Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UNIPROT:P30044 (
antioxidant enzyme
)
8,037
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Angiotensin II (Ang II), as a crucial factor of endothelial dysfunction, participates in endothelial oxidative damage and inflammation, which is present in all cardiovascular disease (CVD).
Celastrol
, extracted from Trypterygiun wilfordii Hook F. ("Thunder of God Vine"), is a natural compound with antioxidant and anti-inflammatory activities. In this study, the protective effects of
celastrol
on human umbilical vein endothelial cell (HUVEC) injury induced by Ang II were observed and its mechanisms were elucidated. Compared with the control group, Ang II significantly increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, enhanced reactive oxygen species levels and proinflammatory cytokines, decreased
antioxidant enzyme
activities, and suppressed cellular viability and promoted cell apoptosis. It accomplished this via inhibition of the nuclear factor erythroid 2-related factor 2 (Nrf2), increasing the expression levels of Nox2 and AngII type 1 receptor (AT
1
receptor), and inducing the phosphorylation of extracellular signal regulated kinase (ERK1/2). In contrast,
celastrol
effectively suppressed reactive oxygen species generation, improved endothelial cell activity, and ameliorated Ang II-mediated HUVEC injury through activation of Nrf2, inhibition of Nox2/AT
1
receptor expression, and upregulated phosphorylation of ERK1/2. After treatment with brusatol, a specific inhibitor of Nrf2, the protective effects of
celastrol
on Ang II-induced damage in HUVECs were remarkably alleviated. Taken together,
celastrol
-induced activation of Nrf2 and inhibition of NADPH oxidase activity were critical for the inhibition of Ang II-mediated endothelial dysfunction, and demonstrated the potential application of
celastrol
in CVD therapy.
...
PMID:Celastrol attenuates angiotensin II mediated human umbilical vein endothelial cells damage through activation of Nrf2/ERK1/2/Nox2 signal pathway. 2811 74
Peroxiredoxin I (Prx I) plays an important role in cancer development and inflammation. It is a dual-functional protein which acts as both an
antioxidant enzyme
and a molecular chaperone. While there have been intensive studies on its peroxidase activity, Prx I's chaperone activity remains elusive, likely due to the lack of chaperone inhibitors. Here we report that natural product triptolide selectively inhibits the chaperone activity of Prx I, but not its peroxidase activity. Through direct interaction with corresponding cysteines, triptolide triggers dissociation of high-molecular-weight oligomers of Prx I, and thereby inhibits its chaperone activity in a dose-dependent manner. We have also identified
celastrol
and withaferin A as novel Prx I chaperone inhibitors that are even more potent than triptolide in the chaperone activity assay. By revealing the exact molecular mechanisms of interaction and inhibition, the current study provides the first Prx I chaperone inhibitors as promising pharmacological tools for modulating and dissecting the chaperone function of Prx I.
...
PMID:Natural products triptolide, celastrol, and withaferin A inhibit the chaperone activity of peroxiredoxin I. 2871 68
Background:
Oxidative stress from elevated reactive oxygen species (ROS) has been reported to induce cell apoptosis and may provide a means to target cancer cells.
Celastrol
is a natural bioactive compound that was recently shown to increase ROS levels and cause apoptosis in cancer cells. However, the underlying mechanism for this cytotoxic action remains unclear and direct molecular targets of
Celastrol
have not been identified.
Methods:
Proteome microarray, surface plasmon resonance, isothermal titration calorimetry and molecular simulation were used to identify the molecular target of
Celastrol
. Binding and activity assays were used to validate the interaction of
Celastrol
with target protein in cell-free and gastric cancer cell lysates. We then assessed target transcript levels in in biopsy specimens obtained from patients with gastric cancer. Gastric cancer growth-limiting and cytotoxic activity of
Celastrol
was evaluated in BALB/c nu/nu mice.
Results:
Our data show that
Celastrol
directly binds to an
antioxidant enzyme
, peroxiredoxin-2 (Prdx2), which then inhibits its enzyme activity at both molecular and cellular level. Inhibition of Prdx2 by
Celastrol
increased cellular ROS levels and led to ROS-dependent endoplasmic reticulum stress, mitochondrial dysfunction, and apoptosis in gastric cancer cells. Functional tests demonstrated that
Celastrol
limits gastric cancer cells, at least in part, through targeting Prdx2.
Celastrol
treatment of mice implanted with gastric cancer cells also inhibited tumor growth, associated with Prdx2 inhibition and increased ROS. Analysis of human gastric cancer also showed increased Prdx2 levels and correlation with survival.
Conclusion:
Our studies have uncovered a potential
Celastrol
-interacting protein Prdx2 and a ROS-dependent mechanism of its action. The findings also highlight Prdx2 as a potential target for the treatment of gastric cancer.
...
PMID:Celastrol induces ROS-mediated apoptosis via directly targeting peroxiredoxin-2 in gastric cancer cells. 3292 49
