The molecular mechanisms underlying the severe lung pathology that occurs during SARS-CoV infections remain incompletely understood. The largest of the SARS-CoV accessory protein open reading frames (SARS 3a) oligomerizes, dynamically inserting into late endosomal, lysosomal, and trans-Golgi-network membranes. While previously implicated in a non-inflammatory apoptotic cell death pathway, here we extend the range of SARS 3a pathophysiologic targets by examining its effects on necrotic cell death pathways. We show that SARS 3a interacts with Receptor Interacting Protein 3 (Rip3), which augments the oligomerization of SARS 3a helping drive necrotic cell death. In addition, by inserting into lysosomal membranes SARS 3a triggers lysosomal damage and dysfunction. Consequently, Transcription Factor EB (TFEB) translocates to the nucleus increasing the transcription of autophagy- and lysosome-related genes. Finally, SARS 3a activates caspase-1 either directly or via an enhanced potassium efflux, which triggers NLRP3 inflammasome assembly. In summary, Rip3-mediated oligomerization of SARS 3a causes necrotic cell death, lysosomal damage, and caspase-1 activation—all likely contributing to the clinical manifestations of SARS-CoV infection.

BackgroundPeriodontal disease is thought to arise from the interaction of various factors, including the susceptibility of the host, the presence of pathogenic organisms, and the absence of beneficial species. The genetic factors may play a significant role in the risk of periodontal diseases. Cytokines initiate, mediate and control immune and inflammatory responses. The aim of this study is to compare genotypes and soluble protein of pro and anti-inflammatory cytokines (IL-1α, IL-1β, IL-6, IFN-γ, IL-10, TNF-α and IL-4) in subjects with or free of chronic periodontitis.MethodsA total of 1,290 Chinese subjects were recruited to this clinical trial: 850 periodontally healthy controls and 440 periodontal patients. All subjects were free of systemic diseases. Oral examinations were performed, and the following parameters were recorded for each subject: supragingival/subgingival calculus, gingival recession, bleeding on probing (BOP), probing depth (PD), clinical attachment loss (CAL), gingival recession and tooth mobility. The peripheral blood samples were collected for genetic and enzyme linked immunosorbent assay (ELISA) analysis. Restriction enzymes were used for digestion of amplified fragments of IL-1α, IL-1β, IL-6, IFN-γ, IL-10, TNF-α and IL-4.ResultsThe protein expressions of patient and control samples for IL-1α, IL-1β, IL-6, TNF-α, IFN-γ, IL-10, and IL-4 measured by ELISA confirmed a statistically significant difference (p < 0.001). The digestion of fragments of various genes showed that the pro-inflammatory cytokines IL-1α and TNF-α, and the anti-inflammatory cytokines IL-4 and IL-10 demonstrated a correlation with chronic inflammation in patients (X2: p < 0.001). The remaining genes investigated in patients and healthy subjects (IL-1β, IL-6, IFN-γ and IL-10) did not show any significant difference.ConclusionsThe cytokine gene polymorphisms may be used as a marker for periodontitis susceptibility, clinical behaviour and severity. This detection offers early diagnosis and induction of prophylaxis to other family members against disease progression.

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BackgroundDNA methylation of certain genes frequently occurs in neoplastic cells. Although the cause remains unknown, many genes have been identified with such atypical methylation in neoplastic cells. The hypermethylation of E-Cadherin and Cyclooxygenase 2 (COX-2) in chronic inflammation such as chronic periodontitis may demonstrate mild lesion/mutation epigenetic level. This study compares the hypermethylation status of E-Cadherin and COX-2 genes which are often found in breast cancer patients with that in chronic periodontitis.MethodsTotal DNA was extracted from the blood samples of 108 systemically healthy non-periodontitis subjects, and the gingival tissues and blood samples of 110 chronic periodontitis patient as well as neoplastic tissues of 106 breast cancer patients. Methylation-specific PCR for E-Cadherin and COX-2 was performed on these samples and the PCR products were analyzed on 2% agarose gel.ResultsHypermethylation of E-Cadherin and COX-2 was observed in 38% and 35% of the breast cancer samples, respectively. In chronic periodontitis patients the detection rate was 25% and 19% respectively, and none was found in the systemically healthy non-periodontitis control subjects. The hypermethylation status was shown to be correlated among the three groups with statistical significance (p < 0.0001). The methylation of CpG islands in E-Cadherin and COX-2 genes in periodontitis patients occurs more frequently in periodontitis patients than in the control subjects, but occurs less frequently than in the breast cancer patients.ConclusionsThis set of data shows that the epigenetic change in E-Cadherin and Cyclooxygenase-2 is associated with chronic periodontitis. The epigenetic changes presented in chronic inflammation patients might demonstrate an irreversible destruction in the tissues or organs similar to the effects of cancer. Chronic periodontitis to some extent might be associated with DNA hypermethylation which is related to cancer risk factors.