3-4-methylenedioxy-beta-nitrostyrene and Disease-Models--Animal

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

There is a major clinical need for new therapies for the treatment of chronic itch. Many of the molecular components involved in itch neurotransmission are known, including the neuropeptide NPPB, a transmitter required for normal itch responses to multiple pruritogens in mice. Here, we investigated the potential for a novel strategy for the treatment of itch that involves the inhibition of the NPPB receptor NPR1 (natriuretic peptide receptor 1). Because there are no available effective human NPR1 (hNPR1) antagonists, we performed a high-throughput cell-based screen and identified 15 small-molecule hNPR1 inhibitors. Using in vitro assays, we demonstrated that these compounds specifically inhibit hNPR1 and murine NPR1 (mNPR1). In vivo, NPR1 antagonism attenuated behavioral responses to both acute itch- and chronic itch-challenged mice. Together, our results suggest that inhibiting NPR1 might be an effective strategy for treating acute and chronic itch.

Topics: Animals; Behavior, Animal; Cell-Free System; Dermatitis, Contact; Disease Models, Animal; Ganglia, Spinal; Humans; Mice, Inbred C57BL; Mice, Knockout; Neurons; Pruritus; Receptors, Atrial Natriuretic Factor; Reproducibility of Results; Signal Transduction; Small Molecule Libraries

Burn wound progression remains a challenging problem in the clinic. Secondary tissue damage caused by unlimited inflammatory response is considered to be one of the key factors contributing to this clinical problem. Nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome has recently been found to play important roles in immune activation and the inflammatory response after burn/trauma. This experimental study aims (1) to observe the expression and distribution of NLRP3 inflammasome in burn wounds of a rat burn model and (2) to study whether inhibiting the NLRP3 inflammasome activation would ameliorate burn wound progression.. A deep second-degree burn was inflicted on the backs of Wistar rats. The expression of NLRP3 inflammasome components and interleukin-1β were determined by Western blot and coimmunoprecipitation. The distribution of NLRP3 inflammasome was assessed by immunohistochemical staining and double-labeling immunofluorescence. Neutrophil infiltration, wound perfusion, burn depth, and wound healing time were assessed.. Burn induced remarkable NLRP3 inflammasome activation and cleavage of interleukin-1β. The NLRP3 inflammasome was observed mainly in macrophages of the zone of stasis. 3,4-Methylenedioxy-β-nitrostyrene significantly inhibited NLRP3 inflammasome activation and inflammatory cytokine production in burn wounds. Consequently, neutrophil infiltration was reduced, wound perfusion was restored, burn wound progression was ameliorated, and wound healing was accelerated.. In this study, the authors demonstrated that burn induced NLRP3 inflammasome activation and inflammatory response in wounds, which may be associated with burn wound progression. Treatment with 3,4-methylenedioxy-β-nitrostyrene inhibited NLRP3 inflammasome activation, ameliorated burn wound progression, and promoted wound healing.

Topics: Analysis of Variance; Animals; Blotting, Western; Burns; Carrier Proteins; Dioxolanes; Disease Models, Animal; Disease Progression; Enzyme-Linked Immunosorbent Assay; Immunohistochemistry; Injections, Intraperitoneal; Laser-Doppler Flowmetry; Male; NLR Family, Pyrin Domain-Containing 3 Protein; Random Allocation; Rats; Rats, Wistar; Reference Values; Wound Healing