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Involvement of different protein kinases and phospholipases A2 in phorbol ester (TPA)-induced arachidonic acid liberation in bovine platelets  [PDF]
M. Lehr,K. Griessbach
Mediators of Inflammation , 2000, DOI: 10.1080/09629350050024357
Abstract: The effect of various phospholipase A2 and protein kinase inhibitors on the arachidonic acid liberation in bovine platelets induced by the protein kinase activator 12-O-tetradecanoylphorbol–13-acetate (TPA) was studied. TPA stimulates arachidonic acid release mainly by activating group IV cytosolic PLA2 (cPLA2), since inhibitors of this enzyme markedly inhibited arachidonic acid formation. However, group VI Ca2
Nordihydroguaiaretic Acid from Creosote Bush (Larrea tridentata) Mitigates 12-O-Tetradecanoylphorbol-13-Acetate-Induced Inflammatory and Oxidative Stress Responses of Tumor Promotion Cascade in Mouse Skin
Shakilur Rahman,Rizwan Ahmed Ansari,Hasibur Rehman,Suhel Parvez,Sheikh Raisuddin
Evidence-Based Complementary and Alternative Medicine , 2011, DOI: 10.1093/ecam/nep076
Abstract: Nordihydroguaiaretic acid (NDGA) is a phenolic antioxidant found in the leaves and twigs of the evergreen desert shrub, Larrea tridentata (Sesse and Moc. ex DC) Coville (creosote bush). It has a long history of traditional medicinal use by the Native Americans and Mexicans. The modulatory effects of topically applied NDGA was studied on acute inflammatory and oxidative stress responses in mouse skin induced by stage I tumor promoting agent, 12-O-tetradecanoylphorbol-13-acetate (TPA). Double TPA treatment adversely altered many of the marker responses of stage I skin tumor promotion cascade. Pretreatment of NDGA in TPA-treated mice mitigated cutaneous lipid peroxidation and inhibited production of hydrogen peroxide. NDGA treatment also restored reduced glutathione level and activities of antioxidant enzymes. Elevated activities of myeloperoxidase, xanthine oxidase and skin edema formation in TPA-treated mice were also lowered by NDGA indicating a restrained inflammatory response. Furthermore, results of histological study demonstrated inhibitory effect of NDGA on cellular inflammatory responses. This study provides a direct evidence of antioxidative and anti-inflammatory properties of NDGA against TPA-induced cutaneous inflammation and oxidative stress corroborating its chemopreventive potential against skin cancer.
Role of JWA in acute promyelocytic leukemia cell differentiation and apoptosis triggered by retinoic acid, 12-tetradecanoylphorbol-13-acetate and arsenic trioxide
Haixia Cao,Wei Xia,Qun Shen,Hua Lu,Jian Ye,Aiping Li,Changping Zou,Jianwei Zhou
Chinese Science Bulletin , 2002, DOI: 10.1360/02tb9188
Abstract: JWA, a cytoskeleton associated gene, was primarily found to be regulated by all trans-retinoic acid (ATRA), 13 cis-retinoic acid (13 cis-RA) and 12-tetradecanoylphorbol-13-acetate (TPA). Our previous data showed that JWA might be involved in both cellular differentiation and apoptosis induced by several chemicals. In this study, we addressed the possible mechanism of JWA in the regulation of cell differentiation and apoptosis in NB4, a human acute promyelocytic leukemia cell line. CD11b/CD33 expression and cell cycle were analyzed for detecting of cell differentiation and apoptosis. Both reverse-transcription polymerase chain reaction (RT-PCR) and Western blot assays were used for understanding the expressions of JWA. The results showed that under the indicated concentrations ATRA (10 6 mol/L) and AS2O3 (10 6 mol/L) induced cell differentiation and apoptosis separately; while both 4HPR (10 6 mol/L) and TPA (10 7 mol/L) showed dual-directional effects on NB4 cells, they not only trigger cells’ differentiation but also induce cells apoptosis at the same time. All chemicals up-regulated JWA expression whatever they trigger cells either differentiation or apoptosis; however, it seems that the chemicals have no effect on PML/RARα in the treated NB4 cells. Anti-sense JWA oligonucleotide could partially block the ability of TPA in inducing cell differentiation and apoptosis via direct signal pathway. Interestingly, a high molecular weight JWA protein (JWAF) was identified only in de novo primary APL cells and it was also responsible for ATRA treatment. It raises questions of whether the JWAF is a novel APL specific marker and, how it was involved in the known mechanism of APL.
ngal基因新型tpa反应元件结合蛋白的研究  [PDF]
孟令英?,缪成贵?,杜则澎?,蔡唯佳?,许丽艳?,李恩民?
生物化学与生物物理进展 , 2008,
Abstract: 以往研究发现,食管癌细胞的中性粒细胞明胶酶相关脂质运载蛋白(neutrophilgelatinase-associatedlipocalin,ngal)基因的过表达具有明显的12-o-十四烷酰佛波醇-13-醋酸酯(12-o-tetradecanoylphorbol-13-acetate,tpa)诱导性,在启动子-152~-60区段存在着一种新型的tpa反应元件(tparesponseelement,tre),但是该元件的结合蛋白尚未被鉴定出来.采用寡核苷酸dna亲和层析法(oligonucleotidetrapping)从食管癌细胞中分离纯化了ngal基因tre结合蛋白;经sds-page进一步分离,银染显示目标蛋白带.人工切取各目标蛋白带进行maldi-tof-ms分析,通过mascot软件搜索ncbi数据库,根据蛋白质的功能、细胞定位和分子质量大小等指标确定8个核蛋白因子:c19、kiaa1949、tdrd1、rxrβ、fam54a、klf15、klf10和yy-1.最后,利用rt-pcr验证了这些核蛋白因子表达的tpa反应性,结果表明c19、kiaa1949、tdrd1、rxrβ和klf15等编码基因的转录表现出了明显的tpa反应性,提示可能是食管癌细胞中应答tpa刺激,参与ngal基因过表达的转录激活因子.
Enhancing Endosomal Escape of Transduced Proteins by Photochemical Internalisation  [PDF]
Kevin Mellert, Markus Lamla, Klaus Scheffzek, Rainer Wittig, Dieter Kaufmann
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0052473
Abstract: Induced internalisation of functional proteins into cultured cells has become an important aspect in a rising number of in vitro and in vivo assays. The endo-lysosomal entrapment of the transduced proteins remains the major problem in all transduction protocols. In this study we compared the efficiency, cytotoxicity and protein targeting of different commercially available transduction reagents by transducing a well-studied fluorescently labelled protein (Atto488-bovine serum albumin) into cultured human sarcoma cells. The amount of internalised protein and toxicity differed between the different reagents, but the percentage of transduced cells was consistently high. Furthermore, in all protocols the signals of the transduced Atto488-BSA were predominantly punctual consistent with an endosomal localisation. To overcome the endosomal entrapment, the transduction protocols were combined with a photochemical internalisation (PCI) treatment. Using this combination revealed that an endosomal disruption is highly effective in cell penetrating peptide (CPP) mediated transduction, whereas lipid-mediated transductions lead to a lower signal spreading throughout the cytosol. No change in the signal distribution could be achieved in treatments using non-lipid polymers as a transduction reagent. Therefore, the combination of protein transduction protocols based on CPPs with the endosomolytic treatment PCI can facilitate protein transduction experiments in vitro.
tpa完成临床试验  [PDF]
邹福强
中国生物工程杂志 , 1987,
Abstract: 经美国国家卫生院(nih)批准,genentech公司进行了tpa(tissueplasminogenactivator,血纤蛋白溶酶原激活剂)的试验。试验报告说,tpa能溶解三分之二以上心脏病患者的凝块;而通常使用的链激酶(st-eptokinase)只能溶解37%病人的凝块。
Topical anti-inflammatory activity of Calea prunifolia HBK (Asteraceae) in the TPA model of mouse ear inflammation
Gómez, Milton;Gil, Juan F.;
Journal of the Brazilian Chemical Society , 2011, DOI: 10.1590/S0103-50532011001200021
Abstract: phytochemical study of calea prunifolia hbk identified two compounds derived from p-hydroxyacetophenone, the 1-(2-hydroxy-5-(1-methoxyethyl)phenyl)-3-methylbut-2 -en-1-one showed a satisfactory anti-inflammatory activity (58.33%), when considering that this is a natural product. although the two derived compounds are structurally similar, the anti-inflammatory activity of 1-(2-hydroxy-5-methoxyphenyl)-3-methylbut-2-en-1-one was not significant (2.08%). the test was conducted in a model of inflammation induced by topical application of 12-o-tetradecanoylphorbol-13-acetate (tpa) in the ear of mice. the positive control was tested with indomethacin and the negative control was done only with vehicle. these results allow the identification of a pharmacophore group that through molecular modeling studies and organic synthesis can result in compounds with improved anti-inflammatory activity.
Inhibition of HIV derived lentiviral production by TAR RNA binding domain of TAT protein
Michael Y Mi, Jiying Zhang, Yukai He
Retrovirology , 2005, DOI: 10.1186/1742-4690-2-71
Abstract: We synthesized a short peptide named Tat-P, which contained the TAR RNA binding and PTD domains to examine whether the peptide has the potential of inhibiting TAT dependent HIV replication. We investigated the inhibiting effects of Tat-P in vitro using a HIV derived lentiviral vector model. We found that the TAT PTD domain not only efficiently transduced test cells, but also effectively inhibited the production of lentiviral particles in a TAT dependent manner. These results were also supported by data derived from the TAT activated LTR-luciferase expression model and RNA binding assays.Tat-P may become part of a category of anti-HIV drugs that competes with full length TAT proteins to inhibit HIV replication. In addition, this study indicates that the HIV derived lentiviral vector system is a safe and reliable screening method for anti-HIV drugs, especially for those targeting the interaction of TAT and TAR RNAs.The HIV TAT protein is a key regulator of viral replication [1]. Binding of the TAT protein to the TAR element, a 59 nt sequence at the 5' end of nascent RNA, is the first critical step for producing full length HIV RNA. The transcription of HIV RNA from both integrated and non-integrated HIV genome is dependent on TAT protein [2]. Thus, interruption of this TAT-TAR interaction has been considered as a possible way to inhibit HIV replication [3]. TAR RNA decoys have been shown to be able to interfere with the binding of TAT proteins to native TAR elements, thus inhibiting HIV replication [4-6]. However, delivery of oligonucleotides in vivo is not trivial. Conversely, small synthetic substances, or short TAT peptides mimicking the TAT and TAR RNA binding domains have been shown to be promising inhibitors of HIV replication [7,8]. Furthermore, a different fragment of the TAT protein could compete for the binding site of the CXCR4 receptor on T cells and inhibit HIV entry [9]. Recently, several research groups have identified the TAR RNA binding domain of the
Functional Substitution by TAT-Utrophin in Dystrophin-Deficient Mice  [PDF]
Kevin J. Sonnemann,Hanke Heun-Johnson,Amy J. Turner,Kristen A. Baltgalvis,Dawn A. Lowe,James M. Ervasti
PLOS Medicine , 2009, DOI: 10.1371/journal.pmed.1000083
Abstract: Background The loss of dystrophin compromises muscle cell membrane stability and causes Duchenne muscular dystrophy and/or various forms of cardiomyopathy. Increased expression of the dystrophin homolog utrophin by gene delivery or pharmacologic up-regulation has been demonstrated to restore membrane integrity and improve the phenotype in the dystrophin-deficient mdx mouse. However, the lack of a viable therapy in humans predicates the need to explore alternative methods to combat dystrophin deficiency. We investigated whether systemic administration of recombinant full-length utrophin (Utr) or ΔR4-21 “micro” utrophin (μUtr) protein modified with the cell-penetrating TAT protein transduction domain could attenuate the phenotype of mdx mice. Methods and Findings Recombinant TAT-Utr and TAT-μUtr proteins were expressed using the baculovirus system and purified using FLAG-affinity chromatography. Age-matched mdx mice received six twice-weekly intraperitoneal injections of either recombinant protein or PBS. Three days after the final injection, mice were analyzed for several phenotypic parameters of dystrophin deficiency. Injected TAT-μUtr transduced all tissues examined, integrated with members of the dystrophin complex, reduced serum levels of creatine kinase (11,290±920 U versus 5,950±1,120 U; PBS versus TAT), the prevalence of muscle degeneration/regeneration (54%±5% versus 37%±4% of centrally nucleated fibers; PBS versus TAT), the susceptibility to eccentric contraction-induced force drop (72%±5% versus 40%±8% drop; PBS versus TAT), and increased specific force production (9.7±1.1 N/cm2 versus 12.8±0.9 N/cm2; PBS versus TAT). Conclusions These results are, to our knowledge, the first to establish the efficacy and feasibility of TAT-utrophin-based constructs as a novel direct protein-replacement therapy for the treatment of skeletal and cardiac muscle diseases caused by loss of dystrophin.
Mitochondrial Uncoupling Inhibits p53 Mitochondrial Translocation in TPA-Challenged Skin Epidermal JB6 Cells  [PDF]
Fei Wang,Xueqi Fu,Xia Chen,Xinbin Chen,Yunfeng Zhao
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013459
Abstract: The tumor suppressor p53 is known to be able to trigger apoptosis in response to DNA damage, oncogene activation, and certain chemotherapeutic drugs. In addition to its transcriptional activation, a fraction of p53 translocates to mitochondria at the very early stage of apoptosis, which eventually contributes to the loss of mitochondrial membrane potential, generation of reactive oxygen species (ROS), cytochrome c release, and caspase activation. However, the mitochondrial events that affect p53 translocation are still unclear. Since mitochondrial uncoupling has been suggested to contribute to cancer development, herein, we studied whether p53 mitochondrial translocation and subsequent apoptosis were affected by mitochondrial uncoupling using chemical protonophores, and further verified the results using a siRNA approach in murine skin epidermal JB6 cells. Our results showed that mitochondrial uncoupling blocked p53 mitochondrial translocation induced by 12-O-tetradecanoylphorbol 13-acetate (TPA), a known tumor promoter to induce p53-mediated apoptosis in skin carcinogenesis. This blocking effect, in turn, led to preservation of mitochondrial functions, and eventually suppression of caspase activity and apoptosis. Moreover, uncoupling protein 2 (UCP2), a potential suppressor of ROS in mitochondria, is important for TPA-induced cell transformation in JB6 cells. UCP2 knock down cells showed enhanced p53 mitochondrial translocation, and were less prone to form colonies in soft agar after TPA treatment. Altogether, our data suggest that mitochondrial uncoupling may serve as an important regulator of p53 mitochondrial translocation and p53-mediated apoptosis during early tumor promotion. Therefore, targeting mitochondrial uncoupling may be considered as a novel treatment strategy for cancer.
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