• Journal of Life Science
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• v.22 no.8
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• pp.1009-1017
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• 2012

The orf282 gene of Rhodobacter sphaeroides is located between the ccoNOQP operon encoding $cbb_3$ terminal oxidase and the fnrL gene encoding an anaerobic activator, FnrL. Its function remains unknown. In an attempt to reveal the function of the orf282 gene, we disrupted the gene by deleting a portion of the orf282 gene and constructed an orf282-knockout mutant. Two FnrL binding sites were found to be located upstream of orf282, and it was demonstrated that orf282 is positively regulated by FnrL. The orf282 gene is not involved in the regulation of spectral complex formation. The $cbb_3$ oxidase activity detected in the orf282 mutant was comparable to that in the wild-type sample, indicating that the orf282 gene is not involved in the regulation of the ccoNOQP operon and the biosynthesis of the cbb3 cytochrome c oxidase. The elevated promoter activity of the nifH and nifA genes, which are the structural genes of nitrogenase and its regulator, respectively, in the orf282 mutant, suggests that the orf282 gene product acts as a negative effector for nifH and nifA expression.

• Journal of Life Science
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• v.19 no.8
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• pp.1047-1054
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• 2009

Oral squamous carcinoma (OSC) cells present resistance to chemotherapeutic agents-mediated apoptosis in the late stages of malignancy. Advances in the understanding of bacterial toxins have produced new strategies for the treatment of cancers. It was demonstrated here that Pseudomonas aeruginosa exotoxin A (PEA) significantly decreased the viability of chemoresistant YD-9 cells in the apoptosis mechanism. Apoptotic manifestations were evident through changes in nuclear morphology and generation of DNA fragmentation. PEA treatment induced caspase-3, -6 and -9 cleavage, and activation. These events preceded proteolysis of the caspase substrates poly (ADP-ribose) polymerase (PARP), DNA fragmentation factor 45 (DFF45), and lamin A in YD-9 cells. The reduction of mitochondrial membrane potential, release of cytochrome c and SmacjDlABLO from mitochondria to cytosol, andtranslocation of AlF into nucleus were shown. While p53, p21 and $14-3-3{\gamma}$ were upregulated, cyclin Band cdc2 were downregulated by PEA treatment. Taken together, PEA induces apoptosis in chemoresistant YD-9 cells via activation of caspases, mitochondrial events and regulation of cell cycle genes.

• Biomolecules & Therapeutics
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• v.3 no.4
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• pp.304-310
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• 1995

This study was done to investigate the effect of vitamin C on hepatic biliary and microsomal function during ischemia and reperfusion. Rats were treated with vitamin C(20, 100, 400, 1600 mg/kg) or with vehicle(saline) and then subjected to 60 min no-flow hepatic ischemia in vivo. Control animals were time-matched sham ischemic animals. After 1 or 5 hr of reperfusion, bile was collected, blood was obtained from the abdominal aorta, and liver microsomes were isolated. In vehicle-treated ischemic rats, serum ALT and AST levels peaked at 5 hr and were significantly attenuated by vitamin C 20 mg/kg and 100 mg/kg treatment. Similarly, hepatic wet weight-to-dry weight ratio was decreased in the vehicle-treated ischemic group. Vitamin C 20 mg/kg and 100 mg/kg treatment minimized the increase in this ratio. Lipid peroxidation was elevated in vehicle-treated ischemic group, but this elevation was also inhibited by vitamin C 20 mg/kg and 100 mg/kg treatment. Bile flow and cholate output, but not bilirubin output, were markedly decreased by ischemia/reperfuzion. Vitamin C 20 mg/kg and 100mg/kg treatment restored the secretion but vitamin C 1600 mg/kg reduced the cholate output. Cytochrome P-450 content was decreased by ischemia/reperfusion and restored by vitamin C 20 mg/kg and 100 mg/kg treatment to the level of sham operated group but decreased by vitamin C 1600 mg/kg. Aminopyrine N-demethylase activity was decreased and aniline p-hydroxylase activity was increased by ischemia/reperfusion. The changes in the activities of aminopyrine were prevented by vitamin C 20 mg/kg and 100 mg/kg treatment, but not by 400 mg/kg and 1600 mg/kg treatment. Our findings suggest that ischemia/reperfusion diminishes hepatic secretory functions as well as microsomal drug metabolizing systems, small doses(20, 100 mg/kg) of vitamin C significantly ameliorates and large doses(400, 1600 mg/kg) of vitamin C aggravated these ischemia/reperfusion-induced changes.

• Journal of Pharmaceutical Investigation
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• v.41 no.3
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• pp.153-159
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• 2011

This study was designed to investigate the effects of silibinin on the pharmacokinetics of carvedilol after oral administration of carvedilol in rats. Carvedilol was administered orally (3 mg/kg) with oral silibinin (0.3, 1.5 or 6 mg/kg) and intravenously (1 mg/kg) to rats. The effects of silibinin on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 2C9 and CYP2D6 activity were also evaluated. Silibinin inhibited CYP2C9 and CYP2D6 enzyme activity with 50% inhibition concentration ($IC_{50}$) of 5.2 ${\mu}M$ and 85.4 ${\mu}M$, respectively. In addition, silibinin significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. Compared with the control group, the area under the plasma concentration-time curve was significantly increased by 36.3-57.1%, and the peak concentration was significantly increased by 51.1-88.5% in the presence of silibinin after oral administration of carvedilol. Consequently, the relative bio-availability of carvedilol was increased by 1.13- to 1.57-fold and the absolute bioavailability was significantly increased by 38.6-59.7%. The time to reach peak concentration and the terminal half-life were not significant. The enhanced oral bio-availability of carvedilol may result from inhibition of CYP2C9-mediated metabolism and P-gp-mediated efflux of carvedilol rather than inhibition of CYP2D6-mediated metabolism in the intestine and/or in the liver by silibinin.

• IMMUNE NETWORK
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• v.5 no.2
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• pp.99-104
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• 2005

Background: Malignant gliomas are the most common primary tumors in the central nervous system. Methods: We investigated the combined effect of PG490 and LPS on the induction of the apoptotic pathway in human astroglioma cells. Results: Treatment of U87 cells with combination of 50nM of PG490 and $50{\mu}g/ml$ of LPS resulted in increased internucleosomal DNA fragmentation, cleavage of PLC-${\gamma}1$, and downregulation of cIAP1 and XIAP. The combination of LPS and PG490 treatment-induced apoptosis is mediated through the activation of caspase, which is inhibited by the caspase inhibitor, z-VAD-fmk. Also, release of cytochrome c was found in PG490 and LPS-cotreated U87 cell. Conclusion: Taken together, combination of PG490 and LPS appears to be a potent inducer of apoptosis in astrogliaoma cells, and might have some benefit in the treatment of glioma patients.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.11
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• pp.6669-6672
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• 2013

Colon cancer (CRC) is a serious health problem throughout the world. Development of novel drugs without side effects for this cancer is crucial. Luteolin (LUT), a bioflavonoid, has many beneficial effects such as antioxidant, anti-inflammatory and anti-proliferative potential. was a potent chemical carcinogen used for the induction of colon cancer. Colon carcinogenesis was initiated by intraperitoneal injection of azoxymethane (AOM) to mice at the dose of 15 mg/body kg weight in Balb/C mice for 3 weeks. Mice were treated with LUT at the dose of 1.2 mg/body kg weight orally. Mitochondrial enzymes such as isocitrate dehydrogenase (ICDH), ${\alpha}$-keto dehydrogenase (${\alpha}$-KDH), succinate dehydrogenase (SDH) and the activities of respiratory chain enzymes NADH dehydrogenase and cytochrome c oxidase were found to be elevated in AOM-treated animals. Treatment with LUT decreased the activities of all the parameters significantly. Hence, LUT might be a potent anticancer agent against colorectal cancer.

• Microbiology and Biotechnology Letters
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• v.47 no.1
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• pp.43-53
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• 2019

The anticancer activity of guava (Psidium guajava L.) leaf extract (GLE) occurs via the induction of apoptosis in cancer cells. However, the mechanism behind GLE-induced apoptosis in the human hepatocellular carcinoma cell line HepG2 remains unclear. In the present study, we investigated the apoptotic effects and mechanism of action of GLE in cultured HepG2 cells. The results showed that GLE induced reactive oxygen species (ROS) synthesis and disrupted the mitochondrial membrane potential (${\Delta}{\Psi}m$). Moreover, GLE increased the expression of apoptotic pathway proteins, such as the cleaved forms of caspase-3, -8, and -9; the translocation of Bax and cytochrome c (cyt-c) from the mitochondria to the cytosol; and the downregulation of Bcl-2. In addition, p53 protein expression was increased upon GLE treatment. These observations indicate that the GLE-induced apoptosis in HepG2 cells is mediated by mitochondrial ROS generation, followed by caspase activation and cyt-c release, suggesting that GLE may be a promising candidate for the development of novel drugs for the treatment of liver cancers.

• Development and Reproduction
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• v.28 no.2
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• pp.37-45
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• 2024

This study aimed to elucidate the potential of Homeobox A11 (HOXA11) as a therapeutic target and a diagnostic methylation marker for cervical cancer. Gene expression analysis using cDNA microarray in cervical cancer cell lines revealed significantly reduced expression of the HOXA11 gene. Subsequent investigation of HOXA11 promoter methylation in samples from normal individuals and invasive cervical cancer patients showed over 53.2% higher methylation in cancer scrapes compared to normal scrapes. Furthermore, overexpression of HOXA11, which is downregulated in cervical cancer, strongly suppressed cell growth in cervical cancer cell lines, HeLa and HT3. Additionally, we performed transferase dUTP nick end labeling assay and confirmed that the inhibition of cervical cancer cell proliferation occurred via apoptosis. Mechanistically, overexpression of HOXA11 led to mitochondrial apoptosis characterized by PARP cleavage due to increased c-Myc and enhanced cytochrome C secretion into the cytoplasm. These findings suggest that HOXA11 could potentially serve as a methylation marker for diagnosing cervical cancer and as a novel therapeutic target for its treatment.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.2
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• pp.769-773
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• 2014

Fangchinoline (Fan) inhibits cell proliferation and induces apoptosis in several cancer cell lines. The effects of Fan on cell growth and proliferation in breast cancer cells remain to be elucidated. Here, we show that Fan inhibited cell proliferation in the MDA-MB-231 breast cancer cell line through suppression of the AKT/Gsk-3beta/cyclin D1 signaling pathway. Furthermore, Fan induced apoptosis by increasing the expression of Bax (relative to Bcl-2), active caspase 3 and cytochrome-c. Fan significantly inhibited cell proliferation of MDA-MB-231 cells in a concentration and time dependent manner as determined by MTT assay. Flow cytometry analysis demonstrated that Fan treatment of MDA-MB-231 cells resulted in cell cycle arrest at the G1 phase, which correlated with apparent downregulation of both mRNA and protein levels of both PCNA and cyclin D1. Further analysis demonstrated that Fan decreased the phosphorylation of AKT and GSK-3beta. In addition, Fan up-regulated active caspase3, cytochrome-c protein levels and the ratio of Bax/Bcl-2, accompanied by apoptosis. Taken together, these results suggest that Fan is a potential natural product for the treatment of breast cancer.

• Journal of Life Science
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• v.21 no.11
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• pp.1549-1557
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• 2011

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in many types of transformed cells; however, some human hepatocellular carcinoma cells are particularly resistant to the effects of TRAIL. Although genistein, a natural isoflavonoid phytoestrogen, has been shown to have pro-apoptotic activity against human cancer cell lines, little is known about the mechanism of genistein in terms of TRAIL-induced apoptosis. In the present study, it was investigated whether or not combined treatment with genistein and TRAIL synergistically induced apoptosis in Hep3B hepatocarcinoma cells. Results indicate that treatment with TRAIL in combination with nontoxic concentrations of genistein sensitized TRAIL-resistant Hep3B cells to TRAIL-induced apoptosis, which was associated with mitochondrial dysfunction. Further, the inhibition of p38 mitogen-activated protein kinase (MAPK) activation markedly decreased genistein and TRAIL-induced cell viability and apoptosis by enhanced truncation of Bid, increase of pro-apoptotic Bax, decrease of anti-apoptotic Bcl-2, and release of cytochrome c from mitochondria to cytoplasm. Activation of caspases and degradation of poly (ADP-ribose) polymerase induced by the combined treatment was also markedly increased by the inhibition of p38 MAPK, through the mitochondrial amplification step. In conclusion, our data suggest that genistein sensitizes TRAIL-induced-apoptosis via p38 MAPK-dependent pathway.