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Wang H.,Shanghai JiaoTong University | Li X.,Shanghai JiaoTong University | Chen T.,Shanghai JiaoTong University | Wang W.,Shanghai JiaoTong University | And 4 more authors.
Oncology Reports

Gallbladder cancer (GBC) is highly malignant with a low response rate after chemotherapy and platinum drugs are currently prominent in the treatment of biliary tract cancers. Therefore, the development of novel strategies to enhance the sensitivity of GBC to platinum drugs is required. In the present study, we examined the effects of verapamil, a classic chemosensitizer whose reported mechanisms of action include inhibiting the transport function of P-glycoprotein (MDR1) or stimulating glutathione (GSH) transport by multidrug resistance-related protein 1 (MRP1), in combination with cisplatin (CDDP), carboplatin (CBP) or oxaliplatin on the GBC cell lines, SGC996 and GBC-SD. Our results demonstrated that the co-treatment with verapamil markedly enhanced the chemosensitivity of GBC cells in comparison with platinum drug treatment alone. The mechanisms involved included GSH reduction and MRP1 downregulation. Verapamil/CDDP co-treatment inhibited tumor xenograft growth via the down-regulation of MRP1 expression. MRP1 was highly expressed in human GBC tissue compared to non-tumorous gallbladder tissue. Our data demonstrate that verapamil may be used as a safe chemosensitizer for platinum drugs in the treatment of GBC. It functions by ROS and ATP-binding cassette transporter-related mechanisms. Source

Yu S.,Institutes of Medical science | Ren J.,Institutes of Medical science | Ni J.,Institutes of Medical science | Tao J.,Institutes of Medical science | And 3 more authors.
Journal of Infectious Diseases

Salmonella causes a range of diseases in different hosts, including enterocolitis and systemic infection. Lysine acetylation regulates many eukaryotic cellular processes, but its function in bacteria is largely unexplored. The acetyltransferase Pat and NAD+-dependent deacetylase CobB are involved in the reversible protein acetylation in Salmonella Typhimurium. Here, we used cell and animal models to evaluate the virulence of pat and cobB deletion mutants in S. Typhimurium and found that pat is critical for bacterial intestinal colonization and systemic infection. Next, to understand the underlying mechanism, genome-wide transcriptome was analyzed. RNA sequencing data showed that the expression of Salmonella pathogenicity island 1 (SPI-1) is partially dependent on pat. In addition, we found that HilD, a key transcriptional regulator of SPI-1, is a substrate of Pat. The acetylation of HilD by Pat maintained HilD stability and was essential for the transcriptional activation of HilA. Taken together, these results suggest that a protein acetylation system regulates SPI-1 expression by controlling HilD in a posttranslational manner to mediate S. Typhimurium virulence. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. Source

Lee Y.-C.,Buddhist Tzu Chi General Hospital | Lee Y.-C.,Institutes of Medical science | Lee Y.-C.,Tzu Chi University | Chang H.-H.,Institutes of Medical science | And 11 more authors.

BACKGROUND-: Perivascular adipose tissue (PVAT)-derived relaxing factor (PVATRF) significantly regulates vascular tone. Its chemical nature remains unknown. We determined whether palmitic acid methyl ester (PAME) was the PVATRF and whether its release and/or vasorelaxing activity decreased in hypertension. METHODS AND RESULTS-: Using superfusion bioassay cascade technique, tissue bath myography, and gas chromatography/mass spectrometry, we determined PVATRF and PAME release from aortic PVAT preparations of Wistar Kyoto rats and spontaneously hypertensive rats. The PVAT of Wistar Kyoto rats spontaneously and calcium dependently released PVATRF and PAME. Both induced aortic vasorelaxations, which were inhibited by 4-aminopyridine (2 mmol/L) and tetraethylammonium 5 and 10 mmol/L but were not affected by tetraethylammonium 1 or 3 mmol/L, glibenclamide (3 μmol/L), or iberiotoxin (100 nmol/L). Aortic vasorelaxations induced by PVATRF-and PAME-containing Krebs solutions were not affected after heating at 70°C but were equally attenuated after hexane extractions. Culture mediums of differentiated adipocytes, but not those of fibroblasts, contained significant PAME and caused aortic vasorelaxation. The PVAT of spontaneously hypertensive rats released significantly less PVATRF and PAME with an increased release of angiotensin II. In addition, PAME-induced relaxation of spontaneously hypertensive rats aortic smooth muscle diminished drastically, which was ameliorated significantly by losartan. CONCLUSIONS-: We found that PAME is the PVATRF, causing vasorelaxation by opening voltage-dependent K channels on smooth muscle cells. Diminished PAME release and its vasorelaxing activity and increased release of angiotensin II in the PVAT suggest a noble role of PVAT in pathogenesis of hypertension. The antihypertensive effect of losartan is attributed partly to its reversing diminished PAME-induced vasorelaxation. © 2011 American Heart Association, Inc. Source

Lee R. H.-C.,Institutes of Medical science | Chen P.-Y.,Tzu Chi University | Liu C.-H.,Institute of Life science | Liu C.-H.,Tzu Chi University | And 9 more authors.
American Journal of Physiology - Heart and Circulatory Physiology

The α7-nicotinic ACh receptor (α7-nAChR) on sympathetic neurons innervating basilar arteries of pigs crossed bred between Landrace and Yorkshire (LY) is known to mediate nicotine-induced, β-amyloid (Aβ)-sensitive nitrergic neurogenic vasodilation. Preliminary studies, however, demonstrated that nicotine-induced cerebral vasodilation in pigs crossbred among Landrace, Yorkshire, and Duroc (LYD) was insensitive to Aβ and α-bungarotoxin (α-BGTX). We investigated nAChR subtype on sympathetic neurons innervating LYD basilar arteries. Nicotine-induced relaxation of porcine isolated basilar arteries was examined by tissue bath myography, inward currents on nAChR-expressing oocytes by two-electrode voltage recording, and mRNA and protein expression in the superior cervical ganglion (SCG) and middle cervical ganglion (MCG) by reverse transcription PCR and Western blotting. Nicotine-induced basilar arterial relaxation was not affected by Aβ, α-BGTX, and α-conotoxin IMI (α7-nAChR antagonists), or α-conotoxin AuIB (α3β4-nAChR antagonist) but was inhibited by tropinone and tropane (α3-containing nAChR antagonists) and α-conotoxin MII (selective α3β2-nAChR antagonist). Nicotine-induced inward currents in α3β2-nAChR-expressing oocytes were inhibited by α-conotoxin MII but not by α-BGTX, Aβ, or α-conotoxin AuIB. mRNAs of α3-, α7-, β2-, and β4-subunits were expressed in both SCGs and MCGs with significantly higher mRNAs of α3-, β2-, and β4-subunits than that of α7-subunit. The Aβ-insensitive sympathetic α3β2-nAChR mediates nicotine-induced cerebral nitrergic neurogenic vasodilation in LYD pigs. The different finding from Aβ- sensitive α7-nAChR in basilar arteries of LY pigs may offer a partial explanation for different sensitivities of individuals to Aβ in causing diminished cerebral nitrergic vasodilation in diseases involving Aβ. © 2011 by the American Physiological Society. Source

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