1-methylpropyl-2-imidazolyl-disulfide and Disease-Models--Animal

The thioredoxin-1 (Trx-1) inhibitor, PX-12, is active against several cancer types. This study aimed to evaluate its effects on local osteosarcoma (OS) progression and to describe PX-12-related signal transduction pathways.. Publicly available expression cohort data were analyzed to determine the relationship between the expression levels of TXN, which codes for the Trx protein, and survival in patients with OS. Murine LM8 OS cells were stimulated with PX-12. Apoptosis-related protein levels, cell viability, caspase activity, and wound healing were evaluated. PX-12 efficacy in suppressing tumor progression was evaluated in C3H mice injected with LM8 cells.. High TXN expression was a negative prognostic factor for metastasis and overall survival in OS patients. PX-12 induced apoptosis in OS cells via the oxidative stress-MAPK-caspase 3 pathway and suppressed OS cell migration. PX-12 suppressed local OS progression.. PX-12 is a potential therapeutic agent for use in suppressing local OS progression.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Disease Models, Animal; Disease Progression; Disulfides; Dose-Response Relationship, Drug; Humans; Imidazoles; Mice; Oxidative Stress; Thioredoxins; Xenograft Model Antitumor Assays

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

Complex regional pain syndrome (CRPS) is related to microcirculation impairment associated with tissue hypoxia and peripheral cytokine overproduction in the affected limb. Previous studies suggest that the pathogenesis involves hypoxia inducible factor-1α (HIF-1α) and exaggerated regional inflammatory response. 1-methylpropyl 2-imidazolyl disulfide (PX-12) acts as the thioredoxin-1 (Trx-1) inhibitor and decreases the level of HIF-1α, and can rapidly be metabolized for Trx-1 redox inactivation. This study hypothesized that PX-12 can decrease the cytokine production for nociceptive sensitization in the hypoxia-induced pain model. CD1 mice weighing around 30 g were used. The animal CRPS model was developed via the chronic post-ischaemic pain (CPIP) model. The model was induced by using O-rings on the ankles of the mice hind limbs to produce 3-h ischaemia-reperfusion injury on the paw. PX-12 (25 mg/kg, 5 mg/kg) was given through tail vein injection immediately after ischaemia. Animal behaviour was tested using the von Frey method for 7 days. Local paw skin tissue was harvest from three groups (control, 5 mg/kg, 25 mg/kg) 2 h after injection of PX-12. The protein expression of interleukin-1β (IL-1β) and HIF-1α was analysed with the Western blotting method. Mice significantly present an anti-allodynia effect in a dose-related manner after the PX-12 administration. Furthermore, PX-12 not only decreased the expression of HIF-1α but also decreased the expression of IL-1β over the injured palm. This study, therefore, shows the first evidence of the anti-allodynia effect of PX-12 in a CPIP animal model for pain behaviour. The study concluded that inhibition of HIF-1α may produce an analgesic effect and the associated suppression of inflammatory cytokine IL-1β in a CPIP model.

Topics: Animals; Behavior, Animal; Complex Regional Pain Syndromes; Cytokines; Disease Models, Animal; Disulfides; Hyperalgesia; Hypoxia-Inducible Factor 1, alpha Subunit; Imidazoles; Inflammation; Male; Mice