Netrin-1 (NTN-1) plays a vital role in the progress of nervous system development and inflammatory diseases. However, the role and underlying mechanism of NTN-1 in inflammatory pain (IP) are unclear. BV2 microglia were treated with LPS to mimic the cell status under IP. Adeno-associated virus carrying the NTN-1 gene (AAV-NTN-1) was used to overexpress NTN-1. Complete Freund's Adjuvant (CFA)-induced mouse was recruited as an in vivo model. MTT and commercial kits were utilized to evaluate cell viability and cell death of BV2 cells. The mRNA expressions and secretions of cytokines were measured using the ELISA method. Also, the pyroptosis and activation of BV2 cells were investigated based on western blotting. To verify the role of Rac1/NF-kappaB signaling, isochamaejasmin (ISO) and AAV-Rac1 were presented. The results showed that NTN-1 expression was decreased in LPS-treated BV2 microglia and spinal cord tissues of CFA-injected mice. Overexpressing NTN-1 dramatically reversed cell viability and decreased cell death rate of BV2 microglia under lipopolysaccharide (LPS) stimulation, while the level of pyroptosis was inhibited. Besides, AAV-NTN-1 rescued the activation of microglia and inflammatory injury induced by LPS, decreasing IBA-1 expression, as well as iNOS, IL-1beta and IL-6 secretions. Meanwhile AAV-NTN-1 promoted the anti-inflammation response, including increases in Arg-1, IL-4 and IL-10 levels. In addition, the LPS-induced activation of Rac1/NF-kappaB signaling was depressed by NTN-1 overexpression. The same results were verified in a CFA-induced mouse model. In conclusion, NTN-1 alleviated IP by suppressing pyroptosis and promoting M2 type activation of microglia via inhibiting Rac1/NF-?B signaling, suggesting the protective role of NTN-1 in IP. Keywords: Netrin-1, Inflammatory pain, Pyroptosis, Microglia M2 activation, Rac1/NF-kappaB.

• MeSH
• bolest metabolismus   MeSH
• buněčné linie MeSH
• lipopolysacharidy MeSH
• mikroglie * metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• netrin-1 * metabolismus   MeSH
• neuropeptidy * MeSH
• NF-kappa B * metabolismus   MeSH
• pyroptóza * fyziologie   účinky léků   MeSH
• rac1 protein vázající GTP * metabolismus   MeSH
• signální transdukce * MeSH
• zánět * metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• lipopolysacharidy MeSH
• netrin-1 * MeSH
• neuropeptidy * MeSH
• NF-kappa B * MeSH
• Ntn1 protein, mouse MeSH Prohlížeč
• rac1 protein vázající GTP * MeSH
• Rac1 protein, mouse MeSH Prohlížeč

Recent efforts to repurpose disulfiram, a drug used in alcohol-aversion therapy for decades, for other diseases suggest the molecule is almost an in vitro panacea: it seems to be effective against various cancers (by multiple mechanisms of action), Alzheimer's disease, obesity and metabolic syndrome, pythiosis, lyme borreliosis, COVID-19, and sepsis. The problem is that the molecule almost does not exist in the body after ingestion and, most importantly, is not the pharmacologically active entity in alcoholic patients, being rather a prodrug. This prodrug is widely and misleadingly used in many in vitro and in vivo experiments regardless of its physiologically reachable concentration or its metabolism in vivo.

• Publikační typ
• časopisecké články MeSH

Pyroptosis is a form of cell death associated with inflammation. In the maintenance of airway homeostasis, pyroptosis goes through activation and assembly of Inflammasome. The pyroptosis pathway is mediated by caspase which activates the pore-forming effect of substrate gasdermin family members. It eventually leads to lysis and release of the cell contents and then induces an inflammatory response. In this process, it participates in airway homeostasis regulation by affecting airway immunity, airway epithelial structure and airway microbiota. Therefore, we discussed the correlation between airway immunity, airway epithelial structure, airway microbiota and the mechanism of pyroptosis to describe the role of pyroptosis in airway homeostasis regulation which is of great significance for understanding the occurrence and treatment of airway inflammatory diseases.

• MeSH
• homeostáza MeSH
• inflamasomy * metabolismus   MeSH
• kaspasy metabolismus   MeSH
• lidé MeSH
• pyroptóza * fyziologie   MeSH
• zánět MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• inflamasomy * MeSH
• kaspasy MeSH

The current Coronavirus 2019 (COVID-19) pandemic has shown us that the pharmaceutical research community can organize and administer large nonprofit clinical trials (RECOVERY and SOLIDARITY) and achieve the swift development of common, unpatentable drugs for a new indication: in this case an old, inexpensive drug, dexamethasone, for COVID-19. Why is it that such nonprofit efforts are so rare and are not organized as a systemic, routine part of drug development in the public interest? Based on my own experience with repurposing the alcohol-abuse drug disulfiram (Antabuse) for cancer, I identify at least four serious deadlocks to development of nonprofit drugs. All of these obstacles should be addressed to leverage the potential of the COVID-19 pandemic for better future healthcare systems in all countries around the world.

• Klíčová slova
• Biomedicine, COVID-19, Clinical trials, Dexamethasone, Disulfiram, Nonprofit drugs,
• MeSH
• COVID-19 * MeSH
• disulfiram MeSH
• lidé MeSH
• neziskové organizace MeSH
• pandemie * MeSH
• poskytování zdravotní péče MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• disulfiram MeSH