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#29049998   2017/10/19 Save this To Up

Endoplasmic Reticulum Stress Is Involved in Cochlear Cell Apoptosis in a Cisplatin-Induced Ototoxicity Rat Model.

Endoplasmic reticulum (ER) stress arises when excessive improperly folded proteins accumulate in the ER lumen. When ER stress occurs, the unfolded protein response (UPR) is subsequently activated to restore ER proteostasis. However, severe ER stress leads to apoptosis. Recent studies have suggested that cisplatin cytotoxicity may be related to ER stress. The purpose of this study was to determine whether ER stress participates in cochlear cell apoptosis in a cisplatin-induced ototoxicity rat model and to also determine the possible relationship between ER stress and hearing loss. Our results revealed that treatment with cisplatin upregulated the expression of active caspase-12 in cochlear cells, which is indicative of cisplatin-induced activation of ER-specific apoptosis. Increased expression of C/EBP homologous protein (CHOP) and cleaved caspase-9 suggested a close relationship between severe ER stress and mitochondria-dependent apoptosis in the cochlear cells of cisplatin-treated rats. In addition, we found that tauroursodeoxycholic acid (TUDCA), a promoter of ER proteostasis, had a protective effect on cisplatin-induced hearing loss. These results demonstrate that ER stress is involved in the cisplatin-induced apoptosis of cochlear cells in vivo.

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#29048755   2017/10/19 Save this To Up

Nifedipine prevents apoptosis of alcohol-exposed first trimester trophoblast cells.

Maternal alcohol abuse leading to fetal alcohol spectrum disorder (FASD) includes fetal growth restriction (FGR). Ethanol induces apoptosis of human placental trophoblast cells, possibly disrupting placentation and contributing to FGR in FASD. Ethanol facilitates apoptosis in several embryonic tissues, including human trophoblasts, by raising intracellular Ca(2+) . We previously found that acute ethanol exposure increases trophoblast apoptosis due to signaling from both intracellular and extracellular Ca(2+) . Therefore, nifedipine, a Ca(2+) channel blocker that is commonly administered to treat preeclampsia and preterm labor, was evaluated for cytoprotective properties in trophoblast cells exposed to alcohol.

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#29048630   2017/10/19 Save this To Up

Metastatic genes targeted by an antioxidant in an established radiation- and estrogen-breast cancer model.

Breast cancer remains the second most common disease worldwide. Radiotherapy, alone or in combination with chemotherapy, is widely used after surgery as a treatment for cancer with proven therapeutic efficacy manifested by reduced incidence of loco-regional and distant recurrences. However, clinical evidence indicates that relapses occurring after radiotherapy are associated with increased metastatic potential and poor prognosis in the breast. Among the anticarcinogenic and antiproliferative agents, curcumin is a well-known major dietary natural yellow pigment derived from the rhizome of the herb Curcuma longa (Zingiberaceae). The aim of the present study was to analyze the differential expression of metastatic genes in radiation- and estrogen-induced breast cancer cell model and the effect of curcumin on such metastatic genes in breast carcinogenesis. Expression levels of TGF-α and TGFβ1 genes were upregulated in MCF-10F and downregulated in Tumor2 cell lines treated with curcumin. Expression levels of other genes such as caspase 9 and collagen 4 A2 were upregulated in both MCF-10F and Tumor2-treated cell lines. Integrin α5 and cathepsin B and D decreased its expression in Tumor2, whereas E-Cadherin, c-myc and CD44 expressions were only increased in MCF-10F. It can be concluded that metastatic genes can be affected by curcumin in cancer progression and such substance can be used in breast cancer patients with advanced disease without side-effects commonly observed with therapeutic drugs.

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#29046047   2017/10/19 Save this To Up

Apoptosis pattern and alterations of expression of apoptosis-related factors of supporting cells in Kölliker's organ in vivo in early stage after birth in rats.

Kölliker's organ is a temporary but indispensable structure in the development of the cochlea. Supporting cells (SCs) within it release adenosine 5'-triphosphate (ATP), which may play a crucial role in cochlear development before the onset of hearing. To reveal the apoptosis of Kölliker's organ in new-born rats, we studied the morphological changes and expression of apoptosis-related factors during early postnatal development. We found SCs in Kölliker's organ decreased in number and changed in appearance along the cochlea apex-to-base gradient, and the expression of caspase-3, caspase-8, caspase-9 and bcl-2 in Kölliker's organ of the cochlea fluctuated along the course of postnatal development, with an expression peak at postnatal day 3. This study demonstrates a time-dependent degeneration of Kölliker's organ during postnatal cochlea development, which might be triggered by endogenous factors.

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#29044755   2017/10/18 Save this To Up

Epoxyazadiradione Purified from the Azadirachta indica Seed Induced Mitochondrial Apoptosis and Inhibition of NFκB Nuclear Translocation in Human Cervical Cancer Cells.

Epoxyazadiradione (EAD) is an important limonoid present in Neem (Azadirachta indica) plant. In the present study, we have purified EAD from Neem seed and studied its anticancer potential in human cervical cancer (HeLa) cells. Cell proliferation inhibition studies indicated that the GI50 value of EAD is 7.5 ± 0.0092 μM in HeLa cells, whereas up to 50 μM concentrations EAD did not affect the growth of normal H9C2 cells. The control drug cisplatin inhibited the growth of both HeLa and H9C2 cells with a GI50 value of 2.92 ± 1.192 and 4.22 ± 1.568 μM, respectively. Nuclear DNA fragmentation, cell membrane blebbing, phosphatidylserine translocation, upregulation of Bax, caspase 3 activity and poly (ADP ribose) polymerase cleavage and downregulation of BCl2 in HeLa cells on treatment with EAD indicated the apoptotic cell death. Increase in caspase 9 activity and release of active cytochrome c to the cytoplasm on treatment with EAD confirmed that the apoptosis was mediated through the mitochondrial pathway. Epoxyazadiradione also inhibited the nuclear translocation of nuclear factor κB in HeLa cells. Thus, our studies demonstrated EAD as a potent and safe chemotherapeutic agent when compared with the standard drug cisplatin that is toxic to both cancer and normal cells equally. Copyright © 2017 John Wiley & Sons, Ltd.

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#29043662   2017/10/18 Save this To Up

Stryphnodendron adstringens ("Barbatimão") Leaf Fraction: Chemical Characterization, Antioxidant Activity, and Cytotoxicity Towards Human Breast Cancer Cell Lines.

We evaluated the chemical composition, antioxidant activity, and antitumor potential of a fraction that was isolated from Stryphnodendron adstringens (barbatimão) leaf aqueous extract. Fraction is composed by gallic acid, procyanidin dimer B1, and (-)-epicatechin-3-O-gallate and it exhibits antioxidant and cytotoxic activities. Fraction was cytotoxic against two human breast cancer cell lines, ER (+) and MCF-7 and the triple-negative, MDA-MB-435. The sulforhodamine B assay showed that, as compared to normal control cells, the fraction significantly (P < 0.05) decreased cancer cell viability. The morphological alterations noted in the treated cancer cells were cell rounding-up, shrinkage, and nuclear condensation reduction of cell diameter and length. Treatment with fraction increased cancer cell expression of Bax, caspase-9, active caspase-3, caspase-8, LC-3, and beclin-1 and decreased Bcl-2, caspase-3, and pro-caspase-8 expression. Altogether, fraction is cytotoxic to both breast cancer cell lines, induces cell death, and its mechanism of action seems to include the induction of apoptosis. Our data support a positive role of the fraction as a chemopreventive agent for antineoplastic drug development.

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#29042985   2017/10/18 Save this To Up

Long noncoding RNA eosinophil granule ontogeny transcript inhibits cell proliferation and migration and promotes cell apoptosis in human glioma.

Glioma is the most common primary brain tumor and represents one of the most aggressive and lethal types of human cancer. Recent advances have implicated long noncoding RNAs (lncRNAs) as crucial mediators of cancer development and progression. The present study aimed to investigate the role of a newly-discovered lncRNA, termed eosinophil granule ontogeny transcript (EGOT), in the aggressive abilities of cells in human glioma. It was initially found that the relative transcription level of EGOT in glioma cancerous tissues was significantly lower than that in adjacent non-cancerous tissues. EGOT was differentially expressed in a series of glioma cell lines, with its lowest level in high aggressive U251 and U87 cells. When EGOT was overexpressed by an expression plasmid, cell viability was significantly inhibited in U251 and U87 cells. Furthermore, with EGOT overexpression, the cell cycle was arrested at G0/G1 phase and consequently, cell apoptosis was significantly promoted along with the activities of caspase-3 and caspase-9. The migration abilities of EGOT-overexpressed cells were inhibited by 71.4% in U251 cells and by 69.5% in U87 cells. These data suggest that overexpression of EGOT inhibits cell proliferation and migration, and promotes cell apoptosis in glioma. Therefore, EGOT has potent anticancer activity and may function as a tumor suppressor in human glioma.

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#29042952   2017/10/18 Save this To Up

Protective effect of ulinastatin on severe pulmonary infection under immunosuppression and its molecular mechanism.

The objective of the present study was to investigate the protective effect of ulinastatin on severe pulmonary infection under immunosuppression, and its molecular mechanism. Mice were treated with methylprednisolone and lipopolysaccharide (LPS) to establish the model of severe pulmonary infection under immunosuppression. Mice were randomly divided into group A (model group; treated with equal volumes of saline), group B (treated with 1×10(5) U/kg ulinastatin), and group C (normal control group). Bronchoalveolar lavage fluid (BALF) was collected, and the concentrations of cytokines in BALF were measured by enzyme-linked immunosorbent assay (ELISA). Pathological changes in lung tissues were observed by hematoxylin and eosin (H&E) staining. The mRNA levels of M1 and M2 macrophage markers in lung tissues were detected by real-time polymerase chain reaction (PCR). Specific protein levels in lung tissues were measured by western blotting. Apoptosis in lung tissues was detected by the terminal-deoxynucleoitidyl transferase mediated nick end-labeling (TUNEL) method. The concentrations of TNF-α, IL-6, and IL-1β in BALF, the mRNA levels of the three M1 macrophage markers, and the protein levels of p-Janus Kinase 2 (p-JAK2), p-signal transducer and activator of transcription-3 (p-STAT-3), cleaved caspase-9, and cleaved poly-ADP-ribose polymerase (PARP), and the number of apoptotic cells in lung tissues in group A were significantly higher than those in groups B and C (P<0.05), whereas the concentrations of IL-4, IL-10, and IL-13 and the mRNA levels of the three M2 macrophage markers were significantly lower than those in groups B and C (P<0.05). Immunofluorescence showed that the nuclei of lung epithelial macrophages in group A became smaller and moved towards the side of nuclear membranes. In conclusion, ulinastatin can improve the inflammatory response caused by severe infection under immunosuppression, which balances the inflammatory microenvironment and inhibits apoptosis at least partially through inhibiting JAK2/STAT-3 and/or caspase pathway activity, ultimately playing a role in lung protection.

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#29042944   2017/10/18 Save this To Up

Pien Tze Huang induces apoptosis and inhibits proliferation of 5-fluorouracil-resistant colorectal carcinoma cells via increasing miR-22 expression.

The well-known traditional Chinese medicine formula Pien Tze Huang (PZH) has long been used to treat various malignancies, including colorectal cancer (CRC). It was recently reported that PZH possesses the ability to overcome multidrug resistance in CRC cells. In the present study, a 5-fluorouracil (5-FU) resistant human CRC cell line (HCT-8/5-FU) was used to further evaluate the effect of PZH on chemotherapy (chemo)-resistance and investigate the mechanisms through which this occurs. The results identified that PZH significantly reduced the viability and cell density of HCT-8/5-FU cells in a dose- and time-dependent manner (P<0.05). PZH inhibited cell survival, reduced the proportion of cells in S-phase, and suppressed the expression of pro-proliferative proteins cyclin D1 and cyclin-dependent kinase 4. In addition, PZH treatment induced nuclear condensation and fragmentation, activated caspase-9 and -3 and increased the pro-apoptotic Bcl-2-associated X protein/B-cell lymphoma 2 protein ratio. Furthermore, PZH treatment upregulated the expression of microRNA-22 (miR-22) and downregulated the expression of c-Myc (a target gene of miR-22). In conclusion, the findings from the present study suggest that PZH can overcome chemo-resistance in cancer cells, likely through increasing miR-22 expression, and by reversing the imbalance between levels of proliferation and apoptosis.

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#29040959   2017/10/17 Save this To Up

Marantodes pumilum (Kacip fatimah) enhances in-vitro glucose uptake in 3T3-L1 adipocyte cells and reduces pancreatic complications in streptozotocin-nicotinamide induced male diabetic rats.

Marontades pumilum is claimed to have beneficial effects in the treatment of diabetes mellitus (DM), however the underlying mechanisms were not fully identified. In this study, we hypothesized that M. pumilum could help to enhance cellular glucose uptake and reduces pancreatic complications, which contributed towards its beneficial effects in DM.

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