mead-acid 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

Coconut oil is used as a dietary oil worldwide, and its healthy effects are recognized by the fact that coconut oil is easy to digest, helps in weight management, increases healthy cholesterol, and provides instant energy. Although topical application of coconut oil is known to reduce skin infection and inflammation, whether dietary coconut oil has any role in decreasing skin inflammation is unknown. In this study, we showed the impact of dietary coconut oil in allergic skin inflammation by using a mouse model of contact hypersensitivity (CHS). Mice maintained on coconut oil showed amelioration of skin inflammation and increased levels of cis-5, 8, 11-eicosatrienoic acid (mead acid) in serum. Intraperitoneal injection of mead acid inhibited CHS and reduced the number of neutrophils infiltrating to the skin. Detailed mechanistic studies unveiled that mead acid inhibited the directional migration of neutrophils by inhibiting the filamentous actin polymerization and leukotriene B

Topics: 8,11,14-Eicosatrienoic Acid; Actins; Animals; Biomarkers; Capillary Permeability; Chemotaxis; Coconut Oil; Dermatitis, Atopic; Dermatitis, Contact; Dietary Fats, Unsaturated; Disease Models, Animal; Female; Immunohistochemistry; Immunophenotyping; Leukotriene B4; Lipid Metabolism; Mice; Neutrophils; Skin

The present studies have demonstrated that topical application of a low concentration of eicosa-5,8,11-trienoic acid (a 20:3,n9 fatty acid previously reported to inhibit competitively the activity of the sheep vesicular cyclooxygenase) to skin of normal fed hairless mice produced severe scaly dermatosis which is characterized by marked hyperplasia and acanthosis of the epidermal layer. The precise mechanism of this induction of scaly dermatosis is presently unclear. It is nonetheless interesting that the treatment of skin with similar concentrations of other unsaturated fatty acids produced no visible or histologic effects. Furthermore, endogenous levels of arachidonic acid in epidermal phospholipid and triglyceride fractions were shown to increase significantly (p < 0.01) in skin treated with the 20:3,n9 fatty acid while the endogenous level of PGE2 in the same tissue decreased markedly. This latter observation is consistent at least in part, with a previous report from this laboratory in which the 20:3,n9 fatty acid inhibited in vitro the activity of the sheep vesicular cyclooxygenase (the rate limiting enzyme in the transformation of arachidonic acid into the prostaglandin endoperoxides) although the increase in arachidonic acid may also reflect an increased incorporation of this fatty acid into the epidermal lipids by the hyperproliferative tissue. Evaluation of the proliferative status of 20:3,n9 fatty acid-treated skin showed a significant increase (p < 0.01) in labeling and mitotic indices. The use of this potentially endogenous fatty acid may be a useful tool for further investigations of hyperproliferative skin diseases where dietary deficiency of essential fatty acids does not exist.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Arachidonic Acids; Cell Division; Disease Models, Animal; Fatty Acids, Unsaturated; Female; Lipids; Mice; Mice, Nude; Prostaglandins E; Skin; Skin Diseases