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Mutni, A. N. "Effects on anti-hyperlipidaemic drugs on the liver". Thesis, Bucks New University, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.382585.
Pełny tekst źródłaSilberstein, D. J. "The effect of renal failure on the elimination of drugs by the liver". Thesis, University of Leeds, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.379649.
Pełny tekst źródłaTeng, Shuzhi, i 滕曙智. "Hepatocellular injury induced by endotoxin and galactosamine". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2000. http://hub.hku.hk/bib/B31241037.
Pełny tekst źródłaAbumansour, Hamza M. A. "Quantitative pharmacoproteomics investigation of anti-cancer drugs in mouse : development and optimisation of proteomics workflows for evaluating the effect of anti-cancer drugs on mouse liver". Thesis, University of Bradford, 2016. http://hdl.handle.net/10454/15724.
Pełny tekst źródłaKassahun, Kelem. "Mechanistic studies of valproic acid hepatotoxicity : identification and characterization of thiol conjugates". Thesis, University of British Columbia, 1991. http://hdl.handle.net/2429/30831.
Pełny tekst źródłaPharmaceutical Sciences, Faculty of
Graduate
Rodgers, Amie D. Rusyn Ivan. "Modeling adverse liver effects of drugs using kNN QSAR method". Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2009. http://dc.lib.unc.edu/u?/etd,2463.
Pełny tekst źródłaTitle from electronic title page (viewed Sep. 3, 2009). "... in partial fulfillment of the requirements for the degree of Masters of Sciences in the School of Medicine Toxicology." Discipline: Toxicology; Department/School: Medicine.
Stevens, Jeffrey Charles 1963. "Selective inactivation of four rat liver microsomal androstenedione hydroxylases by chloramphenicol analogs". Thesis, The University of Arizona, 1988. http://hdl.handle.net/10150/276700.
Pełny tekst źródłaAbdelhadi, Mohamed Mohamed. "Posttransplantation bone disease : the effect of immunosuppressive drugs on bone: clinical and experimental studies /". Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-384-8/.
Pełny tekst źródłaSiebert, Gerhard A. "Disposition pharmacokinetics and effects of solutes and drugs in perfused organ systems /". [St. Lucia, Qld.], 2004. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe18644.pdf.
Pełny tekst źródłaNicholls-Grzemski, Felicity April. "The effect of short-term pretreatment with peroxisome proliferators on the acute toxicity of various toxicants, including paracetamol /". Title page, table of contents and abstract only, 1998. http://web4.library.adelaide.edu.au/theses/09PH/09phn6158.pdf.
Pełny tekst źródłaVaino, Andrew Rein. "Synthesis of agents for the targeting of drugs to the human liver and elucidation of the reverse anomeric effect". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ31959.pdf.
Pełny tekst źródłaWeng, Yu-I. "Acute and chronic ethanol effects on liver p42/44 mitogen activated protein kinase". free to MU campus, to others for purchase, 2001. http://wwwlib.umi.com/cr/mo/fullcit?p3036867.
Pełny tekst źródłaPittaya, Kanchanapakonchai Amnuay Thithapandha. "Effects of vitamin B6 on CC14 toxicities in rats /". abstract, 1986. http://mulinet3.li.mahidol.ac.th/thesis/2529/29E-Pittaya-K.pdf.
Pełny tekst źródłaAllen, Portia SueAnn. "The effect of drugs and nutraceuticals on the prevention and treatment of non-alcoholic fatty liver disease using rats as a model for humans". [Ames, Iowa : Iowa State University], 2010. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:1476270.
Pełny tekst źródłaPlumb, Sarah. "The art of addiction : a phenomenological study of the lived experiences of cocaine dependents". Thesis, Nelson Mandela Metropolitan University, 2009. http://hdl.handle.net/10948/902.
Pełny tekst źródłaGronert, Álvarez Anna Christina [Verfasser], i Hans-Heinrich [Akademischer Betreuer] Wedemeyer. "Regulatory T cells in liver transplantation : phenotypical characterisation and effects of immunosuppressive drugs / Anna Christina Gronert Álvarez. Klinik für Gastroenterologie, Hepatologie und Endokrinologie der Medizinischen Hochschule Hannover. Betreuer: Hans-Heinrich Wedemeyer". Hannover : Bibliothek der Medizinischen Hochschule Hannover, 2014. http://d-nb.info/1050008200/34.
Pełny tekst źródłaVivas, Ana Paula Molina. "Avaliação de manifestações bucais em pacientes pediátricos submetidos ao transplante hepático". Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/23/23141/tde-13092012-112810/.
Pełny tekst źródłaIntroduction. Liver transplantation has become the main therapeutic option for the treatment of various liver diseases. Subsequent to transplantation, it is necessary to administer immunosuppressive treatment to avoid rejection of the graft. A dental evaluation is critical to eliminate or prevent the emergence of infectious foci. Moreover, it is necessary to monitor the side effects in the oral cavity related to the use of immunosuppressive drugs. Objectives. To evaluate the dental conditions prior to liver transplantation and to identify oral abnormalities presented after liver transplantation. Pacients and methods. A retrospective study of 265 pediatric patients who underwent liver transplantation at Hospital A.C. Camargo, São Paulo-SP, between January 2002 and December 2009 was performed. Clinical information such as age, gender, diagnosis of liver disease, date of transplantation, immunosuppressive therapy (type, dose and duration), dental treatment and oral changes after transplantation were collected from medical records. Statistical analysis was performed in order to establish relevant information about the risks and possible predictive factors for the development of oral manifestations. Results. The age at liver transplantation ranged from 3.5 to 210.7 months, with a median of 15.5 months. Of the 265 patients, 150 patients (56.6%) were female and 165 (62.3%) were Caucasian. Among the diseases, biliary atresia was the most frequent, with 170 (64.1%) patients. A total of 73 patients were evaluated by the Department of Stomatology prior to transplantation, and 34 (46.6%) children presented caries. Regarding the presence of tooth pigmentation caused by bilirubin, 172 patients were evaluated and out of these, 100 (58.1%) had pigmentation. Regarding the presence of enamel hypoplasia, the change was observed in 56 (34.4%) of 163 patients. Interestingly, of the 100 patients with bilirubin pigmented teeth, 97 had cholestatic diseases (p<0.001). Of the cases of enamel hypoplasia, 52 (92.9%) belonged to the group of cholestatic diseases (p<0.001). Several changes in the oral mucosa were found after transplantation, whereas 135 patients had some complication. Of the 265 patients studied, the main problem was herpes simplex virus infection, found in 48 patients and 66.7% of cases occurred after 12 months from transplantation. The second most common infectious disease was oral candidiasis, observed in 39 patients and 61.5% of cases occurred during the first six months post-transplant. Important oral abnormalities were found in patients using tacrolimus such as the hypertrophy of the lingual papillae, dry lips, swollen lips, fissured lips, fissured tongue, angular cheilitis, cobblestoning and loss of tongue papillae, observed in 45, 39, 39, 38, 27, 11 and 6 patients respectively. The drug-induced gingival overgrowth was observed in 13 patients, and 8 of them were taking cyclosporine, while all others were using tacrolimus in addition to calcium channel blockers. The post-transplant complication that occurred earlier in patients was lymphoproliferative disease, on average 5.2 months after transplantation. Conclusions. The rate of caries was high, reflecting poor oral health status of these patients. The bilirubin pigmentation of teeth and enamel hypoplasia are abnormalities associated with cholestatic diseases, although they may occur in patients with non-cholestatic diseases that present periods of cholestasis. The most common oral infectious lesions were caused by herpes simplex virus and candidiasis. The drug-induced gingival overgrowth is associated with the use of cyclosporin and calcium channel blockers, while tacrolimus does not appear to induce this effect. Oral alterations such as hypertrophy of the lingual papillae, fissured tongue, loss of tongue papillae, dry, swollen and fissured lips; angular cheilitis and cobblestoning were found in patients using tacrolimus and usually occured after 2 years from transplantation.
Mets, Berend. "Lignocaine extraction ratio and clearance as an indicator of hypoxic hepatic injury : a study using the in situ and the isolated perfused pig liver". Doctoral thesis, University of Cape Town, 1992. http://hdl.handle.net/11427/27152.
Pełny tekst źródłaHauton, David. "The effects of diet on drug metabolism in the rat". Thesis, University of Surrey, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.484200.
Pełny tekst źródłaTacon, Geoffrey Reginald Russell. "Mathematical modelling of liver kinetics /". [St. Lucia, Qld.], 2005. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe19399.pdf.
Pełny tekst źródłaNielsch, A. S. "Effects of prostaglandins and prostaglandin synthetase inhibitors on liver toxicity". Thesis, University of Aberdeen, 1987. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU499301.
Pełny tekst źródłaBradshaw, Jennifer Jean. "Isoflurane : interaction with hepatic microsomal enzymes". Doctoral thesis, University of Cape Town, 1992. http://hdl.handle.net/11427/27138.
Pełny tekst źródłaJokinen, Mika. "Effects of drug interactions and liver disease on the pharmacokinetics of ropivacaine". Helsinki : University of Helsinki, 2003. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/jokinen/.
Pełny tekst źródłaEng, Heather Sui-Fong. "Evaluating the use of cryopreserved hepatocytes for the prediction of in vivo hepatic clearance /". See Full Text at OhioLINK ETD Center (Requires Adobe Acrobat Reader for viewing), 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=toledo1091638312.
Pełny tekst źródłaTypescript. "A thesis [submitted] as partial fulfillment of the requirements of the Master of Science degree in Pharmaceutical Sciences." Bibliography: leaves 64-68.
Chang, Ping. "Quantitative evaluation of hepatic morphological alterations and pharmacokinetic changes of cationic drugs in fibrosis-inducing hepatic diseases /". St. Lucia, Qld, 2001. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16767.pdf.
Pełny tekst źródłaAnwar, Khurshid. "Role of apoptosis (programmed cell death) in acute liver failure". Thesis, University of Surrey, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.370058.
Pełny tekst źródłaYildirim, Pinar. "Acquisition Of Liver Specific Parasites-bacteria-drugs-diseases-genes Knowledge From Medline". Phd thesis, METU, 2011. http://etd.lib.metu.edu.tr/upload/12613143/index.pdf.
Pełny tekst źródłaCook, Andrew T. "The effect of accelerated aging on peelable medical products seals /". Online version of thesis, 1994. http://hdl.handle.net/1850/11980.
Pełny tekst źródłaWeise-Kelly, Lorraine Ann. "Drug-induced ataxia : effect of the self-administration contingency /". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0030/NQ66245.pdf.
Pełny tekst źródłaMcLure, James Alexander, i james mclure@flinders edu au. "Physicochemical determinants of the non-specific binding of drugs to human liver microsomes". Flinders University. Medicine, 2008. http://catalogue.flinders.edu.au./local/adt/public/adt-SFU20081102.165952.
Pełny tekst źródłaChang, Robert Chao Sun Wei. "Biofabrication of three-dimensional liver cell-embedded tissue constructs for in vitro drug metabolism models /". Philadelphia, Pa. : Drexel University, 2009. http://hdl.handle.net/1860/3069.
Pełny tekst źródłaBai, Shuang. "Effect of immunosuppressive agents on drug metabolism in rats". Thesis, Full text (PDF) from UMI/Dissertation Abstracts International, 2001. http://wwwlib.umi.com/cr/utexas/fullcit?p3008270.
Pełny tekst źródłaHammann, Felix. "Prediction of transport, pharmacokinetics, and effect of drugs /". Basel : [s.n.], 2009. http://edoc.unibas.ch/diss/DissB_8905.
Pełny tekst źródłaBaser, Deniz Fulya. "Characterization And Modulation By Drugs And Other Effectors Of Bovine Liver Microsomal Flavin Monooxygenase (fmo)". Master's thesis, METU, 2004. http://etd.lib.metu.edu.tr/upload/12604749/index.pdf.
Pełny tekst źródłaE.C.1.14.13.8) are microsomal NADPH and oxygen-dependent flavoprotein enzymes that catalyze the oxidation of a wide variety of xenobiotics, including drugs and environmental toxicants. Nucleophiles containing nitrogen, sulfur, phosphorus and selenium heteroatoms are the substrates of FMO. Bovine liver microsomal FMO enzyme activity was characterized using methimazole as substrate, which is a highly specific substrate for FMO. From 12 different bovine liver samples, microsomes were prepared and the average specific activity of bovine liver microsomal FMO was found to be 2.37 &
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0.30 nmol/min/mg (Mean &
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SE, n=12). The rate of reaction was linear up to 0.5 mg of bovine liver microsomal protein. The maximum FMO enzyme activity was detected at 37 &
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C and at pH 8.0. Effects of detergents
Triton X-100 and Emulgen 913, on FMO activity were determined and found that enzyme activity increased by the addition of either detergent at all concentrations (0.1%-1.0%). The apparent Vmax and Km values of bovine liver microsomal FMO for methimazole substrate were found as 1.23 nmol/min/mg and 0.11 mM, respectively. Thermostability of bovine liver microsomal FMO was studied at four different temperatures
24 &
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C, 37 &
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C, 50 &
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C and 65 &
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C. The incubation time required for the complete loss of enzyme activity was 5 minutes at 65 &
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C, 10 minutes at 50 &
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C and 6.5 hours at 37 &
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C. 68 % of the activity was still detectable at the end of 53 hours at 24 &
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C. Bovine liver microsomal activity towards two drug substrates, imipramine and chlorpromazine, was also determined and found to be 3.73 and 3.75 nmol NADPH oxidized/min/mg, respectively. Effects of two drug substrates, imipramine and chlorpromazine, on bovine liver microsomal FMO-catalyzed methimazole oxidation activity was also studied and found that they inhibit FMO activity at all concentrations studied. Modulation of bovine liver microsomal FMO activity was studied using three different heavy metal ions
Ni+2, Cd+2 and Hg+2. At all other concentrations studied for each heavy metal ion and at all substrate methimazole concentrations (0.1, 0.2, 0.5, 1.0 mM), FMO-catalyzed methimazole oxidation activity decreased compared to control activity. KI values for Ni+2, Cd+2 and Hg+2 were found to be 0.5 mM, 0.085 mM, 4.6 &
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M, respectively. From the Dixon plot, the pattern of inhibition for three heavy metal ions was observed to be noncompetitive.
Owoseni, Seun Emmanuel. "The Study of Alcoholic Liver Diseases". Digital Commons @ East Tennessee State University, 2018. https://dc.etsu.edu/etd/3493.
Pełny tekst źródłaMazza, Rosangela Passos de Jesus. "Influência da infusão parenteral de aminoácidos sobre a expressão gênica de fatores de crescimento de timidina quinase no remanescente hepático de ratos desnutridos". Universidade de São Paulo, 2004. http://www.teses.usp.br/teses/disponiveis/5/5160/tde-15102014-090956/.
Pełny tekst źródłaGlutamine dipeptide (Gln) improve hepatic regeneration of nourished rats. To evaluate molecular effect of Gln on liver remnant 52 rats was classified into: 1. Nourished with partial hepatectomy (PH) and Gln (N-Gln=10) or proline (N-Pro=10); 2. Malnourished (MN) with PH: (MN-Gln=10) or (MN-Pro=10); 3. Nourished and Malnourished rat without PH (N-Control=6) and (MN-Control=6). Results: DNA = (MN-Gln, MN-Pro and MN-Control < N-Gln, N-Pro and N-control), (N-Gln, N-Pro, MN-Gln and MN-Pro < N and MN-Control), (N-Gln > MN-Gln); RNA= (N-Gln, N-Pro, MN-Gln and MN-Pro < N and MN-Control), (N-Gln > MN-Gln and N-Pro). There was no difference on transcript genes (TG) for HGF, TGF-a and thymidine kinase. Conclusions: Malnutrition and PH decrease hepatic DNA and RNA; Gln does not modify TG studied 96 hours after PH in MN rats
McConnachie, Lisa A. "Effects of genotype and RNA expression on activity of cytochrome P450 2D6 : a highly polymorphic drug metabolizing enzyme /". Thesis, Connect to this title online; UW restricted, 2002. http://hdl.handle.net/1773/7973.
Pełny tekst źródłaHoa, Nguyen Khanh. "Assessment of anti-diabetic effect of Vietnamese herbal drugs /". Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-585-2/.
Pełny tekst źródłaElliott-Pearce, Ruth Ann. "The effect of drugs on isolated detrusor muscle contraction". Thesis, University of Leicester, 1996. http://hdl.handle.net/2381/34339.
Pełny tekst źródłaDalal, Suntanu. "Amphetamine drugs potentiate morphine analgesia in the formalin test". Thesis, McGill University, 1994. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=55488.
Pełny tekst źródłaTang, Chi-man Terence. "The effect of celecoxib on hepatocellular carcinoma". Click to view the E-thesis via HKUTO, 2005. http://sunzi.lib.hku.hk/hkuto/record/B35774393.
Pełny tekst źródłaLui, Lik-hang Eric. "The effect of AMN107 on hepatocellular carcinoma". Click to view the E-thesis via HKUTO, 2007. http://sunzi.lib.hku.hk/HKUTO/record/B39557248.
Pełny tekst źródłaTeran, Claudia. "Efficacy and Mechanism of Action of a Novel Class of Antic-Cancer Drugs". Thesis, Université d'Ottawa / University of Ottawa, 2016. http://hdl.handle.net/10393/34412.
Pełny tekst źródłaXia, Ying. "Risk of Acute Liver Injury Associated with the Use of Orlistat: Cohort and Self-Controlled Case Series Studies Using the MarketScan® Commercial Claims Database". University of Cincinnati / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1490354985131296.
Pełny tekst źródłaTannuri, Ana Cristina Aoun. "Modelos de regeneração hepática em animais em crescimento: estudos histológicos, moleculares e avaliação de efeitos de imunossupressores". Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/5/5132/tde-19082007-113440/.
Pełny tekst źródłaINTRODUCTION: Partial liver transplantation has been performed in children with increasing frequency, and this emphasizes the importance of the studies of hepatic regeneration and the effects of immunosuppressive drugs on this phenomenon. Liver regeneration is controlled by the balance between cell proliferation and apoptosis (defined as a programmed cell death that results from the expression of pro-apoptotic genes - Bax and Bak - and anti-apoptotic genes - Bcl-2 and Bcl-XL). Among proteins related to hepatocyte proliferation, interleukin-6 is an important one. Although the adult rat model of 70% hepatectomy has been widely utilized for studies of liver regeneration, there are no studies using growing animals. METHODS: In the current paper, two experimental models were created utilizing newborn and weaning rats: using a cotton thread, the vascular hilum and the hepatic vein were ligated and the left lateral, left medial and right medial lobes were resected. The remaining liver was immediately harvested and weighted to be compared to control livers. The animals were sacrificed on days 1, 2, 3, 4, and 7 after the operation, the remnant livers were weighted and harvested for histological examinations. Then, 36 animals (18 newborn and 18 weaning animals) were divided into the following groups: control, sham and hepatectomy. One day after, the expressions of IL-6 gene, pro-apoptotic and anti-apoptotic genes were studied in the remnant livers. Immunohistochemical stainings for cell antigens related to cell proliferation (PCNA) and apoptosis (TUNEL) were also performed utilizing tissue microarray sections. In another group of 36 animals (18 newborn and 18 weaning animals), immunosuppressive drugs were administered just after the hepatectomy (methylprednisolone, cyclosporine A or tacrolimus separately), and the remnant liver submitted to the same molecular and immunohistochemical studies. RESULTS: The resected liver corresponded to 70% of the total liver weight. The mortality rates after hepatectomy were 30% and 0% for newborn and weaning rats, respectively. The histological examinations showed a great number of mitoses of hepatocytes on the third day in newborns and on the second day in weaning rats, and normalization of histological aspects by 7 days after hepatectomy and weight recuperation. In the newborn group liver regeneration was related to an intense steatosis. Hepatectomy promoted an increase in the expression of IL-6 gene of the remnant liver, a decreased expression of pro-apoptotic genes in both models, and an increased expression of anti-apoptotic Bcl-2 gene in weaning rats. The study of the effects of immunosuppressants showed different results from those described in adult animals, with no alterations in the number of cells in proliferation (PCNA positive) and apoptosis (TUNEL positive). Drugs had no effect in expression of IL-6 gene. Methylprednisolone and tacrolimus promoted an increased expression of anti-apoptotic gene Bcl-2. In addition, methylprednisolone and cyclosporine promoted an increase in the expression of the pro-apoptotic gene Bak in newborn rats. CONCLUSIONS: The experimental models were feasible and adequate for the current investigations; hepatectomy stimulated hepatocyte proliferation and inhibited hepatic cells apoptosis; the utilized immunosuppressant drugs did not affect hepatocyte proliferation although an increased expression of apoptosis-related genes was verified.
Smith, Cornel. "The effect of preserving liver tissue in formalin on the concentration of trace minerals in the liver". Pretoria : [s.n.], 2005. http://upetd.up.ac.za/thesis/available/etd-08052005-101056/.
Pełny tekst źródłaMorrison, Roxanne. "The development of an in vitro system for the production of drug metabolites using microsomal enzymes from bovine liver". Thesis, Rhodes University, 2011. http://hdl.handle.net/10962/d1007698.
Pełny tekst źródłaLange, Jeremy David. "The effect of anti-malarial drugs on the pituitary gland". Thesis, University of Leeds, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.238726.
Pełny tekst źródłaFigueiredo, João Daniel Amaral. "The effect of anticancer drugs prodiginines in PP1 in melanoma". Master's thesis, Universidade de Aveiro, 2011. http://hdl.handle.net/10773/6861.
Pełny tekst źródłaUm dos principais mecanismos reguladores da função celular é a fosforilação de proteínas. É de focar que a fosforilação anormal de proteínas-chave pode estar associada a várias patologias, incluindo o cancro. Embora já existam muitos estudos sobre cinases no cancro, o conhecimento sobre as fosfatases que antagonizam a acção das cinases é muito menos. A PP1, uma das principais proteínas fosfatase de serina/treonina expressa em todas as células eucarióticas, está envolvida em vários processos celulares incluindo apoptosis e ciclo celular. Na realidade, diversos estudos demonstram que a PP1 regula variadas proteínas que são elementos-chave no processo de tumorigenesis. A AKT, uma cinase serina/treonina que se encontra desregulada em vários tipos de cancro, é um factor crucial na progressão e sobrevivência de melanoma. Prodigiosina, um membro da família de metabolitos secundários tripirrolicos pigmentados de vermelho, as prodigininas, demonstra propriedades anticancerigenas em vários tipos de cancro. Na verdade alguns estudos verificaram que a AKT é desfosforilada pela prodigiosina embora ainda seja desconhecido o mecanismo pelo qual tal acontece. Dada a importância da AKT na progressão e sobrevivência do melanoma e a capacidade da PP1 em desfosforilar a AKT é possível que a PP1 esteja envolvida em tal mecanismo. Os resultados preliminares demonstraram que a PP1 liga-se a um membro da família das prodigininas provando a interacção entre estas moléculas. Por outro lado, ensaios em linhas celulares de melanoma usando tratamentos com prodigiosina e cantaridina, um inibidor da PP1, demonstraram que a prodigiosina afecta isoformas da PP1 diferencialmente. Estes resultados sugerem que a prodigiosina actua em duas vias de sinalização distintas em melanoma, a via da AKT e a da MAPK, uma vez que alteração nos níveis de PP1α, uma das isoformas da PP1, se correlaciona com a variação dos níveis de fosforilação da AKT e as mudanças nos níveis da PP1γ com a variação dos níveis de fosforilação da MAPK. Com estes resultados propomos um modelo de como a prodigiosina desfosforila a AKT e como este processo contribui para a indução da morte celular em células de melanoma. Esperamos que este modelo ajude na compreensão do mecanismo de acção da prodigiosina bem como no reconhecimento das fosfatases como novos alvos terapêuticos no tratamento de cancro.
Protein phosphorylation is a major regulatory mechanism for cell function. It is noteworthy that several pathologies, including cancer to be associated with abnormal phosphorylation of key proteins. Although many studies have addressed the kinases that are misregulated in cancer, much less is known about the phosphatases that counteract their actions. PP1, a major serine/threonine protein phosphatase that is ubiquitously expressed in all eukaryotic cells, is involved in many cellular processes including apoptosis and cell cycle. In fact, several studies demonstrate that PP1 regulates several proteins that are key elements in the tumorogenesis process. AKT, a serine/threonine kinase that is disregulated in several types of cancer is a crucial factor in melanoma progression and survival. Prodigiosin, a family member of the natural red pigmented tripyrrolic secondary metabolites, prodiginines, show anticancer properties in numerous types of cancer. In fact, some prodigiosin studies demonstrate that AKT is dephosphorylated by prodigiosin by an unknown mechanism. Given the importance of AKT in melanoma progression and survival and the capacity of PP1 to dephosphorylate AKT it is possible that PP1 is involved in this mechanism. Our preliminary results showed that PP1 binds to one member of prodiginine family proving the interaction between these molecules. On the other hand, experiments with melanoma cell lines, using prodigiosin and cantharidin, a PP1 inhibitor, treatments, demonstrate that prodigiosin affect differently PP1 isoforms. These results suggest that prodigiosin acts in a different way in two altered pathways in melanoma, AKT and MAPK, since the alterations in PP1α levels, one of PP1 isoforms, are correlated with the conversion in AKT dephosphorylation and the variations in PP1γ levels with the changes in MAPK dephosphorylation. Given these results we propose a model of how prodigiosin dephosphorylates AKT and how this process contributes to induce cell death in melanoma cells. We expect that this model helps to understand prodigiosin action mechanism as well as acknowledge phosphatases as a therapy target in cancer treatment.
Ngamratanapaiboon, Surachai. "Metabolomics investigations of the effect of drugs on mammalian cells". Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/41178/.
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