different concentration The percent inhibition of tyrosinase activity is calculated as follow: 42 % inhibition= In 96 well plates,70 µL of different Rutin extract concentrations is combined with 30 µL of tyrosinase (1000U/mL in potassium phosphate) in triplicate After incubation at room temperature for min, 110µl of substrates L-DOPA 5mM is added each well Incubation commenced for 30 at room temperature Optical densities of the wells are determined at 492nm with ELISA reader (A-B)/A× 100 Where A= absorbtionance at 492nm without test sample, and B= absorbtionance at 492 nm with test sample Table 3.7: The volume of components in each ELISA well No Components Volume (µL) Rutin extract concentrations/buffer/arbutin 70 Enzyme tyrosinase 30 L-DOPA subtrate 110 Total volume 210 Experimental design Column 1: blank, negative control, positive control Column 2: Rutin concentration at 50 µg/mL Column 3: Rutin concentration at 400 µg/mL Column 4: Rutin concentration at 800 µg/mL Column 5: Rutin concentration at 1000 µg/mL Experiment 5: Determination of the inhibition type and inhibition constant In 96 well plates,70 µL of 50 µg/mL Rutin/ ZER extract concentration is combined with 30 µL of tyrosinase (1000U/mL in potassium phosphate) in triplicate After incubation at room temperature for minutes, 110µl of substrates L-DOPA 1,2,3, 5mM is added each well Incubation commenced for 30 minutes at room temperature Optical densities of the wells are determined at 492nm with ELISA reader Do the experiments as well as in 400, 800 and 1000 µg/mL in triplicate 43 CHAPTER 4: RESULTS AND DISCUSSION 4.1 Results 4.1.1 The effect of sample states in the productivity of ZER from Z zerumbet Smith Zingiber zerumbet Smith is a plant which grows mainly in Southeast Asia As a main component extracted from the essential volatile oil of Z zerumbet, ZER is a phytochemical compound used for its properties Figure 4.1 ZER extract According to the process of isolating the state-level project ZER by Assoc.Van Ngoc Huong Then, the essential oil is fractionally crystallized according to temperature and time to obtain ZER, reaching the productivity of ZER 0.38% under fresh ginger material ZER isolation method by hydraulic pressing, extraction and segmental crystallization method presented in section 3.1.2.2, obtained the highest ZER content of 0.35% according to fresh materials ZER percentages of samples taken from Z zerumbet are shown in Table 4.1 Table 4.1 The total of ZER isolated from fresh rhizomes, leaves and stems Fresh weigh (g) ZER (g) The percent ZER (%) Rhizome 50 0.175 0.35 Leaves 50 0.05 0.1 Stem 50 0.017 0.034 44 The percent components of ZER extracted from the rhizomes, leaves and stems from Z zerumbet were: 0.35%, 0.1% and 0.034%, respectively The rhizome sample obtained the highest ZER content, the stem contains the most water getting the least ZER content 4.1.2 The effect of the extracting solvents in the productivity of Rutin from Sophora japonica bud flowers The productivity of extraction differed by using different solvents, extraction of 10 g dry S janponica flowers and buds by ethanol solvent produced 2.38 g extract, while applying the same method of extraction with ethylacetate as a solvent produced 1.54 g extract and water as solvent produced 0.32 g That means respectively, 23.8%, 15.4% and 3.3% as percentage productivitys The highest extraction productivity by using highest extraction productivity by using ethanol 96o solvent was with Soxhlet method Table 4.2: The different solvents efficiency in the productivity of Rutin Initial weight (g) Extracting weight (g) The percent of Rutin (%) Pure water 10 0.32 3.3 Ethanol 96o 10 2.38 23.8 Ethyl acetate 10 1.54 15.4 Solvents However, Ethanol 96o solvent is more commonly used than Ethyl acetate because of its low cost and polarity The solvent of distilled water does not last long, be easily damaged 4.1.3 Tyrosinase inhibitory activities of ZER and Rutin 4.1.3.1 Determination of tyrosinase concentration The concentration of the tyrosianse enzyme in the melanin-producing reaction is just as important as the number of workers handling part of the work remains constant Evaluate the reaction speed in the absence of a participating inhibitor, from which a maximum concentration of 30 U can be obtained The more enzymes involved 45 in the 5mM L-DOPA substrate breakdown have an optimal effect However, when the L-DOPA substrate concentration does not change, with a concentration of 50U, the effect decreases according to the chart shown below Figure 4.2 The determination of tyrosinase concentrations Determination of substrate L-DOPA concentrations The negative control has the absorbtiontion of 1.846 Evaluation of ZER and Rutin is ability to inhibit the enzyme tyrosinase by measuring the fluorescence absorbtionance at 492 nm Product of the process is L-Dopaquinon, the main ingredient that creates the phenomenon of pigmentation, darkening of the skin on the body The fluorescence absorption of L-Dopaquinon by two inhibitors ZER and Rutin was presented in Tables 4.3 and Table 4.4, shown that ZER inhibitor ability was better than Rutin 46 Table 4.3 The absorbtiontion of ZER inhibitor in anti-tyrosinase activity assay at 492nm Concentration (µg/mL) 50 400 800 1000 1.602 0.591 0.34 0.251 1.59 0.537 0.361 0.255 1.605 0.546 0.355 0.246 Mean value 1.599±0.008 0.558±0.006 0.352±0.008 0.25±0.045 Time Table 4.4 The absorbtion of Rutin inhibitor in anti-tyrosinase activity assay at 492nm Concentration (µg/mL) 50 400 800 1000 1.792 1.052 0.692 0.55 1.790 1.130 0.675 0.597 1.704 0.995 0.68 0.565 Mean value 1.762±0.007 1.059±0.0081 0.68±0.008 0.57±0.05 Time The percent inhibition of tyrosinase activity is calculated as follow: % inhibition= (A-B)/A× 100 Where A= absorbtionance at 492nm without test sample, and B= absorbtionance at 492 nm with test sample: Table 4.5: The percent of Tyrosianse inhibitory from ZER and Rutin Concentration (µg/mL) The percent inhibitory (%) 50 400 800 1000 ZER 13.38 69.77 80.93 86.46 Rutin 4.55 42.63 63.16 70.03 47 Following the calculation of tyrosinase inhibition percentage from ZER and Rutin, the ZER and Rutin concentrations were lowest at 50 ug/mL, reaching 13.38%, 4.55%, when at the highest concentration 1000 ug/mL reaching 86.46% and 70.03% Figure 4.3 The percent inhibition of tyrosinase activity from ZER and Rutin The result was expressed as the half maximal inhibitory concentration (IC 50 ) of ZER and Rutin extract compared with Arbutin (positive control) IC 50 represents the concentration of extract (or Arbutin) that is required for 50% inhibition of tyrosinase activity The ZER and Rutin extracts were examined for anti-tyrosinase activity compared with Arbutin IC50 of Arbutin was 100.80 µg/mL (217.8 mM) whereas IC 50 of ZER and Rutin extract were 265.8 µg/mL and 512.7 µg/mL (Figure 4.3) which were more less than Arbutin However, ZER and Rutin extracs are inexpensive and more efficiency and be from natural sources 4.1.5 Enyme kinetics of ZER and Rutin inhibitors To determine the inhibitory mechanism of ZER and Rutin, we used a kinetic model: Lineweaver–Burk plots Enzyme inhibition was evaluated using various concentrations of ZER and Rutin different concentrations of L-DOPA as substrates, respectively Thus, we performed kinetic analyses using Lineweaver-Burk as Figure 48 4.4 (a, b), the graphical analysis of the Lineweaver-Burk plot for ZER and Rutin against tyrosinase showed competitive inhibition, as treatment with ZER and Rutin resulted in double reciprocal straight line plots with different slopes that increased the y-axis at the same point y = ax+ b = ] + The graphical analysis of ZER: y= 16.92+ 9.812  Km= 1.843 mM Rutin: y= 29.065+ 13.34  Km= 2.195 mM (a) (b) Figure 4.4 Linewear- Burk plot for tyrosinase enzyme inhibition of by ZER and Rutin (a), (b) Tyrosinase inhibition was analyzed in the presence of different sample concentration as follow 50, 400, 800 and 1000 µg/mL The effect of ZER and Rutin in the presence of different concentration of substrate L- DOPA 1, 2, 3, 5mM These data suggested that ZER and Rutin can competitively interact with substrate-binding site in order to inhibit enzyme activity when co-treated with various concentrations of L-DOPA as substrates Lineweaver–Burk plot is a well-accepted method for analyzing the enzyme inhibition type and determining the Km value for an enzyme inhibitor complex, where in the Km is represented by the value of the x-axis As shown in Figure 4.4 and 4.5, the Km values of ZER and Rutin were 1.843 mM and 2.195 mM, for L-DOPA substrates, respectively The Km values represents concentrations required to form an enzyme inhibitor complex Thus, inhibitors with lower Km values means greater tyrosinase inhibitory activity, suggesting it could be useful in the development of preventive and therapeutic agents 4.2 Discussion This review has clearly indicated that ZER from Zingiber zerumbet Smith possesses various beneficial in vitro and in vivo biological activities The findings 49 from all the researches reviewed in this paper are conclusive evidences that ZER is a strong potential candidate for anticancer compound There is need to conduct animal studies and human clinical trials to ascertain the efficacy, usefulness, and safety of this compound as an intended pharmaceutical drug To determine the cosmetic drug to conduct between ZER and Rutin radio 1:1 in tyrosinase inhibitory activities 50 CHAPTER CONCLUSION As a main component extracted from the essential volatile oil of Zingiber zerumbet Smith, ZER is a phytochemical compound used for its properties against virus infection, inflammatory diseases, treatment of leukemia and cancers ZER in total has three double bonds (one isolated and two conjugated), as well as an 11membrane ring structure containing a double conjugated carbonyl group In this review paper, the Solvents extraction technique has given the productivity of ZER in different samples rhizomes (0.35%), leaves (0.1%) and stem (0.034%) in the fresh material The results showed that the content of Rutin increased with the increase of processing temperature, but if the processing time is too long Rutin content will gradually decrease Under certain processing conditions, different solvents also have effected to the productivity of Rutin, then the Rutin content in water 3.3 %, Ethanol 96° (23.8%) and Ethyl acetate (15.4) Following the calculation of tyrosinase inhibition percentage from ZER and Rutin, the ZER and Rutin concentrations were lowest at 50 ug/mL, reaching 13.38%, 4.55%, when at the highest concentration 1000 ug/mL reaching 86.46% and 70.03% The ZER and Rutin extracts were examined for anti-tyrosinase activity compared with Arbutin IC50 of Arbutin was 100.80 µg/mL (217.8 mM) whereas IC 50 of ZER and Rutin extract were 265.8 µg/mL and 512.7 µg/mL The Km values of ZER and Rutin were 1.843 mM and 2.195 mM, for L-DOPA substrates ZER has 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