Citrullination, a posttranslational modification, is catalyzed by peptidylarginine deiminases (PADs), a unique family of enzymes that converts peptidyl-arginine to peptidyl-citrulline. Overexpression and/or increased PAD activity is observed in rheumatoid arthritis (RA), Alzheimer’s disease, multiple sclerosis, and cancer. Moreover, bacterial PADs, such as Porphyromonas gingivalis PAD (PPAD), may have a role in the pathogenesis of RA, indicating PADs as promising therapeutic targets. Herein, six novel compounds were examined as potential inhibitors of human PAD4 and PPAD, and compared to an irreversible PAD inhibitor, Cl-amidine. Four of the tested compounds (compounds 2, 3, 4, and 6) exhibited a micromolar-range inhibition potency against PAD4 and no effect against PPAD in the in vitro assays. Compound 4 was able to inhibit the PAD4-induced citrullination of H3 histone with higher efficiency than Cl-amidine. In conclusion, compound 4 was highly effective and presents a promising direction in the search for novel RA treatment strategies.
Peptidylarginine deiminase (PPAD) is a virulence factor unique to pathogenic Porphyromonas species, especially P. gingivalis. Mechanistically, PPAD activity, in conjunction with Arg-specific gingipains, generates protein fragments with citrullinated C-termini. Such polypeptides are potential de novo epitopes that are key drivers of rheumatoid arthritis. This process could underlie the observed clinical association between rheumatoid arthritis and periodontitis. However, the role of PPAD in host colonization by P. gingivalis and, subsequently, in triggering periodontitis is not known. Therefore, the aim of the current study was to delineate the role of PPAD in bacterial biofilm formation, and to define whether adherence to, invasion of, and host responses to bacteria of gingival keratinocytes depend on PPAD activity. We studied these aspects using PPAD-competent and PPAD-incompetent strains of P. gingivalis, and demonstrated that neither biofilm formation nor its composition was affected by PPAD activity. Similarly, flow cytometry revealed that PPAD did not impact the ability of P. gingivalis to adhere to and, subsequently, invade keratinocytes. Network analyses of gene expression patterns, however, revealed a group of host genes that were sensitive to PPAD activity (CXCL8, IL36G, CCL20, and IL1B). These genes can be categorized as potent immune modulators belonging to the interleukin 1 system, or chemoattractants of lymphocytes and neutrophils. Thus, we conclude that PPAD, although it is a potent modulator of the immune response, does not affect bacterial biofilm formation or the ability of P. gingivalis to adhere to and invade gingival epithelial cells.
Background: Statins effectively reduce risk of cardiovascular-related morbidity and mortality in patients with hyperlipidemia, hypertension, or type 2 diabetes. In addition to lowering cholesterol levels, several studies have attributed statins with immunomodulatory and bactericidal properties. Therefore, the aim of this study was to investigate statins' antimicrobial activity against periodontal homeostasis bacteria.Methods: Statin effect on bacterial growth was tested using planktonic monocultures and multibacterial biofilms. The latter consisted of five microbial species (Porphyromonas gingivalis, Fusobacterium nucleatum, Actinomyces naeslundii, Tannerella forsythia, and Streptococcus gordonii) associated with dysbiosis of the oral microbiota underlying establishment and perpetuation of periodontitis.Results: All four tested statins efficiently inhibited P. gingivalis growth and significantly decreased the cumulative bacterial load in developing and established biofilms. Simvastatin was most efficient and decreased P. gingivalis counts more than 1,300-fold relative to the control. Conclusions:These findings suggest that similar effects on bacterial composition of the dental plaque may occur in vivo in patients on statins, thus, leading to a shift of the oral microbiome from a dysbiotic to a more homeostatic one. Simvastatin, being highly effective against P. gingivalis while not affecting commensal microbiota, possesses many properties qualifying it as a potential adjunctive treatment for chronic periodontitis. Further studies are needed to evaluate whether similar effects on bacterial composition of the dental plaque may occur in vivo in patients on statins, thus, leading to a shift of the oral microflora from dysbiotic to a more homeostatic one.
Monocyte chemoattractant protein-induced protein-1 (MCPIP-1) is a potent inhibitor of inflammatory response to pathogens. Acting as endonuclease against transcripts of inflammatory cytokines or transcription factors MCPIP-1 can significantly reduce the cytokine storm, thus limiting the tissue damage. As the adequate resolution of inflammation depends also on the efficient clearance of accumulated neutrophils, we focused on the role of MCPIP-1 in apoptosis and retention of neutrophils. We used peritoneal neutrophils from cell-specific MCPIP-1 knockout mice and showed prolonged survival of these cells. Moreover, we confirmed that MCPIP-1-dependent degradation of transcripts of antiapoptotic genes, including BCL3, BCL2A1, BCL2L1, and for the first time MCL-1, serves as an early event in spontaneous apoptosis of primary neutrophils. Additionally, we identified previously unknown miRNAs as potential binding partners to the MCPIP-1 transcript and their regulation suggest a role in MCPIP-1 half-life and translation. These phenomena may play a role as a molecular switch that balances the MCPIP-1-dependent apoptosis. Besides that, we determined these particular miRNAs as integral components of the GM-CSF-MCPIP-1 axis. Taken together, we identified the novel anti-inflammatory role of MCPIP-1 as a regulator of accumulation and survival of neutrophils that simultaneously promotes an adequate resolution of inflammation.
Lavandula angustifolia, one of the most popular medicinal plants, is the source of a bioactive essential oil characterized by a wide spectrum of biological activity, e.g., antiseptic, analgesic, and anticancer effects. In dermatology, the oil helps to relieve skin inflammation and exhibit wound healing potential. However, the mechanism of action of the lavender oil depends on its composition, which in turn is dependent on the origin and growing conditions. Our study aimed to compare the composition and proregenerative properties of the commercially-available narrow-leaved lavender oil produced in Provence, France, with the oil obtained from the narrow-leaved lavender cultivated locally in Poland. GC/MS analysis showed that self-manufactured essential oil had lower linalool content than commercial oil (23.2 vs. 40.2%), comparable linalyl acetate content (40.6 vs. 44%), while the proportion of lavandulyl acetate was significantly higher (23.2 vs. 5.5%). To determine the influence of lavender oil on the production of proinflammatory cytokines and proregenerative growth factors, gene expression of the selected signaling molecules by HaCaT cells was investigated using real-time PCR. Results showed a concentration-dependent effect of lavender oils on the production of IL-6, IL-8, and VEGF by the keratinocyte cell line. Finally, the potential of the lavender oil to increase the production of VEGF, the most important angiogenic factor, with the in-house preparation performing significantly better in the in vitro cell models was identified.
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