Triterpenoid From Persimmon Leaves (Diospyros kaki L.f.) Exerted Anti–Type 2 Diabetic Effects and No Toxicity in Experimental Animals
Hung Van Nguyen
Faculty of Traditional Medicine, Hanoi Medical University, Hanoi, Vietnam
Faculty of Traditional Medicine, Hue University of Medicine and Pharmacy, Hue University, Hue City, Vietnam
Contribution: Conceptualization, Methodology, Investigation, Writing - original draft
Search for more papers by this authorHa Thu Thi Nguyen
Faculty of Traditional Medicine, Hanoi Medical University, Hanoi, Vietnam
Contribution: Investigation, Writing - original draft
Search for more papers by this authorNhan Trong Le
Faculty of Pharmacy, Hue University of Medicine and Pharmacy, Hue University, Hue City, Vietnam
Contribution: Investigation, Formal analysis
Search for more papers by this authorTrang Quynh Tran
Department of Pharmacology, Hanoi Medical University, Hanoi, Vietnam
Contribution: Investigation, Data curation
Search for more papers by this authorLoan Thanh Thi Nguyen
Department of Pharmacology, Hanoi Medical University, Hanoi, Vietnam
Contribution: Validation, Writing - review & editing
Search for more papers by this authorThanh Phuong Mai
Department of Pharmacology, Hanoi Medical University, Hanoi, Vietnam
Contribution: Methodology, Software
Search for more papers by this authorPhong Xuan Pham
Military Institute of Traditional Medicine, Hanoi, Vietnam
Contribution: Methodology, Investigation
Search for more papers by this authorCorresponding Author
Anh Van Thi Pham
Department of Pharmacology, Hanoi Medical University, Hanoi, Vietnam
Correspondence:
Anh Van Thi Pham ([email protected])
Hoai Thi Nguyen ([email protected])
Contribution: Data curation, Visualization, Writing - review & editing, Supervision
Search for more papers by this authorCorresponding Author
Hoai Thi Nguyen
Faculty of Pharmacy, Hue University of Medicine and Pharmacy, Hue University, Hue City, Vietnam
Correspondence:
Anh Van Thi Pham ([email protected])
Hoai Thi Nguyen ([email protected])
Contribution: Conceptualization, Project administration, Writing - review & editing, Supervision
Search for more papers by this authorHung Van Nguyen
Faculty of Traditional Medicine, Hanoi Medical University, Hanoi, Vietnam
Faculty of Traditional Medicine, Hue University of Medicine and Pharmacy, Hue University, Hue City, Vietnam
Contribution: Conceptualization, Methodology, Investigation, Writing - original draft
Search for more papers by this authorHa Thu Thi Nguyen
Faculty of Traditional Medicine, Hanoi Medical University, Hanoi, Vietnam
Contribution: Investigation, Writing - original draft
Search for more papers by this authorNhan Trong Le
Faculty of Pharmacy, Hue University of Medicine and Pharmacy, Hue University, Hue City, Vietnam
Contribution: Investigation, Formal analysis
Search for more papers by this authorTrang Quynh Tran
Department of Pharmacology, Hanoi Medical University, Hanoi, Vietnam
Contribution: Investigation, Data curation
Search for more papers by this authorLoan Thanh Thi Nguyen
Department of Pharmacology, Hanoi Medical University, Hanoi, Vietnam
Contribution: Validation, Writing - review & editing
Search for more papers by this authorThanh Phuong Mai
Department of Pharmacology, Hanoi Medical University, Hanoi, Vietnam
Contribution: Methodology, Software
Search for more papers by this authorPhong Xuan Pham
Military Institute of Traditional Medicine, Hanoi, Vietnam
Contribution: Methodology, Investigation
Search for more papers by this authorCorresponding Author
Anh Van Thi Pham
Department of Pharmacology, Hanoi Medical University, Hanoi, Vietnam
Correspondence:
Anh Van Thi Pham ([email protected])
Hoai Thi Nguyen ([email protected])
Contribution: Data curation, Visualization, Writing - review & editing, Supervision
Search for more papers by this authorCorresponding Author
Hoai Thi Nguyen
Faculty of Pharmacy, Hue University of Medicine and Pharmacy, Hue University, Hue City, Vietnam
Correspondence:
Anh Van Thi Pham ([email protected])
Hoai Thi Nguyen ([email protected])
Contribution: Conceptualization, Project administration, Writing - review & editing, Supervision
Search for more papers by this authorFunding: This work was supported by Hue University (DHH2024-04-210).
Hung Van Nguyen and Ha Thu Thi Nguyen equally contributed to this paper.
BCPT recognizes the potential of Natural Product studies in the identification of new therapies but wishes to emphasize that findings based on uncharacterized mixtures of compounds are preliminary in nature and serve primarily as hypothesis-generating to form the basis for more elaborate investigations.
ABSTRACT
The acute and subchronic toxicity, along with the anti–type 2 diabetic effects, of a triterpenoid extract from persimmon leaves (Tri DKL) was evaluated in animals. Acute oral toxicity was assessed in Swiss mice, whereas subchronic toxicity was investigated in Wistar rats given Tri DKL at 125 and 375 mg/kg body weight (BW) daily for 90 days. Type 2 diabetes was induced in Swiss mice via an 8-week high-fat diet, followed by a single intraperitoneal injection of streptozotocin (100 mg/kg BW). Diabetic mice were subsequently treated with Tri DKL at 250 and 750 mg/kg BW/day for 2 weeks. Results showed that Tri DKL, even at the highest dose of 2500 mg/kg, did not produce any signs of acute toxicity in mice. In rats, subchronic administration of 125 and 375 mg/kg BW/day caused no significant alterations in general behaviours, haematological parameters or hepatic/renal function markers. In diabetic mice, Tri DKL significantly reduced blood glucose levels at both doses. It also lowered total cholesterol and hepatic malondialdehyde levels. Notably, at 250 mg/kg BW/day, Tri DKL decreased triglyceride levels while improving liver and pancreatic tissue histology. Overall, Tri DKL exhibited no acute or subchronic toxicity in animals and demonstrated hypoglycemic and lipid-lowering effects in type 2 diabetic mice, suggesting potential therapeutic benefits.
Summary
This study examined the safety and potential therapeutic effects of a triterpenoid extract from persimmon leaves (Tri DKL) in the management of type 2 diabetes. A high dose of Tri DKL did not induce acute toxicity in mice. Tri DKL caused no subchronic toxicity after 90 days of administration in rats. In type 2 diabetic mice, Tri DKL lowered blood glucose and cholesterol levels, reduced oxidative stress in the liver and supported the recovery of kidney, liver and pancreatic tissues. These results highlight Tri DKL's potential as a natural treatment for type 2 diabetes.
Conflicts of Interest
The authors declare no conflicts of interest.
Open Research
Data Availability Statement
The datasets generated during and/or analysed during the current study are available from the corresponding authors upon request.
References
- 1D. B. Sacks, M. Arnold, G. L. Bakris, et al., “Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus,” Clinical Chemistry 69, no. 8 (2023): 808–868, https://doi.org/10.1093/clinchem/hvad080.
- 2J. Harreiter and M. Roden, “Diabetes Mellitus: Definition, Classification, Diagnosis, Screening and Prevention (Update 2023),” Wiener Klinische Wochenschrift 135, no. Suppl 1 (2023): 7–17, https://doi.org/10.1007/s00508-022-02122-y.
- 3D. J. Magliano and E. J. Boyko “ IDF Diabetes Atlas,” Brussels (2021).
- 4 World Health Organization, “ Traditional Medicine Growing Needs and Potenital,” WHO Policy Perspective on Medicines, (2002): 1–6.
- 5P. Annadurai, V. Annadurai, M. Yongkun, A. Pugazhendhi, and K. Dhandayuthapani, “Phytochemical Composition, Antioxidant and Antimicrobial Activities of Plecospermum spinosum Trecul,” Process Biochemistry 100 (2021): 107–116, https://doi.org/10.1016/j.procbio.2020.09.031.
- 6R. B. Aygun, G. Zengin, E. Yıldıztugay, S. Jugreet, M. A. Yılmaz, and F. M. Mahomoodally, “Chemical Characterization, Anti-Oxidant and Anti-Enzymatic Properties of Extracts From Two Silene Species: A Focus on Different Plant Parts and Extraction Methods,” Process Biochemistry 116 (2022): 206–213, https://doi.org/10.1016/j.procbio.2022.03.016.
- 7H. Lyu, J. Chen, and W. L. Li, “Natural Triterpenoids for the Treatment of Diabetes Mellitus: A Review,” Natural Product Communications 11, no. 10 (2016): 1579–1586.
- 8H. Saleem, U. Khurshid, M. I. Tousif, et al., “A Comprehensive Review on the Botany, Traditional Uses, Phytochemistry, Pharmacology and Toxicity of Anagallis arvensis (L).: A Wild Edible Medicinal Food Plant,” Food Bioscience 52 (2023): 102328, https://doi.org/10.1016/j.fbio.2022.102328.
10.1016/j.fbio.2022.102328 Google Scholar
- 9P. Dzubak, M. Hajduch, D. Vydra, et al., “Pharmacological Activities of Natural Triterpenoids and Their Therapeutic Implications,” Natural Product Communications 23, no. 3 (2006): 394–411, https://doi.org/10.1039/b515312n.
- 10A. Alqahtani, K. Hamid, A. Kam, et al., “The Pentacyclic Triterpenoids in Herbal Medicines and Their Pharmacological Activities in Diabetes and Diabetic Complications,” Current Medicinal Chemistry 20, no. 7 (2013): 908–931.
- 11E. Harlev, E. Nevo, N. Mirsky, and R. Ofir, “Antidiabetic Attributes of Desert and Steppic Plants: A Review,” Planta Medica 79, no. 6 (2013): 425–436, https://doi.org/10.1055/s-0032-1328331.
- 12A. Bishayee, S. Ahmed, N. Brankov, and M. Perloff, “Triterpenoids as Potential Agents for the Chemoprevention and Therapy of Breast Cancer,” Frontiers in Bioscience-Landmark (FBL) 16, no. 3 (2011): 980–996, https://doi.org/10.2741/3730.
- 13S. Y. Park, H.-J. Kim, K. R. Kim, et al., “Betulinic Acid, a Bioactive Pentacyclic Triterpenoid, Inhibits Skeletal-Related Events Induced by Breast Cancer Bone Metastases and Treatment,” Toxicology and Applied Pharmacology 275, no. 2 (2014): 152–162, https://doi.org/10.1016/j.taap.2014.01.009.
- 14S. C. Tan, R. Rajendran, S. K. Bhattamisra, et al., “Effect of Madecassoside in Reducing Oxidative Stress and Blood Glucose in Streptozotocin-Nicotinamide-Induced Diabetes in Rats,” Journal of Pharmacy and Pharmacology 75, no. 8 (2023): 1034–1045, https://doi.org/10.1093/jpp/rgad063.
- 15M. F. Ahmad, F. A. Ahmad, N. Hasan, et al., “Ganoderma lucidum: Multifaceted Mechanisms to Combat Diabetes Through Polysaccharides and Triterpenoids: A Comprehensive Review,” International Journal of Biological Macromolecules 268, no. Pt 1 (2024): 131644, https://doi.org/10.1016/j.ijbiomac.2024.131644.
- 16B. Dik, T. M. Parlak, M. B. Ates, and O. Tufan, “Exploring the Combined Therapeutic Efficacy of Bexarotene and Icariin in Type 2 Diabetic Rats,” Journal of Pharmacy and Pharmacology 76, no. 11 (2024): 1474–1481, https://doi.org/10.1093/jpp/rgae100.
- 17U. J. Bae, S. H. Park, S. Y. Jung, B. H. Park, and S. W. Chae, “Hypoglycemic Effects of Aqueous Persimmon Leaf Extract in a Murine Model of Diabetes,” Molecular Medicine Reports 12, no. 2 (2015): 2547–2554, https://doi.org/10.3892/mmr.2015.3766.
- 18C. Xie, Z. Xie, X. Xu, and D. Yang, “Persimmon (Diospyros kaki L.) Leaves: A Review on Traditional Uses, Phytochemistry and Pharmacological Properties,” Journal of Ethnopharmacology 163 (2015): 229–240, https://doi.org/10.1016/j.jep.2015.01.007.
- 19J. Kwon, J. E. Park, J. S. Lee, et al., “Chemical Constituents of the Leaves of Diospyros kaki (Persimmon),” Plants (Basel) 10, no. 10 (2021): 2032, https://doi.org/10.3390/plants10102032.
- 20K. Kawakami, Y. Shibukura, T. Kanno, T. Furuki, S. Aketa, and M. Hirayama, “Identification of 2″-Galloylated Flavonol 3-o-Glycosides Accumulating in Developing Leaves of Persimmon,” Phytochemical Analysis 22, no. 5 (2011): 403–410, https://doi.org/10.1002/pca.1295.
- 21L. Liu, R. L. Liu, J. Zhang, and Z. Q. Zhang, “Study on the PEG-Based Microwave-Assisted Extraction of Flavonoid Compounds From Persimmon Leaves,” Journal of Separation Science 35, no. 23 (2012): 3412–3420, https://doi.org/10.1002/jssc.201200495.
- 22G. Chen, H. Lu, C. Wang, et al., “Effect of Five Triterpenoid Compounds Isolated From Leaves of Diospyros kaki on Stimulus-Induced Superoxide Generation and Tyrosyl Phosphorylation in Human Polymorphonuclear Leukocytes,” Clinica Chimica Acta 320, no. 1–2 (2002): 11–16, https://doi.org/10.1016/s0009-8981(02)00021-9.
- 23G. Chen, Z. Q. Wang, and J. M. Jia, “Three Minor Novel Triterpenoids From the Leaves of Diospyros kaki,” Chemical and Pharmaceutical Bulletin 57, no. 5 (2009): 532–535, https://doi.org/10.1248/cpb.57.532.
- 24P. T. Thuong, C. H. Lee, T. T. Dao, et al., “Triterpenoids From the Leaves of Diospyros kaki (Persimmon) and Their Inhibitory Effects on Protein Tyrosine Phosphatase 1B,” Journal of Natural Products 71, no. 10 (2008): 1775–1778, https://doi.org/10.1021/np800298w.
- 25V. H. Nguyen, T. N. Le, N. T. N. Le, et al., “Extraction, Purification, and Evaluation of Bioactivities of Total Triterpenoids From Persimmon (Diospyros kaki L.f.) Leaves,” Process Biochemistry 139 (2024): 70–80, https://doi.org/10.1016/j.procbio.2024.01.025.
- 26J. M. Castellano, S. Ramos-Romero, and J. S. Perona, “Oleanolic Acid: Extraction, Characterization and Biological Activity,” Nutrients 14, no. 3 (2022): 623, https://doi.org/10.3390/nu14030623.
10.3390/nu14030623 Google Scholar
- 27J. H. Hsu, Y. C. Wu, I. M. Liu, and J. T. Cheng, “Release of Acetylcholine to Raise Insulin Secretion in Wistar Rats by Oleanolic Acid, One of the Active Principles Contained in Cornus officinalis,” Neuroscience Letters 404, no. 1–2 (2006): 112–116, https://doi.org/10.1016/j.neulet.2006.05.025.
- 28T. Teodoro, L. Zhang, T. Alexander, J. Yue, M. Vranic, and A. Volchuk, “Oleanolic Acid Enhances Insulin Secretion in Pancreatic Beta-Cells,” FEBS Letters 582, no. 9 (2008): 1375–1380, https://doi.org/10.1016/j.febslet.2008.03.026.
- 29 U.S. Food and Drug Administration (FDA), “ Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers,” Silver Spring, (2005).
- 30 World Health Organization, “ Research Guidelines for Evaluating the Safety and Efficacy of Herbal Medicines,” (1993).
- 31J. T. Litchfield, Jr. and F. Wilcoxon, “A Simplified Method of Evaluating Dose-Effect Experiments,” Journal of Pharmacology and Experimental Therapeutics 96, no. 2 (1949): 99–113.
- 32R. Hristu, S. G. Stanciu, A. Dumitru, et al., “Influence of Hematoxylin and Eosin Staining on the Quantitative Analysis of Second Harmonic Generation Imaging of Fixed Tissue Sections,” Biomedical Optics Express 12, no. 9 (2021): 5829–5843, https://doi.org/10.1364/BOE.428701.
- 33F. Rivera-Ramírez, G. N. Escalona-Cardoso, L. Garduño-Siciliano, C. Galaviz-Hernández, and N. Paniagua-Castro, “Antiobesity and Hypoglycaemic Effects of Aqueous Extract of Ibervillea sonorae in Mice Fed a High-Fat Diet With Fructose,” Journal of Biotechnology and Biomedicine 2011, no. 1 (2011): 968984, https://doi.org/10.1155/2011/968984.
10.1155/2011/968984 Google Scholar
- 34K. Srinivasan and P. Ramarao, “Animal Models in Type 2 Diabetes Research: An Overview,” Indian Journal of Medical Research 125, no. 3 (2007): 451–472.
- 35W. Chatuphonprasert, T. Lao-Ong, and K. Jarukamjorn, “Improvement of Superoxide Dismutase and Catalase in Streptozotocin–Nicotinamide-Induced Type 2-Diabetes in Mice by Berberine and Glibenclamide,” Pharmaceutical Biology 52, no. 4 (2014): 419–427, https://doi.org/10.3109/13880209.2013.839714.
- 36S. Welday Kahssay, G. S. Hailu, and K. Taye Desta, “Design, Synthesis, Characterization and In Vivo Antidiabetic Activity Evaluation of Some Chalcone Derivatives,” Drug Design, Development and Therapy 15, no. 2021 (2021): 3119–3129, https://doi.org/10.2147/DDDT.S316185.
- 37P. Tveden-Nyborg, B. Yang, U. Simonsen, and J. Lykkesfeldt, “BCPT Perspectives on Studies Involving Natural Products, Traditional Chinese Medicine and Systems Pharmacology,” Basic & Clinical Pharmacology & Toxicology 135, no. 6 (2024): 782–785, https://doi.org/10.1111/bcpt.14109.
- 38R. Vigneshwar, A. Arivuchelvan, P. Mekala, and K. Imayarasi, “Sex-Specific Reference Intervals for Wistar Albino Rats: Hematology and Clinical Biochemistry,” Indian Journal of Animal Health 60, no. 1 (2021): 55–67.
10.36062/ijah.60.1.2021.58-65 Google Scholar
- 39L. Luzi and G. Pozza, “Glibenclamide: An Old Drug With a Novel Mechanism of Action?,” Acta Diabetologica 34, no. 4 (1997): 239–244, https://doi.org/10.1007/s005920050081.
- 40A. Tahara, A. Matsuyama-Yokono, and M. Shibasaki, “Effects of Antidiabetic Drugs in High-Fat Diet and Streptozotocin-Nicotinamide-Induced Type 2 Diabetic Mice,” European Journal of Pharmacology 655, no. 1–3 (2011): 108–116, https://doi.org/10.1016/j.ejphar.2011.01.015.
- 41L. Eliasson, E. Renstrom, C. Ammala, et al., “PKC-Dependent Stimulation of Exocytosis by Sulfonylureas in Pancreatic Beta Cells,” Science 271, no. 5250 (1996): 813–815, https://doi.org/10.1126/science.271.5250.813.
- 42L. C. Groop, N. Barzilai, K. Ratheiser, et al., “Dose-Dependent Effects of Glyburide on Insulin Secretion and Glucose Uptake in Humans,” Diabetes Care 14, no. 8 (1991): 724–727, https://doi.org/10.2337/diacare.14.8.724.
- 43M. G. Saklayen, “The Global Epidemic of the Metabolic Syndrome,” Current Hypertension Reports 20, no. 2 (2018): 12, https://doi.org/10.1007/s11906-018-0812-z.
- 44M. Strauss, C. J. Lavie, G. Lippi, et al., “A Systematic Review of Prevalence of Metabolic Syndrome in Occupational Groups—Does Occupation Matter in the Global Epidemic of Metabolic Syndrome?,” Progress in Cardiovascular Diseases 75 (2022): 69–77, https://doi.org/10.1016/j.pcad.2022.09.003.
- 45A. M. Ramirez-Rodriguez, M. Gonzalez-Ortiz, E. Martinez-Abundis, and N. Acuna Ortega, “Effect of Ursolic Acid on Metabolic Syndrome, Insulin Sensitivity, and Inflammation,” Journal of Medicinal Food 20, no. 9 (2017): 882–886, https://doi.org/10.1089/jmf.2017.0003.
- 46I. Sanchez-Crisostomo, E. Fernandez-Martinez, R. Carino-Cortes, G. Betanzos-Cabrera, and R. A. Bobadilla-Lugo, “Phytosterols and Triterpenoids for Prevention and Treatment of Metabolic-Related Liver Diseases and Hepatocellular Carcinoma,” Current Pharmaceutical Biotechnology 20, no. 3 (2019): 197–214, https://doi.org/10.2174/1389201020666190219122357.
- 47H. Sharma, P. Kumar, R. R. Deshmukh, A. Bishayee, and S. Kumar, “Pentacyclic Triterpenes: New Tools to Fight Metabolic Syndrome,” Phytomedicine 50 (2018): 166–177, https://doi.org/10.1016/j.phymed.2018.09.011.
- 48R. Ryu, H. J. Kim, B. Moon, et al., “Ethanol Extract of Persimmon Tree Leaves Improves Blood Circulation and Lipid Metabolism in Rats Fed a High-Fat Diet,” Journal of Medicinal Food 18, no. 7 (2015): 715–723, https://doi.org/10.1089/jmf.2014.3307.
- 49T. A. Woreta and S. A. Alqahtani, “Evaluation of Abnormal Liver Tests,” Medical Clinics of North America 98, no. 1 (2014): 1–16, https://doi.org/10.1016/j.mcna.2013.09.005.
- 50A. Madrazo-Ibarra and P. Vaitla, “ Histology, Nephron”, Treasure Island (FL) (2023).
- 51R. Simeonova, M. Kondeva-Burdina, V. Vitcheva, and M. Mitcheva, “Some In Vitro/In Vivo Chemically-Induced Experimental Models of Liver Oxidative Stress in Rats,” BioMed Research International 2014, no. 1 (2014): 706302, https://doi.org/10.1155/2014/706302.
- 52J. C. Tsai, C. S. Chiu, Y. C. Chen, et al., “Hepatoprotective Effect of Coreopsis Tinctoria Flowers Against Carbon Tetrachloride-Induced Liver Damage in Mice,” BMC Complementary and Alternative Medicine 17, no. 1 (2017): 139, https://doi.org/10.1186/s12906-017-1604-8.
- 53D. M. Tanase, E. M. Gosav, C. F. Costea, et al., “The Intricate Relationship between Type 2 Diabetes Mellitus (T2DM), Insulin Resistance (IR), and Nonalcoholic Fatty Liver Disease (NAFLD),” Journal of Diabetes Research 2020, no. 1 (2020): 3920196, https://doi.org/10.1155/2020/3920196.
- 54S. A. Saganuwan, “Toxicity Studies of Drugs and Chemicals in Animals: An Overview,” Bulgarian Journal of Veterinary Medicine 20, no. 4 (2017): 291–318.
10.15547/bjvm.983 Google Scholar
- 55 OECD, “ Guidelines for the Testing of Chemicals Repeated Dose Oral Toxicity Study in Rodents”, (2008).
- 56 World Health Organization, “ General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine,” (2000).
- 57N. N. Etim, M. E. Williams, U. Akpabio, and E. E. Offiong, “Haematological Parameters and Factors Affecting Their Values,” Agricultural Sciences 2, no. 1 (2014): 37–47.
- 58N. Grenier, P. Merville, and C. Combe, “Radiologic Imaging of the Renal Parenchyma Structure and Function,” Nature Reviews Nephrology 12, no. 6 (2016): 348–359, https://doi.org/10.1038/nrneph.2016.44.
- 59J. F. Moore and J. D. Sharer, “Methods for Quantitative Creatinine Determination,” Current Protocols in Human Genetics 93, no (2017): A.3o.1–A.3o.7, https://doi.org/10.1002/cphg.38.
10.1002/cphg.38 Google Scholar
- 60H. Olson, G. Betton, D. Robinson, et al., “Concordance of the Toxicity of Pharmaceuticals in Humans and in Animals,” Regulatory Toxicology and Pharmacology 32, no. 1 (2000): 56–67, https://doi.org/10.1006/rtph.2000.1399.
- 61J. J. Ramírez-Espinosa, M. Y. Rios, S. López-Martínez, et al., “Antidiabetic Activity of Some Pentacyclic Acid Triterpenoids, Role of PTP-1B: In Vitro, In Silico, and In Vivo Approaches,” European Journal of Medicinal Chemistry 46, no. 6 (2011): 2243–2251, https://doi.org/10.1016/j.ejmech.2011.03.005.
- 62D. Gao, Q. Li, Y. Li, et al., “Antidiabetic Potential of Oleanolic Acid From Ligustrum lucidum Ait,” Canadian Journal of Physiology and Pharmacology 85, no. 11 (2007): 1076–1083, https://doi.org/10.1139/Y07-098.
- 63Y. Li, J. Wang, T. Gu, J. Yamahara, and Y. Li, “Oleanolic Acid Supplement Attenuates Liquid Fructose-Induced Adipose Tissue Insulin Resistance Through the Insulin Receptor Substrate-1/Phosphatidylinositol 3-Kinase/Akt Signaling Pathway in Rats,” Toxicology and Applied Pharmacology 277, no. 2 (2014): 155–163, https://doi.org/10.1016/j.taap.2014.03.016.
- 64B. Jayaprakasam, L. K. Olson, R. E. Schutzki, M. H. Tai, and M. G. Nair, “Amelioration of Obesity and Glucose Intolerance in High-Fat-Fed C57BL/6 Mice by Anthocyanins and Ursolic Acid in Cornelian cherry (Cornus mas),” Journal of Agricultural and Food Chemistry 54, no. 1 (2006): 243–248, https://doi.org/10.1021/jf0520342.
- 65S. M. Jang, S. T. Yee, J. Choi, et al., “Ursolic Acid Enhances the Cellular Immune System and Pancreatic Beta-Cell Function in Streptozotocin-Induced Diabetic Mice Fed a High-Fat Diet,” International Immunopharmacology 9, no. 1 (2009): 113–119, https://doi.org/10.1016/j.intimp.2008.10.013.
- 66J. Deng, J. Xiao, and H. Yang, “ Dietary Triterpenoids,” Singapore (2020): 1–53.
- 67F. H. Kamisan, F. Yahya, N. A. Ismail, et al., “Hepatoprotective Activity of Methanol Extract of Melastoma malabathricum Leaf in Rats,” Journal of Acupuncture and Meridian Studies 6, no. 1 (2013): 52–55, https://doi.org/10.1016/j.jams.2012.08.002.
- 68S. Li, H. Y. Tan, N. Wang, et al., “The Role of Oxidative Stress and Antioxidants in Liver Diseases,” International Journal of Molecular Sciences 16, no. 11 (2015): 26087–26124, https://doi.org/10.3390/ijms161125942.
- 69I. Moreno, S. Pichardo, A. Jos, et al., “Antioxidant Enzyme Activity and Lipid Peroxidation in Liver and Kidney of Rats Exposed to Microcystin-LR Administered Intraperitoneally,” Toxicon 45, no. 4 (2005): 395–402, https://doi.org/10.1016/j.toxicon.2004.11.001.
- 70J. Medina and R. Moreno-Otero, “Pathophysiological Basis for Antioxidant Therapy in Chronic Liver Disease,” Drugs 65, no. 17 (2005): 2445–2461, https://doi.org/10.2165/00003495-200565170-00003.
- 71Q. Wang, J. Wang, N. Li, et al., “A Systematic Review of Orthosiphon stamineus Benth. in the Treatment of Diabetes and Its Complications,” Molecules 27, no. 2 (2022): 444, https://doi.org/10.3390/molecules27020444.
- 72V. Poitout and R. P. Robertson, “Glucolipotoxicity: Fuel Excess and Beta-Cell Dysfunction,” Endocrine Reviews 29, no. 3 (2008): 351–366, https://doi.org/10.1210/er.2007-0023.