ap-10 and Disease-Models--Animal

In this work, we found that 14-deoxy-11,12-didehydroandrographolide (2), a derivative of andrographolide (AP, 1), had greatly reduced cytotoxicity compared with AP and exhibited moderate anti-osteoclastogenesis activity. Thirty compounds were synthesized by introducing anti-osteoporosis chemotypes at C-19 of 2. Six of them exhibited stronger inhibition of osteoclastogenesis than AP. Of note, compound 12g displayed the most potent activity with IC

Topics: Animals; Bone Resorption; Cell Differentiation; Disease Models, Animal; Diterpenes; Dose-Response Relationship, Drug; Female; Mice; Mice, Inbred C57BL; Molecular Structure; Osteoclasts; Osteogenesis; Osteoporosis; RAW 264.7 Cells; Structure-Activity Relationship

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

Our group recently reported novel anti-inflammatory effects of andrographolide (2), a bioactive molecule isolated from Andrographis paniculata, in a mouse asthma model. However, 2 has been shown to possess cytotoxic activity. 14-Deoxy-11,12-didehydroandrographolide (1) is an analogue of 2 that can be isolated from A. paniculata. We hypothesized that 1 retains the anti-inflammatory effects for asthma but is devoid of cytotoxicity. In contrast to 2, 1 did not elicit any cytotoxic activity in A549 and BEAS-2B human lung epithelial cells and rat basophilic leukemia (RBL)-2H3 cells using a MTS assay. Compound 1 dose-dependently inhibited ovalbumin (OVA)-induced increases in total and eosinophil counts, IL-4, IL-5, and IL-13 levels in lavage fluid, and serum OVA-specific IgE level in a mouse asthma model. Compound 1 attenuated OVA-induced airway eosinophilia, mucus production, mast cell degranulation, pro-inflammatory biomarker expression in lung tissues, and airway hyper-responsiveness. This substance also blocked p65 nuclear translocation and DNA-binding activity in the OVA-challenged lung and in TNF-α-stimulated human lung epithelial cells. The present findings reveal for the first time that 1 retains the anti-inflammatory activities of 2 for asthma probably through the inhibition of NF-κB. 14-Deoxy-11,12-didehydroandrographolide (1) may be considered as a safer analogue of 2 for the potential treatment of asthma.

Topics: Andrographis; Animals; Anti-Inflammatory Agents; Asthma; Disease Models, Animal; Diterpenes; Humans; Lung; Mice; NF-kappa B; Ovalbumin; Rats; Tumor Necrosis Factor-alpha