{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T09:35:56Z","timestamp":1764581756615,"version":"3.46.0"},"reference-count":44,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI","doi-asserted-by":"publisher","award":["23K16138"],"award-info":[{"award-number":["23K16138"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Diabetes is a significant risk factor for bisphosphonate-related osteonecrosis of the jaw (BRONJ), a severe oral complication with limited treatment options. Salivary testing offers a noninvasive approach for monitoring BRONJ risk; however, few studies have investigated salivary biomarkers in BRONJ. This study screened salivary biomarkers that reflect the progression of BRONJ under diabetic conditions. A diabetic BRONJ rat model was established to screen for diabetes-related biochemical biomarkers in saliva. Streptozotocin (STZ) administration elevated blood glucose and glycated albumin levels and altered lipid and renal function markers, confirming diabetes induction. Subsequent zoledronic acid (ZA) administration and extraction of the maxillary first molar delayed epithelialization, inflammatory cell infiltration, bone exposure, and necrosis in extraction sockets, indicating successful establishment of a diabetic BRONJ model. This model showed reductions in submandibular and sublingual gland size, as well as in acinar cell number. Although salivary secretion volume was reduced, saliva samples were successfully collected from all groups. Screening identified elevated urea nitrogen (UN) and total ketone bodies (T-KB) in the STZ + ZA group. These findings suggest that salivary UN and T-KB may reflect disease progression and serve as potential biomarkers for predicting BRONJ risk under diabetic conditions.<\/jats:p>","DOI":"10.3390\/cimb47121002","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T08:13:49Z","timestamp":1764576829000},"page":"1002","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Screening of Salivary Biomarkers of Bisphosphonate-Related Osteonecrosis of the Jaw in a Diabetic Rat Model"],"prefix":"10.3390","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0517-5454","authenticated-orcid":false,"given":"Ke","family":"Qin","sequence":"first","affiliation":[{"name":"Department of Oral Anatomy, Osaka Dental University, 8-1 Kuzuhahanazono-cho, Hirakata 573-1121, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3778-8906","authenticated-orcid":false,"given":"Masato","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"Department of Oral Anatomy, Osaka Dental University, 8-1 Kuzuhahanazono-cho, Hirakata 573-1121, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoichi","family":"Sumi","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Osaka Dental University, 8-1 Kuzuhahanazono-cho, Hirakata 573-1121, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Baiyan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Geriatric Dentistry, Osaka Dental University, 8-1 Kuzuhahanazono-cho, Hirakata 573-1121, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1876-0035","authenticated-orcid":false,"given":"Mamoru","family":"Uemura","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Osaka Dental University, 8-1 Kuzuhahanazono-cho, Hirakata 573-1121, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4392-2318","authenticated-orcid":false,"given":"Yoshitomo","family":"Honda","sequence":"additional","affiliation":[{"name":"Department of Oral Anatomy, Osaka Dental University, 8-1 Kuzuhahanazono-cho, Hirakata 573-1121, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"107843","DOI":"10.1016\/j.diabres.2019.107843","article-title":"Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the international diabetes federation diabetes atlas, 9(th) edition","volume":"157","author":"Saeedi","year":"2019","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"446","DOI":"10.4239\/wjd.v10.i8.446","article-title":"Development of therapeutic options on type 2 diabetes in years: Glucagon-like peptide-1 receptor agonist\u2019s role intreatment; from the past to future","volume":"10","author":"Dogruel","year":"2019","journal-title":"World J. Diabetes"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1186\/s12933-024-02427-4","article-title":"Altered oxidant and antioxidant levels are associated with vascular stiffness and diabetic kidney disease in type 1 diabetes after exposure to acute and chronic hyperglycemia","volume":"23","author":"Adeshara","year":"2024","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Cecerska-Heryc, E., Engwert, W., Michalow, J., Marciniak, J., Birger, R., Serwin, N., Heryc, R., Polikowska, A., Goszka, M., and Wojciuk, B. (2025). Oxidative stress markers and inflammation in type 1 and 2 diabetes are affected by BMI, treatment type, and complications. Sci. Rep., 15.","DOI":"10.1038\/s41598-025-05818-z"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"430","DOI":"10.4012\/dmj.2023-262","article-title":"Detection of senescent cells in the mucosal healing process on type 2 diabetic rats after tooth extraction for biomaterial development","volume":"43","author":"Luo","year":"2024","journal-title":"Dent. Mater. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1016\/j.joms.2022.02.008","article-title":"American association of oral and maxillofacial surgeons\u2019 position paper on medication-related osteonecrosis of the jaws-2022 update","volume":"80","author":"Ruggiero","year":"2022","journal-title":"J. Oral Maxillofac. Surg."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Tani, M., Hatano, K., Yoshimura, A., Horibe, Y., Liu, Y., Sassi, N., Oka, T., Okuda, Y., Yamamoto, A., and Uemura, T. (2024). Cumulative incidence and risk factors for medication-related osteonecrosis of the jaw during long-term prostate cancer management. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-64440-7"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Frutuoso, F., Freitas, F., Vilares, M., Francisco, H., Marques, D., Carames, J., and Moreira, A. (2024). Medication-related osteonecrosis of the jaw: A systematic review of case reports and case series. Diseases, 12.","DOI":"10.3390\/diseases12090205"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Takaoka, K., Yamamura, M., Nishioka, T., Abe, T., Tamaoka, J., Segawa, E., Shinohara, M., Ueda, H., Kishimoto, H., and Urade, M. (2015). Establishment of an animal model of bisphosphonate-related osteonecrosis of the jaws in spontaneously diabetic torii rats. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0144355"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2300","DOI":"10.1002\/jbmr.2577","article-title":"Bisphosphonate induces osteonecrosis of the jaw in diabetic mice via nlrp3\/caspase-1-dependent il-1beta mechanism","volume":"30","author":"Zhang","year":"2015","journal-title":"J. Bone Miner. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1111\/odi.12204","article-title":"Salivary proteomics in bisphosphonate-related osteonecrosis of the jaw","volume":"21","author":"Michalowicz","year":"2015","journal-title":"Oral Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1111\/odi.14201","article-title":"Quantitative proteomics in medication-related osteonecrosis of the jaw: A proof-of-concept study","volume":"29","author":"Bravo","year":"2023","journal-title":"Oral Dis."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Suryani, I.R., Ahmadzai, I., That, M.T., Shujaat, S., and Jacobs, R. (2023). Are medication-induced salivary changes the culprit of osteonecrosis of the jaw? A systematic review. Front. Med., 10.","DOI":"10.3389\/fmed.2023.1164051"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Ghio, C., Gravier-Dumonceau, R., Lafforgue, P., Giorgi, R., and Pham, T. (2025). Identifying a predictive level of serum c-terminal telopeptide associated with a low risk of medication-related osteonecrosis of the jaw secondary to oral surgery: A systematic review and meta-analysis. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0318260"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Oh, S., Park, M., Hwang, H., Park, J.H., Kim, K.S., Kim, J.W., and Lee, H.J. (2025). Comprehensive profiling of plasma and exosomal micrornas in medication-related osteonecrosis of the jaw. Sci. Rep., 15.","DOI":"10.1038\/s41598-025-21269-y"},{"key":"ref_16","first-page":"e26","article-title":"Biomarkers to predict the onset of biphosphonate-related osteonecrosis of the jaw: A systematic review","volume":"24","author":"Bagan","year":"2019","journal-title":"Med. Oral Patol. Oral Cir. Bucal"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Kammerhofer, G., Vegh, D., Banyai, D., Vegh, A., Joob-Fancsaly, A., Hermann, P., Geczi, Z., Hegedus, T., Somogyi, K.S., and Bencze, B. (2023). Association between hyperglycemia and medication-related osteonecrosis of the jaw (mronj). J. Clin. Med., 12.","DOI":"10.3390\/jcm12082976"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Zhang, B., Kawamoto, A., Nakagawa, M., Honda, Y., and Takahashi, K. (2024). Cmpk2 gene and protein expression in saliva or salivary glands of dyslipidemic mice. Appl. Sci., 14.","DOI":"10.3390\/app142412004"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Sarf, E.A., and Bel\u2019skaya, L.V. (2025). Salivary bcaa, glutamate, glutamine and urea as potential indicators of nitrogen metabolism imbalance in breast cancer. Curr. Issues Mol. Biol., 47.","DOI":"10.3390\/cimb47100837"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Samodova, D., Stankevic, E., Sondergaard, M.S., Hu, N., Ahluwalia, T.S., Witte, D.R., Belstrom, D., Lubberding, A.F., Jagtap, P.D., and Hansen, T. (2025). Salivary proteomics and metaproteomics identifies distinct molecular and taxonomic signatures of type-2 diabetes. Microbiome, 13.","DOI":"10.1186\/s40168-024-01997-5"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Relvas, M., Mendes-Frias, A., Goncalves, M., Salazar, F., Lopez-Jarana, P., Silvestre, R., and Viana da Costa, A. (2024). Salivary il-1beta, il-6, and il-10 are key biomarkers of periodontitis severity. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25158401"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Poimenidou, A.A., Geraki, P., Davidopoulou, S., Kalfas, S., and Arhakis, A. (2025). Oxidative stress and salivary physicochemical characteristics relative to dental caries and restorative treatment in children. Antioxidants, 14.","DOI":"10.3390\/antiox14040405"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Ahmad, M.M., Hassan, H.A., Saadawy, S.F., Ahmad, E.A., Elsawy, N.A.M., and Morsy, M.M. (2024). Antox targeting age\/rage cascades to restore submandibular gland viability in rat model of type 1 diabetes. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-68268-z"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"111903","DOI":"10.1016\/j.diabres.2024.111903","article-title":"Salivary glycated albumin could be as reliable a marker of glycemic control as blood glycated albumin in people with diabetes","volume":"218","author":"Aihara","year":"2024","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1111\/jcpe.14048","article-title":"Salivary and serum inflammatory biomarkers during periodontitis progression and after treatment","volume":"51","author":"Teles","year":"2024","journal-title":"J. Clin. Periodontol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Furman, B.L. (2021). Streptozotocin-induced diabetic models in mice and rats. Curr. Protoc., 1.","DOI":"10.1002\/cpz1.78"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Imada, M., Yagyuu, T., Ueyama, Y., Maeda, M., Yamamoto, K., Kurokawa, S., Jo, J.I., Tabata, Y., Tanaka, Y., and Kirita, T. (2019). Prevention of tooth extraction-triggered bisphosphonate-related osteonecrosis of the jaws with basic fibroblast growth factor: An experimental study in rats. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0211928"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/j.archoralbio.2008.02.008","article-title":"Effect of experimental diabetes on craniofacial growth in rats","volume":"53","author":"Abbassy","year":"2008","journal-title":"Arch. Oral Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1158\/1078-0432.CCR-10-1614","article-title":"Effect of zoledronate on oral wound healing in rats","volume":"17","author":"Yamashita","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/978-1-0716-1028-2_15","article-title":"Preparation of Thin Frozen Sections from Nonfixed and Undecalcified Hard Tissues Using Kawamoto\u2019s Film Method","volume":"Volume 2230","author":"Hilton","year":"2021","journal-title":"Skeletal Development and Repair: Methods and Protocols"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1034\/j.1600-0463.2001.090306.x","article-title":"Stereological study on the submandibular gland in hypothyroid rats","volume":"109","author":"Noorafshan","year":"2001","journal-title":"APMIS"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Rehman, H.U., Ullah, K., Rasool, A., Manzoor, R., Yuan, Y., Tareen, A.M., Kaleem, I., Riaz, N., Hameed, S., and Bashir, S. (2023). Comparative impact of streptozotocin on altering normal glucose homeostasis in diabetic rats compared to normoglycemic rats. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-29445-8"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1016\/j.sjbs.2021.09.045","article-title":"Urolithin A prevents streptozotocin-induced diabetic cardiomyopathy in rats by activating sirt1","volume":"29","author":"Albasher","year":"2022","journal-title":"Saudi J. Biol. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Venuti, M.T., Roda, E., Brandalise, F., Sarkar, M., Cappelletti, M., Speciani, A.F., Soffientini, I., Priori, E.C., Giammello, F., and Ratto, D. (2025). A pathophysiological intersection between metabolic biomarkers and memory: A longitudinal study in the stz-induced diabetic mouse model. Front. Physiol., 16.","DOI":"10.3389\/fphys.2025.1455434"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"AlZeer, I., AlBassam, A.M., AlFeraih, A., AlMutairi, A., AlAskar, B., Aljasser, D., AlRashed, F., Alotaibi, N., AlGhamdi, S., and AlRashed, Z. (2025). Correlation between glycated hemoglobin (hba1c) levels and lipid profile in patients with type 2 diabetes mellitus at a tertiary hospital in saudi arabia. Cureus, 17.","DOI":"10.7759\/cureus.80736"},{"key":"ref_36","first-page":"101130","article-title":"Prevalence and severity of chronic kidney disease in a population with type 1 diabetes from a united states health system: A real-world cohort study","volume":"47","author":"Tuttle","year":"2025","journal-title":"Lancet Reg. Health Am."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Hassan, S.S., and Alqahtani, M.S. (2024). Early alterations of cytoskeletal proteins induced by radiation therapy in the parenchymal cells of rat major salivary glands: A comparative immunohistochemical analysis. Cureus, 16.","DOI":"10.7759\/cureus.75634"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2933","DOI":"10.1002\/ar.25395","article-title":"Distribution of alpha-synuclein in rat salivary glands","volume":"307","author":"Nishitani","year":"2024","journal-title":"Anat. Rec."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1002\/ar.21481","article-title":"Estrogen and insulin replacement therapy modulates the expression of insulin-like growth factor-i receptors in the salivary glands of diabetic mice","volume":"294","author":"Yashida","year":"2011","journal-title":"Anat. Rec."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.jcms.2020.01.005","article-title":"Saliva diagnostics in patients suffering from bisphosphonate-associated osteonecrosis of the jaw: Results of an observational study","volume":"48","author":"Stockmann","year":"2020","journal-title":"J. Craniomaxillofac. Surg."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1515\/cclm-2023-1285","article-title":"The correlation of urea and creatinine concentrations in sweat and saliva with plasma during hemodialysis: An observational cohort study","volume":"62","author":"Adelaars","year":"2024","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Kumaran, R., Abdalla, M.M.I., Caszo, B.A., and Somanath, S.D. (2025). Saliva urea nitrogen for detection of kidney disease in adults: A meta-analysis of diagnostic test accuracy. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0324251"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Kovalcikova, A.G., Pavlov, K., Liptak, R., Hladova, M., Renczes, E., Boor, P., Podracka, L., Sebekova, K., Hodosy, J., and Tothova, L. (2020). Dynamics of salivary markers of kidney functions in acute and chronic kidney diseases. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-78209-1"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3282","DOI":"10.1111\/epi.18465","article-title":"Serial correlation between saliva and blood beta-hydroxybutyrate levels in children commencing the ketogenic diet for epilepsy","volume":"66","author":"Kaul","year":"2025","journal-title":"Epilepsia"}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/47\/12\/1002\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T09:31:40Z","timestamp":1764581500000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/47\/12\/1002"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,28]]},"references-count":44,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["cimb47121002"],"URL":"https:\/\/doi.org\/10.3390\/cimb47121002","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,28]]}}}