homoharringtonine and Disease-Models--Animal

Accumulating evidence suggests an implication of neuroinflammation in Alzheimer's disease (AD) pathogenesis. Homoharringtonine (HHT) is an antitumor reagent with anti-inflammatory activity. This study investigates whether and how HHT plays a role in disease progression in a mouse AD model.. HHT was injected into APP/PS1 mice every other day for 6 months. The effects of HHT on cognitive function were assessed by behavioral assays. β-Amyloid accumulation was assessed by ELISA analysis of Aβ40 and Aβ42. Neuronal loss and synaptic function were determined by levels of NeuN, synaptophysin, and PSD95. Neuroinflammation was assessed by glial markers and pro-inflammatory cytokines. Signal transducer and activator of transcription 3 (STAT3) signaling was evaluated by phosphorylated STAT3 and SOCS3 expression.. We found that HHT at 2 mg/kg significantly alleviated cognitive deficits in APP/PS1 mice. HHT reduced soluble and insoluble Aβ40 and Aβ42 accumulation and attenuated the impairments of synaptic function in the AD mouse hippocampus. Finally, HHT inhibited neuroinflammation, suppressed STAT3 activation, and increased SOCS3 expression in the APP/PS1 mouse hippocampus.. Our results indicate that HHT inhibits disease progression in APP/PS1 mice by suppressing neuroinflammation through modulating the STAT3 signaling. Our findings suggest that HHT may potentially be used for preventing or slowing down AD pathogenesis and warrants further investigation.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Disease Progression; Homoharringtonine; Humans; Mice; Mice, Transgenic; Neuroinflammatory Diseases; Presenilin-1; Signal Transduction; STAT3 Transcription Factor

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

Homoharringtonine (HHT), an inhibitor of protein synthesis, has been used to treat leukemia. Its therapeutic effects on non-small cell lung adenocarcinoma carrying KRAS mutation and their immune system are less understood. The present study examined the therapeutic efficacy and the immune effects of HHT in two murine lung tumor models, xenograft and transgenic, carrying the Kras mutation G12D and G12C respectively. HHT exhibited efficient anticancer activity, significantly suppressing lung tumor growth in vitro and in vivo. The levels of 22 cytokines and chemokines in splenocytes of tumor-bearing mice were examined. Interleukin-12 expression was lower in splenocytes of HHT-treated mice when compared to the controls as demonstrated by a cytokine array and an enzyme-linked immunosorbent assay. The expression levels of CD80, CD86, and CD69 in B220

Topics: Adenocarcinoma; Animals; Cell Line, Tumor; Disease Models, Animal; Genes, ras; Homoharringtonine; Humans; Lung Neoplasms; Mice; Mutation

In this study, we confirmed that combining HHT with ACR can result in synergistic cytotoxicity to AML cells in vitro and in vivo. Combining HHT and ACR simultaneously inhibited PI3K/AKT and WNT/β-catenin signaling in AML cells. Significant increases in growth inhibition and apoptosis were induced by an AKT inhibitor when the WNT3A gene of THP-1 cells was silenced. HHT+ACR could synergistically induce the apoptosis of CD34(+)/CD38(-) primary AML cells. These results highlight β-catenin and AKT are promising targets for combination therapy for AML.

Topics: Aclarubicin; Animals; Antineoplastic Agents; Apoptosis; beta Catenin; Caspases; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Drug Synergism; Female; Gene Silencing; Glucose; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Mice; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Wnt Proteins; Xenograft Model Antitumor Assays

Anorexia-cachexia syndrome (ACS) is a major determinant of cancer-related death that causes progressive body weight loss due to depletion of skeletal muscle mass and body fat. Here, we report the development of a novel preclinical murine model of ACS in which lymphomas harbor elevated Myc and activated mTOR signaling. The ACS phenotype in this model correlated with deregulated expression of a number of cytokines, including elevated levels of interleukin-10 which was under the direct translational control of mTOR. Notably, pharmacologic intervention to impair protein synthesis restored cytokine production to near-normal levels, delayed ACS progression, and extended host survival. Together, our findings suggest a new paradigm to treat ACS by strategies which target protein synthesis to block the production of procachexic factors.

Topics: Animals; Anorexia; Antineoplastic Agents; Body Weight; Cachexia; Cell Line, Tumor; Colonic Neoplasms; Disease Models, Animal; Female; Harringtonines; Homoharringtonine; Humans; Interleukin-10; Kaplan-Meier Estimate; Lymphoma; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Protein Biosynthesis; Proto-Oncogene Proteins c-myc; Signal Transduction; Sirolimus; Syndrome; TOR Serine-Threonine Kinases