Periodontitis is a dysbiotic disease characterized by an imbalance of the microbial community within the periodontal tissues, leading to chronic inflammation and destruction of the tooth’s supporting structures (Eriksson et al., 2019; Inanc et al., 2021; Giannini et al., 2022). As a common inflammatory disease, periodontitis affects 10%–15% of adults and can eventually lead to tooth loss (Rajbhandari and Shrestha, 2018). It may have significant implications on an individual’s oral and systemic health. The current understanding of periodontitis has shifted from clinical parameters to the pathogenesis of the disease, and the involvement of microbial composition, immune response, and genetic susceptibility.

The etiopathogenesis of periodontitis is complex, involving both host and microbial factors (Maulani et al., 2021). Dysbiosis, or microbial imbalance, is thought to be the primary driver of periodontitis and is characterized by an overabundance of pathogenic bacteria and a reduction in symbiotic bacteria (Na et al., 2020). The virulence factors of periodontal bacteria include lipopolysaccharides (LPS), proteases, and other enzymes that disrupt the host immune response and promote tissue destruction (Wang H. Y. et al., 2017; Zhou et al., 2023). LPS is highly immunogenic and has the ability to induce the production of pro-inflammatory cytokines. Proteases are involved in the destruction of extracellular matrix and host immune proteins (Blasco-Baque et al., 2017). Other bacterial virulence factors, including fimbriae, capsules, and toxins, as well as host variables such as genetic susceptibility and systemic diseases like diabetes, also contribute to the development of periodontitis (Xu et al., 2020).

Periodontitis is usually associated with activation of polymorphonuclear leukocytes, which in turn may generate reactive oxygen species (ROS) during inflammatory conditions (Hatipoğlu et al., 2015). Oxidative stress is a complex biological process characterized by the excessive production of ROS, which act as destroyers to the redox balance in body and induce oxidative damage (Rotariu et al., 2022). All the metabolisms are impaired in oxidative stress and even nucleic acid balance is influenced. ROS causes oxidative damage to the tissues via multiple mechanisms, including DNA damage, protein oxidation and lipid peroxidation (LPO) damage (Heinkele et al., 2021). Periodontitis is associated epidemiologically with several chronic diseases, such as cardiovascular disease, type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease. Oxidative stress plays an important role in the impact of periodontitis on systemic disease (Ye et al., 2012). The following is an overview of research on the relationship between oxidative stress, periodontitis, and systemic disease.

Oxidative stress is an imbalance between the production of ROS and the antioxidant capacity of cells, which damages biological systems due to increased ROS production and dysfunction of the antioxidant system (Ibrahim et al., 2020; Kim et al., 2021). Under physiological conditions intracellular ROS are normal components of signal transduction cascades. And the levels of ROS are maintained by a complex antioxidants systems participating in the in-vivo redox homeostasis (Obeng-Gyasi, 2018). However, inflammatory responses can also be stimulated by ROS through protein kinases, transcription factors, and genomic expression of inflammatory factors genomic expression (Besednova et al., 2022). Increased ROS accumulation leads to oxidative stress, which contributes to major cellular components damage, including DNA, proteins, and lipids (Perera et al., 2020; Jia et al., 2021).

Oxidative DNA lesions can be formed through two distinct pathways, including: 1) direct oxidation of a base (purine/pyrimidine) in DNA; 2) misincorporation of oxidized deoxy nucleoside triphosphates into DNA by DNA polymerase. All four bases of the DNA can undergo direct oxidation, forming various oxidized purines. Among the various forms of oxidative DNA damage, 8-oxoDG and 8-hydroxy-2′deoxyguanosine (8-OHdG) are the most studied and recognized markers of oxidative DNA alterations (Caliri et al., 2021).

Oxidative damage to proteins is divided in two categories, including the reversible and irreversible protein modifications (Caliri et al., 2021; Fu et al., 2022). Protein carbonylation is an irreversible protein modification, resulting from oxidative damage, that often leads to loss of protein function (Matsuo et al., 2021). The specificity of multiple amino acids to undergo carbonylation has made this modification a widely used biomarker for assessing oxidative damage to proteins (Caliri et al., 2021). Reversible oxidation of proteins with adjacent cysteine residues, possibly including protein kinases and phosphatases, can regulate protein function and redox signaling pathways in various stress responses (Caliri et al., 2021; Sologova et al., 2022).

ROS can induce degradation of polyunsaturated fatty acids resulting in the formation of a variety of products (Caliri et al., 2021; Emanuelli et al., 2022). Lipid peroxidation can directly damage phospholipids to form oxidized phospholipids, which induces cell death through apoptosis, necrosis, pyroptosis, or ferroptosis, and involved in a variety of inflammatory responses (Zhu et al., 2022). Biomembranes are prone to undergo lipid peroxidation, and it is possibly via two pathways: non-enzymatic and enzymatic (Su et al., 2019; Ruan et al., 2021). The non-enzymatic pathway is an iron-dependent lipid peroxidation (Chen et al., 2022). The enzymatic pathway involves a highly organized oxygenation center, wherein oxidation occurs on only one class of phospholipids (Su et al., 2019).

After host defense responses are triggered by periodontal pathogenic bacteria in biofilm, neutrophils become the most common inflammatory cells that accumulate in periodontal tissue and gingival sulcus (Chu et al., 2021). Neutrophils are believed to be the predominant sources of ROS in periodontitis (Wang Y. et al., 2017). During phagocytosis of periodontal pathobionts, neutrophils can release excess ROS via the NADPH oxidase pathway (Sui et al., 2020). However, ROS has a very short half-life, and it is not easy to be detected. Therefore, ROS-related degradants and enzymatic and non-enzymatic antioxidant activity are ideal candidates for assessing the impact of oxidative stress-related events on the pathological process of periodontitis (Monmeesil et al., 2019). Changes in local concentrations of oxidative stress biomarkers are closely associated with the progression of periodontitis. It suggested that the oxidative stress biomarker level can be used for periodontitis diagnosis and therapeutic efficacy evaluation (Wang Y. et al., 2017).

Various explanations have been offered for the relationship between the concentration of local markers of oxidative stress and the progression of periodontitis. For example, higher levels of malondialdehyde (MDA), hydrogen peroxide, and oxidative DNA damage have been reported in patients with periodontitis (Wu et al., 2016). Several studies have shown that decreased activity of enzymatic antioxidants such as superoxide dismutase (SOD) and catalase (CAT) is associated with periodontitis (Almerich-Silla et al., 2015). The study also showed significant differences in the levels of oxidative stress biomarkers (total antioxidant capacity, MDA, glutathione peroxidase, nitric oxide, total oxidative status, and 8-hydroxydeoxyguanosine) at the site between patients with periodontitis and healthy controls (Almerich-Silla et al., 2015).

The pathogenesis of periodontal tissue destruction is believed to involve oxidative stress (Zhang et al., 2022). Almerich-Silla et al. (2015) raised that oxidative stress levels in periodontium were significantly higher in the periodontal disease groups than in the gingivitis groups and healthy groups, the oxidative stress showed a linear trend associated with periodontal worsening as well as bleeding on probing (BOP). Patients with periodontitis had elevated levels of biomarkers of ROS-induced tissue damage and elevated levels of antioxidant enzymes corresponding to oxidative stress in inflamed periodontal tissue and gingival fluid (De Angelis et al., 2022).

Recent studies have focused on the involvement of ROS in the pathogenesis of periodontitis, focusing on apoptosis of human periodontal ligament stem cells (hPDLSCs), migration of periodontal ligament fibroblasts (PDLFs), and alveolar bone loss (Sui et al., 2020). At the right concentration, ROS plays a key role in cell proliferation, migration, apoptosis, and wound healing (Tottoli et al., 2020; Cordani et al., 2021). ROS can increase the expression of dynamin-related protein 1 (Drp1), a key regulator of mitochondrial fission, leading to mitochondrial dysfunction, including abnormal mitochondrial membrane potential and reduced ATP levels, ultimately leading to hPDLSC apoptosis (Sui et al., 2020). In addition, at low concentrations, ROS may stimulate proliferation and differentiation of PDLF in culture. While ROS at high concentrations may have cytotoxic effects on periodontal tissue (Liu et al., 2017).

Periodontitis is triggered by a shift in the oral microbiome towards a community enriched in anaerobic Gram-negative bacteria (Munteanu et al., 2022). These microorganisms are equipped with intrinsic virulence factors, including endotoxin and LPS, which is the main constituent of the Gram-negative bacterial outer membrane. Upon its release, LPS triggers a complex immune response mediated by a variety of host-derived factors that perpetuate the inflammatory processes (Jia et al., 2019; Sidhu et al., 2020). Additionally, LPS may activate immune cells, supplementing the generation of bioactive molecules such as ROS, leading to oxidative stress and further destruction of periodontal tissues (Vo et al., 2020). The contributions of LPS and oxidative stress are crucial in the pathogenesis of periodontitis. LPS can stimulate the generation of proinflammatory cytokines, which provoke and sustain immune cell recruitment and activation as well as tissue damage in periodontal tissues (Han et al., 2022). Concurrently, oxidative stress causes direct harm to cells and tissues, leading to further tissue damage, as well as inflammatory responses that increase the microbial dysbiosis (Liu et al., 2023). Cumulatively, the shift towards an anaerobic Gram-negative bacterial community, along with the presence of LPS and oxidative stress, act synergistically to promote chronic inflammation and to foster the exacerbation of periodontal diseases (Willmann et al., 2018). Liang et al. found that treatment of PDLF with LPS overproduces ROS and induces the binding of thioredoxin (TXNIP) and NOD-like receptor protein 3 (NLRP3) to form NLRP3 inflammasomes (Sui et al., 2020). As intracellular signaling transduction molecules, ROS also promote osteoclast formation, leading to alveolar bone resorption and periodontal tissue damage (Sui et al., 2020).

Experiments have shown that antioxidants can mitigate the irreversible teeth-supporting tissues damage caused by excess ROS. Local vitamin C (an important water-soluble vitamin with antioxidant and immunomodulatory properties) inhibits inflammatory resorption by the alveolar bone and reduces oxidative stress and tissue destruction induced by inflammation (Toraman et al., 2020). Local vitamin C may be a therapeutic agent that can be used in the treatment of periodontitis (Toraman et al., 2020). Proanthocyanin, a potent grape seed antioxidant, has been reported to reduce inflammation and alveolar bone loss due to periodontitis by decreasing HIF-1α and MMP-8 levels and increasing osteoblast activity in diabetic rats periodontitis (Toker et al., 2018). In a study of rats with ligamentous periodontitis, melatonin treatment appeared to suppress the production of inflammatory cytokines and relieve gingival inflammation (Permuy et al., 2017; Li L. et al., 2021). The authors concluded that melatonin could reduce oxidative stress and periodontal inflammation by decreasing the levels of inflammatory cytokines and restoring antioxidant levels in the tissues (Permuy et al., 2017; Li L. et al., 2021). Results of a murine periodontitis model clearly demonstrated that polydopamine nanoparticles could remove ROS and decrease the periodontal inflammation as robust antioxidants (Li Q. et al., 2021).

The above studies show a close relationship between periodontitis and oxidative stress, with periodontitis triggering the mechanism of oxidative damage and oxidative stress influencing the development of periodontitis and further aggravating the damage to periodontal tissues.

Periodontitis causes systemic inflammation and oxidative stress, which can lead to a number of diseases (Kurek-Gorecka et al., 2022; Xu et al., 2022; Yeh et al., 2022). Bacteria in inflamed gingival tissue and virulence factors are capable of entering the bloodstream to induce systemic inflammatory response, thus influencing the pathological process of many diseases, such as cardiovascular diseases, diabetes, chronic kidney disease, as well as liver injury.

In summary, periodontitis causes an imbalance between oxidants and antioxidants, triggering a mechanism of oxidative stress pathological damage that not only damages periodontal tissues but also affects the development of systemic diseases. The study of the relationship between periodontitis and systemic diseases is of great significance in the prevention and treatment of many systemic diseases. It is expected to provide new therapeutic approaches to raise awareness of oral hygiene and thus help to provide new treatment options to reduce the risk of periodontitis-related comorbidities.