grayanotoxin-i 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

Delayed healing and non-union of fractures have a significant effect upon patient morbidity. Studies have therefore largely concentrated on accelerating fracture healing. This study was intended to compare the effect of "mad honey" and propolis on fracture healing using radiological and histopathological analysis.. Femur fracture was surgically performed on 48 rats, followed by fixation. Animals were then divided into 8 groups: 2 control groups (15- and 30-day) and 6 treatment groups (15- and 30-day normal honey, 15- and 30-day "mad honey," and 15- and 30-day propolis). Rats were sacrificed at the end of these periods, and radiological and histological examinations were performed.. Radiological healing in the propolis group after 15-day therapy was statistically better than in the control (p = 0.004) and normal honey (p = 0.006) groups. After 30-day therapy, healing in the propolis group (p = 0.005) and grayanotoxin-containing "mad honey" group (p = 0.007) were significantly better than in the control group. Histologically, there was a statistically significant difference between the 15-day propolis group and the other groups (control, honey, mad honey: p = 0.003, p = 0.003, and p = 0.002, respectively). We also found a statistically significant difference when the 30-day propolis group (p = 0.005) and "mad honey" group (p = 0.007) were compared to the control group.. This study shows that grayanotoxin-containing "mad honey" and propolis can accelerate fracture healing.

Topics: Animals; Disease Models, Animal; Diterpenes; Euthanasia, Animal; Female; Femoral Fractures; Fracture Healing; Honey; Propolis; Randomized Controlled Trials as Topic; Rats; Rats, Sprague-Dawley; Time Factors; Treatment Outcome