Histological effects of Aqueous extract from Aquilaria malaccensis and Aquilaria subintegra towards ICR mice

<p>The study was conducted to investigate the acute toxicity of aqueous extract from Aquilaria</p><p>malaccensis (AMAE) and Aquilaria subintegra (ASAE) leaves and their histological effects</p><p>on several organ in ICR mice. Comp...

Full description

Saved in:
Bibliographic Details
Main Author: Azam Muzafar Ahmad Mokhtar
Format: thesis
Language:eng
Published: 2022
Subjects:
Online Access:https://ir.upsi.edu.my/detailsg.php?det=9267
Tags: Add Tag
No Tags, Be the first to tag this record!
id oai:ir.upsi.edu.my:9267
record_format uketd_dc
institution Universiti Pendidikan Sultan Idris
collection UPSI Digital Repository
language eng
topic QH Natural history
spellingShingle QH Natural history
Azam Muzafar Ahmad Mokhtar
Histological effects of Aqueous extract from Aquilaria malaccensis and Aquilaria subintegra towards ICR mice
description <p>The study was conducted to investigate the acute toxicity of aqueous extract from Aquilaria</p><p>malaccensis (AMAE) and Aquilaria subintegra (ASAE) leaves and their histological effects</p><p>on several organ in ICR mice. Comparison between both extracts was included in order to</p><p>determine which toxicity is more potent. A total of 156 ICR mice was used in this study</p><p>consisted of 78 male and 78 female with the age of 12 weeks old. The mice were divided</p><p>into 13 groups containing 12 mice (6 males and 6 females) in each group. 12 groups orally</p><p>received one type of extract either AMAE or ASAE with only one type concentration. The</p><p>concentrations used were 4000, 5000, 6000, 7000, 8000, 9000 mg/kg body weight. One</p><p>group on the other hand act as the control and treated with distilled water. Extract</p><p>administration was conducted only once on the first day. Mice body weight and organ weight</p><p>were compared and analyzed using one-way ANOVA and evaluation of abnormalities in</p><p>term of appearance and behavioral were conducted. After the 14th day, mice undergone</p><p>euthanisation approved by UPSI ethics committee (reference number: 2021-0002-03) in</p><p>order to conduct histological analysis on their organs which were liver, kidney and stomach.</p><p>Evaluation on their cellular structure were also conducted. Results showed significant</p><p>differences in both AMAE and ASAE male mice body weight. AMAE also showed higher</p><p>significant difference when compared with ASAE using t-test. On top of that, all treated mice</p><p>displayed drowsiness and their fur seems to be affected, primarily AMAE and ASAE female</p><p>mice face fur which appeared to be balding. Faeces condition in some AMAE treatment</p><p>groups also showed abnormalities. In terms of histological evaluation, mice liver, kidney and</p><p>stomach tissues were also affected. Some livers portal vein and sinusoids in AMAE</p><p>treatment were filled with blood. All treated mice glomerulus expanded while some</p><p>glomeruli burst in AMAE treatment. All treated mice mucosa length reduced and some</p><p>gastric glands in AMAE treatment showed abnormal changes. Therefore, it can be stated that</p><p>both Aquilaria malaccensis and Aquilaria subintegra is toxic due to the adverse effects it</p><p>caused on mice appearance, behaviour and organ tissues. Furthermore, Aquilaria</p><p>malaccensis showed more adverse reactions compared to Aquilaria subintegra indicating</p><p>higher toxicity. This implicates that both Aquilaria malaccensis and Aquilaria subintegra</p><p>can be toxic and unsafe if being use in a higher concentration.</p>
format thesis
qualification_name
qualification_level Master's degree
author Azam Muzafar Ahmad Mokhtar
author_facet Azam Muzafar Ahmad Mokhtar
author_sort Azam Muzafar Ahmad Mokhtar
title Histological effects of Aqueous extract from Aquilaria malaccensis and Aquilaria subintegra towards ICR mice
title_short Histological effects of Aqueous extract from Aquilaria malaccensis and Aquilaria subintegra towards ICR mice
title_full Histological effects of Aqueous extract from Aquilaria malaccensis and Aquilaria subintegra towards ICR mice
title_fullStr Histological effects of Aqueous extract from Aquilaria malaccensis and Aquilaria subintegra towards ICR mice
title_full_unstemmed Histological effects of Aqueous extract from Aquilaria malaccensis and Aquilaria subintegra towards ICR mice
title_sort histological effects of aqueous extract from aquilaria malaccensis and aquilaria subintegra towards icr mice
granting_institution Universiti Pendidikan Sultan Idris
granting_department Fakulti Sains dan Matematik
publishDate 2022
url https://ir.upsi.edu.my/detailsg.php?det=9267
_version_ 1776104609409925120
spelling oai:ir.upsi.edu.my:92672023-08-02 Histological effects of Aqueous extract from Aquilaria malaccensis and Aquilaria subintegra towards ICR mice 2022 Azam Muzafar Ahmad Mokhtar QH Natural history <p>The study was conducted to investigate the acute toxicity of aqueous extract from Aquilaria</p><p>malaccensis (AMAE) and Aquilaria subintegra (ASAE) leaves and their histological effects</p><p>on several organ in ICR mice. Comparison between both extracts was included in order to</p><p>determine which toxicity is more potent. A total of 156 ICR mice was used in this study</p><p>consisted of 78 male and 78 female with the age of 12 weeks old. The mice were divided</p><p>into 13 groups containing 12 mice (6 males and 6 females) in each group. 12 groups orally</p><p>received one type of extract either AMAE or ASAE with only one type concentration. The</p><p>concentrations used were 4000, 5000, 6000, 7000, 8000, 9000 mg/kg body weight. One</p><p>group on the other hand act as the control and treated with distilled water. Extract</p><p>administration was conducted only once on the first day. Mice body weight and organ weight</p><p>were compared and analyzed using one-way ANOVA and evaluation of abnormalities in</p><p>term of appearance and behavioral were conducted. After the 14th day, mice undergone</p><p>euthanisation approved by UPSI ethics committee (reference number: 2021-0002-03) in</p><p>order to conduct histological analysis on their organs which were liver, kidney and stomach.</p><p>Evaluation on their cellular structure were also conducted. Results showed significant</p><p>differences in both AMAE and ASAE male mice body weight. AMAE also showed higher</p><p>significant difference when compared with ASAE using t-test. On top of that, all treated mice</p><p>displayed drowsiness and their fur seems to be affected, primarily AMAE and ASAE female</p><p>mice face fur which appeared to be balding. Faeces condition in some AMAE treatment</p><p>groups also showed abnormalities. In terms of histological evaluation, mice liver, kidney and</p><p>stomach tissues were also affected. Some livers portal vein and sinusoids in AMAE</p><p>treatment were filled with blood. All treated mice glomerulus expanded while some</p><p>glomeruli burst in AMAE treatment. All treated mice mucosa length reduced and some</p><p>gastric glands in AMAE treatment showed abnormal changes. Therefore, it can be stated that</p><p>both Aquilaria malaccensis and Aquilaria subintegra is toxic due to the adverse effects it</p><p>caused on mice appearance, behaviour and organ tissues. Furthermore, Aquilaria</p><p>malaccensis showed more adverse reactions compared to Aquilaria subintegra indicating</p><p>higher toxicity. This implicates that both Aquilaria malaccensis and Aquilaria subintegra</p><p>can be toxic and unsafe if being use in a higher concentration.</p> 2022 thesis https://ir.upsi.edu.my/detailsg.php?det=9267 https://ir.upsi.edu.my/detailsg.php?det=9267 text eng closedAccess Masters Universiti Pendidikan Sultan Idris Fakulti Sains dan Matematik <p>Abba S, Omotoso O Dare, & Faculty of Basic Medical Sciences, Department of Anatomy, College of Health Sciences, Kogi State University Anyigba, Nigeria. (2018). Hemorrhagic Centrolobar Necrosis and Cytoplasmic Vacuolation of the Hepatocytes in Syzygium Guineense Chronic Treated Mice. International Journal of Anatomy and Applied Physiology, 99102. https://doi.org/10.19070/2572-7451-1800018</p><p>Abdul Razak, R. N. H., Ismail, F., Md Isa, M. L., Abdul Wahab, A. Y., Muhammad, H., Ramli, R., & Raja Ismail, R. A. S. (2019). Ameliorative Effects of Aquilaria malaccensis Leaves Aqueous Extract on Reproductive Toxicity Induced by Cyclophosphamide inMaleRats. Malaysian Journal of Medical Sciences,26(1), 44 57. https://doi.org/10.21315/mjms2019.26.1.4</p><p>Abera, B. (2014). Medicinal plants used in traditional medicine by Oromo people, Ghimbi District,Southwest Ethiopia. Journal of Ethnobiology and Ethnomedicine,10(1), 40. https://doi.org/10.1186/1746-4269-10-40</p><p>Abeysekera, R. A., Wijetunge, S., Nanayakkara, N., Wazil, A. W. M.,Ratnatunga, N. V. I., Jayalath, T., & Medagama, A. (2015).Starfruit toxicity:A cause of both acute kidney injury and chronic kidney disease: a reportof two cases. BMC Research Notes, 8(1), 796. https://doi.org/10.1186/s13104-015-1640-8</p><p>Abid, R., & Mahmood, R. (2018). Acute and sub-acute oral toxicity of ethanol extract of Cassia fistula fruit in male rats. Avicenna Journal of Phytomedicine, (Online First). https://doi.org/10.22038/ajp.2018.11615</p><p>Acharzo, A. K., Bodhankar, S., Mohan, & Thakurdesai, P.(2015). Acuteand repeated doses (28 days)oral toxicity study of glycosidesbased standardizedfenugreek seed extract in laboratory mice. Regulatory Toxicology and Pharmacology, 72(2), 323334. https://doi.org/10.1016/j.yrtph.2015.05.003</p><p>Adamson, R. H. (2016). The acute lethal dose 50 (LD50) of caffeine in albino rats. Regulatory Toxicology and Pharmacology, 80, 274276. https://doi.org/10.1016/j.yrtph.2016.07.011</p><p>Ahmed, M., & Azmat, A. (2014). Acute toxicity (lethal dose 50 calculation) and histopathological effects of methanolic extract of Berberis vulgaris in mice. World J. Pharmacol. Res., 3, 14391448.</p><p>Aimi Zafirah, Lee, S. Y., & Mohamed, R. (2017). Pharmacological properties of agarwood tea derived from Aquilaria (Thymelaeaceae) leaves: An emerging contemporary herbal drink. Journal of Herbal Medicine, 10, 3744. https://doi.org/10.1016/j.hermed.2017.06.002</p><p>Aimi Zafirah, Tajuddin, S. N., Runglawan, S., Chaveerach, A., UH, A., MN, M., & Mohamed, R. (2018). Chemical constituents and toxicity effects of leaves from several agarwood tree species (Aquilaria). JOURNAL OF TROPICAL FOREST SCIENCE, 30(3), 342353. https://doi.org/10.26525/jtfs2018.30.3.342353</p><p>Ajani, E., Sabiu, S., Bamisaye, F., Ibrahim, S., & Salau, B. (2015). Evaluation of the Acute and Sub-acute Toxicity Effects of Ethanolic Leaves Extract of Lagenaria brevifolia (Bitter gourd) on Hepatic and Renal Function of Rats. European Journal of Medicinal Plants, 5(2), 210219. https://doi.org/10.9734/EJMP/2015/13400</p><p>Ajao, M. Y., & Akindele, A. J. (2013). Anxiolytic and sedative properties of hydroethanolic extract of Telfairia occidentalis leaves in mice.Revista Brasileira de Farmacognosia, 23(2), 301309. https://doi.org/10.1590/S0102-695X2012005000138</p><p>Akter, S., Islam, M. T., Zulkefeli, M., & Khan, S. I. (2013). Agarwood production-a multidisciplinary field to be explored in Bangladesh. International Journal of Pharmaceutical and Life Sciences, 2(1), 2232.</p><p>Alam, J., Mujahid, Md., Badruddeen, Jahan, Y., Bagga, P., & Rahman, Md. A. (2017). Hepatoprotective potential of ethanolic extract of Aquilaria agallocha leaves against paracetamol induced hepatotoxicity in SD rats. Journal of Traditional and Complementary Medicine, 7(1), 913. https://doi.org/10.1016/j.jtcme.2015.12.006</p><p>Alebachew, M., Kinfu, Y., Makonnen, E., Bekuretsion, Y., Urga, K., & Afework, M. (2015). Toxicological evaluation of methanol leaves extract of Vernonia bipontini Vatke in blood, liver and kidney tissues of mice. African Health Sciences, 14(4), 1012. https://doi.org/10.4314/ahs.v14i4.33</p><p>Ali, H. S., Caballero, C. E., Maunting, N. G., Patricio, M. J. S., & Reyes, L. D. D. (2014). The Effect of Peperomia pellucida (Shiny Bush) Leaf Crude Extract on the Body Temperature of Boiled Milk-Induced Male White Mice. Advancing Pharmacy Research, 1(1).</p><p>Anisuzzman, Md., Hasan, Md. M., Acharzo, A. K., Das, A. K., & Rahman, S. (2017). In Vivo and In Vitro Evaluation of Pharmacological Potentials of Secondary Bioactive Metabolites of Dalbergia candenatensis Leaves. Evidence-Based Complementary and Alternative Medicine, 2017, 110. https://doi.org/10.1155/2017/5034827</p><p>Aniszewski, T. (2015). Alkaloids: Chemistry, biology, ecology, and applications (Second). Elsevier.</p><p>Arantes-Rodrigues, R., Henriques, A., Pinto-Leite, R., Faustino-Rocha, A., Pinho-Oliveira, J., Teixeira-Guedes, C., Oliveira,P. A. (2012). The effects of repeated oral gavage on the health of male CD-1 mice. Lab Animal, 41(5), 129134. https://doi.org/10.1038/laban0512-129</p><p>Arsad, S., Esa, N., & Hamzah, H. (2014). Histopathologic Changes in Liver and Kidney Tissues from Male Sprague Dawley Rats Treated with Rhaphidophora Decursiva (Roxb.) Schott Extract. Journal of Cytology & Histology, s4(01). https://doi.org/10.4172/2157-7099.S4-001</p><p>Asma Wil, Adila Omar, Noorhuda Awang@Ibrahim, & Saiful Tajuddin. (2014). In Vitro Antioxidant Activity andPhytochemical Screening of A. Malaccensis Leaf Extracts. Journal of Chemical and Pharmaceutical Research, 6(12), 688693.</p><p>Assouly, P. (2018). Hair Loss Associated With Cucurbit Poisoning. JAMA Dermatology, 154(5), 617. https://doi.org/10.1001/jamadermatol.2017.6128</p><p>Azwanida. (2015). A Review on the Extraction Methods Use in Medicinal Plants, Principle, Strength and Limitation. Medicinal & Aromatic Plants, 04(03). https://doi.org/10.4172/2167-0412.1000196</p><p>Bahrani, H.,Mohamad, J., Paydar,M., & Rothan, H. (2014). Isolation and Characterisation of Acetylcholinesterase Inhibitors from Aquilaria subintegra for the Treatment of Alzheimers Disease (AD). Current Alzheimer Research, 11(2), 206214. https://doi.org/10.2174/1567205011666140130151344</p><p>Balch, P. A. (2010). Prescription for nutritional healing: The A-to-Z guide to supplements. New York: Avery.</p><p>Barden, A., Awang, N., Mulliken, T., & Song, M. (2000). Heart of the matter: Agarwood use and trade and CITES implementation for Aquilaria malaccensis. Cambridge, UK: TRAFFIC International. Retrieved from https://portals.iucn.org/library/efiles/documents/Traf-072.pdf</p><p>Basit, S. A., Stone, C. D., & Gish, R. (2015). Portal Vein Thrombosis. Clinics in Liver Disease, 19(1), 199221. https://doi.org/10.1016/j.cld.2014.09.012</p><p>Bassam Abdul Rasool Hassan. (2012). Medicinal Plants (Importance and Uses). Pharmaceutica Analytica Acta,03(10). https://doi.org/10.4172/2153-2435.1000e139</p><p>Becker, B. N. (1996). Ginseng-Induced Diuretic Resistance. JAMA: The Journal of the American Medical Association, 276(8), 606. https://doi.org/10.1001/jama.1996.03540080028021</p><p>Bian, X., Chi, L., Gao, B., Tu, P., Ru, H., & Lu, K. (2017). The artificial sweetener acesulfame potassium affects the gut microbiome and body weight gain in CD-1 mice. PLOS ONE, 12(6), e0178426. https://doi.org/10.1371/journal.pone.0178426</p><p>Bnninghoff, R., Schwenke, K., Keese, M., Magdeburg, R., Bitter-Suermann, H., Otto, M., Sturm, J. (2012). Effect of different liver resection methods on liver damage and regenerationfactorsVEGFand FGF-2 in mice. Canadian Journal of Surgery, 55(6), 389393. https://doi.org/10.1503/cjs.007911</p><p>Bregman, C. L., Adler, R. R., Morton, D. G., Regan, K. S., & Yano, B. L. (2003). Recommended TissueList for Histopathologic Examination inRepeat-Dose Toxicity and Carcinogenicity Studies: A Proposal of the Society of Toxicologic Pathology (STP). Toxicologic Pathology, 31(2), 252253. https://doi.org/10.1080/01926230390183751</p><p>Burch, J. B., Augustine, A. D., Frieden, L. A., Hadley, E., Howcroft, T. K., Johnson, R., Wise, B. C. (2014). Advances in Geroscience: Impact on Healthspan and Chronic Disease. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 69(Suppl 1), S1S3. https://doi.org/10.1093/gerona/glu041</p><p>Campos-Vega, R., & Oomah, B. D. (2013). Chemistry and classification of phytochemicals. In B. K. Tiwari, N. P. Brunton, & C. S. Brennan (Eds.), Handbook of Plant Food Phytochemicals (pp. 548). Oxford: John Wiley & Sons Ltd. https://doi.org/10.1002/9781118464717.ch2</p><p>Carro-Jurez, M., Franco, M. ., & Rodrguez-Pea, M. de L. (2014). Increase of the Ejaculatory Potency by the Systemic Administration of Aqueous Crude Extracts of Cihuapatli ( Montanoa Genus) Plants in Spinal Male Rats. Journal of Evidence-Based Complementary & Alternative Medicine, 19(1), 4350. https://doi.org/10.1177/2156587213510006</p><p>Chapman, K., Sewell, F., Allais, L., Delongeas, J.-L., Donald, E., Festag, M., Robinson, S. (2013). A globalpharmaceutical company initiative: An evidence-based approach to define the upperlimit of body weight lossin shortterm toxicity studies. Regulatory Toxicology and Pharmacology, 67(1), 2738. https://doi.org/10.1016/j.yrtph.2013.04.003</p><p>Chebaibi, M., Bousta, D., Chbani, L., Ez zoubi, Y., Touiti, N., & Achour, S. (2019). Acute toxicity of plants mixture used in traditional treatment of edema and colic renal in Morocco. Scientific African, 6, e00152. https://doi.org/10.1016/j.sciaf.2019.e00152</p><p>Chen, Kuo, Yang, Chien, Chu, Huang, Chen. (2014). Identification of cucurbitacins and assembly of a draft genome for Aquilaria agallocha. BMC Genomics, 15(1), 578. https://doi.org/10.1186/1471-2164-15-578</p><p>Chen, S., Lalazar, G., Barak, O., Adar, T., Doviner, V., & Mizrahi, M. (2012). Protein-Loosing Entropathy Induced by Unique Combination of CMV and HP in an Immunocompetent Patient. Case Reports in Medicine, 2012, 14. https://doi.org/10.1155/2012/361892</p><p>Chinedu, E., Arome, D., & Ameh, F. (2013). A new method for determining acute toxicity in animal models. Toxicology International, 20(3), 224. https://doi.org/10.4103/0971-6580.121674</p><p>Chowdhury, M., Hussain, M. D., Chung, S.-O., Kabir, E., & Rahman, A. (2016). Agarwood manufacturing: A multidisciplinary opportunity for economy of Bangladesh-a review. Agricultural Engineering International: CIGR Journal, 18(3), 171178.</p><p>Chukwuebuka, N., Kelechi, A., Nwanneamaka, E., & Stephen, U. (2018). Toxicity Studies and Phytochemical Screening of Aqueous Extractof Cissus aralioidesPlant. Journal of Advances in Medical and Pharmaceutical Sciences, 17(1), 17. https://doi.org/10.9734/JAMPS/2018/41425</p><p>Cole, T. B., Coburn, J., Dao, K., Roqu, P., Chang, Y.-C., Kalia, V., Costa, L. G. (2016). Sex and genetic differences in the effects of acute diesel exhaust exposure on inflammation and oxidative stress in mouse brain. Toxicology, 374, 19. https://doi.org/10.1016/j.tox.2016.11.010</p><p>Colerangle, J. B. (2017). Preclinical Development of Nononcogenic Drugs (Small and Large Molecules). In A Comprehensive Guide to Toxicology in Nonclinical Drug Development (pp. 659683). Elsevier. https://doi.org/10.1016/B978-0-12-8036204.00025-6</p><p>Cook, H. C. (1997). Origins of ... Tinctorial methods in histology. Journal of Clinical Pathology, 50(9), 716720. https://doi.org/10.1136/jcp.50.9.716</p><p>Costa, J. P., Ferreira, P. B., De Sousa, D. P., Jordan, J., & Freitas, R. M. (2012). Anticonvulsant effectof phytolin a pilocarpine model in mice.Neuroscience Letters, 523(2), 115118. https://doi.org/10.1016/j.neulet.2012.06.055</p><p>Cremades, A., Sanchez-Capelo, A., Monserrat, A., Monserrat, F., & Peafiel, R. (2003). Effects of potassium deficiency on potassium, polyaminesand amino acids in mouse tissues. Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 134(3), 647654. https://doi.org/10.1016/S1095-6433(02)00369-0</p><p>Dahham, S., Tabana, Y., Iqbal, M., Ahamed, M., Ezzat, M., Majid, A., & Majid, A.(2015). The Anticancer, Antioxidant and Antimicrobial Properties of the Sesquiterpene -Caryophyllene from the Essential Oil of Aquilariacrassna. Molecules,20(7), 11808 11829. https://doi.org/10.3390/molecules200711808</p><p>Dalen, J. E. (1998). Conventional and Unconventional Medicine: Can They Be Integrated? Archives of Internal Medicine, 158(20), 2179. https://doi.org/10.1001/archinte.158.20.2179</p><p>Dar, R. A., Shahnawaz, M., & Qazi, P. H. (2017). General overview of medicinal plants: A review. The Journal of Phytopharmacology, 6(6),349351.</p><p>Debelo, N., & Afework, M. (2016). Assessment of Hematological, Biochemical and Histopathological Effects of Acute and Sub-chronic Administration of the Aqueous LeavesExtract of Thymus schimperiin Rats. Journal of Clinical Toxicology,06(02). https://doi.org/10.4172/2161-0495.1000286</p><p>Doke, S. K., & Dhawale, S. C. (2015). Alternatives to animal testing: A review. Saudi Pharmaceutical Journal, 23(3), 223229. https://doi.org/10.1016/j.jsps.2013.11.002</p><p>Duke, J. A., Telatnik, M. A., & Duke, P.-A. K. (2007). Herbs of the Bible: 2000 years of plant medicine. Warsaw, Ind.: Whitman Publications.</p><p>Eaton, D. L., & Gallagher, E. P. (2010). Comprehensive Toxicology (2nd ed.). Elsivier.</p><p>Ekeanyanwu, R. C., & Njoku, O. U. (2014). Acute and subacute oral toxicity study on the flavonoid rich fraction of Monodora tenuifolia seed in albino rats. Asian Pacific Journal of Tropical Biomedicine, 4(3), 194202. https://doi.org/10.1016/S22211691(14)60231-8</p><p>Ekor, M. (2014). The growing use of herbal medicines: Issues relating to adverse reactions and challenges in monitoring safety. Frontiers in Pharmacology, 4. https://doi.org/10.3389/fphar.2013.00177</p><p>Elliott, R. (2005). Mechanisms of genomic and non-genomic actions of carotenoids. Biochimica et Biophysica Acta (BBA) -Molecular Basis of Disease, 1740(2), 147 154. https://doi.org/10.1016/j.bbadis.2004.12.009</p><p>El-Soud, N. A. (2010). Herbal Medicine in Ancient Egypt. Journal of Medicinal Plants Research, 4(2), 082086. https://doi.org/10.5897/JMPR09.013</p><p>Elvin-Lewis, M. (2001). Should we be concerned about herbal remedies. Journal of Ethnopharmacology, 75(23), 141164. https://doi.org/10.1016/S03788741(00)00394-9</p><p>Erhirhie, E. O., Ihekwereme, C. P., & Ilodigwe, E. E. (2018). Advances in acute toxicity testing: Strengths, weaknesses and regulatory acceptance. Interdisciplinary Toxicology, 11(1), 512. https://doi.org/10.2478/intox-2018-0001</p><p>Esfandiarpour, I., Farajzadeh, S., & Abbaszadeh, M. (2008). Evaluation of serum iron and ferritin levels in alopecia areata. Dermatology Online Journal, 14(3).</p><p>Ezeja, Anaga, & Asuzu. (2014). Acute and sub-chronic toxicity profile of methanol leaf extract of Gouanialongipetala inrats. Journal of Ethnopharmacology,151(3), 1155 1164. https://doi.org/10.1016/j.jep.2013.12.034</p><p>Faisal, R., Shinwari, L., Aziz, I., & Khalil, A. T. (2019). Therapeutic andAdverseEffectsof Commonly Used Medicinal Plants: Standardization and Quality Assurance.Proceedings of the Pakistan Academy of Sciences: B. Life and Environmental Sciences, 56(3), 1-9-19.</p><p>Faqi (Ed.). (2017). A comprehensive guide to toxicology in nonclinical drug development (Second edition). Amsterdam: Academic Press is an imprint of Elsevier.</p><p>Fatemeh Jamshidi-Kia, Zahra Lorigooini, & Hossein Amini-Khoei. (2018). Medicinal plants: Pasthistory and future perspective. Journal of Herbmed Pharmacology, 7(1), 17. https://doi.org/10.15171/jhp.2018.01</p><p>Fauzi Elias, Husni Ibrahim, & Wan Rusmawati Wan Mahamod. (2017). A Review on the Malaysian Aquilaria species in Karas Plantation and Agarwood Production. International Journal of Academic Research in Business and Social Sciences, 7(4), 10211029. https://doi.org/10.6007/IJARBSS/v7-i4/2911</p><p>Feng, J., Yang, X.-W., & Wang, R.-F. (2011). Bio-assay guided isolation and identification of a-glucosidase inhibitors from the leaves of Aquilaria sinensis. Phytochemistry, 72(23), 242247. https://doi.org/10.1016/j.phytochem.2010.11.025</p><p>Fischer, A. H., Jacobson, K. A., Rose, J., & Zeller, R. (2008). Hematoxylin and Eosin Staining of Tissue and Cell Sections. Cold Spring Harbor Protocols, 2008(6), pdb.prot4986-pdb.prot4986. https://doi.org/10.1101/pdb.prot4986</p><p>Fogelson, A. L., & Neeves, K. B.(2015). Fluid Mechanics of Blood Clot Formation. Annual Review of Fluid Mechanics, 47(1), 377403. https://doi.org/10.1146/annurev-fluid010814-014513</p><p>Gad, S. C. (2014). Rodents model for toxicity testing and biomarkers. In Biomarkers in Toxicology (pp. 769). Elsevier. https://doi.org/10.1016/B978-0-12-4046306.00002-6</p><p>Gao, Y., Wang, T., Wang, G., Li, G., Sun, C.,Jiang, Z., Cho, S. (2019). Preclinical safety of ginsenoside compound K: Acute, and 26-week oral toxicity studies in mice and rats. Food and Chemical Toxicology, 131, 110578. https://doi.org/10.1016/j.fct.2019.110578</p><p>Gautam, M. K., & Goel, R. K. (2014). Toxicological Study of Ocimum sanctum Linn Leaves: Hematological, Biochemical, and Histopathological Studies. Journal of Toxicology, 2014, 19. https://doi.org/10.1155/2014/135654</p><p>George, P. (2011). Concerns regarding the safety and toxicity of medicinal plants-An overview. Journal of Applied Pharmaceutical Science, 1(6), 4044.</p><p>Ghan, S. Y., Chin, J. H., Thoo, Y. Y., Yim, H. S., & Ho, C. W. (2016). Acute oral toxicity study of Aquilaria crassna and a-tocopherol in mice. International Journal of Pharmaceutical Sciences and Research, 7(4), 14561461.</p><p>Golub, M. S., Hogrefe, C. E., Germann, S. L., Tran, T. T., Beard, J. L., Crinella, F. M., & Lonnerdal, B. (2005). Neurobehavioral evaluation of rhesus monkey infants fed cows milk formula, soy formula, or soy formula with added manganese. Neurotoxicology and Teratology, 27(4), 615627. https://doi.org/10.1016/j.ntt.2005.04.003</p><p>Goudah, A., Abdo-El-Sooud, K., & Yousef, M. A. (2015). Acute and subchronic toxicity assessment model of Ferula assa-foetida gum in rodents. Veterinary World, 8(5), 584589. https://doi.org/10.14202/vetworld.2015.584-589</p><p>Guo, J., Wang, W., Fang, H., Liu, Q., Zhang, W., Yin, D., Liu, H. (2002). Agarofuan derivatives, their preparation, pharmaceutical composition containing them and their use as medicine.</p><p>Gupta, P. K. (2016). Fundamentals of toxicology: Essential concepts and applications. India : Amsterdam; Boston: BSPublications ; Elseiver/AP, Academic Press is an imprint of Elsevier.</p><p>Hamada, C. (2018). Statistical analysis for toxicity studies. Journal of Toxicologic Pathology, 31(1), 1522. https://doi.org/10.1293/tox.2017-0050</p><p>Hamidpour, M., Hamidpour, R., Hamidpour, S., & Shahlari, M. (2014). Chemistry, Pharmacology, and Medicinal Property of Sage (Salvia) toPrevent and Cure Illnesses such asObesity,Diabetes, Depression, Dementia, Lupus, Autism, HeartDisease, and Cancer. Journal of Traditional and Complementary Medicine, 4(2), 8288. https://doi.org/10.4103/2225-4110.130373</p><p>Haschek, W. M., Rousseaux, C. G., & Wallig, M. A. (2010). Fundamentals of toxicologic pathology (2nd ed). Amsterdam: Elsevier.</p><p>Hashim, Y. Z.-Y., Phirdaous, A., & Azura, A. (2014). Screening of anticancer activity from agarwood essential oil. Pharmacognosy Research, 6(3), 191. https://doi.org/10.4103/0974-8490.132593</p><p>Hassanzadeh-Taheri, M., Hosseini, M., Salimi, M., Moodi, H., & Dorranpour, D. (2018). Acute and Sub-Acute Oral Toxicity Evaluation of Astragalus hamosus Seedpod Ethanolic Extract in Wistar Rats. Pharmaceutical Sciences, 24(1), 2330. https://doi.org/10.15171/PS.2018.05</p><p>Hau, J., & Schapiro, S. J. (Eds.). (2011). Handbook of laboratory animal science (3rd ed). Boca Raton, FL: CRC Press.</p><p>Hommos, M. S., Zeng, C., Liu, Z., Troost, J. P., Rosenberg, A. Z., Palmer, M., Rule, A.D. (2018). Global glomerulosclerosis with nephrotic syndrome; the clinical importance of age adjustment. Kidney International, 93(5), 11751182. https://doi.org/10.1016/j.kint.2017.09.028</p><p>Hori, T., Ohashi, N., Chen, F., Baine, A.-M. T., Gardner, L. B., Jermanus, S., & Nguyen, J.</p><p>H. (2011). Simple and sure methodology for massive hepatectomy in the mouse. Annals of Gastroenterology, 24(4), 307318.</p><p>Huang, Chen, Yu, Zhou, & Ning.(2016). Effects of different ratios of Aquilaria sinensis leaf meal on the growth performance, slaughterperformance and nutrients digestibility of broiler. China Feed, 11, 3642.</p><p>Huang, Xiao, Burton-Freeman, B. M., & Edirisinghe, I. (2016). Chemical Changes of Bioactive Phytochemicals during Thermal Processing. In Reference Module in Food Science (p. B9780081005965031000). Elsevier. https://doi.org/10.1016/B978-0-08100596-5.03055-9</p><p>Iannaccone, P. M., & Jacob, H. J. (2009). Rats! Disease Models & Mechanisms,2(56), 206 210. https://doi.org/10.1242/dmm.002733</p><p>ICH Harmonised TripartiteGuideline. (2009). Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals M3 (R2). Presented at the International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use.</p><p>Iizuka, R., Kawakami, K., Izawa, N., & Chiba, K. (2009). Phenols produced by gutbacteria affect the skinin hairless mice. Microbial Ecology in Health and Disease,21(1), 50 56. https://doi.org/10.1080/08910600802688910</p><p>Inamul Haq. (2004). Safety ofmedicinal plants. Pak J Med Res, 43(4), 203210.</p><p>International Agency for Research on Cancer (Ed.). (2002). Some traditional herbal medicines, some mycotoxins, naphthalene and styrene: This publication represents the views and expert opinions of an IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, which met in Lyon, 12 -19 February 2002. Lyon: IARC.</p><p>Iwu, M. M. (2014). Handbook of African Medicinal Plants (0 ed.). CRC Press. https://doi.org/10.1201/b16292</p><p>Jamison, D. T., Breman, J. G., Measham, A. R., Alleyne, G., Claeson, M., Evans, D. B., Mills, A. (2006). Complementary and Alternative Medicine. In Disease Control Priorities in Developing Countries. 2nd edition. (2nd ed., pp. 12811291). Washington, DC: The World Bank Group.</p><p>Jangra, A., Lukhi, M. M., Sulakhiya, K., Baruah, C. C., & Lahkar, M. (2014). Protective effect of mangiferin against lipopolysaccharide-induced depressive and anxiety-like behaviour in mice. European Journal of Pharmacology, 740, 337345. https://doi.org/10.1016/j.ejphar.2014.07.031</p><p>Jefferson, J. A., & Shankland, S. J. (2014). The Pathogenesis of Focal Segmental Glomerulosclerosis. Advances in Chronic Kidney Disease, 21(5), 408416. https://doi.org/10.1053/j.ackd.2014.05.009</p><p>Jegathambigai Naidu, Rusli Ismail, & Sreenivasan Sasidharan. (2014). Acute Oral Toxicity and Brine Shrimp Lethality of Methanol Extract of Mentha Spicata L (Lamiaceae). Tropical Journal of Pharmaceutical Research, 13(1), 101. https://doi.org/10.4314/tjpr.v13i1.15</p><p>Jennette, J. C., Olson, J. L., Silva, F. G., DAgati, V., & Heptinstall, R. H. *1920-* (Eds.). (2015). Heptinstalls pathology of the kidney: Includes interactive eBook with complete content (Seventh edition). Philadelphia [u.a. ]:Wolters Kluwer.</p><p>Jiang, S., & Tu, P.-F. (2011). Effects of 95% ethanol extract of Aquilariasinensis leaves on hyperglycemia in diabeticdb/db mice. Journal of Chinese Pharmaceutical Sciences, 20(6). https://doi.org/10.5246/jcps.2011.06.079</p><p>Jimenez-Garcia, S. N., Vazquez-Cruz, M. A., Garcia-Mier, L., Contreras-Medina, L. M., Guevara-Gonzlez, R. G., Garcia-Trejo, J. F., & Feregrino-Perez, A. A. (2018). Phytochemical and PharmacologicalProperties of Secondary Metabolites in Berries. In Therapeutic Foods (pp. 397427). Elsevier. https://doi.org/10.1016/B978-0-12811517-6.00013-1</p><p>Jingcheng Dong. (2013). The Relationship between Traditional Chinese Medicine and Modern Medicine.Evidence-Based Complementary and Alternative Medicine,2013, 110. https://doi.org/10.1155/2013/153148</p><p>Kacew, S., Yi, P., & Lu, F. C. (2013). Lus basic toxicology: Fundamentals, target organs, and risk assessment. Retrieved from http://www.crcnetbase.com/isbn/9781841849546</p><p>Kakino, M., & Hara,H. (2016). PharmacologicalEffects of Aquilariaspp.Leaves and Their Chemical Constituents. In R. Mohamed (Ed.), Agarwood (pp. 125136). Singapore: Springer Singapore. https://doi.org/10.1007/978-981-10-0833-7_8</p><p>Kakino, M., Tazawa, S., Maruyama, H., Tsuruma, K., Araki, Y., Shimazawa, M., & Hara,H. (2010). Laxative effects of agarwood on low-fiber diet-induced constipation in rats. BMC Complementary and Alternative Medicine, 10(1), 68. https://doi.org/10.1186/1472-6882-10-68</p><p>Kamonwannasit, S., Nantapong, N., Kumkrai, P., Luecha, P., Kupittayanant, S., & Chudapongse, N. (2013). Antibacterial activity of Aquilaria crassna leaf extract against Staphylococcus epidermidis by disruption of cell wall. Annals of Clinical Microbiology and Antimicrobials, 12(1), 20. https://doi.org/10.1186/1476-0711-1220</p><p>Karmaus, A., Fitzpatrick,J., Allen, D., Patlewicz, G., Kleinstreuer, N., &Casey, W. (2018). Variability of LD50 Values from Rat Oral Acute Toxicity Studies: Implications for Alternative Model Development. Society of Toxicology, San Antonio, TX, 3, 1115.</p><p>Kelly, K. (2009). Early civilizations: Prehistoric times to 500 C.E. NewYork, NY: Factson File.</p><p>Kerr, R. W. (2015). Herbalism Through the Ages. San Jose, CA: Supreme Grand Lodge Of The Ancient and Mystical Order Rosae Crucis. Retrieved from https://f5db1a33c5d48483c6891033844f9683e62055e615f7d9cc8875.ssl.cf5.rackcdn.com/Herbalism%20Through %20the%20Ages%20-%20Ralph%20Whiteside%20Kerr.pdf</p><p>Khalil, A. S., Rahim, A. A., Taha, K. K., & Abdallah, K. B. (2013). Characterization of methanolicextracts of agarwood leaves. Journal of Applied and Industrial Sciences, 1(3), 7888.</p><p>Kim, J. E., Nam, J. H., Cho, J. Y., Kim, K. S., & Hwang, D. Y. (2017). Annual tendency of researchpapersused ICR miceas experimental animals in biomedical research fields. Laboratory Animal Research, 33(2), 171178. https://doi.org/10.5625/lar.2017.33.2.171</p><p>Kisby, G. E., Fry, R. C., Lasarev, M. R., Bammler, T. K., Beyer, R. P., Churchwell, M., Spencer, P. S. (2011). The Cycad Genotoxin MAM Modulates Brain Cellular Pathways Involved in Neurodegenerative Disease and Cancer in a DNA Damage-Linked Manner. PLoS ONE, 6(6), e20911. https://doi.org/10.1371/journal.pone.0020911</p><p>Kleisiaris, C. F., Sfakianakis, C., & Papathanasiou, I. V. (2014). Health care practices in ancient Greece: The Hippocratic ideal. Journal of Medical Ethics and History of Medicine, 7.</p><p>Knecht, D. A., LaFleur, R. A., Kahsai, A. W., Argueta, C. E., Beshir, A. B., & Fenteany, G. (2010). Cucurbitacin I Inhibits Cell Motility by Indirectly Interfering with Actin Dynamics. PLoS ONE, 5(11), e14039. https://doi.org/10.1371/journal.pone.0014039</p><p>Krieger, R. I. (Ed.). (2010). Hayes handbook of pesticide toxicology (Third edition). Amsterdam ; Boston: Elsevier/AP.</p><p>Kuete, V. (Ed.). (2014). Toxicological survey of african medicinal plants (First edition). Amsterdam Boston Heidelberg London New York Oxford Paris San Diego San Francisco Singapore Sydney Tokyo: Elsevier.</p><p>Kumar, G., & Kiernan, J. (2010). Special Stains and H & E (Second). California: Dako.</p><p>Kumphune, S., Prompunt, E., Phaebuaw, K., Sriudwong, P., Pankla, R., & Thongyoo, P. (2011). Anti-inflammatory effects of the ethyl acetate extract of Aquilaria crassna inhibits LPS-induced tumour necrosis factor-alpha production by attenuating P38 MAPK activation. International Journal of Green Pharmacy, 5(1), 43. https://doi.org/10.4103/0973-8258.82099</p><p>Lalitha, Sripathi, S., & Jayanthi. (2012). Acute toxicity study of extracts of Eichhornia Crassipes (Mart.) Solms. Asian Journal of Pharmaceutical and Clinical Research, 5(4), 5961.</p><p>Lambert, R. (2009). Breeding strategies for maintaining colonies of laboratory mice. TJ Laboratory.</p><p>Law Kim Sooi & Soon Lean Keng. (2013). Herbal Medicines: Malaysian Womens Knowledgeand Practice. Evidence-Based Complementary and Alternative Medicine, 2013, 110. https://doi.org/10.1155/2013/438139</p><p>Lee, S. Y., & Mohamed, R. (2016). The Origin and Domestication of Aquilaria, an Important Agarwood-Producing Genus. Tropical Forestry, 120. https://doi.org/10.1007/978981-10-0833-7_1</p><p>Li, B. S., Pasch, M. C., & Maibach,H. I. (2018).Hair Disorders Induced byExternal Factors. In S. M. John, J. D. Johansen, T. Rustemeyer, P. Elsner, & H. I. Maibach (Eds.), Kanervas Occupational Dermatology (pp. 125). Cham: Springer International Publishing. https://doi.org/10.1007/978-3-319-40221-5_26-2</p><p>Li, Jiang, &Mei. (2013). Comparative study on the effect of Aquilaria sinensis leaf tea and agarwood on promoting small intestine propulsion. Asia-Pacific Tradit. Med, 9(6), 2425.</p><p>Li, Shi, & Guo. (2017). Acute and SubacuteOral Toxicity Evaluation of Eriobotrya japonica Leaf Triterpene Acids inICR Mice. Evidence-Based Complementary and Alternative Medicine, 2017, 19. https://doi.org/10.1155/2017/4837839</p><p>Lin, C.-C., Chan, T. Y. K., & Deng, J.-F. (2004). Clinical features and management of herb-induced aconitine poisoning. Annals of Emergency Medicine, 43(5), 574579. https://doi.org/10.1016/j.annemergmed.2003.10.046</p><p>Lissiman, E., Bhasale, A. L., & Cohen, M. (2014). Garlic for the common cold. Cochrane Database of Systematic Reviews. https://doi.org/10.1002/14651858.CD006206.pub4</p><p>Liu, C., Zheng, Y., Xu, W., Wang, H., & Lin, N. (2014). Rhubarb Tannins Extract Inhibits the Expression of Aquaporins 2 and 3 in Magnesium Sulphate-Induced Diarrhoea Model. BioMed Research International, 2014, 114. https://doi.org/10.1155/2014/619465</p><p>Liu, Chen, Yang, Zhang, Wei, Meng, Chen. (2013). Whole-tree Agarwood-Inducing Technique: An Efficient Novel Technique forProducing High-Quality Agarwood in Cultivated Aquilaria sinensis Trees. Molecules, 18(3), 30863106. https://doi.org/10.3390/molecules18033086</p><p>Liyana Zulkifle, Adila Omar, Tajuddin, S. N., & Shaari, R. (2013). Antidiabetic Activities of Malaysian Agarwood (Aquilaria SPP) Leaves Extract. Antidiabetic Activities of Malaysian Agarwood (Aquilaria SPP) Leaves Extract. Presented at the Cenference on Industry-Acedemia Joint Initiatives in Biotechnology, University Malaysia Pahang, Malaysia.</p><p>Liyana Zulkifle, Amalina Sabri, Adila Omar, Rosly Shaari, & Saiful Nizam Tajuddin. (2018). Acute and sub-chronic toxicity studyof Aquilariamalaccensis leaves extract in Sprague-Dawley rats. Chemistry of Advanced Materials, 3(1), 815.</p><p>Loha, M., Mulu, A., Abay, S. M., Ergete, W., & Geleta, B. (2019). Acute and Subacute Toxicity of Methanol Extract of Syzygium guineense Leaveson the Histology of the Liverand Kidney and Biochemical Compositions of Blood in Rats. Evidence-Based Complementary and Alternative Medicine, 2019, 115. https://doi.org/10.1155/2019/5702159</p><p>Lpez-Sampson, A., & Page, T. (2018). History of Use and Trade of Agarwood. Economic Botany, 72(1), 107129. https://doi.org/10.1007/s12231-018-9408-4</p><p>Mamat, M.F., Yacob, M. R., Fui, L. H., & Rdam, A. (2010). Costsand Benefits Analysis of Aquilaria Species on Plantation forAgarwood Production in Malaysia. International Journal of Business and Social Science, 1(2), 162174.</p><p>Martini, N. D., Katerere, D. R. P., & Eloff, J. N. (2004). Biological activity of five antibacterial flavonoids from Combretum erythrophyllum (Combretaceae). Journal of Ethnopharmacology, 93(23), 207212. https://doi.org/10.1016/j.jep.2004.02.030</p><p>Maryam Farooqui, Mohamed Azmi Hassali, Aishah Knight Abdul Shatar, Muhammad AslamFarooqui, FahadSaleem,Noman ul Haq,& CheNoriah Othman.(2016). Use of complementary and alternative medicines among Malaysian cancer patients: A descriptive study. Journal of Traditional and Complementary Medicine, 6(4), 321 326. https://doi.org/10.1016/j.jtcme.2014.12.008</p><p>Maxwelll, L. P., John, C., Noel, N., Steven, S., & Naanlep, M. (2007). The histopathologic effects of Securidaca longepedunculata on heart, liver, kidney and lungs of rats. African Journal of Biotechnology, 6(5), 591595.</p><p>Maynard, R.L., Downes,N., & Finney, B. (2015). Histological techniques: An introduction for beginners in toxicology. Retrieved from https://nls.ldls.org.uk/welcome.html?ark:/81055/vdc_100035370566.0x000001</p><p>Mehra, A., Bajpai, O.,& Joshi, H. (2014). Diversity,utilization andsacred values of ethnomedicinal plants of Kumaun Himalaya. Tropical Plant Research, 1(3), 8086.</p><p>Mei, Q., Li, H., Lin, H., Wu, X., Liang, L., Yang, H., & Lan, Z. (2013). Comparative study on hypoglycemic effect between Aquilaria sinensis leaves and agarwood. Lishizhen Med. Mat. Med. Res, 24, 16061607.</p><p>Mengesha, G. G. (2016). Ethnobotanical survey of medicinal plants used in treating human and livestock health problems in ManduraWoreda of BenishangulGumuz, Ethiopia. Adv Med Plant Res, 4(1), 1126.</p><p>Mikail, H. G. (2018). Phytochemical screening, elemental analysis and acute toxicity of aqueous extract of Allium sativum L. bulbs in experimental rabbits. Journal of Medicinal Plants Research, 4(4), 322326.</p><p>Miller, M. A. (2001). Gender-Based Differences in the Toxicity of PharmaceuticalsThe Food and Drug Administrations Perspective. International Journal of Toxicology, 20(3), 149152. https://doi.org/10.1080/109158101317097728</p><p>More, B. (2016). Overview of Medicine-Its Importance and Impact. DJ International Journal Medical Research, 1(1), 18. https://doi.org/10.18831/djmed.org/2016011001</p><p>Mrvos, R., Dean, B. S., & Krenzelok, E. P. (1991). Philodendron/Dieffenbachia Ingestions: Are They a Problem? Journal of Toxicology: Clinical Toxicology, 29(4), 485491. https://doi.org/10.3109/15563659109025745</p><p>Mulhern, S.,Stroube, W., & Jacobs, R. (1986). Alopecia induced in youngmice by exposure to excess dietary zinc. Experientia, 42(5), 551553.</p><p>Murphy, S. J., Smith, P., Shaivitz, A. B., Rossberg, M. I., & Hurn, P. D. (2001). The effect of brief halothane anesthesia during daily gavage on complications and body weight in rats. Contemporary Topics in Laboratory Animal Science, 40(2), 912.</p><p>Musumeci, G. (2014). Past, present and future: Overview on histology and histopathology. Journal of Histology and Histopathology, 1(1), 5. https://doi.org/10.7243/2055091X-1-5</p><p>Najafi, S. (2013). Phytochemical screening and antibacterial activity of leaf extract of Ziziphus mauritiana Lam. International Research Journal of Applied and Basic Sciences, 4(10), 32743276.</p><p>Nath, P., & Yadav, A. (2015). Acute and sub-acute oral toxicity assessment of the methanolic extract from leaves of Hibiscus rosa-sinensis L. in mice. Journal of Intercultural Ethnopharmacology, 4(1), 70. https://doi.org/10.5455/jice.20141028021746</p><p>Nor Azah, Chang, Mailina, Abu Said, Abd. Majid J., Saidatul Husni, Nik Yasmin. (2008). Comparisonof Chemical Profiles of Selected GaharuOils from Peninsular Malaysia. The Malaysian Journal of Analytical Sciences, 12(2), 338340.</p><p>Nur Hidayat Che Musa, Haniza Hanim Mohd Zain, & Husni Ibrahim. (2018). Aphrodisiac properties of Aquilaria malaccensis leaves aqueous extract in ICR mice. Journal of Research in Pharmacy, 23(1), 130140. https://doi.org/10.12991/jrp.2018.117</p><p>Nur Hidayat Che Musa, Haniza Hanim Mohd Zain, Husni Ibrahim, & Nor Nasibah Mohd Jamil. (2019). Evaluation of Acute and Sub-acute Oral Toxicity Effect of Aquilaria malaccensis Leaves Aqueous Extract in Male ICR Mice. Natural Product Sciences, 25(2), 157. https://doi.org/10.20307/nps.2019.25.2.157</p><p>OConnor, A., & OMorin, C. (2014). Digestive Function of the Stomach. Digestive Diseases, 32(3), 186191. https://doi.org/10.1159/000357848</p><p>Ogbuehi, I. H., Ebong, O. O., & Obianime, A. W. (2015). Oral acute toxicity (LD50) study of different solvent extracts of Abrus precatorius Linn leaves in wistar rats. Eur. J. Exp. Biol, 5, 1825.</p><p>Okugawa, H., Ueda, R., Matsumoto, K., Kawanishi, K., & Kato, A. (1993). Effects of Agarwood Extracts on the Central Nervous System in Mice. Planta Medica, 59(01), 3236. https://doi.org/10.1055/s-2006-959599</p><p>OMS. (2009). The WHO recommended classification of pesticides by hazard and guidelines to classifications 1992-1993. Ginebra: World Health Organization.</p><p>Onwusonye, J. C., Uwakwe, A. A., Iwuanyanwu, P., & Iheagwam, U. (2014). Oral acute toxicity (LD50) study of methanol extract of Annona senegalensis leaf in albino mice. Sky J. Biochem. Res, 3(5), 4648.</p><p>Organisation forEconomic Co-operation and Development. (2008a).Test No. 407: Repeated dose 28-day oral toxicity study in rodents. Paris: OECD Publishing. Retrieved from https://doi.org/10.1787/9789264070691-fr</p><p>Organisation for Economic Co-operation and Development. (2008b). Test No. 425: Acute Oral Toxicity: Up-and-Down Procedure. Paris: OECD Publishing. https://doi.org/10.1787/9789264071049-en</p><p>Pagadala, P., Shankar, M. V., & Kutty, K. (2019). Feeding Behaviour and its Association with Stress:A Review. JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH. https://doi.org/10.7860/JCDR/2019/40508.12725</p><p>Paramitha, D., Ulum, M. F., Purnama, A., Wicaksono, D. H. B., Noviana, D., & Hermawan,</p><p>H. (2017). Monitoring degradation products and metal ions in vivo. In Monitoring and Evaluation of Biomaterials and their Performance In Vivo (pp. 1944). Elsevier. https://doi.org/10.1016/B978-0-08-100603-0.00002-X</p><p>Parashar, U.D., Johnson, H., Steele, A. D., & Tate, J. E. (2016). Health Impactof Rotavirus Vaccination in Developing Countries: Progressand Way Forward. Clinical Infectious Diseases, 62(suppl 2), S91S95. https://doi.org/10.1093/cid/civ1015</p><p>Parker, V., Wong, A. bert H., Boon, H. S., & Seeman, M. V. (2001). Adverse Reactions to St Johns Wort. The Canadian Journal of Psychiatry, 46(1), 7779. https://doi.org/10.1177/070674370104600112</p><p>Peters, E. M. J., Arck, P. C., & Paus, R. (2006). Hair growth inhibition bypsychoemotional stress: A mouse model for neural mechanisms in hair growth control. Experimental Dermatology, 15(1), 113. https://doi.org/10.1111/j.0906-6705.2005.00372.x</p><p>Petrovska,B. (2012).Historicalreview of medicinal plants' usage. Pharmacognosy Reviews, 6(11), 1. https://doi.org/10.4103/0973-7847.95849</p><p>Phirdaous Abbas, Yumi Zuhanis Has-Yun Hashim, Azura Amid, Hamzah Mohd Salleh, Parveen Jamal, & Irwandi Jaswir. (2013). Anti-cancer Potential of Agarwood Distillate. Anti-Cancer Potential of Agarwood Distillate, 4144. International Islamic University Malaysia (USIM), Malaysia: Journal of Pure and Applied Microbiology 8.</p><p>Phirdaous Abbas, Yumi Zuhanis Has-Yun Hashim, & Hamzah Mohd Salleh. (2018). CYTOTOXIC EFFECTS AND RESPONSE SURFACE OPTIMIZATION OF SOLVENT EXTRACTION OF CRUDE EXTRACTS FROM Aquilaria subintegra UNINFECTED BRANCH. Science Heritage Journal, 2(2), 1015. https://doi.org/10.26480/gws.02.2018.10.15</p><p>Pizzo, F., Gadaleta, D., Lombardo, A., Nicolotti, O., & Benfenati, E. (2015). Identification of structural alerts for liver and kidney toxicity using repeated dose toxicity data. Chemistry Central Journal, 9(1), 62. https://doi.org/10.1186/s13065-015-0139-7</p><p>Plonka, P. M., Handjiski, B., Popik, M., Michalczyk, D., & Paus, R. (2005). Zinc as an ambivalent but potent modulator of murine hair growth in vivo-preliminary observations. Experimental Dermatology, 14(11), 844853. https://doi.org/10.1111/j.1600-0625.2005.00365.x</p><p>Porwal, M., Khan, N., & Maheshwari, K. (2017). Evaluation of Acute and Subacute Oral Toxicity Induced by Ethanolic Extract of Marsdenia tenacissima Leaves in Experimental Rats. Scientia Pharmaceutica, 85(3), 29. https://doi.org/10.3390/scipharm85030029</p><p>Prakash, B. (Ed.). (2020).Functional and preservative properties of phytochemicals.London San Diego, CA Cambridge, MA Oxford: Academic Press, an imprint of Elsevier.</p><p>Pranakhon, R., Pannangpetch, P., & Aromdee, C. (2011). Antihyperglycemic activity of agarwood leaf extracts inSTZ-induced diabetic rats and glucose uptakeenhancement activity in rat adipocytes. Songklanakarin Journal of Science & Technology, 33(4), 405410.</p><p>Pratibha Thakur, Suravi Shrivastava, Renu Shrivastava, & Vinoy Shrivastava. (2018). IMPAIRMENT OF OVARIAN BIOCHEMICAL CONTENTS AND ENZYMES ACTIVITIES DURING POTASSIUM BROMATE (KBRO3-) INTOXICATION IN ALBINO MICE MUS MUSCULUS. INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES AND RESEARCH, 9(12), 53575362.</p><p>Premaratna, R., Weerasinghe, M. S., Premawardana, Nuwan. P., & de Silva, H. J. (2015). Gloriosa superba poisoning mimicking an acute infection-a case report. BMC Pharmacology and Toxicology,16(1),27. https://doi.org/10.1186/s40360-015-00296</p><p>Prussin, C. (2013). Eosinophil CellCell Communication. In Eosinophils in Health and Disease (pp. 329390). Elsevier. https://doi.org/10.1016/B978-0-12-3943859.00011-0</p><p>Rahman, H., Eswaraiah, M. C., & Dutta, A. M. (2016). Anti-arthritic activity of leaves and oil of Aquilaria agallocha. The Saudi Journal of Life Sciences, 1, 3443.</p><p>Randriamiharisoa, M. N., Kuhlman, A. R., Jeannoda, V., Rabarison, H., Rakotoarivelo, N., Randrianarivony, T., Bussmann, R. W. (2015). Medicinal plants sold in the markets of Antananarivo, Madagascar. Journal of Ethnobiology and Ethnomedicine, 11(1), 60. https://doi.org/10.1186/s13002-015-0046-y</p><p>Redzuan Razak, Suzanah Rahman, Asmah Hamdan, Roszaman Ramli, Lokman Md Isa, Hussin Muhammad,& Nik Fakhuruddin Nik Hassan. (2018).Evaluation of acute and sub-acute oral toxicity of the aqueous extract of Aquilaria malaccensis leaves in SpragueDawley rats. Asia Pacific Journal of Molecular Biology and Biotechnology, 27(1), 2032. https://doi.org/10.35118/apjmbb.2019.027.1.03</p><p>Rgent, D., Crois-Laurent, V., Mathias, J., Fairise, A., Ropion-Michaux, H., & Proust, C. (2010). Acute Gastritis and Enteritis. In P. Taourel (Ed.), CT of the Acute Abdomen (pp. 239271). Berlin, Heidelberg: Springer Berlin Heidelberg. https://doi.org/10.1007/174_2010_84</p><p>Rosidah, Yam, M. F., Sadikun, A., Ahmad, M., Akowuah, G. A., & Asmawi, Mohd. Z. (2009). Toxicology evaluation of standardized methanol extract of Gynura procumbens. Journal of Ethnopharmacology, 123(2), 244249. https://doi.org/10.1016/j.jep.2009.03.011</p><p>Roy, Ukil, & Lyndem. (2016). Acute and sub-acute toxicity studies on the effect of Senna alata in Swiss Albino mice. Cogent Biology, 2(1). https://doi.org/10.1080/23312025.2016.1272166</p><p>Rutidosperma, C. (2018). Evaluation of Sedative and Hypnotic Activities of Ethanolic Extract of Leavesof Cleome Rutidosperma DC.(Capparidaceae)inMice. Journal of Pharmaceutics and Therapeutics, 4(1), 215223.</p><p>Saad Sabbar Dahham, Mohamed B. Khadeer Ahamed, Sultan Mohamad Saghir, Fouad Saleih Alsuede, Muhammad Adnan Iqbal, & Amin Malik Shah Abdul Majid. (2014). Bioactive essential oils from Aquilaria crassna for cancer prevention and treatment. https://doi.org/10.13140/2.1.3315.7125</p><p>Said, F., & Kamaluddin, M. T. (2016). Theodorus 2016 Efficacy of the Aquilaria malaccensis leaves active fraction in glucose uptake in skeletal muscle on diabetic wistar rats. International Journal of Health Sciences and Research, 6(7), 162167.</p><p>Sadana, D., Mahjoub, S., Boussaada, O., Chriaa, J., Mahjoub, M. A., Chraif, I., Helal, A. N. (2008). Antibacterial and Antifungal Activities of the Essential Oils of Two Saltcedar Species from Tunisia. Journal of the American Oil Chemists Society, 85(9), 817826. https://doi.org/10.1007/s11746-008-1251-9</p><p>Snchez, B., Casalots-Casado, J., Quintana, S., Arroyo, A., Martn-Fumad, C., & Galts, I. (2012). Fatal manganese intoxicationdue to an error in the elaboration of Epsom salts for a liver cleansing diet. Forensic Science International, 223(13), e1e4. https://doi.org/10.1016/j.forsciint.2012.07.010</p><p>Sandler, B., & Aronson, P. (1993). Yohimbine-induced cutaneous drug eruption, progressive renal failure, and lupus-like syndrome. Urology, 41(4), 343345. https://doi.org/10.1016/0090-4295(93)90592-X</p><p>Satishprakash Shukla. (2017). SIGNIFICANCE OF DIFFERENCE BETWEEN MEANS. https://doi.org/10.13140/RG.2.2.21228.97924</p><p>Sattayasai, J., Bantadkit, J., Aromdee, C., Lattmann, E., & Airarat, W. (2012). Antipyretic, analgesic and anti-oxidative activities of Aquilaria crassna leaves extract in rodents. Journal of Ayurveda and Integrative Medicine, 3(4), 175. https://doi.org/10.4103/0975-9476.104427</p><p>Satyapa, Vilasrao Kadam, & Rumi Ghosh. (2008). Hepatoprotective Activity of Livobond A Polyherbal Formulation Against CCl4 Induced Hepatotoxicity in Rats. International Journal of Pharmacology, 4(6), 472476. https://doi.org/10.3923/ijp.2008.472.476</p><p>Serra, I., Yamamoto, M., Calvo, A., Cavada, G., Bez, S., Endoh, K., Tajima, K. (2002). Association of chili pepper consumption, low socioeconomic status and longstanding gallstones with gallbladder cancer in a Chilean population: Gallstones and Gallbladder Cancer in Chile. International Journal of Cancer, 102(4), 407411. https://doi.org/10.1002/ijc.10716</p><p>Shakya, A. K. (n.d.). Medicinal Plants: Future Source of New Drugs. International Journal of Herbal Medicine, 4(4), 2016. https://doi.org/10.13140/rg.2.1.1395.6085</p><p>Shatoor. (2011). Acute and Sub-acute Toxicity of Crataegus Aronia Syn. Azarolus (L.) Whole Plant Aqueous Extract in Wistar Rats. American Journal of Pharmacology and Toxicology, 6(2), 3745. https://doi.org/10.3844/ajptsp.2011.37.45</p><p>Singh. (2015). Medicinal plants: A review. Journal of Plant Sciences, 3(11), 5055. https://doi.org/10.11648/j.jps.s.2015030101.18</p><p>Singh, T., Sinha, N., & Singh, A. (2013). Biochemical and histopathological effects on liver due to acute oral toxicity of aqueous leaf extract of Ecliptaalba on female Swiss albino mice. Indian Journal of Pharmacology, 45(1), 61. https://doi.org/10.4103/0253-7613.106437</p><p>Slaoui, M., & Fiette, L. (2011). Histopathology Procedures: From Tissue Sampling to Histopathological Evaluation. In J.-C. Gautier (Ed.), Drug Safety Evaluation (Vol. 691, pp. 6982). Totowa, NJ: Humana Press. https://doi.org/10.1007/978-1-60761849-2_4</p><p>Stubblefield, W. A., McKee, R. H., Kapp, R. W., & Hinz, J. P. (1989). An evaluation of the acute toxic properties of liquids derived from oil sands. Journal of Applied Toxicology, 9(1), 5965. https://doi.org/10.1002/jat.2550090111</p><p>Subasinghe, & Hettiarachchi. (2013). Agarwood resin production and resin quality of Gyrinops walla Gaertn. International Journal of Agricultural Sciences, 3(1), 357 262. https://doi.org/10.13140/2.1.4907.8405</p><p>Subramanian, K., Sankaramourthy, D., & Gunasekaran, M. (2018). Toxicity StudiesRelated to Medicinal Plants. In Natural Products and Drug Discovery (pp. 491505). Elsevier. https://doi.org/10.1016/B978-0-08-102081-4.00018-6</p><p>Subramanion Jothy, Zuraini Zakaria, Yeng Chen, Yee Ling Lau, Lachimanan Yoga Latha, & Sreenivasan Sasidharan. (2011). Acute Oral Toxicity of Methanolic Seed Extract of Cassia fistula in Mice. Molecules, 16(6), 52685282. https://doi.org/10.3390/molecules16065268</p><p>Sultana, N., Al-Khatib, A., & Kadir, M. (2014). Review on Some Malaysian Traditional Medicinal Plants with Therapeutic Properties. Journal of Basic & Applied Sciences, 10, 149159. https://doi.org/10.6000/1927-5129.2014.10.20</p><p>Sundberg, J. P., Boggess, D., Silva, K. A., McElwee, K. J., King, L. E., Li, R., Cox, G. A. (2003). Major Locus on Mouse Chromosome 17 and Minor Locus on Chromosome 9 are Linked with Alopecia Areata in C3H/HeJ Mice. Journal of Investigative Dermatology, 120(5), 771775. https://doi.org/10.1046/j.15231747.2003.12135.x</p><p>Sutrisni, N., Soewandhi, S., Adnyana, I., & Sasongko, L. (2019). Acute and Subchronic (28day) Oral Toxicity Studies on the Film Formulation of k-Carrageenan and Konjac Glucomannan for Soft Capsule Application. Scientia Pharmaceutica, 87(2), 9. https://doi.org/10.3390/scipharm87020009</p><p>Suwannasing. (2012). Anti-ischemic effect of ethyl acetate extract of Aquilaria crassna by attenuation of p38-MAPK activation. Journal of Applied Pharmaceutical Science, 2(10), 026030. https://doi.org/10.7324/JAPS.2012.21005</p><p>Taiwo & Joel. (2015). Acute toxicity and histopathological assessment of methanol extract of Cleome viscosa (Linn.) whole plant. Journal of Medicinal Plants Research,9(11), 360369. https://doi.org/10.5897/JMPR2014.5756</p><p>Takemoto, H., Ito, M., Shiraki, T., Yagura, T., & Honda, G. (2007). Sedative effects of vapor inhalation of agarwood oil and spikenard extract and identification of their active components. Journal of Natural Medicines, 62(1), 4146. https://doi.org/10.1007/s11418-007-0177-0</p><p>Tamizhazhagan, V. (2017). Histological Methods in Life Science. International Journal of Biomedical Materials Research, 5(6), 68. https://doi.org/10.11648/j.ijbmr.20170506.11</p><p>Tan, C. S., Isa, N. M., Ismail, I., & Zainal, Z. (2019). Agarwood Induction: Current Developments and Future Perspectives. Frontiers in Plant Science, 10, 122. https://doi.org/10.3389/fpls.2019.00122</p><p>Teo, S., Stirling, D., Thomas, S., Hoberman, A., Kiorpes, A., & Khetani, V. (2002). A 90day oral gavage toxicity study of d-methylphenidate and d,l-methylphenidate in SpragueDawley rats. Toxicology, 179(3), 183196. https://doi.org/10.1016/S0300483X(02)00338-4</p><p>Thakur, M., Singh, K., & Khedkar, R. (2020). Phytochemicals. In Functional and Preservative Properties of Phytochemicals (pp. 341361). Elsevier. https://doi.org/10.1016/B978-0-12-818593-3.00011-7</p><p>Traesel, G. K., de Souza, J. C., de Barros, A. L., Souza, M. A., Schmitz, W. O., Muzzi, R. M., Arena, A. C. (2014). Acute and subacute (28 days) oral toxicity assessment of the oil extracted from Acrocomia aculeata pulp in rats. Food and Chemical Toxicology, 74, 320325. https://doi.org/10.1016/j.fct.2014.10.026</p><p>Ugochukwu, S. C., Uche, A., & Ifeanyi, O. (2013). Preliminary phytochemical screening of different solvent extracts of stem bark and roots of Dennetia tripetala G. Baker. Asian Journal of Plant Science and Research, 3(3), 1013.</p><p>Wang. (2008). Determination of Genkwanin in the leaves of Aquilaria sinensis(Lour.) Gilg with HPLC. Guiding J. Trad. Chin. Med. Pharm, 14, 6970.</p><p>Wang, Li, Luo, Zhao, Ma, & Liu. (2018). GC-MS Study of the Chemical Components of Different Aquilariasinensis(Lour.) Gilgorgansand Agarwood from DifferentAsian Countries. Molecules, 23(9), 2168. https://doi.org/10.3390/molecules23092168</p><p>Wang, Yan, Niu, Li, Lin, Liu, Li. (2014). Mangiferin and its aglycone, norathyriol, improve glucose metabolism by activation of AMP-activated protein kinase. Pharmaceutical Biology, 52(1), 6873. https://doi.org/10.3109/13880209.2013.814691</p><p>Ward, H. A., Kuhnle, G. G., Mulligan, A. A., Lentjes, M. A.,Luben, R. N., & Khaw, K.-T. (2010). Breast, colorectal, and prostate cancer risk in the European Prospective Investigation into Cancer and Nutrition-Norfolk in relation to phytoestrogen intake derived from an improved database. American Journal of Clinical Nutrition, 91(2), 440448. https://doi.org/10.3945/ajcn.2009.28282</p><p>Watson, R. R., Gerald, J. K., & Preedy, V. R. (Eds.). (2011). Nutrients, dietary supplements, and nutriceuticals: Cost analysis versus clinical benefits. New York: Humana Press.</p><p>Wesam Kooti, Maryam Moradi, Sara Ali-Akbari,Majid Asadi-Samani, & Damoon Ashtary-Larky. (2015). Therapeutic and pharmacological potential of Foeniculum vulgare Mill: A review. Journal of HerbMed Pharmacology, 4(1), 19.</p><p>Wider, B., Pittler, M. H., & Ernst, E. (2015). Feverfew for preventing migraine. Cochrane Database of Systematic Reviews. https://doi.org/10.1002/14651858.CD002286.pub3</p><p>World Health Organization (Ed.). (1999). WHO Monographs on Selected Medicinal Plants. Geneva: World Health Organization.</p><p>World Health Organization. (2002). The General Design Of Non-Clinical Safety (Toxicity) Testing Programmes For Pharmaceuticals In International Guidelines. In Non-Clinical Safety Testing (pp. 2730). Geneza, Switzerland: World Health Organization. Retrieved from https://www.who.int/tdr/publications/documents/safety_handbook.pdf</p><p>Wu, Li, Mei, Lin, Liang,Yang, &Lan. (2013). A comparativestudyontheasthma effect of Aquilaria leaves and agarwood. Pharm. Today, 23, 346347.</p><p>Wu, Q., Tanaka, H., Hirukawa, T., Endoh, M., & Fukagawa, M. (2012). Characterization and quantification of proliferating cell patterns in endocapillary proliferation.Nephrology Dialysis Transplantation, 27(8), 32343241. https://doi.org/10.1093/ndt/gfr797</p><p>Wu, Zhu, Lin, Chen, Yao, & Liao. (2012). The active ingredient for hypolipidemic effect in Aquilaria sinensis leaves. Chinese Phamacertical Association. Proceedings of the National Symposium on the Twelfth Chinese Medicine and Natural Medicine, 24. Beijing.</p><p>Xie, R., Xu, J., Xiao, Y., Wu, J., Wan, H., Tang, B., Yang,S. (2017). Calcium Promotes Human Gastric Cancer via a Novel Coupling of Calcium-Sensing Receptor and TRPV4 Channel. Cancer Research, 77(23), 64996512. https://doi.org/10.1158/0008-5472.CAN-17-0360</p><p>Yi, P., Kacew, S., Kim, H., & Lu, F. C. (Eds.). (2018). Lus basic toxicology: Fundamentals, target organs, and risk assessment (Seventh edition). Boca Raton:CRC Press, Taylor & Francis Group.</p><p>Yuslianti, E.R., M. Bachtia, B., F. Suniart, D., &B. Sutjiat, A. (2016). Effect of Rambutan Honey (Nephelium lappaceum) Acute Administration on Mortality, Body Weight, Toxicity Symptoms and Relative Organ Weight of Swiss Websters Mice. Research Journal of Toxins, 8(1), 17. https://doi.org/10.3923/rjt.2016.1.7</p><p>Zakaria, Y., Azlan, N. Z., Fakhuruddin, N., Hassan, N., & Muhammad, H. (2016). Phytochemicals and acute oral toxicity studies of the aqueous extract of Vernonia amygdalina from state of Malaysia. Journal of Medicinal Plants Studies, 4(3), 15.</p><p>Zeman, T., Buchtov, M., Docekal, B., Mek, I., Navrtil, J., Mikuka, P., Vecera, Z. (2015). Organ weight changes in mice after long-term inhalation exposure to manganese oxides nanoparticles. Journal of Physics: Conference Series, 617, 012018. https://doi.org/10.1088/1742-6596/617/1/012018</p><p>Zhao, Y.-L., Su, M., Shang, J.-H., Wang, X., Njateng, G. S. S., Bao, G.-L., Luo, X.-D. (2020). Acute and Chronic Toxicity of Indole Alkaloids from Leaves of Alstonia scholaris (L.) R. Br. In Mice and Rats. Natural Products and Bioprospecting, 10(2), 7788. https://doi.org/10.1007/s13659-020-00237-1</p><p>Zhong, M., Liu, Y., Liu, J., Di, D., Xu, M., Yang, Y., Liu, J. (2014). Isocorydine Derivatives and Their Anticancer Activities. Molecules, 19(8), 1209912115. https://doi.org/10.3390/molecules190812099</p><p>Zhou, M., Wang, H., Suolangjiba, Kou, J., & Yu, B. (2008). Antinociceptive and anti-inflammatory activities of Aquilaria sinensis (Lour.)Gilg. Leaves extract. Journal of Ethnopharmacology, 117(2), 345350. https://doi.org/10.1016/j.jep.2008.02.005</p><p>Zhou, Yang, & Wang. (2016). Higher cytotoxicity and genotoxicity of cultivated versus natural agarwood incense smoke. Environmental Chemistry Letters, 14(4), 501506. https://doi.org/10.1007/s10311-016-0567-1</p><p></p>