micheliolide and Disease-Models--Animal

Progressive peritoneal fibrosis is a worldwide public health concern impacting patients undergoing peritoneal dialysis (PD), yet there is no effective treatment. Our previous study revealed that a novel compound, micheliolide (MCL) inhibited peritoneal fibrosis in mice. However, its mechanism remains unclear. Brahma-related gene 1 (BRG1) is a key contributor to organ fibrosis, but its potential function in PD-related peritoneal fibrosis and the relationship between MCL and BRG1 remain unknown.. The effects of MCL on BRG1-induced fibrotic responses and TGF-β1-Smads pathway were examined in a mouse PD model and in vitro peritoneal mesothelial cells. To investigate the targeting mechanism of MCL on BRG1, coimmunoprecipitation, MCL-biotin pulldown, molecular docking and cellular thermal shift assay were performed.. BRG1 was markedly elevated in a mouse PD model and in peritoneal mesothelial cells cultured in TGF-β1 or PD fluid condition. BRG1 overexpression in vitro augmented fibrotic responses and promoted TGF-β1-increased-phosphorylation of Smad2 and Smad3. Meanwhile, knockdown of BRG1 diminished TGF-β1-induced fibrotic responses and blocked TGF-β1-Smad2/3 pathway. MCL ameliorated BRG1 overexpression-induced peritoneal fibrosis and impeded TGF-β1-Smad2/3 signaling pathway both in a mouse PD model and in vitro. Mechanically, MCL impeded BRG1 from recognizing and attaching to histone H3 lysine 14 acetylation by binding to the asparagine (N1540) of BRG1, in thus restraining fibrotic responses and TGF-β1-Smad2/3 signaling pathway. After the mutation of N1540 to alanine (N1540A), MCL was unable to bind to BRG1 and thus, unsuccessful in suppressing BRG1-induced fibrotic responses and TGF-β1-Smad2/3 signaling pathway.. Our research indicates that BRG1 may be a crucial mediator in peritoneal fibrosis and MCL targeting N1540 residue of BRG1 may be a novel therapeutic strategy to combat PD-related peritoneal fibrosis.

Topics: Animals; Disease Models, Animal; Mice; Molecular Docking Simulation; Peritoneal Dialysis; Peritoneal Fibrosis; Transforming Growth Factor beta1

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

Micheliolide (MCL) is a naturally derived anti-inflammatory agent. In the present investigation, we examined the protective potential of MCL against doxorubicin (DOX)-induced cardiotoxicity in mice. Mice were injected with a single 15-mg/kg intraperitoneal dose of DOX at day 1 and the study groups received daily 12.5, 25, and 50 mg/kg doses of MCL for 7 days. Cardiac histopathology, cardiac function, serum markers of cardiac injury, and tissue markers of inflammation, and oxidative stress were examined. MCL decreased serum levels of creatinine kinase MB (CK-MB) and cardiac troponin I (cTnI) levels, ameliorated cardiac tissue architecture, and improved cardiac stroke volume. Apart from reducing the activities of NF-kB p65 subunit, MCL attenuated the cardiac levels of PI3K, phosphorylated (p)-Akt, p-Bad, and caspase-3 levels and simultaneously elevated p-PTEN levels. While the gene expressions of tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) were decreased, the tissue activities of superoxide dismutase (SOD) as well as gene expressions of heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase-1 (NQO1) were increased after treatment with MCL. Furthermore, tissue levels of malondialdehyde (MDA) were also decreased. Collectively, these findings point to the protective effects of MCL against DOX-induced cardiotoxicity by regulating PI3K/Akt/NF-kB signaling pathway in mice.

Topics: Animals; Anti-Inflammatory Agents; Cardiotoxicity; Disease Models, Animal; Doxorubicin; Heart Diseases; Inflammation Mediators; Male; Mice, Inbred C57BL; Myocytes, Cardiac; NF-kappa B; Oxidative Stress; Phosphatidylinositol 3-Kinase; Phosphorylation; Proto-Oncogene Proteins c-akt; Sesquiterpenes, Guaiane; Signal Transduction

Leukemic stem cells (LSCs) greatly contribute to the initiation, relapse, and multidrug resistance of leukemia. Current therapies targeting the cell cycle and rapidly growing leukemic cells, including conventional chemotherapy, have little effect due to the self-renewal and differentiated malignant cells replenishment ability of LSCs despite their scarce supply in the bone marrow. Micheliolide (MCL) is a natural guaianolide sesquiterpene lactone (GSL) which was discovered in michelia compressa and michelia champaca plants, and has been shown to exert selective cytotoxic effects on CD34+CD38- LSCs. In this study, we demonstrate that DMAMCL significantly prolongs the lifespan of a mouse model of human acute myelogenous leukemia (AML). Mechanistic investigations further revealed that MCL exerted its cytotoxic effects via inhibition of NF-κB expression and activity, and by generating intracellular reactive oxygen species (ROS). These results provide valuable insight into the mechanisms underlying MCL-induced cytotoxicity of LSCs, and support further preclinical investigations of MCL-related therapies for the treatment of AML.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Self Renewal; Disease Models, Animal; Humans; Leukemia, Myeloid, Acute; Magnoliaceae; Mice; Mice, SCID; Neoplastic Stem Cells; NF-kappa B; Reactive Oxygen Species; Sesquiterpenes, Guaiane; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Rheumatoid arthritis (RA) is a systemic autoimmune disease and collagen-induced arthritis (CIA) is an animal model for RA. Micheliolide (MCL) is a novel compound with strong anti-inflammatory effects. The present study was conducted to evaluate the therapeutic effects of MCL on RA. Mice were randomly divided into four groups and the CIA model mice were treated with methotrexate (MTX), MCL and dimethyl sulfoxide. A score associated with the severity of arthritis was assigned on alternate days from the 22nd day for 60 days. Histopathological changes and the serum levels of cytokines were measured on day 85. The results demonstrated that the MCL treatment group had arthritis scores lower than the CIA group and higher than the MTX group; compared with the CIA group, MCL and MTX significantly reduced the swelling of the paws and suppressed the degeneration of articular cartilage. Expression levels of macrophage colony-stimulating factor (M-CSF), tissue inhibitors of metalloproteinases-1 (TIMP-1) and complement component 5a (C5/C5a) were lower in the mice with arthritis compared with normal mice, however, following treatment with MCL and MTX, all the mice exhibited significant recovery to differing degrees. Unlike the MTX group, the MCL group failed to recover the level of soluble intercellular adhesion molecule-1. In addition, the cytokine of B-lymphocyte chemoattractant (BLC) solely presented in the MCL group. These results suggest that MCL may be considered for use as a novel therapeutic treatment against RA and that changes in the expression of cytokines C5/C5a, TIMP-1, M-CSF and BLC may underlie the mechanism by which MCL effects changes in this disease.

Topics: Animals; Antirheumatic Agents; Arthritis, Experimental; Arthritis, Rheumatoid; Cytokines; Disease Models, Animal; Female; Immunosuppressive Agents; Male; Methotrexate; Mice; Sesquiterpenes, Guaiane