Project description:Cadmium treatment induces slow but long lasting nitric oxide production in plant tissues. This NO production can be suppressed using the commonly used Nitric Oxide Synthase inhibitor L-NAME. This inhibitor tends to partially alleviate Cd toxicity. This effect is correlated with a strong diminution of Cd content in roots of plants treated both with Cd and L-NAME compared to roots from plants treated with Cd only. The main goal of this study is the identification of transcriptionnal changes caused by Cd-induced nitric oxide, and that could potentially result in enhanced Cd root accumulation.
Project description:Chronic inflammation drives many diseases, including cancer, where inflammation is associated with metastasis, the cause of death in 90% of cancer fatalities. Tumor inflammation drives inducible nitric oxide synthase (NOS2 or iNOS) and cyclooxygenase 2 (COX2) expression, each of which is associated with poor outcomes in cancer. Here, we knocked out the NOS2 gene in the murine triple negative breast cancer allograft tumor model 4T1 and examined metastatic spread from primary mammary tumors to lung in BALB/c mice with intact immune systems. Remarkably, while the parental 4T1 tumors were highly metastatic, metastasis from 4T1 NOS2-/- tumors was nearly eliminated. In cell culture, we find that nitric oxide from NOS2 induces a glycolytic phenotype, epitrascriptomic dysregulation, DNA damage, and prostaglandin E2 synthesis by stimulating COX2. Human colorectal cancer cell line DLD1 yielded similar results. RNA sequencing revealed NOS2-dependent loss of mRNA associated with regulation of chromosome and DNA replication, including cell cycle checkpoints, as well as mRNA associated with RNA demethylation, including tRNA demethylation. Immunoprofiling of the tumor microenvironment revealed immunosuppressed tumors that were low in T cells and high in myeloid derived suppressor cells expressing interferon gamma, which induces NOS2 expression. Others have shown nitric oxide from immune cells suppresses tumor immunity. Here, we show nitric oxide from tumor cells plays a critical role in metastasis. Taken together, these data suggest high NOS2 in tumor cells drives metastasis through a broad accumulation of cancer-associated factors – including metabolic dysregulation, genetic instability, and immunosuppression – all of which contribute to aggressive metastasis.
Project description:In this model, TLR2-TLR6 mediates MyD88 pathway gets activated, which activates IL-12 production and induces iNOS expression when the Macrophage is infected with Leishmania parasite. The early induction of IL-10 takes place which leads to the induction of NFIL3, HDAC3, and SHP-1. They inhibit IL-12 production and thus hamper IL-12 induced IFN-gamma mediated; Nitric oxide production. A key transcription factor NFAT5 connects IL-12 and IL-10 pathways. It upregulates IL-12 and downregulates IL-10. In this model, NFAT5 is downregulated which is also inhibiting IL-12.
Project description:To elucidate the epithelial cell diversity within the nasal inferior turbinates, a comprehensive investigation was conducted comparing control subjects to individuals with house dust mite-induced allergic rhinitis. This study aimed to delineate the differential expression profiles and phenotypic variations of epithelial cells in response to allergic rhinitis. This research elucidated distinct subpopulations and rare cell types of epithelial cells within the nasal turbinates, discerning alterations induced by allergic rhinitis. Furthermore, by interrogating transcriptomic signatures, the investigation provided novel insights into the cellular dynamics and immune responses underlying allergic rhinitis pathogenesis
Project description:Escherichia coli A0 34/86 (EcO83) is a probiotic bacterium used in newborns to prevent nosocomial infections and diarrhoea. Mechanistically, EcO83 induces the production of pro- and anti-inflammatory cytokines in vitro and in vivo and, when administered intranasally, inhibits allergic airway inflammation in mice by interacting with innate pattern recognition receptors. Despite the proven therapeutic benefit, there is a concern about the use of live bacteria due to the risk of systemic infections and bacterial gene transfer. Therefore, EcO83-derived extracellular vesicles (EcO83-EVs) could represent a safer alternative to live bacteria. However, the exact mechanism of interaction between EV and host remains to be elucidated. Here, we have isolated, purified, and characterised EcO83-EVs following the Minimal Information of Studies of Extracellular Vesicles (MISEV) guidelines. Our ex vivo studies in human nasal epithelial cells showed that EcO83-EVs increased the expression of proteins linked to oxidative stress and inflammation, indicating an effective interaction between EVs and the host cells. Further in vivo studies in mice demonstrated that EcO83-EVs interact with nasal-associated lymphoid tissue, are internalised by airway macrophages, and stimulate neutrophil recruitment in the lung. In vitro analyses revealed that EcO83-EVs activate the NF-κΒ signalling pathway, resulting in the nitric oxide production. Our findings suggest that EcO83-EVs could be an effective and safer postbiotic alternative to live bacteria. Further research is needed to explore the potential of EVs from probiotic bacteria for clinical applications, particularly for mucosal vaccines or targeted immunotherapies.