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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 February 2026 | Viewed by 4017

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Special Issue Editors

Dr. Yago Leira

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Guest Editor

Periodontology Unit, Faculty of Medicine and Dentistry, University of Santiago de Compostela, Santiago de Compostela, Spain
Interests: dentistry; periodontitis; inflammation; infection; education; comorbidities; systemic health

Dr. João Botelho

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Guest Editor

Clinical Research Unit, Centro de Investigação Interdisciplinar Egas Moniz, Egas Moniz—Cooperativa de Ensino Superior, CRL, 2829-511 Almada, Portugal
Interests: periodontal diseases; periodontitis; systemic inflammation; cardiovascular diseases; neurological conditions; metabolic disorders; systematic review; meta-analysis
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Special Issue Information

Dear Colleagues,

Periodontitis is one of the most prevalent diseases worldwide. The pathophysiology of this disease is complex, and several molecular mechanisms have been described on the interaction between the host and the bacterial challenge. In individuals with susceptibility to periodontitis, the host response is ineffective, dysregulated, and destructive. While the bacteria are required for disease pathogenesis, it is predominantly the host inflammatory response to this microbial challenge that can ultimately lead to damage on the periodontal tissues. In the last decade, periodontitis has been associated with a wide variety of systemic conditions, mainly with atherosclerotic vascular diseases and diabetes. Different biological mechanisms have been proposed to explain these associations including bacteraemia and increased systemic inflammatory response.

This Special Issue aims to advance our knowledge of different biological and molecular pathways through which periodontal tissue breakdown could occur. Novel biological pathways linking periodontitis with systemic diseases are also relevant for this issue. Therefore, we welcome preclinical and clinical original papers and review articles dealing with novel molecular pathways of periodontitis as well as scientific contributions describing biological mechanisms underlying the perio-systemic link. In addition, we encourage authors to submit papers with educational content dealing with methods to explain complex biological processes in periodontitis and its systemic impact.

Dr. Yago Leira
Dr. João Botelho
Guest Editors

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Keywords

periodontitis
general medicine
inflammation
bacteraemia
education

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Published Papers (4 papers)

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Research

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21 pages, 4769 KB

Open AccessArticle

Porphyromonas gingivalis Vesicles Control Osteoclast–Macrophage Lineage Fate

by Elizabeth Leon, Shin Nakamura, Satoru Shindo, Maria Rita Pastore, Tomoki Kumagai, Alireza Heidari, Elaheh Dalir Abdolahinia, Tomoya Ueda, Takumi Memida, Ana Duran-Pinedo, Jorge Frias-Lopez, Xiaozhe Han, Xin Chen, Shengyuan Huang, Guoqin Cao, Sunniva Ruiz, Jan Potempa and Toshihisa Kawai

Int. J. Mol. Sci. 2026, 27(2), 831; https://doi.org/10.3390/ijms27020831 - 14 Jan 2026

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Abstract

Porphyromonas gingivalis (Pg), a keystone pathogen of chronic periodontitis, releases outer membrane vesicles (OMVs) that act as nanoscale vehicles to disseminate virulence factors within periodontal tissues and systemically beyond the oral cavity. Although Pg-OMVs are increasingly recognized as critical mediators of host–pathogen interactions, their effects on the differentiation and function of monocyte–macrophage/osteoclast lineage cells remain unclear. Here, we examined the impact of Pg-OMVs on the differentiation of RAW264.7 monocyte/macrophage-like cells into osteoclasts (OC) and/or macrophages (MΦ) in the presence of receptor activator of nuclear factor-κB ligand (RANKL). OMVs were isolated from Pg W83 and applied to RANKL-primed RAW264.7 cells using three distinct stimulation schedules: (1) simultaneous treatment with Pg-OMVs and RANKL at Day 0; (2) RANKL priming at Day 0 followed by Pg-OMV stimulation at Day 1; and (3) RANKL priming at Day 0 followed by Pg-OMV stimulation at Day 3. In all schedules, cells were cultured for 7 days from the initial RANKL exposure. Remarkably, simultaneous exposure to Pg-OMVs and RANKL (Schedule 1) markedly suppressed osteoclastogenesis (OC-genesis) while promoting M1 macrophage polarization. In contrast, delayed Pg-OMV stimulation of RANKL-primed cells (Schedules 2 and 3) significantly enhanced OC-genesis while reducing M1 polarization. These schedule-dependent effects were consistent with altered expression of osteoclastogenic markers, including dc-stamp, oc-stamp, nfatc1, and acp5. Importantly, a monoclonal antibody against OC-STAMP counteracted the Pg-OMV-induced upregulation of OC-genesis in Schedules 2 and 3. Furthermore, levels of Pg-OMV phagocytosis were inversely correlated with osteoclast formation. Finally, co-stimulation with RANKL and Pg-OMVs (Schedule 1) enhanced macrophage migratory capacity, whereas delayed stimulation with Pg-OMVs (Schedules 2 and 3) did not. Collectively, these findings indicate that Pg-OMVs exert stage-specific effects on the OC/MΦ lineage: stimulation at early stages of RANKL priming suppresses OC-genesis and promotes M1 polarization, whereas stimulation at later stages enhances OC-genesis without inducing M1 differentiation. Thus, Pg-OMVs may critically influence the fate of the OC/MΦ unit in periodontal lesions, contributing to disease progression and tissue destruction. Full article

(This article belongs to the Special Issue Molecular Biology of Periodontal Disease and Periodontal Pathogens)

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28 pages, 8091 KB

Open AccessArticle

Identification of Bacterial Networks and Relationship to Host Responses in Early Periodontitis Population over 24 Months

by Aaron R. Biesbrock, Sancai Xie, Ping Hu, Cheryl S. Tansky, Xingtao Wei, Hao Ye, Benjamin Circello, Avi Zini, Guy Tobias, Makio Tamura and Mirjana Parlov

Int. J. Mol. Sci. 2025, 26(22), 10823; https://doi.org/10.3390/ijms262210823 - 7 Nov 2025

Viewed by 783

Abstract

This research examined the effects of daily application of an oral hygiene regimen on the subgingival microbiome over 24 months. Generally healthy adults (107 enrolled, 87 completed) with early periodontitis used a home-care regimen (stannous fluoride paste, cetylpyridinium chloride rinse, power toothbrush, and floss) or usual care (control). Subgingival plaque samples were analyzed enzymatically for bacterial toxins. TLR ligands were measured using TLR-SEAP and TLR-ATP assays. Proinflammatory cytokines and metalloproteinases were quantified via immunoassays. Subgingival DNA was sequenced using a shotgun approach to assess microbial diversity. Increasing levels of bacteria, toxins, TLR activation, inflammatory cytokines, and MMPs were observed for periodontitis versus gingivitis and gingivitis versus healthy sites. The regimen significantly reduced levels of the critical proinflammatory cytokine IL-1β, as well as MMP-1 and MMP-9, at 24 months. By month 6, TLR ligands within subgingival plaques decreased. The abundance of pathogenic bacteria correlated with levels of virulence factors, proinflammatory cytokines, MMPs, and severity of clinical measures. Two distinct constellations of pathogenic bacteria were identified. Gingival sites were categorized into responders and non-responders per clinical symptoms and biomarkers. The regimen yielded more responder sites (70%) versus the control (47%), p = 0.0002914. The regimen reduced pathogenic bacteria, IL-1β, MMP1, and MMP-9, paralleling clinical reductions in periodontal disease. Full article

(This article belongs to the Special Issue Molecular Biology of Periodontal Disease and Periodontal Pathogens)

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Review

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16 pages, 774 KB

Open AccessReview

A Review on the Role of Oral Bacteria in Stroke

by Florencia Gayo, Jorge Moldes, Susana Bravo, Irene Vieitez, Lucía Martínez-Lamas, Manuel Rodríguez-Yáñez, Ramón Iglesias-Rey, Pedro Diz, Tomás Sobrino, Juan Blanco and Yago Leira

Int. J. Mol. Sci. 2025, 26(24), 11913; https://doi.org/10.3390/ijms262411913 - 10 Dec 2025

Viewed by 519

Abstract

Emerging evidence suggests periodontitis may contribute to stroke risk via vascular inflammation and endothelial dysfunction, promoting atherothrombosis and atrial fibrillation. This review aims to synthesize the evidence on the presence of oral bacteria and their products in biological samples from stroke patients and assess their potential impact on stroke pathophysiology, clinical outcomes, and prognosis. We conducted a narrative review of epidemiological, serological, and molecular studies examining the presence of oral bacterial DNA, endotoxins and antibodies against oral pathogens in biological samples (blood, saliva and thrombi) from stroke patients. Seropositivity for periodontal pathogens in blood was associated with incident stroke, as well as with poorer prognosis. Oral bacterial DNA, mainly from Streptococcus spp. and Prevotella spp., was consistently detected in thrombi, whereas no DNA from classic periodontal pathogens was found. The presence of P. gingivalis antibodies in thrombi was associated with lower complete reperfusion rates, while Acinetobacter spp. and Enterobacteriaceae correlated with higher early adverse events and poorer prognosis. DNA detection was limited by low-biomass samples and methodological constraints. These findings support a potential link between periodontitis and ischemic stroke. However, further studies using improved molecular methods are needed to clarify underlying mechanisms and to assess the presence of periodontal pathogen DNA in thrombi. Full article

(This article belongs to the Special Issue Molecular Biology of Periodontal Disease and Periodontal Pathogens)

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12 pages, 430 KB

Open AccessReview

Red Complex Periodontal Pathogens and Their Potential Role in Colorectal Carcinogenesis: A Narrative Review

by Ursa Potocnik Rebersak and Rok Schara

Int. J. Mol. Sci. 2025, 26(20), 10012; https://doi.org/10.3390/ijms262010012 - 15 Oct 2025

Cited by 1 | Viewed by 2002

Abstract

Periodontal disease (PD), a chronic inflammatory condition driven by oral microbial dysbiosis, is increasingly implicated in systemic diseases, including colorectal cancer (CRC). The “red complex” bacteria—Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola—play a central role in PD progression and exhibit virulence factors that promote inflammation, immune evasion, and epithelial colonization. A literature search in PubMed, Google Scholar, and ScienceDirect (English and Slovenian, up to September 2025) identified 12 eligible studies. Only original clinical, in vivo, or in vitro research directly addressing red complex pathogens and colorectal cancer was included. The search results showed that most of the literature focuses on the association between Porphyromonas gingivalis and CRC, particularly its role in tumor immune evasion, alteration of the gut microbiota, creation of a pro-inflammatory microenvironment, and promotion of carcinoma cell proliferation. Infection with Porphyromonas gingivalis has also been linked to poorer cancer prognosis. The other red complex bacteria are primarily mentioned in the context of generating a pro-inflammatory microenvironment and contributing to chronic inflammation, which supports tumor growth and survival. Full article

(This article belongs to the Special Issue Molecular Biology of Periodontal Disease and Periodontal Pathogens)

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