Amorphous selenium inhibits oxidative stress injury of neurons in vascular dementia rats by activating NMDAR pathway.

Vascular dementia (VD) is one of the most common causes of dementia, taking account for about 20% of all cases. Although studies have found that selenium supplementation can improve the cognitive ability of Alzheimer's patients, there is currently no research on the cognitive impairment caused by VD. This study aimed to investigate the role and mechanism of Amorphous selenium nanodots (A SeNDs) in the prevention of VD. The bilateral common carotid artery occlusion (BCCAO) method was used to establish a VD model. The neuroprotective effect of A SeNDs was evaluated by Morris water maze, Transcranial Doppler TCD, hematoxylin-eosin (HE) staining, Neuron-specific nuclear protein (Neu N) staining and Golgi staining. Detect the expression levels of oxidative stress and Calcium-calmodulin dependent protein kinase II (CaMK II), N-methyl-D-aspartate receptor subunit NR2A, and postsynaptic dense protein 95 (PSD95). Finally, measure the concentration of calcium ions in neuronal cells. The results showed that A SeNDs could significantly improve the learning and memory ability of VD rats, restore the posterior arterial blood flow of the brain, improve the neuronal morphology and dendritic remodeling of pyramidal cells in hippocampal CA1 area, reduce the level of oxidative stress in VD rats, increase the expression of NR2A, PSD95, CaMK II proteins and reduce intracellular calcium ion concentration, but the addition of selective NR2A antagonist NVP-AAMO77 eliminated these benefits. It suggests that A SeNDs may improve cognitive dysfunction in vascular dementia rats by regulating the NMDAR pathway.

Amorphous nano-selenium quantum dots prevent pulmonary arterial hypertension through recoupling endothelial nitric oxide synthase.

AIMS: We have previously reported that nano-selenium quantum dots (SeQDs) prevented endothelial dysfunction in atherosclerosis. This study is to investigate whether amorphous SeQDs (A-SeQDs) increase endogenous tetrahydrobiopterin biosynthesis to alleviate pulmonary arterial hypertension. RESULTS: Both A-SeQDs and C-SeQDs were stable under physiological conditions, while the size of A-SeQDs was smaller than C-SeQDs by high resolution-transmission electron microscopy scanning. In monocrotaline-injected mice, oral administration of A-SeQDs was more effective to decrease pulmonary arterial pressure, compared to C-SeQDs and organic selenium. Further, A-SeQDs increased both nitric oxide productions and intracellular BH4 levels, upregulated dihydrofolate reductase activity in lungs, and improved pulmonary arterial remodeling. Gene deletion of dihydrofolate reductase abolished these effects produced by A-SeQDs in mice. Finally, the blood levels of tetrahydrobiopterin and selenium were decreased in patients with pulmonary arterial hypertension. CONCLUSION: A-SeQDs increase intracellular tetrahydrobiopterin to prevent pulmonary arterial hypertension through recoupling endothelial nitric oxide synthase. METHODS: Two polymorphs of SeQDs and A-SeQDs, and a crystalline form of SeQDs (C-SeQDs) were prepared through self-redox decomposition of selenosulfate precursor. Mice were injected with monocrotaline to induce pulmonary arterial hypertension in vivo. Pulmonary arterial pressure was measured.

Knockdown of Bcl-3 inhibits cell growth and induces DNA damage in HTLV-1-infected cells.

Oncoprotein Bcl-3 is perceived as an unusual member of IκB family since it can both stimulate and suppress NF-κB activation. Aberrant Bcl-3 results in increased cell proliferation and survival, suggesting a contribution to malignant potential and elevated levels of Bcl-3 have been observed in many HTLV-1-infected T cell lines and ATL cells. To investigate the specific roles of Bcl-3 in HTLV-1-infected cells, we knocked down Bcl-3 expression using shRNA and then examined the consequences with regard to DNA damage and cell proliferation, as well as NF-κB activation. The HTLV-1 encoded protein Tax promotes Bcl-3 expression and nuclear translocation. In HTLV-1-infected cells, Bcl-3 knockdown obviously induced DNA damage. Cell growth and NF-κB activation were reduced in HTLV-1-infected or Tax positive cells when Bcl-3 expression was decreased. Together, our results revealed positive roles of Bcl-3 in DNA stabilization, growth and NF-κB activation in HTLV-1-infected cells.

Tax is involved in up-regulation of HMGB1 expression levels by interaction with C/EBP.

The high mobility group box 1 (HMGB1) protein is a multifunctional cytokine-like molecule that plays an important role in the pathogenesis of tumors. In this study, real-time polymerase chain reactions and Western blot assays indicated that HMGB1 transcriptional activity and protein level are increased in Tax+-T cells (TaxP). To clarify the mechanisms, a series of HMGB1 deletion reporter plasmids (pHLuc1 to pHLuc6) were transfected into Tax--T cells (TaxN, Jurkat) and Tax+-T cells (TaxP). We found that promoter activity in Tax+-T cells to be higher than that in Tax--T cells, indicating a significant increase in pHLuc6. Bay11-7082 (NF-κB inhibitor) treatment did not block the enhancing effect. Chromatin immunoprecipitation assays revealed that Tax was retained on a HMGB1 promoter fragment encompassing -1163 to -975. Bioinformatics analysis showed six characteristic cis-elements for CdxA, AP-1, AML-1a, USF, v-Myb, and C/EBP in the fragment in question. Mutation of cis- elements for C/EBP reduced significant HMGB1 promoter activity induced by Tax. These findings indicate that Tax enhances the expression of HMGB1 gene at the transcriptional level, possibly by interacting with C/EBP.

SN50 enhances the effects of LY294002 on cell death induction in gastric cancer cell line SGC7901.

INTRODUCTION: In the previous study, we found that the inhibition of phosphatidylinositol 3-kinase (PI3K) by LY294002 induced SGC7901 cell death in vitro. We did not know whether SN50, which is a specific inhibitor of nuclear factor κB (NF-κB), could increase the cell death induction of gastric cancer of LY294002 in vitro, and we also wanted to know the mechanism of it, which might be applied to clinical tumor therapy. MATERIAL AND METHODS: The 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT) assay was used to determine the cytotoxic effects of the drugs. Mitochondrial membrane potential was measured using the fluorescent probe JC-1. Hoechst 33258 staining was used to detect apoptosis and necrosis morphological changes after LY294002 and/or SN50 treatment. Expression of p53, PUMA and Beclin1 were determined with real-time polymerase chain reaction (RT-PCR) analysis. We used transmission electron microscopy to identify ultrastructural changes in SGC7901 cells after LY294002 and/or SN50 treatment. RESULTS: In this study, we found that treating the human gastric cancer cells SGC7901 with SN50 could significantly enhance the effects of LY294002 on inducing cell death after 24 h, compared to the control group (p < 0.05). Detection of mitochondrial potential and transmission electron microscopic examination indicated that the rate of cell death increased progressively. The expression of p53, PUMA and Beclin1 was up-regulated. CONCLUSIONS: The NF-κB inhibitor SN50 could enhance the role of LY294002 on inducing cell death of human gastric cancer cells SGC7901, which might be a promising new approach to gastric cancer therapy.

Lapatinib, a dual inhibitor of EGFR and HER2, has synergistic effects with 5-fluorouracil on esophageal carcinoma.

Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) amplification occurs in over 30% of esophageal carcinomas. Combination therapies with EGFR and HER2-targeting agents and cytotoxic agents are considered a potential therapeutic option for esophageal cancer. We evaluated the antitumor effects of lapatinib, a dual tyrosine kinase inhibitor which simultaneously inhibits EGFR and HER2, 5-fluorouracil (5-Fu) alone and in combination on esophageal cancer cells. The antiproliferative activity of lapatinib, 5-Fu and lapatinib plus 5-Fu was measured by MTT assay and the combination index (CI) values were calculated. Additionally, cell cycle distribution of lapatinib alone and the combination with 5-Fu were detected by flow cytometry analysis. Annexin V-FITC and propidium iodide stain were used for analyzing the apoptotic cells after cells were treated with either agent alone or in combination. The EGFR and HER2 activated signaling pathways were monitored by western blotting. The combination of lapatinib and 5-Fu synergistically inhibited cell proliferation and exhibited an enhanced proapoptotic effect on esophageal cancer cells. The potentiation effect of combined treatment was associated with downregulation of EGFR and HER2 signaling pathways because data from western blot analysis showed that lapatinib in combination with 5-Fu markedly reduced the phosphorylation of EGFR and HER2, and inhibited the activation of downstream signaling molecules, such as AKT and ERK. A significant G1 arrest was also observed in cell cycle analysis after exposing cells to lapatinib, however, combination with 5-Fu did not enhance G1 arrest. These results indicate that the combination of the lapatinib and 5-Fu is a promising treatment option for esophageal carcinoma with HER2 amplification.