tretinoin and celastrol

Alzheimer's disease (AD) is the most common form of dementia affecting the aged population and neuroinflammation is one of the most observed AD pathologies. NF-κB is the central regulator of inflammation and inhibitor κB kinase (IKK) is the converging point in NF-κB activation. Celastrol is a natural triterpene used as a treatment for inflammatory conditions.. This study determines the neuroprotective and inhibitory effect of celastrol on amyloid beta. Retinoic acid differentiated IMR-32 cells were treated with celastrol (1 μM) before treatment with Aβ. Celastrol (1 μM) inhibited Aβ. The decreased expression of pIκBα in celastrol pretreated cells affirms the functional representation of inhibited IKKβ activity in these cells. The neuroprotective potentials of celastrol and its analogues may be related to IKK inhibition.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Anti-Inflammatory Agents; Binding Sites; Cell Line, Tumor; Humans; Hydrogen Bonding; I-kappa B Kinase; Molecular Docking Simulation; Neurons; Neuroprotective Agents; Pentacyclic Triterpenes; Peptide Fragments; Phosphorylation; Protein Binding; Protein Conformation; Protein Kinase Inhibitors; Signal Transduction; Structure-Activity Relationship; Tretinoin; Triterpenes

All-trans retinoic acid (ATRA) is a revolutionary agent for acute promyelocytic leukemia (APL) treatment via differentiation induction. However, ATRA treatment also increases cytokine, chemokine, and adhesive molecule (mainly ICAM-1) expression, which can cause clinical complications, including a severe situation known as differentiation syndrome (DS) which can cause death. Therefore, it is of clinical significance to find a strategy to specifically blunt inflammatory effects while preserving differentiation. Here we report that the natural compound, celastrol, could effectively block lung infiltrations in DS animal models created by loading ATRA-induced APL cell line NB4. In ATRA-treated NB4 cells, celastrol could potently inhibit ICAM-1 elevation and partially reduce TNF-α and IL-1β secretion, though treatment showed no effects on IL-8 and MCP-1 levels. Celastrol's effect on ICAM-1 in ATRA-treated NB4 was related to reducing MEK1/ERK1 activation. Strikingly and encouragingly, celastrol showed no obvious effects on ATRA-induced NB4 differentiation, as determined by morphology, enzymes, and surface markers. Our results show that celastrol is a promising and unique agent for managing the side effects of ATRA application on APL, and suggest that hyper-inflammatory ability is accompanied by, but not necessary for, APL differentiation. Thus we offered an encouraging novel strategy to further improve differentiation therapy.

Topics: Animals; Cell Differentiation; Cell Line, Tumor; Humans; Intercellular Adhesion Molecule-1; Leukemia, Promyelocytic, Acute; Lung; Male; MAP Kinase Signaling System; Mice; Mice, Inbred NOD; Mice, SCID; Pentacyclic Triterpenes; RNA, Messenger; RNA, Neoplasm; Syndrome; Tretinoin; Triterpenes; Tumor Necrosis Factor-alpha

The proteasome inhibition and mitochondrial dysfunction are involved in pathomechanism of Parkinson's disease. The main aim of this study was to assess how particular culture conditions of human dopaminergic neuroblastoma SH-SY5Y cells could affect the extent of neurodegeneration induced by proteasome inhibitor-lactacystin (LC) and mitochondrial toxin-rotenone (Rot). This study revealed that induction of neuronal differentiation of SH-SY5Y cells with retinoic acid (RA-SH-SY5Y) caused a higher resistance of these cells to LC-evoked cell death when compared to undifferentiated cells (UN-SH-SY5Y). In contrast, RA-SH-SY5Y cells were more vulnerable than the UN-SH-SY5Y to Rot-induced cell damage. Furthermore, we found that a prolonged incubation of the cells under low serum condition (PLSC) significantly increased the LC toxicity in both differentiated and undifferentiated cells. Next, the effects of combined treatment with LC and Rot on cell viability were studied in RA-SH-SY5Y cells under PLSC and normal low serum condition (NLSC). At a low concentration, Rot (0.001-1 μM) attenuated the LC-evoked cell death in RA-SH-SY5Y cells exposed to NLSC. In contrast, under PLSC low concentrations of Rot lacked neuroprotective action while its higher levels (10 μM) enhanced the LC toxicity. Further, we showed that low concentrations of celastrol (Cel; 0.001 μM), a putative neuroprotective agent with antioxidant and anti-inflammatory properties, were able to partially attenuate the Rot-evoked toxicity under both PLSC and NLSC. On the other hand, Cel (0.001 and 0.01 μM) attenuated the LC-induced cell damage only under PLSC. Interestingly, higher concentrations of Cel (>1 μM) reduced cell viability in both UN- and RA-SH-SY5Y but only in UN-SH-SY5Y cells the effect was enhanced under PLSC. The obtained data indicate that toxicity of LC and Rot in SH-SY5Y cell line depends on the stage of cell differentiation and is enhanced in cells cultured for a longer time in low serum medium. Moreover, the neuroprotective properties of Rot and Cel against the LC-induced cell damage can be observed only under particular low serum conditions.

Topics: Acetylcysteine; Cell Death; Cell Differentiation; Cell Survival; Cells, Cultured; Culture Media, Serum-Free; Dose-Response Relationship, Drug; Drug Interactions; Humans; Nerve Degeneration; Neuroprotective Agents; Parkinson Disease; Pentacyclic Triterpenes; Rotenone; Time Factors; Tretinoin; Triterpenes

Increasing of adhesion between leukemia cells and endothelial cells during all-trans retinoic acid (ATRA) treatment plays an important role in retinoic acid syndrome. This work observed the effects of tripterine on this ATRA-caused increasing in adhesion.. The effects of tripterine on ATRA-induced expressions of adhesive molecules in acute promyelocytic leukemia cell line NB4 and human umbilical vascular endothelial cells (HUVEC) were detected by flow cytometry. The effects of tripterine on adhesion between ATRA-treated NB4 and HUVEC were determined by adhesive assays.. ATRA caused remarkable elevation of intercellular adhesion molecule-1 (ICAM-1) in NB4 cells, which could be significantly reduced by tripterine (P<0.01). The expressions of E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and ICAM-1 in HUVEC were elevated by conditioned medium from ATRA-induced NB4 (ATRA-NB4-CM) (P<0.01), and inhibited by tripterine with inhibition rates being 25.3%, 42.4% and 61.0% respectively. ATRA increased the adhesion between NB4 and HUVEC, which was reversed completely by tripterine.. Tripterine can inhibit ATRA-caused adhesion between leukemia cells and endothelial cells, and it might be a potential agent for treating retinoic acid syndrome.

Topics: Cell Adhesion; Cell Line; Cell Line, Tumor; E-Selectin; Endothelial Cells; Humans; Intercellular Adhesion Molecule-1; Leukemia, Promyelocytic, Acute; Pentacyclic Triterpenes; Tretinoin; Tripterygium; Triterpenes; Vascular Cell Adhesion Molecule-1