Research Article
Effects of Artesunate on Salivary Secretion in A Model of Type 1 Diabetic Xerostomia
- Biyun Gao *
- Girju Rajbanshi
- Bingge Wang
- Cheng Liang
- Hairong Wang
- Xiaolin Nong
College of Stomatology, Guangxi Medical University, Nanning, Guangxi, PR China.
*Corresponding Author: Biyun Gao, College of Stomatology, Guangxi Medical University, Nanning, Guangxi, PR China.
Citation: Gao B, Rajbanshi G, Wang B, Liang C, Wang H, et al. (2025). Effects of Artesunate on Salivary Secretion in A Model of Type 1 Diabetic Xerostomia, Dentistry and Oral Health Care, BioRes Scientia Publishers. 4(3):1-18. DOI: 10.59657/2993-0863.brs.25.052
Copyright: © 2025 Biyun Gao, this is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Received: October 29, 2025 | Accepted: November 12, 2025 | Published: November 19, 2025
Abstract
Objective: This study aimed to investigate the impact of artesunate on type 1 diabetes mellitus-induced xerostomia and the secretory function of rat submandibular gland acinar cells under hyperglycemic conditions.
Designs: Submandibular glands were excised for histopathological assessment, periodic acid-schiff (PAS) staining, and immunohistochemical analysis of aquaporin 5(AQP5) and amylase (AMY) protein expression, supplemented by RT-PCR and Western blot for AQP5, AMY and mitogen-activated protein kinase (MAPK). Salivary acinar cells were cultured in vitro in a high-glucose environment. Flow cytometry for AQP5 and AMY and Western blot (WB) detection for MAPK were performed.
Results: Histological examination revealed that artesunate with insulin intervention group (ART+INS) treatment mitigated inflammatory infiltration and enhanced granule secretion. The ART+INS group showed an increase in PAS-positive substances. Protein expression of AQP5 and AMY was notably elevated in the intervention group. Western blot analysis indicated a decreased expression of MAPK, with a more pronounced reduction in the ART+INS group compared to the ART group alone (p < 0.05). Flow cytometry results showed an increase in AQP5 positive expression in SMG cells following ART, INS and ART+INS interventions in the diabetes mellitus (DM) group (p < 0.05).
Conclusion: ART or its combination therapy with insulin is suggested to alleviate DM-induced xerostomia and downregulate MAPK expression in Submandibular gland (SMG) cells under hyperglycemic conditions.
Keywords: type 1 diabetes; xerostomia; artesunate; oral flora; salivary secretion
References
- Mauri-Obradors, E., Estrugo-Devesa, A., Jané-Salas, E., Viñas, M., López-López, J. (2017). Oral manifestations of Diabetes Mellitus. A systematic review. Medicina oral, patologia oral y cirugia bucal, 22(5):e586.
Publisher | Google Scholor - Carda, C., Mosquera-Lloreda, N., Salom, L., Gomez de Ferraris, M. E., Peydró, A. (2006). Structural and functional salivary disorders in type 2 diabetic patients. Medicina Oral Patologia Oral y Cirugia Bucal, 11(4):209.
Publisher | Google Scholor - Zeng, X. Z., Zhang, Y. Y., Yang, Q., Wang, S., Zou, B. H., et al. (2020). Artesunate attenuates LPS-induced osteoclastogenesis by suppressing TLR4/TRAF6 and PLCγ1-Ca2+-NFATc1 signaling pathway. Acta Pharmacologica Sinica, 41(2):229-236.
Publisher | Google Scholor - Wang, W., Liang, Y. S. (2016). Artemisinin: a wonder drug from Chinese natural medicines. Chinese Journal of Natural Medicines, 14(1):5-6.
Publisher | Google Scholor - Li, Z., Shi, X., Liu, J., Shao, F., Huang, G., et al. (2019). Artesunate prevents type 1 diabetes in NOD mice mainly by inducing protective IL‐4-producing T cells and regulatory T cells. The FASEB Journal, 33(7):8241-8248.
Publisher | Google Scholor - Cui, F., Hu, M., Li, R., Li, B., Huang, D., et al. (2021). Insulin on changes in expressions of aquaporin-1, aquaporin-5, and aquaporin-8 in submandibular salivary glands of rats with Streptozotocin-induced diabetes. International Journal of Clinical and Experimental Pathology, 14(2):221.
Publisher | Google Scholor - Soetikno, V., Sari, F. R., Sukumaran, V., Lakshmanan, A. P., Mito, S., et al. (2012). Curcumin prevents diabetic cardiomyopathy in streptozotocin-induced diabetic rats: possible involvement of PKC–MAPK signaling pathway. European Journal of Pharmaceutical Sciences, 47(3):604-614.
Publisher | Google Scholor - Bai, S., Zhou, J., Nong, X., Shi, R., Yuan, Z., et al. (2022). Mechanism and effects of artesunate on the liver function of rats with type 1 diabetic periodontitis. Canadian Journal of Physiology and Pharmacology, 100(8):741-754.
Publisher | Google Scholor - Sakai, M., Sakai, T. (2022). Establishment of a mouse submandibular salivary gland organ culture. Current Protocols, 2(9):e543.
Publisher | Google Scholor - Alimi, D. (2015). Xerostomia induced by radiotherapy. Therapeutics and Clinical Risk Management, 1149-1152.
Publisher | Google Scholor - Molania, T., Alimohammadi, M., Akha, O., Mousavi, J., Razvini, R., et al. (2017). The effect of xerostomia and hyposalivation on the quality of life of patients with type II diabetes mellitus. Electronic Physician, 9(11):5814.
Publisher | Google Scholor - Takeuchi, K., Furuta, M., Takeshita, T., Shibata, Y., Shimazaki, Y., et al. (2015). Risk factors for reduced salivary flow rate in a Japanese population: the Hisayama Study. BioMed Research International, 1:381821.
Publisher | Google Scholor - Negrato, C. A., Tarzia, O. (2010). Buccal alterations in diabetes mellitus. Diabetology & Metabolic Syndrome, 2(1):3.
Publisher | Google Scholor - Momm, F., Volegova-Neher, N. J., Schulte-Mönting, J., Guttenberger, R. (2005). Different saliva substitutes for treatment of xerostomia following radiotherapy: a prospective crossover study. Strahlentherapie und Onkologie, 181(4):231-236.
Publisher | Google Scholor - Zyad, A., Tilaoui, M., Jaafari, A., Oukerrou, M. A., et al. (2018). More insights into the pharmacological effects of artemisinin. Phytotherapy Research, 32(2):216-229.
Publisher | Google Scholor - Yu, L., Chen, J. F., Shuai, X., Xu, Y., Ding, Y., et al. (2016). Artesunate protects pancreatic beta cells against cytokine-induced damage via SIRT1 inhibiting NF-κB activation. Journal of Endocrinological Investigation, 39(1):83-91.
Publisher | Google Scholor - Ghazanfar, K., Ganai, B. A., Akbar, S., Mubashir, K., Dar, S. A., et al. (2014). Antidiabetic activity of Artemisia amygdalina Decne in streptozotocin induced diabetic rats. BioMed Research International, 1:185676.
Publisher | Google Scholor - Raina, S., Preston, G. M., Guggino, W. B., Agre, P. (1995). Molecular cloning and characterization of an aquaporin cDNA from salivary, lacrimal, and respiratory tissues. Journal of Biological Chemistry, 270(4):1908-1912.
Publisher | Google Scholor - Nielsen, S., King, L. S., Christensen, B. M., Agre, P. (1997). Aquaporins in complex tissues. II. Subcellular distribution in respiratory and glandular tissues of rat. American Journal of Physiology-Cell Physiology, 273(5):C1549-C1561.
Publisher | Google Scholor - Funaki, H., Yamamoto, T., Koyama, Y., Kondo, D., Yaoita, E., et al. (1998). Localization and expression of AQP5 in cornea, serous salivary glands, and pulmonary epithelial cells. American Journal of Physiology-Cell Physiology, 275(4):C1151-C1157.
Publisher | Google Scholor - Matsuzaki, T., Suzuki, T., Koyama, H., Tanaka, S., Takata, K. (1999). Aquaporin-5 (AQP5), a water channel protein, in the rat salivary and lacrimal glands: immunolocalization and effect of secretory stimulation. Cell and Tissue Research, 295(3):513-521.
Publisher | Google Scholor - He, X., Tse, C. M., Donowitz, M., Alper, S. L., Gabriel, S. E., et al. (1996). Polarized distribution of key membrane transport proteins in the rat submandibular gland. Pflügers Archiv, 433(3):260-268.
Publisher | Google Scholor - Ma, T., Song, Y., Gillespie, A., Carlson, E. J., Epstein, C. J., et al. (1999). Defective secretion of saliva in transgenic mice lacking aquaporin-5 water channels. Journal of Biological Chemistry, 274(29):20071-20074.
Publisher | Google Scholor - Inoue, N., Iida, H., Yuan, Z., Ishikawa, Y., Ishida, H. (2003). Age-related decreases in the response of aquaporin-5 to acetylcholine in rat parotid glands. Journal of Dental Research, 82(6):476-480.
Publisher | Google Scholor - Ishikawa, Y., Inoue, N., Zhenfang, Y., Nakae, Y. (2004). Molecular mechanisms and drug development in aquaporin water channel diseases: the translocation of aquaporin-5 from lipid rafts to the apical plasma membranes of parotid glands of normal rats and the impairment of it in diabetic or aged rats. Journal of Pharmacological Sciences, 96(3):271-275.
Publisher | Google Scholor - Mednieks, M. I., Szczepanski, A., Clark, B., Hand, A. R. (2009). Protein expression in salivary glands of rats with streptozotocin diabetes. International Journal of Experimental Pathology, 90(4):412-422.
Publisher | Google Scholor - Bhattarai, K. R., Lee, S. W., Kim, S. H., Kim, H. R., Chae, H. J. (2017). Ixeris dentata extract regulates salivary secretion through the activation of aquaporin-5 and prevents diabetes-induced xerostomia. Journal of Experimental Pharmacology, 81-91.
Publisher | Google Scholor - Jaiboonma, A., Kaokaen, P., Chaicharoenaudomrung, N., Kunhorm, P., Janebodin, K., et al. (2020). Cordycepin attenuates salivary hypofunction through the prevention of oxidative stress in human submandibular gland cells. International Journal of Medical Sciences, 17(12):1733.
Publisher | Google Scholor - Matsuzaki, T., Susa, T., Shimizu, K., Sawai, N., Suzuki, T., et al. (2012). Function of the membrane water channel aquaporin-5 in the salivary gland. Acta Histochemica et Cytochemica, 45(5):251-259.
Publisher | Google Scholor - Chivasso, C., Nesverova, V., Järvå, M., Blanchard, A., Rose, K. L., et al. (2021). Unraveling human AQP5-PIP molecular interaction and effect on AQP5 salivary glands localization in SS patients. Cells, 10(8):2108.
Publisher | Google Scholor - Li, Z., Zhao, D., Gong, B., Xu, Y., Sun, H., et al. (2006). Decreased saliva secretion and down-regulation of AQP5 in submandibular gland in irradiated rats. Radiation Research, 165(6):678-687.
Publisher | Google Scholor - Wang, D., Iwata, F., Muraguchi, M., Ooga, K., Ohmoto, Y., et al. (2009). Correlation between salivary secretion and salivary AQP5 levels in health and disease. The Journal of Medical Investigation, 56(Supplement):350-353.
Publisher | Google Scholor - Delporte, C., Steinfeld, S. (2006). Distribution and roles of aquaporins in salivary glands. Biochimica et Biophysica Acta (BBA)-Biomembranes, 1758(8):1061-1070.
Publisher | Google Scholor - Wang, D., Yuan, Z., Inoue, N., Cho, G., Shono, M., et al. (2011). Abnormal subcellular localization of AQP5 and downregulated AQP5 protein in parotid glands of streptozotocin-induced diabetic rats. Biochimica et Biophysica Acta (BBA)-General Subjects, 1810(5):543-554.
Publisher | Google Scholor - Cui, F., Hu, M., Li, R., Li, B., Huang, D., et al. (2021). Insulin on changes in expressions of aquaporin-1, aquaporin-5, and aquaporin-8 in submandibular salivary glands of rats with Streptozotocin-induced diabetes. International Journal of Clinical and Experimental Pathology, 14(2):221.
Publisher | Google Scholor - Zheng, C., Baum, B. J. (2005). Evaluation of viral and mammalian promoters for use in gene delivery to salivary glands. Molecular Therapy, 12(3):528-536.
Publisher | Google Scholor - Schibler, U., Hagenbüchle, O., Young, R. A., Tosi, M., Wellauer, P. K. (1982). Tissue specific expression of mouse alpha-amylase genes. Advances in Experimental Medicine and Biology, 158:381-385.
Publisher | Google Scholor - Chen, Y., Li, W., Nong, X., Liang, C., Li, J., et al. (2021). Role of Artesunate on cardiovascular complications in rats with type 1 diabetes mellitus. BMC Endocrine Disorders, 21(1):19.
Publisher | Google Scholor - Sun, Z., Ma, Y., Chen, F., Wang, S., Chen, B., et al. (2018). Artesunate ameliorates high glucose-induced rat glomerular mesangial cell injury by suppressing the TLR4/NF-κB/NLRP3 inflammasome pathway. Chemico-Biological Interactions, 293:11-19.
Publisher | Google Scholor - Li, Z., Shi, X., Liu, J., Shao, F., Huang, G., et al. (2019). Artesunate prevents type 1 diabetes in NOD mice mainly by inducing protective IL-4-producing T cells and regulatory T cells. The FASEB Journal, 33(7):8241-8248.
Publisher | Google Scholor - Li, L., Chen, J., Zhou, Y., Zhang, J., Chen, L. (2023). Artesunate alleviates diabetic retinopathy by activating autophagy via the regulation of AMPK/SIRT1 pathway. Archives of Physiology and Biochemistry, 129(4):943-950.
Publisher | Google Scholor - Matsumoto, N., Omagari, D., Ushikoshi-Nakayama, R., Yamazaki, T., Inoue, H., et al. (2021). Hyperglycemia induces generation of reactive oxygen species and accelerates apoptotic cell death in salivary gland cells. Pathobiology, 88(3):234-241.
Publisher | Google Scholor - Soyfoo, M. S., Bolaky, N., Depoortere, I., Delporte, C. (2012). Relationship between aquaporin-5 expression and saliva flow in streptozotocin‐induced diabetic mice? Oral diseases, 18(5):501-505.
Publisher | Google Scholor
