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Parkinson's disease (PD) is a well-known neurodegenerative disease with a strong association established with systemic inflammation. Recently, the role of the gingipain protease group from was implicated in Alzheimer's disease and here we present evidence, using a fluorescent antibody to detect gingipain R1 (RgpA), of its presence in a PD population. To further elucidate the action of this gingipain, as well as the action of the lipopolysaccharide (LPS) from , low concentrations of recombinant RgpA and LPS were added to purified fluorescent fibrinogen. We also substantiate previous findings regarding PD by emphasizing the presence of systemic inflammation via multiplex cytokine analysis, and demonstrate hypercoagulation using thromboelastography (TEG), confocal and electron microscopy. Biomarker analysis confirmed significantly increased levels of circulating proinflammatory cytokines. In our PD and control blood analysis, our results show increased hypercoagulation, the presence of amyloid formation in plasma, and profound ultrastructural changes to platelets. Our laboratory analysis of purified fibrinogen with added RgpA, and/or LPS, showed preliminary data with regards to the actions of the protease and the bacterial membrane inflammagen on plasma proteins, to better understand the nature of established PD.

Parkinson’s disease (PD) is a well-known neurodegenerative disease. Recently, the role of gingipains from Porphyromonas gingivalis was implicated in Alzheimer’s disease. Here we present evidence of systemic inflammation, accompanied by hypercoagulation; we also show that ginipains from P. gingivalis and its LPS may foster abnormal clotting, and that ginipains are present in PD blood, and thus that ginipain’s action on blood may be relevant to PD pathology. Bloods from both PD and healthy blood samples were analysed using thromboelastography (TEG), confocal and electron microscopies, and for cytokine and other circulating biomarkers. We also probed PD and healthy plasma clots with a polyclonal antibody for the bacterial protease, gingipain R1, from P. gingivalis. Low concentrations of recombinant gingipain R1 were also added to purified fluorescent fibrinogen. TEG, fibrin(ogen) amyloid formation and platelet ultrastructure analysis confirmed profound hypercoagulation, while the biomarker analysis confirmed significantly increased levels of circulating proinflammatory cytokines. We provide evidence for the presence of the protease, gingipain R1 in PD blood, implicating inflammatory microbial cell wall products in PD.

ObjectiveThe aim of the present study is to investigate the participation of NLRP12 in Porphyromonas gingivalis LPS-activated mouse macrophages.MethodsNLRP12-depleted mouse macrophages were stimulated with P. gingivalis LPS (1 μg/ml.). At indicated time points, the treated cells were lysed and the supernatant from treated cells was collected. Gene and protein expression of NLRP12 and iNOS were determined by RT-PCR and immunoblotting, respectively. The level of TNF-α production in the supernatant of the activated cells was determined by ELISA.Results and conclusionNLRP12 was upregulated in response to stimulation with P. gingivalis LPS. In addition, when NLRP12 was depleted in P. gingivalis LPS-treated macrophages, an increase in TNF-α production and iNOS expression were observed when compared to those of the control cells, indicating that NLRP12 downregulates the inflammatory cytokine and antimicrobial molecule production in the macrophages.

Background: IgE and IgG 4 are implicated in atopic development and clinically utilized as major biomarkers. Atopic responses following certain pathogens, such as Porphyromonas gingivalis (Pg), are currently an area of interest for further research. The aim of this study is to measure the level of IgE, IgG 4, and IgG 4/IgE ratio periodically after exposure of periodontal pathogen Pg lipopolysaccharide (LPS). Methods: We used 16 Wistar rats ( Rattus norvegicus) randomly subdivided into four groups: Group 1,  injected with placebo; Group 2, injected with LPS Pg 0.3 µg/mL; Group 3, injected with LPS Pg 1 µg/mL; and Group 4, injected with LPS Pg 3 µg/mL. Sera from all groups were taken from retro-orbital plexus before and after exposure. Results: Levels of IgE and IgG 4 increased significantly following exposure of LPS Pg at day-4 and day-11. Greater increase of IgE rather than IgG 4 contributed to rapid decline of IgG 4/IgE ratio, detected in the peripheral blood at day-4 and day-11. Conclusion: Modulation of atopic responses following exposure to LPS Pg is reflected by a decrease in IgG 4/IgE ratio that accompanies an increase of IgE. Therefore, Pg, a keystone pathogen during periodontal disease, may have a tendency to disrupt atopic biomarkers.

ObjectiveThe aim of this study is to investigate the involvement of TLR9 in the regulation of iNOS expression and nitric oxide (NO) production in Porphyromonas gingivalis LPS-treated mouse macrophages.MethodsMouse macrophage cell line (RAW264.7) was transfected with siRNAs against TLR9 and then stimulated with P. gingivalis LPS. At indicated time points, the activated cells were lysed. Gene and protein expression of iNOS were determined by RT-PCR and immunoblotting, respectively. The level of nitric oxide (NO) production in the supernatant of the activated cells was determined by Griess reaction assay.Results and conclusionDepletion of TLR9 in mouse macrophages demonstrated the markedly decreased iNOS gene and protein expression by P. gingivalis LPS compared to those of the wild-type or control siRNA transfected cells. In consistent with these results, the level of NO secretion was also significantly diminished in TLR9-depleted cells after challenged with P. gingivalis LPS. These results indicate that TLR9 involves in the regulation of the iNOS expression and the NO secretion in P. gingivalis LPS-treated macrophages.

ObjectivesThe aims of this study were to compare the in vitro cytokine response of gingival fibroblasts (GF’s) from healthy and inflamed human gingival tissues and to assess whether GF’s from inflamed gingivae are capable of mounting a secondary inflammatory response after exposure to P. gingivalis LPS.Materials and methodsGF’s were obtained from healthy donors and periodontitis patients and cultured in vitro. Cells were exposed to P. gingivalis LPS for 24h before measurement of MCP-1, GRO, IL-6, IL-8 and VEGF using a bead-based multiplex assay. Statistical comparisons were made between LPS-exposed GF’s and unstimulated cells as well as the two patient groups by two-way ANOVA.ResultsGF’s exposed to P. gingivalis LPS significantly increased their production of MCP-1, GRO, IL-6, IL-8 and VEGF compared to unstimulated cells. GF’s isolated from inflamed tissue from periodontitis patients demonstrated consistently less cytokine production after exposure to P. gingivalis LPS, most notably for GRO and IL-6.ConclusionsThe current study demonstrates that GF’s play an active role in the inflammatory response in periodontal disease by producing a number of chemokines and cytokines. Furthermore, inflamed GF’s may be compromised in their ability to mount an adequate secondary immune response in relation to chemokine/cytokine production.Clinical relevanceThe compromised inflammatory cytokine response of inflamed human gingival fibroblasts to P. gingivalis LPS may impact on their ability to recruit and activate inflammatory cells while maintaining persistent inflammation, a key feature of periodontal disease.

Epidemiological studies have suggested an association between obesity and periodontal disease. Brown adipose tissue (BAT) has an anti-obesity effect. However, the effects of periodontitis on obesity and BAT remain unclear. Therefore, the present study aimed to determine the effects of lipopolysaccharide derived from Porphyromonas gingivalis (P. gingivalis LPS) on brown adipocytes. For this purpose, the present study examined the effects of the intravenous administration of Porphyromonas gingivalis (P. gingivalis) in mice, the treatment of brown adipocytes with P. gingivalis LPS during differentiation, and the administration of small interfering RNA targeting interferon on brown preadipocytes by assessing the expression of genes involved in differentiation, using a long non-coding (lnc)RNA, and pro-inflammatory factors using reverse transcription-quantitative PCR. In addition, the accumulation of lipid droplets was examined using Oil Red O staining. P. gingivalis LPS reduced the expression of uncoupling protein 1 (UCP1) and lncRNA-BATE10 in brown adipocytes during differentiation. Consistent with this finding, P. gingivalis reduced UCP1 and lncRNA-BATE10 expression in the BAT of mice. lncRNA-BATE10 may thus be involved in the regulation of UCP1 expression that occurs during the differentiation of brown adipocytes treated with P. gingivalis LPS. Thus, P. gingivalis LPS may inhibit BAT differentiation by reducing lncRNA-BATE10 expression.

Tet-eleven translocation 1 (TET1) is a dioxygenase that plays an important role in decreasing the abundance of DNA methylation and changing the expression levels of specific genes related to inflammation. Porphyromonas gingivalis (Pg.) lipopolysaccharide (LPS) can induce periodontal diseases that present with severe bone loss and collagen fiber destruction accompanied by a high number of M1 macrophages. M1-polarized macrophages are pivotal immune cells that promote the progression of the periodontal inflammatory response, but the function of TET1 during M1 macrophage activation is still unknown. Our results showed that the mRNA and protein expression levels of TET1 decreased in THP-1 cells during M1 macrophage differentiation. TET1 knockdown resulted in a significant decrease in the production of proinflammatory markers such as IL-6, TNF-α, CCL2, and HLA-DR in Pg. LPS/IFN-γ- and Escherichia coli (E. coli) LPS/IFN-γ-induced M1 macrophages. Mechanistically, TET1 knockdown downregulated the activity of the NF-κB signaling pathway. After treatment with the NF-κB inhibitor BAY 11-7082, M1 marker expression showed no significant difference between the TET1 knockdown group and the control group. Taken together, these results suggest that TET1 depletion inhibited Pg. LPS/IFN-γ-induced M1 macrophage polarization through the NF-κB pathway in THP-1 cells.

Porphyromonas gingivalis (P. gingivalis), a key pathogen in periodontitis, is associated with neuroinflammation. Periodontal disease increases with age; 70.1% of adults 65 years and older have periodontal problems. However, the P. gingivalis- lipopolysaccharide (LPS)induced mitochondrial dysfunction in neurodegenerative diseases remains elusive. In this study, we investigated the possible role of P. gingivalis-LPS in mitochondrial dysfunction during neurodegeneration. We found that P. gingivalis-LPS treatment activated toll-like receptor (TLR) 4 signaling and upregulated the expression of Alzheimer’s disease-related dementia and neuroinflammatory markers. Furthermore, the LPS treatment significantly exacerbated the production of reactive oxygen species and reduced the mitochondrial membrane potential. Our study highlighted the pivotal role of P. gingivalis-LPS in the repression of serum response factor (SRF) and its co-factor p49/STRAP that regulate the actin cytoskeleton. The LPS treatment repressed the genes involved in mitochondrial function and biogenesis. P. gingivalis-LPS negatively altered oxidative phosphorylation and glycolysis and reduced total adenosine triphosphate (ATP) production. Additionally, it specifically altered the mitochondrial functions in complexes I, II, and IV of the mitochondrial electron transport chain. Thus, it is conceivable that P. gingivalis-LPS causes mitochondrial dysfunction through oxidative stress and inflammatory events in neurodegenerative diseases.

Porphyromonas gingivalis triggers a range of innate immune responses in the host that may contribute to the development of periodontitis and dementing diseases including Alzheimer’s disease (AD). This study aimed to assess the mode of action of trans-resveratrol in modulating the P. gingivalis lipopolysaccharide (PgLPS) induced metabolic inflammation in a neuronal cell model. Confluent IMR-32 neuroblastoma cells were treated with trans-resveratrol from Polygonum cuspidatum in the presence or absence of PgLPS. The abundance of messenger ribo-nucleic acid (mRNA) transcripts of a panel of 92 genes was quantitatively assessed through targeted transcriptome profiling technique and the biochemical pathways affected were identified through Ingenuity Pathway Analysis. Gene expression analysis revealed that trans-resveratrol down-regulated the mRNA of multiple gene markers including growth factors, transcription factors, kinases, trans-membrane receptors, cytokines and enzymes that were otherwise activated by PgLPS treatment of IMR-32 neuroblastoma cells. Pathway analysis demonstrated that the cellular oxidative stress caused by the activation of phosphoinositide-3-kinase/Akt1 (PI3K/Akt1) pathway that leads to the production of reactive oxygen species (ROS), chronic inflammatory response induced by the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway and nutrient utilization pathways were favourably modulated by trans-resveratrol in the PgLPS challenged IMR-32 cells. This study demonstrates the potential of trans-resveratrol as a bioactive compound with multiple modes of intracellular action further supporting its therapeutic application in neuroinflammatory diseases.