Immunity
NLRP3 inflammasome can be activated by a variety of pathogen activators (including components of bacteria, viruses and fungi) or “danger signals” (including abnormal metabolites and environmental components), so its activation mechanism is extremely complex. IITZ-01 is a lysosomotropic molecule that can disrupt lysosomal functions. We found that IITZ-01 can activate inflammasome at a low concentration. Then, we determined that IITZ-01 is a specific activator of NLRP3 inflammasome through inflammasome stimulation, ELISA, Western blot and other experiments. Mechanistically, NLRP3 inflammasome activation induced by IITZ-01 is independent of direct binding and ion flow but dependent on mitochondrial damage and mROS accumulation. This study suggests that a lysosomotropic compound can activate NLRP3 inflammasome by impairing mitochondrial functions.
Sphingosine-1-phosphate (S1P) is a widely expressed biologically active sphingolipid that plays an important role in cell differentiation, migration, proliferation, metabolism and apoptosis. S1P activates various signaling pathways, some of which evoke Ca2+ signals in the cytosol. Few studies have focused on the mechanism by which S1P evokes Ca2+ signals in neurons. Here, we show that S1P evokes global Ca2+ signals in SH-SY5Y cells and hippocampal neurons. Removal of extracellular calcium largely abolished the S1P-induced increase in intracellular Ca2+, suggesting that the influx of extracellular Ca2+ is the major contributor to this process. Moreover, we found that S1P-induced Ca2+ mobilization is independent of G protein-coupled S1P receptors. The TRPC6 inhibitor SAR7334 suppressed S1P-induced calcium signals, indicating that the TRPC6 channel acts as the downstream effector of S1P. Using patch-clamp recording, we showed that S1P activates TRPC6 currents. Two Src tyrosine kinase inhibitors, Src-I1 and PP2, dramatically inhibited the activation of TRPC6 by S1P. Taken together, our data suggest that S1P activates TRPC6 channels in a Src-dependent way to induce Ca2+ mobilization in SH-SY5Y cells and hippocampal neurons.
The coronavirus disease 2019 (COVID-19) epidemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused millions of deaths worldwide. Therefore, it is critical to understand the biological basis of SARS-CoV-2 to develop novel approaches to control its spread. The SARS-CoV-2 nucleocapsid (N) protein is an important diagnostic and potent therapeutic target of the disease, as it is involved in numerous important functions in the viral life cycle. Several studies have explained the structural and functional aspects of the SARS-CoV-2 N protein. This review summarizes the currently available data on the evolutionarily conserved N protein of SARS-CoV-2 by providing detailed information on the structural and multifunctional characteristics of the N protein.
Objectives: A growing number of studies have shown that methylation biomarkers play an important role in oncogenesis. This study aimed to explore the diagnostic role of neuropeptide Y (NPY) methylation in colorectal cancer (CRC).
Methods: mRNA and protein expression, methylation, survival benefits, and immune cell infiltration were analyzed using bioinformatics tools across all tumors from The Cancer Genome Atlas. NPY methylation in CRC was further validated in CRC tissues, fecal samples, and cell lines. Analyses of NPY methylation were performed using Sequenome EpiTYPER and quantitative PCR. Retrieval of NPY expression in cell lines was tested using real-time PCR and western blotting.
Results: Bioinformatic analysis showed that the methylation level of NPY increased in most carcinomas (P<0.05). Moreover, statistical correlations were observed between NPY transcriptional expression and CD4+ T cells, macrophages, and dendritic cells in colon cancer (P<0.05). Similar results were obtained for CD4+ T cells, neutrophils, and NPY in rectal cancer (P<0.05). Our results showed that NPY was hypermethylated in CRC tissues and fecal exfoliated cells (P<0.05). Fecal NPY methylation was observed in 82.5% sensitive for primary tumors, 46.3% for intestinal polyps (including adenomatous, serrated, and inflammatory polyps), and 23.4% of healthy controls. Overall, fecal NPY methylation was 76.6% specific. For cell lines, in vivo experiments demonstrated that 5-aza-2′-deoxycytidine downregulated the methylation of NPY and restored its mRNA level (P<0.05).
Conclusions: This study indicates that NPY is hypermethylated in CRC, and that NPY methylation in fecal DNA is a potential noninvasive diagnostic biomarker for Chinese patients with CRC.
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