14 research outputs found
Acacetin reduces intrasynaptosomal Ca<sup>2+</sup> levels but does not alter the synaptosomal membrane potential and Na<sup>+</sup> influx.
<p>Cytosolic free Ca<sup>2+</sup> concentration (nM) (A) or synaptosomal membrane potential (B) was measured in the absence (control) and in the presence of 30 µM acacetin, added 10 min before depolarization with 1 mM 4-AP. C: Na<sup>+</sup> influx was induced by 1 mM 4-AP in the absence (control) or presence of 30 µM acacetin or 2 µM TTX, added 10 min before depolarization. Results are mean ± SEM of independent experiments, using synaptosomal preparations from five animals. ***, <i>P</i><0.001 versus control group.</p
Acacetin suppresses KA-induced microglial activation in the CA3 region of the hippocampus.
<p>Acacetin (10 or 50 mg/kg, i.p.) was administrated 30 min before KA injection, and the hippocampal sections were stained with anti-OX-42 antibody at 3 days after KA injection. Representative photomicrographs illustrating OX-42 immunoreactivity in the hippocampal CA3 region of control, KA, KA + acacetin 10 mg/kg, and KA + acacetin 50 mg/kg. Insets in figure show the morphological changes after KA administration under higher magnification. Representative picture from six independent experiments were presented. Scale bar  = 100 µm for A-D.</p
Acacetin attenuates KA-induced neuronal cell death in the CA3 region of the hippocampus.
<p>Acacetin (10 or 50 mg/kg) was administrated intraperitoneally 30 min before KA injection, and extents of neuronal losses in the hippocampus were evaluated at 3 days after KA injection by staining with neutral red (A-D) and Fluoro-Jade B (E-H). Representative photomicrographs illustrating neuronal cell death in the hippocampal CA3 region of control, KA, KA + acacetin 10 mg/kg, and KA + acacetin 50 mg/kg. (I) Quantification of Fluoro-Jade B-positive neurons in the CA3 region of the hippocampus. Data are expressed as mean ± SEM of six independent experiments. ***<i>P</i><0.001, as compared with the KA-treated group. Scale bar for A-D, E-H = 250 µm, A′-D′ = 100 µm.</p
Neurocytoprotective Effects of Aliphatic Hydroxamates from Lovastatin, a Secondary Metabolite from <i>Monascus</i>-Fermented Red Mold Rice, in 6‑Hydroxydopamine (6-OHDA)-Treated Nerve Growth Factor (NGF)-Differentiated PC12 Cells
Lovastatin, a secondary
metabolite isolated from <i>Monascus</i>-fermented red rice
mold, has neuroprotective activity and permeates
the blood–brain barrier. The aim of this study was to enhance
the activity of lovastatin for potential use as a treatment for neuronal
degeneration in Parkinson’s disease. Six lovastatin-derived
compounds were semisynthesized and screened for neurocytoprotective
activity against 6-hydroxydopamine (6-OHDA)-induced toxicity in human
neuroblastoma PC12 cells. Four compounds, designated as <b>3a</b>, <b>3d</b>, <b>3e</b>, and <b>3f</b>, significantly
enhanced cell viability. In particular, compound <b>3f</b> showed
excellent neurocytoprotective activity (97.0 ± 2.7%). Annexin
V-FITC and propidium iodide double staining and 4′,6-diamidino-2-phenylindole
staining indicated that compound <b>3f</b> reduced 6-OHDA-induced
apoptosis in PC12 cells. Compound <b>3f</b> also reduced caspase-3,
-8, and -9 activities, and intracellular calcium concentrations elevated
by 6-OHDA in a concentration-dependent manner, without inhibiting
reactive oxygen species generation. JC-1 staining indicated that compound <b>3f</b> also stabilized mitochondrial membrane potential. Thus,
compound <b>3f</b> may be used as a neurocytoprotective agent.
Future studies should investigate its potential application as a treatment
for Parkinson’s disease
Total Synthesis of Hispidulin and the Structural Basis for Its Inhibition of Proto-oncogene Kinase Pim‑1
A new method is applied to synthesize
hispidulin, a natural flavone
with a broad spectrum of biological activities. Hispidulin exhibits
inhibitory activity against the oncogenic protein kinase Pim-1. Crystallographic
analysis of Pim-1 bound to hispidulin reveals a binding mode distinct
from that of quercetin, suggesting that the binding potency of flavonoids
is determined by their hydrogen-bonding interactions with the hinge
region of the kinase. Overall, this work may facilitate construction
of a library of hispidulin-derived compounds for investigating the
structure–activity relationship of flavone-based Pim-1 inhibitors
<i>N</i>‑Hydroxycinnamide Derivatives of Osthole Presenting Genotoxicity and Cytotoxicity against Human Colon Adenocarcinoma Cells in Vitro and in Vivo
Osthole
is extracted from the Chinese herbs <i>Cnidium monnieri</i> and <i>Angelica pubescens</i>, and it was found to have
antitumor activity in vitro and in vivo. A series of osthole derivatives
have been synthesized, and the <i>N</i>-hydroxycinnamide
derivatives of osthole, WJ1376-1 and WJ1398-1 were found to have the
greatest potential against human colon adenocarcinoma cells. In contrast
to the parental osthole, both WJ1376-1 and WJ1398-1 were found to
induce multinucleation and polyploidy by microscopic observation and
flow cytometry. WJ1376-1 and WJ1398-1 significantly activated ataxia
telangiectasia and rad3 related (ATR) kinase, which triggered activation
of the checkpoint kinase 2 (Chk2) signaling pathway and then down
regulated Cdc25 phosphatase and Cdc2/cyclin B kinase activities. WJ1376-1
and WJ1398-1 also inhibited the phosphorylation of Aurora A kinase,
which is associated with important processes during mitosis. The presence
of a “comet” DNA fragment and phosphorylation of p53
at Ser 15 clearly indicated that DNA damage occurred with WJ1376-1
and WJ1398-1 treatment. WJ1376-1 and WJ1398-1 ultimately induced apoptosis
as evidenced by the upregulation of Bad and activation of caspases-3,
-7, and -9. Furthermore, WJ1376-1 and WJ1398-1 also showed a great
effect in attenuating tumor growth without affecting the body weight
of xenograft nude mice. Taken together, these results suggest that
the toxic activities of WJ1376-1 and WJ1398-1 were dissimilar to that
of the parental osthole, which can induce cell polyploidy and G<sub>2</sub>/M cell cycle arrest in colon adenocarcinoma cells and may
provide a potential therapeutic target for colon cancer treatment
in the future
Biochemistry tests including GOT, GPT, albumin, BUN, and creatinine.
<p>Biochemistry tests including GOT, GPT, albumin, BUN, and creatinine.</p
Data_Sheet_1.PDF
<p>Growing evidence shows that hydroxamate-based compounds exhibit broad-spectrum pharmacological properties including anti-tumor activity. However, the precise mechanisms underlying hydroxamate derivative-induced cancer cell death remain incomplete understood. In this study, we explored the anti-tumor mechanisms of a novel aliphatic hydroxamate-based compound, WMJ-J-09, in FaDu head and neck squamous cell carcinoma (HNSCC) cells. WMJ-J-09 induced G2/M cell cycle arrest and apoptosis in FaDu cells. These actions were associated with liver kinase B1 (LKB1), AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (p38MAPK) activation, transcription factor p63 phosphorylation, as well as modulation of p21 and survivin. LKB1-AMPK-p38MAPK signaling blockade reduced WMJ-J-09’s enhancing effects in p63 phosphorylation, p21 elevation and survivin reduction. Moreover, WMJ-J-09 caused an increase in α-tubulin acetylation and interfered with microtubule assembly. Furthermore, WMJ-J-09 suppressed the growth of subcutaneous FaDu xenografts in vivo. Taken together, WMJ-J-09-induced FaDu cell death may involve LKB1-AMPK-p38MAPK-p63-survivin signaling cascade. HDACs inhibition and disruption of microtubule assembly may also contribute to WMJ-J-09’s actions in FaDu cells. This study suggests that WMJ-J-09 may be a potential lead compound and warrant the clinical development in the treatment of HNSCC.</p
Tumor growth and body weight of the orthotopic breast cancer model mice treated with IR (4 Gy) or SAHA (25 mg/kgĂ—9) alone or in combination.
<p>(A) Body weight in Balb/c mice measured once per week. (B) The 4T1-luc cells were injected into mammary fat pads of Balb/c mice, observed for luciferase signals and photographed using IVIS 200. (C) Quantification of the luciferase signals. *, <i>p</i><0.05, versus control. (D) IHC staining of the mouse orthotopic tumor tissues. IHC was used to determine the expression levels of LC3 and ÎłH2AX (Ă—100 objective magnification). The percentage of LC3 and ÎłH2AX-positive cells was determined using HistoQuest software (TissueGnostics).</p
SAHA inhibits experimental metastasis in Balb/c mice.
<p>(A) Body weight in Balb/c mice measured once per week. (B) Lung weights of mice. *, <i>p</i><0.05, versus control. (C) The 4T1-luc cells were observed for the luciferase signals and photographed using IVIS 200. (D) Histological characteristics of mouse lungs stained with H&E. Tumor metastasis is indicated by arrows.</p