Protein-based salivary biomarkers for the diagnosis of periodontal diseases: Systematic review and meta-analysis.

Objective: This systematic review and meta-analysis was aimed at determining differentially expressed protein-based biomarkers detectable in the saliva for the diagnosis of major periodontal diseases. Methods: A literature review was conducted through January 31, 2022. The methodological quality and risk of bias were assessed with the Newcastle-Ottawa scale for case-control studies. Heterogeneity among studies was analysed with the Q statistical test and the I2 test. p-values lower than 0.10 and I2 values higher than 50% indicated high heterogeneity among studies; therefore, the random-effects model was used. The analysis of biological pathways associated with the differentially expressed protein markers was performed with the STITCH integration analysis tool and was limited to interactions with high confidence levels (0.7). Results: Of all protein-based biomarkers detected, 12 were suitable for meta-analysis: IL-1ß, MIP-1α, albumin, TNF-α, ICTP, Ig-A, lactoferrin, MMP-8, IL-6, IL-8, IL-17 and PGE2. The salivary markers with high applicability were IL-1ß for differentiating patients with chronic periodontal disease from patients with gingivitis with an OE = 73.5 pg/mL; ICTP for differentiating patients with chronic periodontal disease from healthy control patients with an OE = 0.091 ng/mL; and PGE2 for differentiating patients with chronic periodontal disease from healthy control patients with an OE = 36.3 pg/mL. Conclusions: The biomarkers with the highest differential expression and the greatest potential for clinical applicability are IL-1ß for differentiating periodontitis from gingivitis, and ICTP and PGE2 for differentiating periodontitis from healthy status.

Extracellular vesicles enriched in connexin 43 promote a senescent phenotype in bone and synovial cells contributing to osteoarthritis progression.

The accumulation of senescent cells is a key characteristic of aging, leading to the progression of age-related diseases such as osteoarthritis (OA). Previous data from our laboratory has demonstrated that high levels of the transmembrane protein connexin 43 (Cx43) are associated with a senescent phenotype in chondrocytes from osteoarthritic cartilage. OA has been reclassified as a musculoskeletal disease characterized by the breakdown of the articular cartilage affecting the whole joint, subchondral bone, synovium, ligaments, tendons and muscles. However, the mechanisms that contribute to the spread of pathogenic factors throughout the joint tissues are still unknown. Here, we show for the first time that small extracellular vesicles (sEVs) released by human OA-derived chondrocytes contain high levels of Cx43 and induce a senescent phenotype in targeted chondrocytes, synovial and bone cells contributing to the formation of an inflammatory and degenerative joint environment by the secretion of senescence-associated secretory associated phenotype (SASP) molecules, including IL-1ß and IL-6 and MMPs. The enrichment of Cx43 changes the protein profile and activity of the secreted sEVs. Our results indicate a dual role for sEVs containing Cx43 inducing senescence and activating cellular plasticity in target cells mediated by NF-kß and the extracellular signal-regulated kinase 1/2 (ERK1/2), inducing epithelial-to-mesenchymal transition (EMT) signalling programme and contributing to the loss of the fully differentiated phenotype. Our results demonstrated that Cx43-sEVs released by OA-derived chondrocytes spread senescence, inflammation and reprogramming factors involved in wound healing failure to neighbouring tissues, contributing to the progression of the disease among cartilage, synovium, and bone and probably from one joint to another. These results highlight the importance for future studies to consider sEVs positive for Cx43 as a new biomarker of disease progression and new target to treat OA.

Usefulness of protein-based salivary markers in the diagnosis of oral potentially malignant disorders: A systematic review and meta-analysis.

By using a meta-analytical approach, this study aimed to analyse the diagnostic capacity of protein-based biomarkers in saliva for the differential diagnosis of oral potentially malignant disorders (OPMDs) and oral squamous cell carcinoma (OSCC) from healthy individuals as control group (HCG).Articles on protein-based biomarkers in saliva, which provided quantitative expression in individuals with clinical and histopathological diagnosis of OPMD or oral leukoplakia (OL) were considered eligible. Searches were conducted in eight electronic databases. The methodological quality was assessed using the Quality Assessment of Diagnostic Studies tool (QUADAS-2). Functional analysis was also performed. Meta-analyses were performed using the OpenMeta tool (Analyst).Meta-analysis was possible for 4 of the 11 biomarkers studied. Only the carcinoembryonic antigen (CEA) and the soluble fragment of cytokeratin 19 (CYFRA21) were significant for the OSCC/OPMD subgroup, both with a very low heterogeneity. CEA had an OE = 25.854 (CI95%: 13.215-38.492, p< 0.001, I2 = 0) and CYFRA21 had an OE = 9.317 (CI95%: 9.014-9.619, p< 0.001, I2 = 0). For the OPMD/HCG subgroup, only CYFRA21 was significant, with an OE = 3.679 (CI95%: 0.663-6.696, p= 0.017) although with high heterogeneity (I2 = 91.24).The CEA and CYFRA21 markers proved very useful when differentiating OSCC from OPMD. The CYFRA21 was the only protein that was capable of distinguishing between OPMD and healthy controls.