Assessing Causal Relationships Between Periodontitis and Non-alcoholic Fatty Liver Disease: A Two-Sample Bidirectional Mendelian Randomisation Study.

PURPOSE: To investigate the causality between periodontitis and non-alcoholic fatty liver disease (NAFLD) using a two-sample bidirectional Mendelian randomisation (MR) analysis. MATERIALS AND METHODS: Genetic variations in periodontitis and NAFLD were acquired from genome-wide association studies (GWAS) using the Gene-Lifestyle Interaction in Dental Endpoints, a large-scale meta-analysis, and FinnGen consortia. Data from the first two databases were used to explore the causal relationship between periodontitis and NAFLD ("discovery stage"), and the data from FinnGen was used to validate our results ("validation stage"). We initially performed MR analysis using 5 single nucleotide polymorphisms (SNPs) in the discovery samples and 18 in the replicate samples as genetic instruments for periodontitis to investigate the causative impact of periodontitis on NAFLD. We then conducted a reverse MR analysis using 6 SNPs in the discovery samples and 4 in the replicate samples as genetic instruments for NAFLD to assess the causative impact of NAFLD on periodontitis. We further implemented heterogeneity and sensitivity analyses to assess the reliability of the MR results. RESULTS: Periodontitis was not causally related to NAFLD (odds ratio [OR] = 1.036, 95% CI: 0.914-1.175, p = 0.578 in the discovery stage; OR = 1.070, 95% CI: 0.935-1.224, p = 0.327 in the validation stage), and NAFLD was not causally linked with periodontitis (OR = 1.059, 95% CI: 0.916-1.225, p = 0.439 in the discovery stage; OR = 0.993, 95% CI: 0.896-1.102, p = 0.901 in the validation stage). No heterogeneity was observed among the selected SNPs. Sensitivity analyses demonstrated the absence of pleiotropy and the reliability of our MR results. CONCLUSION: The present MR analysis showed no genetic evidence for a cause-and-effect relationship between periodontitis and NAFLD. Periodontitis may not directly influence the development of NAFLD and vice versa.

Nitazoxanide protects against experimental ulcerative colitis through improving intestinal barrier and inhibiting inflammation.

Ulcerative colitis is a chronic disease with colonic mucosa injury. Nitazoxanide is an antiprotozoal drug in clinic. Nitazoxanide and its metabolite tizoxanide have been demonstrated to activate AMPK and inhibit inflammation, therefore, the aim of the present study is to investigate the effect of nitazoxanide on dextran sulfate sodium (DSS)-induced colitis and the underlying mechanism. Oral administration of nitazoxanide ameliorated the symptoms of mice with DSS-induced colitis, as evidenced by improving the increased disease activity index (DAI), the decreased body weight, and the shortened colon length. Oral administration of nitazoxanide ameliorated DSS-induced intestinal barrier dysfunction and reduced IL-6 and IL-17 expression in colon tissues. Mechanistically, nitazoxanide and its metabolite tizoxanide treatment activated AMPK and inhibited JAK2/STAT3 signals. Nitazoxanide and tizoxanide treatment increased caudal type homeobox 2 (CDX2) expression, increased alkaline phosphatase (ALP) activity and promoted tight junctions in Caco-2 cells. Nitazoxanide and tizoxanide treatment restored the decreased zonula occludens-1(ZO-1) and occludin protein levels induced by LPS or IL-6 in Caco-2 cells. On the other hand, nitazoxanide and tizoxanide regulated macrophage bias toward M2 polarization, as evidenced by the increased arginase-1expression in bone marrow-derived macrophages (BMDM). Nitazoxanide and tizoxanide reduced the increased IL-6, iNOS and CCL2 pro-inflammatory gene expressions and inhibited JAK2/STAT3 activation in BMDM induced by LPS. In conclusion, nitazoxanide protects against DSS-induced ulcerative colitis in mice through improving intestinal barrier and inhibiting inflammation and the underlying mechanism involves AMPK activation and JAK2/STAT3 inhibition.

Roles of Pyroptosis-Related Genes in the Diagnosis and Subtype Classification of Periodontitis.

Pyroptosis is widely involved in many diseases, including periodontitis. Nonetheless, the functions of pyroptosis-related genes (PRGs) in periodontitis are still not fully elucidated. Therefore, we aimed to investigate the role of PRGs in periodontitis. Three datasets (GSE10334, GSE16134, and GSE173078) from the Gene Expression Omnibus (GEO) were selected to analyze the differences in expression values of the PRGs between nonperiodontitis and periodontitis tissue samples using difference analysis. Following this, five hub PRGs (charged multivesicular body protein 2B, granzyme B, Z-DNA-binding protein 1, interleukin-1ß, and interferon regulatory factor 1) predicting periodontitis susceptibility were screened by establishing a random forest model, and a predictive nomogram model was constructed on the basis of these genes. Decision curve analysis suggested that the PRG-based predictive nomogram model could provide clinical benefits to patients. Three distinct PRG patterns (cluster A, cluster B, and cluster C) in the periodontitis samples were revealed according to the 48 significant PRGs, and the difference in the immune cell infiltration among the three patterns was explored. We observed that all infiltrating immune cells, except type 2 T helper cells, differ significantly among the three patterns. To quantify the PRG patterns, the PRG score was calculated by principal component analysis. According to the results, cluster B had the highest PRG score, followed by cluster A and cluster C. In conclusion, PRGs significantly contribute to the development of periodontitis. Our study of PRG patterns might open up a new avenue to guide individualized treatment plans for patients with periodontitis.

Toward real-time and efficient cardiovascular monitoring for COVID-19 patients by 5G-enabled wearable medical devices: a deep learning approach.

Patients with deaths from COVID-19 often have co-morbid cardiovascular disease. Real-time cardiovascular disease monitoring based on wearable medical devices may effectively reduce COVID-19 mortality rates. However, due to technical limitations, there are three main issues. First, the traditional wireless communication technology for wearable medical devices is difficult to satisfy the real-time requirements fully. Second, current monitoring platforms lack efficient streaming data processing mechanisms to cope with the large amount of cardiovascular data generated in real time. Third, the diagnosis of the monitoring platform is usually manual, which is challenging to ensure that enough doctors online to provide a timely, efficient, and accurate diagnosis. To address these issues, this paper proposes a 5G-enabled real-time cardiovascular monitoring system for COVID-19 patients using deep learning. Firstly, we employ 5G to send and receive data from wearable medical devices. Secondly, Flink streaming data processing framework is applied to access electrocardiogram data. Finally, we use convolutional neural networks and long short-term memory networks model to obtain automatically predict the COVID-19 patient's cardiovascular health. Theoretical analysis and experimental results show that our proposal can well solve the above issues and improve the prediction accuracy of cardiovascular disease to 99.29%.

Microstructure and mechanical properties of additive manufactured porous Ti-33Nb-4Sn scaffolds for orthopaedic applications.

Customized porous titanium alloys have become the emerging materials for orthopaedic implant applications. In this work, diamond and rhombic dodecahedron porous Ti-33Nb-4Sn scaffolds were fabricated by selective laser melting (SLM). The phase, microstructure and defects characteristics were investigated systematically and correlated to the effects of pore structure, unit cell size and processing parameter on the mechanical properties of the scaffolds. Fine ß phase dendrites were obtained in Ti-33Nb-4Sn scaffolds due to the fast solidification velocity in SLM process. The compressive and bending strength of the scaffolds decrease with the decrease of strut size and diamond structures showed both higher compressive and bending strength than the dodecahedron structures. Diamond Ti-33Nb-4Sn scaffold with compressive strength of 76 MPa, bending strength of 127 MPa and elastic modulus of 2.3 GPa was achieved by SLM, revealing the potential of Ti-33Nb-4Sn scaffolds for applications on orthopaedic implant.

Effects of Porphyromonas gingivalis LipopolysaccharideTolerized Monocytes on Inflammatory Responses in Neutrophils.

Periodontitis is a chronic inflammatory disease induced by bacteria. Exposure of the host to periodontal pathogens and their virulence factors induces a state of hyporesponsiveness to subsequent stimulations, which is termed endotoxin tolerance. The role and mechanism of lipopolysaccharide (LPS)-tolerized monocytes in inflammatory responses in neutrophils are currently unclear. Here, conditioned supernatants were collected from THP-1 cells treated with or without repeated 1 µg/ml Porphyromonas gingivalis (P.gingivalis) LPS. The chemotactic response of freshly isolated neutrophils recruited by supernatants was determined by a transwell migration assay, which demonstrated a reduced migration of neutrophils stimulated with supernatants from tolerized THP-1 cells in comparison to non-tolerized THP-1 cells. In addition, there was a marked increase in reactive oxygen species (ROS) generation and a significant decrease in Caspase 3 activities in neutrophils treated with supernatants from THP-1 cells that were treated repeatedly with P.gingivalis LPS in comparison to single treatment. A cytokine antibody array was then used to assess cytokine expression patterns in THP-1 cells. In tolerized THP-1 cells, 43 cytokine (43/170) expression levels were decreased, including chemokine ligand 23 (CCL23) and IFN-γ, while 11 cytokine (11/170) expression levels were increased, such as death receptor 6 (DR6). Furthermore, there was decreased production of IFN-γ and epithelial neutrophil activating peptide-78 (ENA-78) in THP-1 cells after stimulation with repeated P. gingivalis LPS in comparison to single challenge, which was confirmed by ELISA. Therefore, P.gingivalis LPS- tolerized THP-1 cells were able to depress neutrophil chemotaxis and apoptosis, and contribute to respiratory burst, which might be related to the changes in cytokine expression patterns in THP-1 cells.