Anti-metastatic Effect of Natural Product-motivated Synthetic PPAR-γ Ligands

Colorectal cancer is one of the most common cancers globally, ranking second for the number of cancer-related deaths. Metastasis has been reported as the main cause of death in patients with colorectal cancer. Peroxisome proliferator-activated receptor gamma (PPAR-γ) is a transcription factor that functions as a tumor suppressor by inhibiting cellular proliferation, migration, and invasion. In our previous efforts to generate natural product-motivated PPAR-γ ligands, the compounds 1 and 2 were obtained. These compounds activated PPAR-γ and inhibited the migration and invasion of HCT116 colorectal cancer cells, and they were also found to inhibit the epithelial-to-mesenchymal transition, which is a key process in cancer metastasis. Compounds 1 and 2 upregulated expression of the epithelial marker (E-cadherin), and downregulated expression of the mesenchymal marker (N-cadherin) and transcriptional factor (Snail). Therefore, the PPAR-γ agonists 1 and 2 could serve as a valuable model for the study on anti-metastatic leads for the treatment of colorectal cancer.

Neuroprotective effects of Suhexiang Wan on the in vitro and in vivo models of Parkinson's disease.

OBJECTIVE: To examine the role of KSOP1009 (a modified formulation of Suhexiang Wan essential oil) in an animal model of Parkinson's disease (PD) induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injection. METHODS: Cell toxicity, apoptosis, and reactive oxygen species (ROS) levels were analyzed in the human neuroblastoma cell line SH-SY5Y. After that, changes in animal behavior and tyrosine hydroxylase (TH) protein levels in the substantia nigra (SN) of MPTP-injected mice were examined. Three different doses of KSOP1009 (30, 100, and 300 mg/kg, n = 8 for each group) were administered daily for 7 d before MPTP injection and 14 d after MPTP injection, totaling 21 d. RESULTS: MPP+, the active metabolite of MPTP, decreased the viability of SH-SY5Y cells, whereas KSOP1009 alleviated MPP+-induced cytotoxicity. KSOP1009 (10 and 50 mg/mL) reduced MPP+-induced ROS generation compared with the control group. Treatment with 1 mM MPP+ increased the percentage of depolarized/live cells, whereas KSOP1009 intake at a dose of 10 mg/mL decreased the percentage of these cells. The mean latency to fall in the rotarod test was reduced in mice treated with MPTP compared with the control group. However, mice receiving three different doses of KSOP1009 performed better than MPTP-treated animals. MPTP-treated mice were more hesitant and took longer to traverse the balance beam than the control animals. In contrast, KSOP1009-treated mice performed significantly better than MPTP- treated mice. Furthermore, the KSOP1009-treated groups had a significantly higher number of TH-positive neurons in the lesioned SN and significantly higher expression of TH in the striatum than the MPTP-treated group. MPTP treatment strongly induced Jun-N-terminal kinase (JNK) activation, whereas KSOP1009 suppressed MPTP-induced JNK activation. In addition, KSOP1009 intake reversed the decrease in the phosphorylation levels of cAMP-response element-binding protein in the brain of MPTP-treated mice. KSOP1009 also restored the decrease in dopaminergic neurons and dopamine levels in the brain of MPTP-treated mice. CONCLUSION: KSOP1009 protected mice against MPTP-induced toxicity by decreasing ROS formation and restoring mitochondrial function.

Gliotoxin is Antibacterial to Drug-resistant Piscine Pathogens

By activity-guided fractionation, gliotoxin was isolated as an antibacterial metabolite of the fungus Penicillium decumbens which was derived from the jellyfish Nemopilema nomurai. Gliotoxin was further evaluated for antibacterial activity against several piscine and human MDR (multidrug resistance) pathogens. Gliotoxin showed significant antibacterial activity against Gram-positive piscine pathogens such as Streptococcus iniae FP5228, Streptococcus iniae FP3187, Streptococcus parauberis FP3287, Streptococcus parauberis SPOF3K, S. parauberis KSP28, and Lactococcus garvieae FP5245. Gliotoxin showed strong activity especially against S. parauberis SPOF3K and S. iniae FP5228, which are resistant to oxytetracycline. It is noteworthy that gliotoxin effectively suppressed streptococci which are the major pathogens for piscine infection and mortality in aquaculture industry. Gliotoxin also showed strong antibacterial activity against multidrug-resistant human pathogens (MDR) including Enterococcus faecium 5270 and MRSA (methicillin-resistant Staphylococcus aureus) 3089.

Dexmedetomidine Oral Mucosa Patch for Sedation Suppresses Apoptosis in Hippocampus of Normal Rats / 대한배뇨장애요실금학회지

PURPOSE: Dexmedetomidine, an α2-adrenergic agonist, provides sedative and analgesic effects without significant respiratory depression. Dexmedetomidine has been suggested to have an antiapoptotic effect in response to various brain insults. We developed an oral mucosa patch using dexmedetomidine for sedation. The effects of the dexmedetomidine oral mucosa patch on cell proliferation and apoptosis in the hippocampus were evaluated. METHODS: A hydrogel oral mucosa patch was adhered onto the oral cavity of physiologically normal rats, and was attached for 2 hours, 6 hours, 12 hours, or 24 hours. Plasma dexmedetomidine concentrations were determined by liquid chromatography– electrospray ionization–tandem mass spectrometry–multiple-ion reaction monitoring (LC-ESI-MS/MS-MRM). Cell proliferation in the hippocampus was detected by Ki-67 immunohistochemistry. Caspase-3 immunohistochemistry, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining, and Western blotting for Bax and Bcl-2 were performed to detect hippocampal apoptosis. The levels of brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) in the hippocampus were also measured by Western blotting. RESULTS: Plasma dexmedetomidine concentration increased according to the attachment time of the dexmedetomidine oral mucosa patch. Hippocampal cell proliferation did not change due to the dexmedetomidine oral mucosa patch, and the dexmedetomidine oral mucosa patch exerted no significant effect on BDNF or TrkB expression. In contrast, the dexmedetomidine oral mucosa patch exerted an antiapoptotic effect depending on the attachment time of the dexmedetomidine oral mucosa patch. CONCLUSIONS: A dexmedetomidine oral mucosa patch can be used as a convenient tool for sedation, and is of therapeutic value due to its antiapoptotic effects under normal conditions.