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Pasteurella multocida Toxin Aggravates Ligatured-Induced Periodontal Bone Loss and Inflammation via NOD-Like Receptor Protein 3 Inflammasome
NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is reportedly involved in periodontal pathogenesis. Pasteurella multocida toxin (PMT) is the major virulence factor of Pasteurella multocida strains, which belongs to the nonoral gram-negative facultative rods (GNFR). The existence of GNFR and their toxin may aggravate periodontitis. Therefore, it is important to unclose the regulatory mechanisms of PMT in periodontitis. However, the involvement of NLRP3 inflammasome and PMT in periodontitis remain unclear. The results showed that NLRP3 expression was increased in periodontitis mice by immunohistochemical staining and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Nlrp3-/- mice showed less periodontal bone loss and lower abundances of Pasteurella multocida by 16S rRNA sequencing. PMT promoted NLRP3 expressions by activating nuclear factor kappa light chain enhancer of B cells (NF-κB) pathway and activated NLRP3 inflammasome. This effect was reversed by NLRP3 inhibitor MCC950. Furthermore, PMT aggravated periodontal bone loss and inflammation in WT mice, while MCC950 attenuated periodontal bone loss and inflammation. The Nlrp3-/- periodontitis models with PMT local injection showed less bone loss and inflammation compared with WT periodontitis mice after PMT treatment. Taken together, our results showed that PMT aggravates periodontal response to the ligature by promoting NLRP3 expression and activating NLRP3 inflammasome, suggesting that NLRP3 may be an effective target for the treatment of periodontitis caused by GNFR and MCC950 may be a potential drug against this disease.
Correlation between HPV PCNA, p16, and p21 Expression in Lung Cancer Patients
Purpose. Evaluate if human papillomavirus (HPV) infection in lung cancer patients might be helping cancer development by altering p16, p21, and PCNA, key human genes involved in cell proliferation and tumor development. Methods. 63 fresh-frozen (FF) and formalin-fixed paraffin-embedded (FFPE) samples from lung tumor patients were used to detect HPV by PCR, followed by genotype through sequencing. The host gene expressions of p21, p16, and PCNA were quantified by qPCR in both FF and FFPE samples, and the expression of viral oncogenes E5, E6, and E7 was also measured by qPCR in 19 FF samples. Results. 74.6% of samples were positive for HPV, 33/44 FFPE samples and 14/19 FF samples. HPV-16 and HPV-18 were detected in 31/33 and 7/33 FFPE, respectively, and HPV-16 was the only type in FF samples. E5, E6, and E7 were expressed in 10/19, 2/19, and 4/19 FF samples, respectively. The p16 RNAm expression was higher in FF HPV+ samples and FFPE+FF HPV+ samples, while p21 showed higher expression in all HPV- samples. In turn, the PCNA expression was higher in HPV+ FF samples; however, in FFPE and FFPE+FF samples, PCNA was higher in HPV- samples. In FF samples, PCNA, p16, and p21 showed a significant positive correlation as well as E5 and E7, and E5 was inversely correlated to p21. In FFPE, also, a positive correlation was observed between PCNA HPV+ and p21 HPV+ and PCNA HPV+ and p16 HPV. In FF+FFPE analysis, a direct correlation was found between PCNA HPV+ and p21 HPV+, p21 HPV+ and p16 HPV+, and PCNA HPV- and p16 HPV-, and an inverse correlation between PCNA HPV+ and p16 HPV+. Also, the p16 protein was positive in 10 HPV+ samples and 1 HPV-. Conclusions. Our data show that lung cancer patients from Northeast Brazil have a high prevalence of HPV, and the virus also expresses its oncogenes and correlates with key human genes involved in tumor development. This data could instigate the development of studies focused on preventive strategies, such as vaccination, used as a prognostic indicator and/or individualized therapy.
lncRNA MANCR Inhibits NK Cell Killing Effect on Lung Adenocarcinoma by Targeting miRNA-30d-5p
Background. NK cells are imperative in spontaneous antitumor response of various cancers. Currently, lncRNAs are considered important modulators of the tumor microenvironment. This study investigated the molecular mechanism by which mitotically associated long noncoding RNA (MANCR) controls killing effect of NK cells on lung adenocarcinoma (LUAD) in the tumor microenvironment. Methods. The interplay between MANCR and miRNA-30d-5p was analyzed by bioinformatics. Expression of MANCR mRNA and miRNA-30d-5p was examined using qRT-PCR. Dual-luciferase reporter and RIP assays were utilized to verify the targeted relationship between MANCR and miRNA-30d-5p. To investigate regulation of MANCR/miRNA-30d-5p axis in NK cell killing effect on LUAD cells, western blot tested the protein level of perforin and granzyme B. ELISA determined the level of IFN-γ. CytoTox 96 Non-Radioactive Cytotoxicity Assay kit was applied for cytotoxicity detection of NK cells. Perforin and granzyme B fluorescence intensity was measured via immunofluorescence, and cell apoptosis levels were also revealed via flow cytometry. Results. MANCR was found to be upregulated, while miRNA-30d-5p expression was downregulated in LUAD tissues. Overexpression of MANCR in LUAD cells significantly reduced NK cell IFN-γ secretion, expression of granzyme B and perforin, and NK cell killing effect. In addition, MANCR could target and downregulate miRNA-30d-5p expression, and miRNA-30d-5p overexpression reversed the inhibition of NK cell killing effect caused by MANCR overexpression. Conclusion. MANCR inhibited the killing effect of NK cells on LUAD via targeting and downregulating miRNA-30d-5p and provided new ideas for antitumor therapy based on tumor microenvironment.
A Live Cell Imaging Microfluidic Model for Studying Extravasation of Bloodborne Bacterial Pathogens
Bacteria that migrate (extravasate) out of the bloodstream during vascular dissemination can cause secondary infections in many tissues and organs, including the brain, heart, liver, joints, and bone with clinically serious and sometimes fatal outcomes. The mechanisms by which bacteria extravasate through endothelial barriers in the face of blood flow-induced shear stress are poorly understood, in part because individual bacteria are rarely observed traversing endothelia in vivo, and in vitro model systems inadequately mimic the vascular environment. To enable the study of bacterial extravasation mechanisms, we developed a transmembrane microfluidics device mimicking human blood vessels. Fast, quantitative, three-dimensional live cell imaging in this system permitted single-cell resolution measurement of the Lyme disease bacterium Borrelia burgdorferi transmigrating through monolayers of primary human endothelial cells under physiological shear stress. This cost-effective, flexible method was 10,000 times more sensitive than conventional plate reader-based methods for measuring transendothelial migration. Validation studies confirmed that B. burgdorferi transmigrate actively and strikingly do so at similar rates under static and physiological flow conditions. This method has significant potential for future studies of B. burgdorferi extravasation mechanisms, as well as the transendothelial migration mechanisms of other disseminating bloodborne pathogens.
Dynamics of DNA Replication during Male Gametogenesis in the Malaria Parasite Plasmodium Falciparum
Malaria parasites undergo a single phase of sexual reproduction in their complex lifecycle. It involves specialised, sexually committed cells called gametocytes, which develop rapidly into mature gametes and mate upon entering the mosquito midgut. Gamete development is unique, involving unprecedentedly fast replication to produce male gametes. Within ~15 minutes a male gametocyte replicates its ~23 Mb genome three times to produce 8 genomes, segregates these into newly-assembled flagellated gametes and releases them to seek female gametes. Here, for the first time, we use fluorescent labelling of de novo DNA synthesis to follow this process at the whole-cell and single-molecule levels. We make several novel observations, including characterising the origin recognition complex protein Orc1 for the first time in gametocytes, finding that cytokinesis is uncoupled from DNA replication (implying a lack of cell cycle checkpoints), and that the single-molecule dynamics of DNA replication are entirely different from the dynamics in asexual schizogony.
Molecular Modeling Guided Drug Designing for the Therapeutic Treatment of Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a systemic inflammatory disorder that can cause destructive joint disease, significant disability, and increased mortality. RA is the most frequent of all chronic inflammatory joint diseases, and its prevalence frequency in Pakistan is 1.6 per thousand people. Different cytokines and receptors were involved in the triggering of RA, including interleukin-6 (ILR-6), major histocompatibility complex (MHC) antigen human leukocyte (HLA-DR) receptor, and CD20. Several studies illustrated RA as an inherent immune response and triggered due to the “shared epitope.” Therefore, the involvement of all these receptors (IL-6, HLA-DR, and CD20) leads to the neurological, ocular, respiratory, cardiac, skin, and hematological manifestations that have been considered a potential therapeutic target for drug design. Various herbal, natural, and synthetic source inhibitors of interleukin-6 (IL-6), human leukocyte (HLA-DR), and CD20 were studied and reported previously. Reported inhibitors are compared to elucidate the best inhibitor for clinical trials, leading to the orally active drug. In this study, a computer-aided drug designing approach disclosed the potential inhibitors for all receptors based on their distinct binding affinity. Moreover, drug suitability was carried out using Lipinski’s rule by considering the adsorption, distribution, metabolism, and excretion (ADME) of ligands. Results elucidated “calycosin 7-O-glucoside” and “angeliferulate” as putative ligands for IL-6 and HLA-DR, respectively. However, the pharmacokinetic properties (ADMET) revealed angeliferulate as an effete ligand for the biological system compared to calycosin 7-O-glucoside. Based on docking, drug toxicity profiling or pharmacokinetics, and MD simulation stability, this study highlights orally active therapeutic inhibitors to inhibit the activity of pivotal receptors (IL6, HLA-DR, and CD20) of RA in humans. After clinical trials, the resultant inhibitors could be potential therapeutic agents in the drug development against RA.