Unveiling the therapeutic potential of Tanshinone-IIa sulfonate in the prevention and treatment of experimental periodontitis in mice

• Grant number: 23/15750-7
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2024
• End date: June 30, 2026
• Field of knowledge: Health Sciences - Dentistry - Periodontology
• Principal Investigator: Rafael Scaf de Molon
• Grantee: Rafael Scaf de Molon
• Host Institution: Faculdade de Odontologia (FOA). Universidade Estadual Paulista (UNESP). Campus de Araçatuba. Araçatuba , SP, Brazil
• Associated researchers: Edilson Ervolino ; Érica Dorigatti de Avila ; Joni Augusto Cirelli ; Letícia Helena Theodoro ; Pedro Paulo Chaves de Souza ; Roberta Okamoto ; Sotirios Tetradis ; Valdir Gouveia Garcia

Abstract

Periodontitis (PD), a highly prevalent multicausal chronic inflammatory and destructive disease, develops as a result from complex host-parasite interactions. The dysbiotic bacterial biofilm in contact with the gingival tissues initiates a cascade of inflammatory events, mediated and modulated by the host immune response, characterized by increased expression of innumerous inflammatory mediators such as cytokines and chemokines in the connective tissue. PD results in the destruction of supporting tissues around the teeth, including periodontal ligament, cementum, and alveolar bone. This process depends on the differentiation and activity of osteoclasts, the cells responsible for resorbing the bone tissue. Thus, inhibiting the differentiation or activity of these cells is a viable strategy for controlling bone resorption during the development of PD. Tanshinones are a new class of cathepsin K inhibitors that have recently emerged as promising drugs in reducing the osteoporotic phenotype in mice. Tanshinona-IIa sulfonate is a derivative of Tanshinona IIA, a natural substance from Salvia miltiorrhiza (Danshen) with diverse biological properties. Such compounds can specifically inhibit the collagenolytic activity of Cathepsin K, an enzyme secreted by osteoclasts that participates in the degradation of the organic phase of the bone matrix, without interfering with osteoclast differentiation. Considering the biological potential of tanshinona IIa sulfonate and the site-specific nature of PD, this project aims to unveiling the therapeutic potential of this compound on bone resorption, inflammation progression, in the immunoinflammatory profile and in its osteogenic potential in preventive and therapeutic approach in a mouse model of ligature-induced bone loss. The outcomes to be analyzed include: evaluation of the inflammatory process in the connective tissue through histological analysis, assessment of alveolar bone loss inhibition by micro-computed tomography, quantification of osteoclasts number (TRAP) by histochemistry, immunolocalization and quantification of bone markers (OPG, RANKL and Cathepsin K) and transcription factors (RUNX-2, NFATc1, and NF-ºB), by immunohistochemistry and the immunoinflammatory profile (anti-CD80, anti-CD206, antiF4/80, anti-CD4, anti-CD8, anti-CD45, e anti-CD3) by immunofluorescence; quantification of bone marker expression (RANKL, OPG, c-fos, NFATc1, OSCAR, cathepsin K, and IL-6), and the expression of immunoinflammatory markers (TGF-²1, TNF-±, IL-1², IL-10, IL-4, INF-g, e Arg2) by RT-qPCR; protein levels of NFATc1, c-fos, and IkB± by western blot; the functional activity of Cathepsin K by fluorimetric assay; and finally, the bone mineral apposition rate (MAR) by dynamic histomorphometry through fluorescence microscopy and serum levels of CTx1, P1NP, OCN, and OSX by ELISA, and the structure and organization of collagen fibers in the periodontal ligament under bright-field and polarized microscopy. (AU)

Scientific publications

(11)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

OLIVEIRA, GABRIELA EZEQUIEL; PELEGRINE, HENRIQUE CASSEBE LEDO; BARROS-FILHO, LUIZ ANTONIO B.; CARDOSO, MAURICIO DE ALMEIDA; RICCI, WEBER ADAD; BARROS, LUIZ ANTONIO BORELLI; DE AVILA, ERICA DORIGATTI; DE MOLON, RAFAEL SCAF. State of the Art in the Treatment of Congenital Agenesis With Implant-Supported Prosthesis: A Comprehensive Multidisciplinary Management. CASE REPORTS IN DENTISTRY, v. 2024, p. 15-pg., 2024-10-17. (23/15750-7)

RODRIGUES, JOAO VICTOR SOARES; DEROIDE, MARIELLA BOARETTI; TAKESHITA, WILTON MITSUNARI; GARCIA, VALDIR GOUVEIA; DE MOLON, RAFAEL SCAF; THEODORO, LETICIA HELENA. Efficacy of Antimicrobial Photodynamic Therapy for Treating Moderate to Deep Periodontal Pockets in Individuals with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis. DENTISTRY JOURNAL, v. 13, n. 1, p. 15-pg., 2025-01-01. (23/15750-7)

BELIZARIO, LICIA CLARA GARCIA; FIGUEREDO, CARLOS MARCELO S.; RODRIGUES, JOAO VICTOR SOARES; CIRELLI, THAMIRIS; DE MOLON, RAFAEL SCAF; GARCIA, VALDIR GOUVEIA; THEODORO, LETICIA HELENA. The Impact of Type 2 Diabetes Mellitus on Non-Surgical Periodontal Treatment: A Non-Randomized Clinical Trial. JOURNAL OF CLINICAL MEDICINE, v. 13, n. 19, p. 13-pg., 2024-10-01. (23/15750-7)

JOÃO VICTOR SOARES RODRIGUES; MARIELLA BOARETTI DEROIDE; AMANDA PAINO SANT'ANA; RAFAEL SCAF DE MOLON; LETICIA HELENA THEODORO. O papel da terapia periodontal não cirúrgica na melhoria da qualidade de vida de pacientes hipertensos com periodontite. Rev. odontol. UNESP, v. 53, 2024-12-16. (23/15750-7)

CAROLINA PINHEIRO DA ROCHA; ANA DAISY ZACHARIAS; ELCIO MARCANTONIO JR; FLÁVIA NOEMY GASPARINI KIATAKE FONTÃO; RAFAEL SCAF DE MOLON; RUBENS MORENO DE FREITAS. Avaliação tomográfica das alterações ósseas volumétricas após regeneração com malha de titânio na região anterior da maxila. Estudo clínico retrospectivo. Rev. odontol. UNESP, v. 53, 2024-11-04. (23/15750-7)

MARIO HENRIQUE ARRUDA VERZOLA; FAUSTO FRIZZERA; PAULO SERGIO CERRI; UBIRAJARA PEREIRA RODRIGUES-FILHO; SILVANA REGINA PEREZ ORRICO; RAFAEL SCAF DE MOLON. Effect of Long-Term Treatment with Alendronate on Bone Repair and Mineralization Around Implants in Rats. Brazilian Dental Journal, v. 35, 2024-12-06. (12/16939-1, 23/15750-7)

OLIVEIRA, GABRIELA EZEQUIEL; BARBIRATO, DAVI DA SILVA; DE MENEZES, BRUNA SILVA; FULY, MILENNA SILVA; LEDO PELEGRINE, HENRIQUE CASSEBE; BONILHA, DEBORA CALIENDO; PEREIRA DE ALENCAR, JULIA GABRIELLE; THEODORO, LETICIA HELENA; DE MOLON, RAFAEL SCAF. Exploring the Impact of Biological Agents on Protecting Against Experimental Periodontitis: A Systematic Review of Animal-Based Studies. BIOMED RESEARCH INTERNATIONAL, v. 2024, p. 26-pg., 2024-12-02. (23/15750-7)

CARDOSO, JANDERSON DE MEDEIROS; ERVOLINO, EDILSON; MIYASAWA, ERTON MASSAMITSU; THEODORO, LETICIA HELENA; MARQUES PADOVAN, LUIS EDUARDO; PEREIRA, ESTEVAO LOPES; DE MOLON, RAFAEL SCAF; GARCIA, VALDIR GOUVEIA. Unveiling the Therapeutic Potential of Systemic Ozone on Skin Wound Repair: Clinical, Histological, and Immunohistochemical Study in Rats. BIOMED RESEARCH INTERNATIONAL, v. 2024, p. 12-pg., 2024-08-20. (23/15750-7)

DE MOLON, RAFAEL SCAF; RODRIGUES, JOAO VICTOR SOARES; DEROIDE, MARIELLA BOARETTI; BARBIRATO, DAVI DA SILVA; GARCIA, VALDIR GOUVEIA; THEODORO, LETICIA HELENA. The Efficacy of Topical or Systemic Antibiotics as Adjuvants to Non-Surgical Periodontal Treatment in Diabetic Patients: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. JOURNAL OF CLINICAL MEDICINE, v. 13, n. 16, p. 27-pg., 2024-08-01. (23/15750-7)

CAROLINE PAIXÃO CUSTÓDIO; RUBENS MORENO DE FREITAS; ELCIO MARCANTONIO JUNIOR; RAFAEL SCAF DE MOLON; VALDIR GOUVEIA GARCIA. Efeitos de um enxaguatório liberador de oxigênio para manutenção da saúde peri-implantar. Estudo piloto clinico, randomizado e controlado. Rev. odontol. UNESP, v. 53, 2024-10-28. (23/15750-7)

PEREIRA, MARTAMARIA ALVES; PIAZZA, RODOLFO; SANTANA, AMANDA PAINO; BARAO, VALENTIM ADELINO RICARDO; MALHEIROS, SAMUEL SANTANA; VAN DEN BEUCKEN, JEROEN J. J. P.; DE MOLON, RAFAEL SCAF; DE AVILA, ERICA DORIGATTI. Unraveling the Applicability of LbL Coatings for Drug Delivery in Dental Implant-Related Infection Treatment. ACS BIOMATERIALS SCIENCE & ENGINEERING, v. N/A, p. 20-pg., 2024-11-30. (18/20719-3, 21/10762-1, 22/16267-5, 23/15750-7, 21/09434-0)