isoliquiritigenin and Disease-Models--Animal

Chemoprevention involves the use of natural or synthetic substances to reduce the risk of developing cancer. Strategies for protecting cells from initiation events include decreasing metabolic enzymes responsible for generating reactive species (phase I enzymes) while increasing phase II enzymes that can deactivate radicals and electrophiles known to intercede in normal cellular processes. Reduction of electrophilic quinones by quinone reductase is an important detoxification pathway. Following evaluation of approximately 3000 plant and marine organism extracts, the number characterized as "active" was established in the range of 12% of the total, and over 60 active compounds have been isolated as quinone reductase inducers. One of them, isoliquiritigenin (1), isolated from tonka bean, was shown to be a monofunctional inducer by having similar quinone reductase inducing ability in wild-type Hepa 1c1c7 cells and two mutant cell lines. To further investigate the mechanism of induction, HepG2 human hepatoma cells stably transfected with ARE-luciferase plasmid were used. Isoliquiritigenin (1) significantly induced the luciferase activity in a dose-dependent manner. On the basis of these results, a full-term cancer chemoprevention study was conducted with 7,12-dimethylbenz[a]anthracene (DMBA)-treated female Sprague-Dawley rats. Dietary administration of 1 increased tumor latency. Based on these promising preliminary results, additional mechanistic studies are underway, as well as full-term carcinogenesis studies with chronic administration schedules.

Topics: Animals; Anticarcinogenic Agents; Biomarkers; Chalcone; Chalcones; Disease Models, Animal; Enzyme Induction; Molecular Structure; NAD(P)H Dehydrogenase (Quinone); Plants, Medicinal; Rats

Gout is a crystalline-related arthropathy caused by the deposition of monosodium urate (MSU). Acute gouty arthritis is the most common first symptom of gout. Studies have shown that NOD-like receptor protein 3 (NLRP3) inflammasome as pattern recognition receptors can be activated by uric acid crystallization, triggering immune inflammation and causing acute gouty arthritis symptoms. Currently, the treatment of gout mainly includes two basic methods: reducing uric acid and alleviating inflammation. In this paper, 22 novel benzoxazole and benzimidazole derivatives were synthesized from deoxybenzoin oxime derivatives. These compounds have good inhibitory effects on NLRP3 and XOD screened by our research group in the early stage. The inhibitory activities of XOD and NLRP3 and their derivatives were also screened. Notably, compound 9b is a multi-targeting inhibitor of NLRP3 and XOD with excellent potency in treating hyperuricemia and acute gouty arthritis.

Topics: Animals; Benzimidazoles; Benzoxazoles; Cell Line; Disease Models, Animal; Gout; Humans; Hyperuricemia; Interleukin-1beta; Liver; Mice; Monocytes; NLR Family, Pyrin Domain-Containing 3 Protein; Oxonic Acid; Rats; Structure-Activity Relationship; Synovial Membrane; Uric Acid; Xanthine Oxidase

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

Licorice has been used as an antitussive and expectorant herbal medicine for a long history. This work evaluated the activities of 14 major compounds and crude extracts of licorice, using the classical ammonia-induced cough model and phenol red secretion model in mice. Liquiritin apioside (1), liquiritin (2), and liquiritigenin (3) at 50 mg/kg (i.g.) could significantly decrease cough frequency by 30-78% (p < .01). The antitussive effects could be partially antagonized by the pretreatment of methysergide or glibenclamide, but not naloxone. Moreover, compounds 1-3 showed potent expectorant activities after 3 days treatment (p < .05). The water and ethanol extracts of licorice, which contain abundant 1 and 2, could decrease cough frequency at 200 mg/kg by 25-59% (p < .05), and enhance the phenol red secretion (p < .05), while the ethyl acetate extract showed little effect. These results indicate liquiritin apioside and liquiritin are the major antitussive and expectorant compounds of licorice. Their antitussive effects depend on both peripheral and central mechanisms.

Topics: Administration, Oral; Ammonia; Animals; Antitussive Agents; Cough; Disease Models, Animal; Dose-Response Relationship, Drug; Expectorants; Glyburide; Glycyrrhiza; Male; Methysergide; Mice; Mice, Inbred ICR; Molecular Structure; Phenolsulfonphthalein; Plant Extracts; Structure-Activity Relationship

Topics: Administration, Oral; Animals; Carbon Tetrachloride; Cell Survival; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Dose-Response Relationship, Drug; Glycyrrhiza; Hep G2 Cells; Humans; Male; Mice; Mice, Inbred ICR; Molecular Structure; NF-E2-Related Factor 2; Plant Extracts; Plant Roots; Rats; Rats, Sprague-Dawley

A new cassane diterpene, dipteryxic acid (1), and a new isoflavonolignan, 5-methoxyxanthocercin A (2), as well as four known active compounds, isoliquiritigenin (3), 6,4'-dihydroxy-3'-methoxyaurone (4), sulfuretin (5), and (+/-)-balanophonin (6), and five known inactive compounds, butin, eriodictyol, 7-hydroxychromone, 7,3'-dihydroxy-8,4'-dimethoxyisoflavone, and (-)-lariciresinol, were isolated from an ethyl acetate-soluble extract of the seeds of Dipteryx odorata, using a bioassay based on the induction of quinone reductase (QR) in cultured Hepa 1c1c7 mouse hepatoma cells to monitor chromatographic fractionation. The structures of compounds 1 and 2 were elucidated by spectroscopic data interpretation. Single-crystal X-ray diffraction analysis was used to confirm the relative stereochemistry of compound 1. Selected compounds (3-5) were evaluated in a mouse mammary organ culture assay, with isoliquiritigenin (3) found to exhibit 76% inhibition at a dose of 10 microg/mL.

Topics: Animals; Anticarcinogenic Agents; Crystallography, X-Ray; Disease Models, Animal; Diterpenes; Drug Screening Assays, Antitumor; Enzyme Induction; Fabaceae; Inhibitory Concentration 50; Isoflavones; Lignans; Mammary Glands, Animal; Mice; Molecular Conformation; Molecular Structure; NAD(P)H Dehydrogenase (Quinone); Nuclear Magnetic Resonance, Biomolecular; Organ Culture Techniques; Peru; Seeds; Stereoisomerism; Tumor Cells, Cultured