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Varisa Pongrakhananon Ubonthip Nimmannit Sudjit Luanpitpong Yon Rojanasakul Pithi Chanvorachote 《Apoptosis : an international journal on programmed cell death》2010,15(5):574-585
Anoikis, an apoptosis triggered by loss of cell anchorage, has been shown to be a principal mechanism of inhibition of tumor
metastasis. Recently, anti-apoptotic Bcl-2 and Cav-1 proteins have been demonstrated to be highly associated with tumor metastasis
and apoptosis resistance. Curcumin, a major active component of turmeric, Curcuma longa, has been shown to inhibit neoplastic evolution and tumor progression; however, the underlying mechanisms are unclear. In
this study, we investigated the effect of curcumin on cell anoikis as a possible mechanism of anti-tumorigenic action of curcumin,
and evaluated the potential role of Bcl-2 and Cav-1 in this process. Our results showed that ectopic expression of either
Bcl-2 or Cav-1 induced anoikis resistance of lung carcinoma H460 cells. Curcumin downregulated Bcl-2 protein during anoikis
and sensitized the cells to detachment-induced apoptosis, whereas it had no significant effect on Cav-1 protein expression.
Bcl-2 down-regulation as well as anoikis enhancement by curcumin were inhibited by superoxide anion scavenger, Mn(III)tetrakis(4-benzoic
acid) porphyrin chloride, but were unaffected by other ROS scavengers including catalase and deferoxamine, suggesting that
superoxide anion is a key player in the downregulation of Bcl-2 by curcumin. Furthermore, we provided evidence that curcumin
decreased Bcl-2 level through ubiquitin-proteasomal degradation which sensitized cells to detachment-induced apoptosis. These
findings indicate a novel pathway for curcumin regulation of Bcl-2 and provide a key mechanism of anoikis regulation that
may be exploited for metastatic cancer treatment. 相似文献
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The aim of this study was to investigate a newly synthesized dextrin–zidovudine (AZT) conjugate designed as a sustained release
prodrug of AZT for parenteral administration. AZT was first reacted with succinic anhydride to form a succinoylated AZT which
was subsequently coupled with dextrin to yield the dextrin–AZT conjugate. The structure of the conjugate was characterized
by FT-IR and 1H-NMR spectroscopy. The drug content of the conjugate was 18.9 wt.%. The release in vitro of free AZT and succinoylated AZT was investigated in buffer solutions at pH 5.5 and 7.4 and in human plasma. AZT and succinoylated
AZT release from the conjugate was 1.4% (pH 5.5), 41.7% (pH 7.4) and 78.4% in human plasma after 24 h. Release was complete
in human plasma after 48 h. A pharmacokinetic study in rats following intravenous administration of the conjugate showed prolonged
plasma levels of AZT compared to free AZT. The use of the conjugate extended the plasma half-life of AZT from 1.3 to 19.3 h
and the mean residence time from 0.4 to 23.6 h. Furthermore, the conjugate provided a significant greater area under the plasma
concentration-time curve and reduced the systemic clearance of AZT. This study suggested the potential of this novel dextrin–AZT
conjugate as a new intravenous preparation of AZT. 相似文献
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Rungtabnapa P Nimmannit U Halim H Rojanasakul Y Chanvorachote P 《American journal of physiology. Cell physiology》2011,300(2):C235-C245
Anoikis or detachment-induced apoptosis plays an essential role in the regulation of cancer cell metastasis. Caveolin-1 (Cav-1) is a key protein involved in tumor metastasis, but its role in anoikis and its regulation during cell detachment are unclear. We report here that Cav-1 plays a key role as a negative regulator of anoikis through a reactive oxygen species (ROS)-dependent mechanism in human lung carcinoma H460 cells. During cell detachment, Cav-1 is downregulated, whereas ROS generation is upregulated. Hydrogen peroxide and hydroxyl radical are two key ROS produced by cells during detachment. Treatment of the cells with hydrogen peroxide scavengers, catalase and N-acetylcysteine, promoted Cav-1 downregulation and anoikis during cell detachment, indicating that produced hydrogen peroxide plays a primary role in preventing anoikis by stabilizing Cav-1 protein. Catalase and N-acetylcysteine promoted ubiquitination and proteasomal degradation of Cav-1, which is a major pathway of its downregulation during cell anoikis. Furthermore, addition of hydrogen peroxide exogenously to the cells inhibited Cav-1 downregulation by preventing the formation of Cav-1-ubiquitin complex, supporting the inhibitory role of endogenous hydrogen peroxide in Cav-1 degradation during cell detachment. Together, these results indicate a novel role of hydrogen peroxide as an endogenous suppressor of cell anoikis through its stabilizing effect on Cav-1. 相似文献
6.
Luanpitpong S Nimmannit U Chanvorachote P Leonard SS Pongrakhananon V Wang L Rojanasakul Y 《Apoptosis : an international journal on programmed cell death》2011,16(8):769-782
Induction of massive apoptosis of hair follicle cells by chemotherapy has been implicated in the pathogenesis of chemotherapy-induced
alopecia (CIA), but the underlying mechanisms of regulation are not well understood. The present study investigated the apoptotic
effect of cisplatin in human hair follicle dermal papilla cells and HaCaT keratinocytes, and determined the identity and role
of specific reactive oxygen species (ROS) involved in the process. Treatment of the cells with cisplatin induced ROS generation
and a parallel increase in caspase activation and apoptotic cell death. Inhibition of ROS generation by antioxidants inhibited
the apoptotic effect of cisplatin, indicating the role of ROS in the process. Studies using specific ROS scavengers further
showed that hydroxyl radical, but not hydrogen peroxide or superoxide anion, is the primary oxidative species responsible
for the apoptotic effect of cisplatin. Electron spin resonance studies confirmed the formation of hydroxyl radicals induced
by cisplatin. The mechanism by which hydroxyl radical mediates the apoptotic effect of cisplatin was shown to involve down-regulation
of the anti-apoptotic protein Bcl-2 through ubiquitin-proteasomal degradation. Bcl-2 was also shown to have a negative regulatory
role on hydroxyl radical. Together, our results indicate an essential role of hydroxyl radical in cisplatin-induced cell death
of hair follicle cells through Bcl-2 regulation. Since CIA is a major side effect of cisplatin and many other chemotherapeutic
agents with no known effective treatments, the knowledge gained from this study could be useful in the design of preventive
treatment strategies for CIA through localized therapy without compromising the chemotherapy efficacy. 相似文献
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This study investigated the utility of a 23 factorial design and optimization process for polylactic-co-glycolic acid (PLGA) nanoparticles containing itraconazole with
5 replicates at the center of the design. Nanoparticles were prepared by solvent displacement technique with PLGAX
1 (10, 100 mg/mL), benzyl benzoateX
2 (5, 20 μg/mL), and itraconazoleX
3 (200, 1800 μg/mL). Particle size (Y
1), the amount of itraconazole entrapped in the nanoparticles (Y
2), and encapsulation efficiency (Y
3) were used as responses. A validated statistical model having significant coefficient figures (P<.001) for the particle size (Y
1), the amount of itraconazole entrapped in the nanoparticles (Y
2), and encapsulation efficiency (Y
3) as function of the PLGA (X
1), benzyl benzoate (X
2), and itraconazole (X
3) were developed: Y1=373.75+66.54X1+52.09X2+105.06X3−4.73X1X2+46.30X1X3; Y2=472.93+73.45X1+ 169.06X2+333.03X3+62.40X1X3+141.49X2X3; Y3= 57.36+6.53X1+15.52X2−12.59X3+1.01X1X3+ 1.73X2X3.X
1,X
2, andX
3 had a significant effect (P<.001) onY
1,Y
2, andY
3. The particle size, the amount of itraconazole entrapped in the nanoparticles, and the encapsulation efficiency of the 4
formulas were in agreement with the predictions obtained from the models (P<.05). An overlay plot for the 3 responses shows the boundary in whichY
1 shows the boundary in which a number of combinations of concentration of PLGA, benzyl benzoate, and itraconazole will result
in a satisfactory process. Using the desirability approach with the same constraints, the solution composition having the
highest overall desirability (D=0.769) was 10 mg/mL of PLGA, 16.94 μg/mL of benzyl benzoate, and 1001.01 μg/mL of itraconazole.
This approach allowed the selection of the optimum formulation ingredients for PLGA nanoparticles containing itraconazole
of 500 μg/mL. 相似文献
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Chanvorachote P Nimmannit U Wang L Stehlik C Lu B Azad N Rojanasakul Y 《The Journal of biological chemistry》2005,280(51):42044-42050
Stimulation of cell surface Fas (CD95) results in recruitment of cytoplasmic proteins and activation of caspase-8, which in turn activates downstream effector caspases leading to programmed cell death. Nitric oxide (NO) plays a key role in the regulation of apoptosis, but its role in Fas-induced cell death and the underlying mechanism are largely unknown. Here we show that stimulation of the Fas receptor by its ligand (FasL) results in rapid generation of NO and concomitant decrease in cellular FLICE inhibitory protein (FLIP) expression without significant effect on Fas and Fas-associated death domain (FADD) adapter protein levels. FLIP down-regulation as well as caspase-8 activation and apoptosis induced by FasL were all inhibited by the NO-liberating agent sodium nitroprusside and dipropylenetriamine NONOate, whereas the NO synthase inhibitor aminoguanidine and NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (PTIO) had opposite effects, indicating an anti-apoptotic role of NO in the Fas signaling process. FasL-induced down-regulation of FLIP is mediated by a ubiquitin-proteasome pathway that is negatively regulated by NO. S-nitrosylation of FLIP is an important mechanism rendering FLIP resistant to ubiquitination and proteasomal degradation by FasL. Deletion analysis shows that the caspase-like domain of FLIP is a key target for S-nitrosylation by NO, and mutations of its cysteine 254 and cysteine 259 residues completely inhibit S-nitrosylation, leading to increased ubiquitination and proteasomal degradation of FLIP. These findings indicate a novel pathway for NO regulation of FLIP that provides a key mechanism for apoptosis regulation and a potential new target for intervention in death receptor-associated diseases. 相似文献
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Preparation of alginate nanocapsules containing turmeric oil 总被引:4,自引:0,他引:4
Pranee Lertsutthiwong Khanittha Noomun Nutthapon Jongaroonngamsang Pornchai Rojsitthisak Ubonthip Nimmannit 《Carbohydrate polymers》2008,74(2):209-214
To encapsulate turmeric oil, a model oily compound, with an alginate biopolymer coating, alginate nanocapsules were prepared in a three-step procedure using emulsification, crosslinking with calcium chloride, and solvent removal. The type of solvent, concentration of turmeric oil, sonication, and oil/alginate mass ratio affected the characteristics of the nanocapsules in terms of average size, zeta potential, morphology, loading capacity, and stability at 4 °C and 25 °C. Dissolution of turmeric oil in ethanol and presence of Tween 80® in the formulation were found to be optimal in the preparation process. An increase in the oil concentration or oil/alginate mass ratio resulted in an increase in the average size of the nanocapsules. To obtain uniform-sized nanocapsules, sonication is required. In addition, alginate nanocapsules show good physical stability in long-term storage at 4 °C and data on loss of oil in key steps in the process may facilitate improvement in the procedure to produce an increased loading capacity. 相似文献
10.
The interaction mechanism between lipopeptide (daptomycin) and polyamidoamine (PAMAM) dendrimers
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Boontarika Chanvorachote Jiang Qiu Walaisiri Muangsiri Ubonthip Nimmannit Lee E. Kirsch 《Journal of peptide science》2015,21(4):312-319
The interaction mechanism of lipopeptide antibiotic daptomycin and polyamidoamine (PAMAM) dendrimers was studied using fluorescence spectroscopy. The fluorescence changes observed are associated with daptomycin–dendrimer interactions. The binding isotherms were constructed by plotting the fluorescence difference at 460 nm from kynurenine (Kyn‐13) of daptomycin in the presence and absence of dendrimer. A one‐site and two‐site binding model were quantitatively generated to estimate binding capacity and affinity constants from the isotherms. The shape of the binding isotherm and the dependence of the estimated capacity constants on dendrimer sizes and solvent pH values provide meaningful insight into the mechanism of interactions. A one‐site binding model adequately describes the binding isotherm obtained under a variety of experimental conditions with dendrimers of various sizes in the optimal binding pH region 3.5 to 4.5. Comparing the pH‐dependent binding capacity with the ionization profiles of daptomycin and dendrimer, the ionized aspartic acid residue (Asp‐9) of daptomycin primarily interact with PAMAM cationic surface amine. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd. 相似文献