Dexamethasone induced apoptosis of A549 cells via the TGF-ß1/Smad2 pathway.

Lung cancers are the most commonly diagnosed malignant tumors, and are one of the leading causes of morbidity and mortality worldwide. Dexamethasone (DEX) serves an important function in the regulation of lung cancer cell proliferation; however, the mechanisms involved still remain unknown. In the present study, the effects of DEX on A549 cell proliferation and apoptosis were examined, in addition to the potential downstream regulatory mechanisms underlying these effects. A549 cells were treated with different concentrations of DEX at 12, 24 and 48 h time points, followed by the addition of SB431542, an inhibitor of the TGF-ß1 receptor, to block the TGF-ß1 signaling pathway. Cell proliferation was analyzed using a 3-(4,5-diethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt. The apoptosis rate was measured by Hoechst 33342 and Annexin V/propidium iodide staining and the expression of transforming growth factor (TGF)-ß1, Smad family member 2 (Smad2) and caspase-3 were assessed by western blot. The results from the present study demonstrated that the proliferation of A549 cells decreased and the apoptosis rate significantly increased following DEX treatment (P<0.05). Furthermore, the expression of TGF-ß1, Smad2 and caspase-3 were significantly increased following DEX stimulation (P<0.05), the effects of which were abrogated by the addition of the TGF-ß1 receptor inhibitor, SB431542 (P<0.05). DEX-induced apoptosis in A549 cells, and this effect was abrogated by SB431542, an inhibitor of TGF-ß1 receptor signaling, which indicated that the TGF-ß1/Smad2 pathway may be associated with this process and SB431542 may function as an antitumor drug in the future.

Upregulating serotonin transporter expression and downregulating monoamine oxidase-A and indoleamine 2, 3-dioxygenase expression involved in the antidepressant effect of sodium valproate in a rat model.

Sodium valproate (VPA) is widely used as an antiepileptic agent and mood stabilizer. In recent years, VPA has been increasingly used as a psychotherapeutic drug to treat depression. In this article, a possible antidepressant mechanism of VPA was investigated by studying the expression and therefore the involvement of tryptophan hydroxylase, serotonin transporter (5-HTT), monoamine oxidase-A (MAO-A), and indoleamine 2, 3-dioxygenase (IDO) in rats exposed to chronic unpredicted stress. Male Sprague-Dawley rats were divided into four groups: the vehicle-treated control group (CG), the VPA-treated control group (VPAC), the vehicle-treated model group (MG), and the VPA-treated model group (VPAM). VPA (300 mg/kg once daily) was administered to VPAC and VPAM rats by means of intragastric gavage while an equivalent volume of vehicle was given to vehicle-treated CG and MG rats. Rat behavior and expression of tryptophan hydroxylase, 5-HTT, MAO-A, and IDO in the hippocampus were determined. A significant reduction in depression-like behaviors was observed with an upregulation of 5-HTT expression and a downregulation of MAO-A and IDO expression in VPAM rats, compared with MG rats. The results may suggest that the antidepressant mechanism of VPA is partly related to elevated serotonin level and its reuse in the vesicles of presynaptic nerve endings.

Histone acetylation and expression of mono-aminergic transmitters synthetases involved in CUS-induced depressive rats.

Histone acetylation has been linked to depression, the etiology of which involves many factors such as genetics, environments, and epigenetics. The aim of the present study was to investigate whether it was associated with epigenetic histone modification and gene expression of enzymes responsible for the biosynthesis of norepinephrine and serotonin in rat depression model induced by chronic unpredictable stress (CUS). Eight-week-old male Sprague-Dawley rats were exposed to CUS over 28 days. It was shown that the CUS-induced rats displayed remarked anxiety- and depression-like behavior with weakened locomotor activity in open field test and prolonged immobility in forced swimming test. Western blot revealed that CUS led to significant decrease in acetylation of H3 at Lysine 9 (K9) and H4 at Lysine 12 (K12) with obviously increasing histone deacetylases 5 (HDAC5) expression in hippocampus of CUS-induced rats. Meanwhile, there was an obviously decreased expression of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) both at protein and mRNA levels. Administration of sodium valproate (VPA), a histone deacetylase 5 (HDAC5) inhibitor, not only significantly relieved the anxiety- and depression-like behaviors of CUS-induced rats but also clearly blunted decrease of H3(K9) and H4(K12) acetylation and expression of TH and TPH, and prevented increase of HDAC5 expression. The results indicate that there exists possible interrelation between TH and TPH gene expression and epigenetic histone acetylation in CUS-induced depressive rats, which at least partly contributes to the etiology of depression.

Antidepressive effect of sodium valproate involving suppression of corticotropin-releasing factor expression and elevation of BDNF expression in rats exposed to chronic unpredicted stress.

Sodium valproate (VPA) is an antiepileptic drug and mood stabilizer used to treat bipolar disorders. Recently, other psychiatric uses for VPA have been based on its antidepressive and neuroprotective effects. In the current work, the antidepressive mechanism of VPA was investigated by studying the expression of brain-derived neurotrophic factor (BDNF) and hypothalamic-pituitary-adrenal axis function in rats exposed to a protocol of chronic unpredicted stress (CUS). Male Sprague-Dawley rats were divided into a vehicle-treated control group (no CUS+vehicle), a VPA-treated control group (no CUS+VPA), a vehicle-treated model group (CUS+vehicle), and a VPA-treated model group (CUS+VPA). VPA (300 mg/kg once daily) was administered to rats (no CUS+VPA and CUS+VPA) by an intragastric gavage, whereas the same volume of vehicle was administered to rats in the no CUS+vehicle and CUS+vehicle groups. Rat behavior, serum corticosterone level, and expression of BDNF in the hippocampus and corticotrophin-releasing factor in the hypothalamus were determined. Compared with the CUS+vehicle rats, the CUS+VPA rats showed a significant relief in depression-like behaviors and a decrease in the corticosterone level and corticotropin-releasing factor expression with increasing expression of BDNF. The results suggest that the antidepressive effect of VPA is at least partly related to improving hypothalamic-pituitary-adrenal axis function and elevating the expression of BDNF.