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Zheng X Chu F Chou PM Gallati C Dier U Mirkin BL Mousa SA Rebbaa A 《American journal of physiology. Cell physiology》2009,296(1):C65-C74
Cathepsin L is a lysosomal enzyme thought to play a key role in malignant transformation. Recent work from our laboratory has demonstrated that this enzyme may also regulate cancer cell resistance to chemotherapy. The present study was undertaken to define the relevance of targeting cathepsin L in the suppression of drug resistance in vitro and in vivo and also to understand the mechanism(s) of its action. In vitro experiments indicated that cancer cell adaptation to increased amounts of doxorubicin over time was prevented in the presence of a cathepsin L inhibitor, suggesting that inhibition of this enzyme not only reverses but also prevents the development of drug resistance. The combination of the cathepsin L inhibitor with doxorubicin also strongly suppressed the proliferation of drug-resistant tumors in nude mice. An investigation of the underlying mechanism(s) led to the finding that the active form of this enzyme shuttles between the cytoplasm and nucleus. As a result, its inhibition stabilizes and enhances the availability of cytoplasmic and nuclear protein drug targets including estrogen receptor-alpha, Bcr-Abl, topoisomerase-IIalpha, histone deacetylase 1, and the androgen receptor. In support of this, the cellular response to doxorubicin, tamoxifen, imatinib, trichostatin A, and flutamide increased in the presence of the cathepsin L inhibitor. Together, these findings provided evidence for the potential role of cathepsin L as a target to suppress cancer resistance to chemotherapy and uncovered a novel mechanism by which protease inhibition-mediated drug target stabilization may enhance cellular visibility and, thus, susceptibility to anticancer agents. 相似文献
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Cysteine protease gene expression and proteolytic activity during senescence of Alstroemeria petals. 总被引:3,自引:0,他引:3
Carol Wagstaff Michael K Leverentz Gareth Griffiths Brian Thomas Usawadee Chanasut Anthony D Stead Hilary J Rogers 《Journal of experimental botany》2002,53(367):233-240
The functional life of the flower is terminated by senescence and/or abscission. Multiple processes contribute to produce the visible signs of petal wilting and inrolling that typify senescence, but one of the most important is that of protein degradation and remobilization. This is mediated in many species through protein ubiquitination and the action of specific protease enzymes. This paper reports the changes in protein and protease activity during development and senescence of Alstroemeria flowers, a Liliaceous species that shows very little sensitivity to ethylene during senescence and which shows perianth abscission 8-10 d after flower opening. Partial cDNAs of ubiquitin (ALSUQ1) and a putative cysteine protease (ALSCYP1) were cloned from Alstroemeria using degenerate PCR primers and the expression pattern of these genes was determined semi-quantitatively by RT-PCR. While the levels of ALSUQ1 only fluctuated slightly during floral development and senescence, there was a dramatic increase in the expression of ALSCYP1 indicating that this gene may encode an important enzyme for the proteolytic process in this species. Three papain class cysteine protease enzymes showing different patterns of activity during flower development were identified on zymograms, one of which showed a similar expression pattern to the cysteine protease cDNA. 相似文献
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Onanong Nuchuchua Usawadee Sakulku Napaporn Uawongyart Satit Puttipipatkhachorn Apinan Soottitantawat Uracha Ruktanonchai 《AAPS PharmSciTech》2009,10(4):1234-1242
The nanoemulsions composed of citronella oil, hairy basil oil, and vetiver oil with mean droplet sizes ranging from 150 to
220 nm were prepared and investigated both in vitro and in vivo. Larger emulsion droplets (195–220 nm) shifted toward a smaller size (150–160 nm) after high-pressure homogenization and
resulted in higher release rate. We proposed that thin films obtained from the nanoemulsions with smaller droplet size would
have higher integrity, thus increasing the vaporization of essential oils and subsequently prolonging the mosquito repellant
activity. The release rates were fitted with Avrami’s equations and n values were in the same range of 0.6 to 1.0, implying that the release of encapsulated limonene was controlled by the diffusion
mechanism from the emulsion droplet. By using high-pressure homogenization together with optimum concentrations of 5% (w/w) hairy basil oil, 5% (w/w) vetiver oil (5%), and 10% (w/w) citronella oil could improve physical stability and prolong mosquito protection time to 4.7 h due to the combination of
these three essential oils as well as small droplet size of nanoemulsion. 相似文献
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Usawadee Dier Dong-Hui Shin L. P. Madhubhani P. Hemachandra Larissa M. Uusitalo Nadine Hempel 《PloS one》2014,9(5)
Epithelial ovarian cancer (EOC) is the most lethal of all gynecological cancers, and encompasses distinct histological subtypes that have specific genetic and tissues-of-origin differences. Ovarian clear cell carcinoma (OCCC) represents approximately 10% of cases and has been termed a stress responsive cancer. OCCC is characterized by increased expression of oxidative stress and glycolysis-related genes. In the present study, we hypothesized that bioenergetic profiling might uniquely distinguish OCCC from other EOC histological subtypes. Using an extracellular flux analyzer, OCCC lines (ES-2, TOV-21-G) were shown to be highly metabolically active, with high oxygen consumption rate (OCR) and high extracellular acidification rate (ECAR), indicative of enhanced mitochondrial oxidative phosphorylation and glycolytic rate, respectively. A high bioenergetics profile was associated with the cell lines'' ability to form anchorage independent spheroids. Given their high glycolytic and mitochondrial activity, OCCC cells displayed strong sensitivity to 2-deoxy-D-glucose and Rotenone growth inhibition, although this chemosensitivity profile was not specific to only OCCC cells. Bioenergetic profiling also identified a non-OCCC cell line, OVCA420, to have severely compromised mitochondrial function, based on low OCR and a lack of stimulation of maximal respiration following application of the uncoupler FCCP. This was accompanied by mitochondrial morphology changes indicative of enhanced fission, increased expression of the mitochondrial fission protein Drp1, a loss of mitochondrial membrane potential and dependence on glycolysis. Importantly, this loss of mitochondrial function was accompanied by the inability of OVCA420 cells to cope with hypoxic stress, and a compromised ability to stabilize HIF-1α in response to 1% O2 hypoxia. This knowledge may be imperative for researchers planning to utilize this cell line for further studies of metabolism and hypoxia, and suggests that altered mitochondrial fission dynamics represents a phenotype of a subpopulation of EOCs. 相似文献
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Uracha Ruktanonchai Piyawan Bejrapha Usawadee Sakulkhu Praneet Opanasopit Nuntavan Bunyapraphatsara Varaporn Junyaprasert Satit Puttipipatkhachorn 《AAPS PharmSciTech》2009,10(1):227-234
Exogenously supplied alpha-lipoic acid (LA) has proven to be effective as an antioxidant. In an effort to develop a water-soluble
formulation for topical administration, LA was formulated in the form of solid lipid nanoparticles (SLN), nanostructure lipid
carriers (NLC), and nanoemulsion (NE) and characterized in terms of physical and biological properties. Mean particle size
of 113, 110, and 121 nm were obtained for NE, NLC, and SLN, respectively, with narrow size distribution. Zeta potential was
approximately in the range of −25 to −40 mV. Disc and spherical structures of nanoparticles were observed by cryo-scanning
electron microscopy. Entrapment efficiency of LA in three formulations was found to be more than 70%. After 120 days of storage
at 25°C, physical stability of all formulations remained unchanged whereas the entrapment efficiency of SLN and NLC could
be maintained, suggesting relative long-term stability. Prolonged release of LA formulation following the Higuchi model was
found where a faster release was observed from NE compared with that of SLN and NLC. More than 80% of cell survivals were
found up to 1 μM of LA concentrations. Antioxidant activity analysis demonstrated that all LA-loaded formulations expressed
antioxidant activity at a similar magnitude as pure LA. These results suggest that chosen compositions of lipid nanoparticles
play an important role on drug loading, stability, and biological activity of nanoparticles. Both SLN and NLC demonstrated
their potential as alternative carriers for aqueous topical administration of LA. 相似文献
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Characterization of a novel lipoxygenase-independent senescence mechanism in Alstroemeria peruviana floral tissue 总被引:3,自引:0,他引:3
Leverentz MK Wagstaff C Rogers HJ Stead AD Chanasut U Silkowski H Thomas B Weichert H Feussner I Griffiths G 《Plant physiology》2002,130(1):273-283
The role of lipoxygenase (lox) in senescence of Alstroemeria peruviana flowers was investigated using a combination of in vitro assays and chemical profiling of the lipid oxidation products generated. Phospholipids and galactolipids were extensively degraded during senescence in both sepals and petals and the ratio of saturated/unsaturated fatty acids increased. Lox protein levels and enzymatic activity declined markedly after flower opening. Stereochemical analysis of lox products showed that 13-lox was the major activity present in both floral tissues and high levels of 13-keto fatty acids were also synthesized. Lipid hydroperoxides accumulated in sepals, but not in petals, and sepals also had a higher chlorophyll to carotenoid ratio that favors photooxidation of lipids. Loss of membrane semipermeability was coincident for both tissue types and was chronologically separated from lox activity that had declined by over 80% at the onset of electrolyte leakage. Thus, loss of membrane function was not related to lox activity or accumulation of lipid hydroperoxides per se and differs in these respects from other ethylene-insensitive floral tissues representing a novel pattern of flower senescence. 相似文献
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