In Vitro Cytotoxicity Assays Of Solid Lipid Nanoparticles In Epithelial And Dermal Cells

In recent years, the interest in nanostructured systems to drug delivery has increased because they offer several advantages over conventional dosage forms. Solid Lipid Nanoparticles (SLN) have been highlighted among these systems because they have advantages such as high physical stability, protection against drug degradation and ease of scale-up and manufacturing, without using organic solvent. The aim of this work was to evaluate the potential of SLN, by in vitro cytotoxicity assays, for dermal drug delivery. SLN of three different lipids were prepared by hot high pressure homogenization and the cytotoxicity was assessed by 3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyl tetrazolium bromide (MTT) test in mouse 3T3 fibroblasts and human HaCaT keratinocytes. SLN showed no cytotoxic potential suggesting a great potential for dermal application.3041Mishra, B., Patel, B.B., Tiwari, S., (2010) Nanomed.-Nanotechnol. Biol. Med., 6, p. 9Mehnert, W., Mäder, K., (2001) Adv. Drug Deliv. Rev., 47, p. 165Pardeike, J., Hommoss, A., Müller, R.H., (2009) Int. J. Pharm., 366, p. 170Lewinski, N., Colvin, V., Drezek, R., (2008) Small, 4, p. 26Schöler, N., Hahn, H., Müller, R.H., Liesenfeld, O., (2002) Int. J. Pharm., 231, p. 167Müller, R.H., Maassen, S., Schwarz, C., Mehnert, W., (1997) J. Control. Release, 47, p. 261Shöler, N., Hahn, H., Müller, R.H., Liesenfeld, O., (2002) Int. J. Pharm., 231, p. 167Weyenberg, W., Filev, P., Plas, D.V., Vandervoort, J., Smet, K.D., Sollie, P., Ludwig, A., (2007) Int. J. Pharm., 337, p. 291Kristl, J., Teskac, K., Milek, M., Rascan, I.M., (2008) Toxicol. Appl.Pharmacol., 232, p. 218Mosmann, T., (1983) J. Immunol. Methods, 65, p. 55Marcato, P.D., Caverzan, J., Rossi-Bergmann, B., Pinto, E.F., MacHado, D., Silva, R.A., Justos, G.Z., Durán, N., (2011) J. Nanosci. Nanotechnol

Catalytic Antibodies: Expanding The Scope Of Enzymatic Catalysis [anticorpos Catalíticos: Expandindo O Alcance Da Catálise Enzimática]

The vast binding repertoire of the immune system has been exploited for the generation of tailor-made selective catalysts. Since the first reports of chemical reactions catalyzed by antibodies were published, research in this field, which borders chemistry and biology, has been rapidly established and a number of catalytic antibodies that carry out a wide range of reactions, have been developed. Recent advances have led to antibodies that catalyse complex, multi-step reactions and difficult chemical transformations, as well as reactions that do not have an organic equivalent at all. Current research in this field has been devoted to practical applications of this technology.2118698Davies, D.R., Chacko, S., (1993) Acc. Chem. Res., 26, p. 421Male, D., Cooke, A., Owen, M., Trowsdale, J., Champion, B., (1996) Advanced Immunology, , MosbyLondonPauling, L., (1948) Am. 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Coagulation And Cancer Therapy: The Potential Of Natural Compounds

In the past few years, it has become clear that the processes of cancer metastasis and invasion are highly dependent on components of the blood coagulation cascade. Metastasis is critically dependent on the formation of new blood vessels and the role of many blood-clotting factors in tumor angiogenesis has been extensively studied. Angiogenesis constitutes an important point in the control of cancer progression and in recent years much attention has been paid to the development of antiangiogenic agents. Natural compounds constitute a promising alternative for application in antiangiogenesis therapy due to their multiple mechanisms of action. Moreover, they can be used as templates for the production of analogues with enhanced activity. 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Xanthine oxidase (XO) has been investigated for its decreased activity in several cancerous tissues and constitutive generation of reactive oxygen species (ROS) in vivo seems to contribute significantly to its inactivation. Singlet oxygen (1O2) production has been suggested to be relevant when considering folic acid metabolism by cancer cells. Thus, the susceptibility of XO to inactivation by 1O2 generated either by the bioenergized systems folic acid/peroxidase/GSH/Mn2+/O2 and malonaldehyde/peroxidase/Mn2+/O2 or by methylene blue (MB) or eosin-sensitized photooxygenation was studied. Our results showed that other ROS were also responsible for XO inactivation when MB was used. In contrast, eosin produced almost exclusively 1O2. Kinetic studies of XO oxidation in the malonaldehyde/peroxidase system showed that histidine (His) is a competitive inhibitor with respect to XO. 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Potential Applications Of Violacein: A Microbial Pigment

Violacein is a versatile pigment from a bacterium Chromobacterium violaceum that exhibits several biological activities and, at present, has gained increasing importance in industrial markets, such as in medicine, cosmetics, and textiles. In this mini-review, we aimed to describe violacein production and to explore its various biological properties in a pharmacological context, including its antioxidant, immunomodulatory, antitumoral, and antiparasitic activities. In addition, its use in the fields of cosmetics, textiles, food, toys, and insecticides has emerged as unusual potential areas of application to be discussed here. © Springer Science+Business Media, LLC 2011.21715241532Ahmetagic, A., Pemberton, J.M., Stable high level expression of the violacein indolocarbazole anti-tumour gene cluster and the Streptomyces lividans amy A gene in E. coli K12 (2010) Plasmid, 63, pp. 79-85Alves, O.L., Gimenez, I.F., De Azevedo, M.M.M., Durán, N., Melo, O.S., Pharmacological use of cyclodextrine-Au-Thiol-derivative/ hydrophobic compound nanoparticles as antitumoral, antibacterial, antiviral and/or antiparasites, its obtention process and formulation (2005), Brazilian Patent PIBr 0502657-1Andrighetti-Frohner, C.R., Antonio, R.V., Creczynski-Pasa, T.B., Barandi, C.R.M., Simões, C.M.O., Cytotoxicity and potential antiviral evaluation of violacein produced by Chromobacterium violaceum (2003) Mem Inst Oswaldo Cruz, 98, pp. 834-848Antonisamy, P., Ignacimuthu, S., Immunomodulatory, analgesic and antipyretic effects of violacein isolated from Chromobacterium violaceum (2010) Phytomedicine, 17, pp. 300-304Antonisamy, P., Kannan, P., Ignacimuthu, S., Anti-diarrhoeal and ulcer-protective effects of violacein isolated from Chromobacterium violaceum in Wistar rats (2009) Fundam Clin Pharmacol, 23, pp. 483-490Aoki, S., Nomura, T., Violacein-containing natural bactericides, their manufacture, and cosmetics containing them (1998), Jpn Kokai Tokkyo Koho JP 10139612Baek, S.H., Kang, H.S., Jang, I.H., Lee, J.S., Kim, S.Y., Baek, J.H., Kang, J.G., Ahn, J.M., (2007) Insecticide and Fungicide Containing Violacein, and Their Preparation Method, , Repub Korean Kongkae Taeho Kongbo KR 2007088150 ABromberg, N., Dreyfuss, J.L., Regatieri, C.V., Palladino, M.V., Durán, N., Nader, H.B., Haun, M., Justo, G.Z., Growth inhibition and proapoptotic activity of violacein in Ehrlich ascites tumor (2010) Chem Biol Interact, , doi:10.1016/j.cbi.2010.04.016Cao, W., Chen, W., Sun, S., Guo, P., Song, J., Tian, C., Cao, W., Tian, C., Investigating the antioxidant mechanism of violacein by density functional theory method. Investigating the antioxidant mechanism of violacein by density functional theory method (2007) J Mol Struct Theochem, 817, pp. 1-4Ftm, C., Justo, G.Z., Durán, N., Nogueira, P.A., Scp, L., The use of violacein in its free and encapsulated form in polymeric systems against malaria (2005), Brazilian Patent PIBr 056399-0De Azevedo Mbm, Alderete, J., Acs, L., Loh, W., Faljoni-Alario, A., Durán, N., Violacein/cyclodextrin inclusion complex by diffusion coefficient and circular dichroism measurements (2000) J Inclusion Phenom Mol Recognit Chem, 37, pp. 67-74De Azevedo, M.B.M., Alderete, J., Rodriguez, J.A., De Souza, A.O., Faljoni-Alario, A., Durán, N., Biological activities of new antitumoral of indole derivatives in a inclusion complex with cyclodextrin (2000) J Inclusion Phenom Mol Recognit Chem, 37, pp. 93-101De Azevedo, M.B.M., Justo, G.Z., Rettori, D., Rodriguez, J.A., Haun, M., Durán, N., Antioxidant activity of an inclusion complex of violacein and β-cyclodextrin (2000) Proc Intern Symp Control Rel Bioact Mater, 27, pp. 506-507De Azevedo, M.B.M., Melo, P.S., Almeida, A.B.A., Souza-Brito, A.R.M., Haun, M., Durán, N., Antiulcerogenic activity of violacein/ beta-cyclodextrin inclusion complexes and violacein (2000) Proc Intern Symp Control Rel Bioact Mater, 27, pp. 508-509De Carvalho, D.D., Costa, F.T.M., Duran, N., Haun, M., Cytotoxic activity of violacein in human colon cancer cells (2006) Toxicol in Vitro, 20, pp. 1514-1521De Moss, R.D., Violacein (1967) Antibiotics, 2, pp. 77-81De Moss, R.D., Happel, M.E., Nutritional requirements of Chromobacterium violaceum (1959) J Bacteriol, 77, pp. 137-141De Souza, A.O., Aily, D.C.G., Sato, D.N., Durán, N., In vitro violacein activity against Mycobacterium tuberculosis H37RA (1999) Rev Inst Adolfo Lutz, 58, pp. 59-62Durán, N., De Azevedo, M.M.M., Compound incorporated in a polymeric nanoparticle with pharmaceutical or a cosmetic, its preparation process and cosmetic or pharmaceutical formulations (2004), Brazilian Patent PIBr 0404306-5Durán, N., De Souza, A.O., Process of violacein application as antimycobacterial compound (2001), Brazilian Patent PIBr 0101346-7Durán, N., Faljoni-Alario, A., Bacterial chemistry-I. Studies of a potential phototherapeutic substance from Chromobacterium violaceum (1980) An Acad Bras Cienc, 52, pp. 297-302Durán, N., Haun, M., Trypanocide. State of art (1991) Mem Inst Oswaldo Cruz Suppl i, 86, pp. 29-30Durán, N., Haun, M., Production, obtention and purification process and antitumoral activity of 3-[1,2-dihydro-5-(5-hydroxy-1H-indol-3-yl)-2-oxo-3H-pyrrol-3-ylidene]-1,3- dihydro-2H-indol-2-one (1997), Brazilian Patent PIBr 9702918Durán, N., Menck, C.F.M., Chromobacterium violaceum: A Review of pharmacological and industrial perspectives (2001) Crit Rev Microbiol, 27, pp. 201-222Durán, N., Justo, G.Z., Melo, P.S., De Azevedo, M.B.M., Souza-Brito, A.R.M., Almeida, A.B.A., Haun, M., Evaluation of the antiulcerogenic activity of violacein and its modulation by the inclusion complexation with beta-cyclodextrin (2003) Can J Physiol Pharmacol, 81, pp. 387-396Durán, N., Erazo, S., Campos, V., Bacterial Chemistry-II. 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Evaluation Of The Antiulcerogenic Activity Of Violacein And Its Modulation By The Inclusion Complexation With β-cyclodextrin

The effects of β-cyclodextrin (βCD) inclusion complexation on the ability of violacein to prevent gastric ulceration in mice were studied. Violacein-βCD inclusion complexes were prepared in 1:1 and 1:2 molar ratios and analysed by differential scanning calorimetry and powder X-ray diffractometry. Violacein previously administered orally at 10 mg/kg significantly reduced indomethacin-induced gastric lesions, as well as 100 mg/kg of cimetidine (positive control). However, βCD complexation in both molar ratios significantly potentiated the protective action of violacein. In the HCl-ethanol-induced gastric ulcer model, violacein and the 1:2 inclusion complex (10 mg/kg, p.o.) inhibited gastric damage by almost 85%, whereas a 63% reduction was observed for the positive control, lansoprazole, at 30 mg/kg. In contrast, treatment with the 1:1 inclusion complex resulted in almost total disappearance of the antiulcer activity in this model. 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Heterozygosis For Cyp21a2 Mutation Considered As 21-hydroxylase Deficiency In Neonatal Screening

Steroid 21-hydroxylase deficiency (21-OHD) accounts for more than 90% of congenital adrenal hyperplasia. CAH newborn screening, in general, is based on 17-hydroxyprogesterone dosage (17-OHP), however it is complicated by the fact that healthy preterm infants have high levels of 17-OHP resulting in false positive cases. We report on molecular features of a boy born pre-term (GA = 30 weeks; weight = 1,390 g) with elevated levels of 17-OHP (91.2 nmol/L, normal < 40) upon neonatal screening who was treated as having CAH up to the age of 8 months. He was brought to us for molecular diagnosis. Medication was gradually suspended and serum 17-OHP dosages mantained normal. The p.V281 L mutation was found in compound heterozygous status with a group of nucleotide alterations located at the 3′ end intron 4 and 5′ end exon 5 corresponding to the splice site acceptor region. Molecular studies continued in order to exclude the possibility of a nonclassical 21-OHD form. The group of three nucleotide changes was demonstrated to be a normal variant since they failed to interfere with the normal splicing process upon minigene studies.52813881392White, P.C., Speiser, P.W., Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (2000) Endocr Rev, 21, pp. 245-291Riepe, F.G., Sippell, W.G., Recent advances in diagnosis, treatment, and outcome of congenital adrenal hyperplasia due to 21-hydroxylase deficiency (2007) Rev Endocr Metab Disord, 8 (4), pp. 349-363New, M., Lorenzen, F., Lerner, A.J., Kohn, B., Oberfield, S.E., Pollack, M.S., Genotyping steroid 21-hydroxylase deficiency: Hormonal reference data (1983) J Clin Endocrinol Metab, 57, pp. 320-326Azziz, R., Hincapie, L.A., Knochenhauer, E.S., Dewailly, D., Fox, L., Boots, L.R., Screening for 21-hydroxylase-deficient nonclassic adrenal hyperplasia among hyperandrogenic women (1999) Fertil Steril, 72, pp. 915-925Bachega, T.A., Brenlha, E.M., Billerbeck, A.E., Marcondes, J.A., Madureira, G., Arnhold, I.J., Mendonca, B.B., Variable ACTH-stimulated 17-hydroxyprogesterone values in 21-hydroxylase deficiency carriers are not related to the different CYP21 gene mutations (2002) J Clin Endocrinol Metab, 87 (2), pp. 786-790Pang, S., Hotchkiss, J., Drash, A.L., Levine, L.S., New, M., Microfilter paper method for 17-hydroxyprogesterone radioimmunoassay: Its application for rapid screening for congenital adrenal hyperplasia (1977) J Clin Endocrinol Metab, 45, pp. 1003-1008Valentino, R., Tommaselli, A.P., Rossi, R., Lombardi, G., Varrone, S., A pilot study for neonatal screening of congenital adrenal hyperplasia due to 21-hydroxylase and 11-hydroxylase deficiency in Campania region (1990) J Endocrinol lnvest, 13, pp. 221-225Janzen, N., Peter, M., Sander, S., Steuerwald, U., Terhardt, M., Holtkamp, U., Sander, J., Newborn screening for congenital adrenal hyperplasia: Additional steroid profile using liquid chromatography-tandem mass spectrometry (2007) J Clin Endocrinol Metab, 92 (7), pp. 2581-2589Pang, S., Murphey, W., Levine, L.S., Lorenzen, F., Levy, D., Lerner, A.J., Rondanini, G.F., New, M., A pilot newborn screening for congenital adrenal hyperplasia in Alaska (1982) J Clin Endocrinol Metab, 55, pp. 413-420Nordenström, A., Wedell, A., Hagenfeldt, L., Marcus, C., Larsson, A., Neonatal screening for congenital adrenal hyperplasia: 17-hydroxyprogesterone levels and CYP21 genotypes in preterm infants (2001) Pediatrics, 108 (4), pp. E68Cardoso, C.B., Fonseca, A.A., Oliveira Mde, F., Pereira, B.B., Guimarães, M.M., Congenital adrenal hyperplasia newborn screening: Rio de Janeiro experience. Arq Bras Endocrinol (2005) Metabol, 49 (1), pp. 112-119Silveira, EL, D.S., Bachega, T.A., van der, Linden Nader, I., Gross, J.L., Elnecave, R.H., The actual incidence of congenital adrenal hyperplasia in Brazil may not be as high as inferred-an estimate based on a public neonatal screening program in the state of Goiás (2008) J Pediatr Endocrinol Metab, 21 (5), pp. 455-460Sambrook, J., Fritsch, E.F., Maniatis, T.E., (1989) Molecular Cloning, a Laboratory Manual, , New York: Cold Spring HarborAraujo, M., Sanches, M.R., Suzuki, L.A., Guerra-Jr, G., Farah, S.B., De Mello, M.P., Molecular analysis of CYP21 and C4 genes in Brazilian families with the classical form of steroid 21-hydroxylase deficiency (1996) Braz J Med Biol Res, 29, pp. 1-13Wilson, R.C., Wei, J.Q., Cheng, K.C., Mercado, A.B., New, M., Rapid deoxyribonucleic acid analysis by allele-specific polymerase chain reaction for detection of mutations in the steroid 21-hydroxylase gene (1995) J Clin Endocrinol Metab, 80 (5), pp. 1635-1640Lau, I.F., Soardi, F.C., Lemos-Marini, S.H., Guerra-Jr, G., Baptista, M.T., De Mello, M.P., H28+C insertion in the CYP21 gene: A novel frameshift mutation in Brazilian patient with the classical form of 21-hydroxylase deficiency (2001) J Clin Endocrinol Metab, 86, pp. 5877-5880Higashi, Y., Yoshioka, H., Yamane, M., Gotoh, O., Fujii-Kuriyama, Y., Complete nucleotide sequence of two steroid 21-hydroxylase genes tandemly arranged in human chromosome: A pseudogene and a genuine gene (1986) Proc Natl Acad Sci USA, 83, pp. 2841-2845Wilson, R.C., Nimkarn, S., Dumic, M., Obeid, J., Azar, M.R., Najmabadi, H., Ethnic-specific distribution of mutations in 716 patients with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency (2007) Mol Genet Metab, 90 (4), pp. 414-421Tusie-Luna, M.T., Traktman, P., White, P.C., Determination of functional effects of mutations in the steroid 21-hydroxylase gene (CYP21) using recombinant vaccinia virus (1990) J Biol Chem, 265 (34), pp. 20916-20922Higashi, Y., Hiromasa, T., Tanae, A., Miki, T., Nakura, J., Kondo, T., Effects of individual mutations in the P-450(C21) pseudogene on the P-450(C21) activity and their distribution in the patient genomes of congenital steroid 21-hydroxylase deficiency (1991) J Biochem, 109 (4), pp. 638-644Bachega, T.A., Billerbeck, A.E., Madureira, G., Marcondes, J.A., Longui, C.A., Leite, M.V., Molecular genotyping in Brazilian patients with the classical and nonclassical forms of 21-hydroxylase deficiency (1998) J Clin Endocrinol Metab, 83 (12), pp. 4416-441

Novel Mutations In Cyp11b1 Gene Leading To 11β-hydroxylase Deficiency In Brazilian Patients

Background: Deficiency of 11β-hydroxylase results in the impairment of the last step of cortisol synthesis. In females, the phenotype of this disorder includes different degrees of genital ambiguity and arterial hypertension. Mutations in the CYP11B1 gene are responsible for this disease. Objective: The objective of the study was to screen the CYP11B1 gene for mutations in two unrelated Brazilian females with congenital adrenal hyperplasia due to 11β-hydroxylase deficiency. Design: The coding and intron-exon junction regions of CYP11B1 were totally sequenced. A putative splice mutation was further investigated by minigene transcription. Results: We report two novel CYP11B1 mutations in these Brazilian patients. An Arabian Lebanese descendent female was found to be homozygous for a cytosine insertion at the beginning of exon 8, changing the 404 arginine to proline. It alters the open reading frame, creating a putative truncated protein at 421 residue, which eliminates the domain necessary for the association of heme prosthetic group. A severely virilized female was homozygous for the g.2791G>A transition in the last position of exon 4. This nucleotide is also part of 5′ intron 4 donor splice site consensus sequence. Minigene experiments demonstrated that g.2791G>A activated an alternative splice site within exon 4, leading to a 45-bp deletion in the transcript. The putative translation of such modified mRNA indicates a truncated protein at residue 280. Conclusions: We describe two novel mutations, g.4671-4672insC and g.2791G>A, that drastically affects normal protein structure. These mutations abolish normal enzyme activity, leading to a severe phenotype of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency. Copyright © 2009 by The Endocrine Society.94934813485White, P.C., Curnow, K.M., Pascoe, L., Disorders of steroid 11β- hydroxylase isoenzymes (1994) Endocr Rev, 15, pp. 421-438White, P.C., Speiser, P.W., Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (2000) Endocrine Reviews, 21 (3), pp. 245-291. , DOI 10.1210/er.21.3.245Mornet, E., Dupont, J., Vitek, A., White, P.C., Characterization of two genes encoding human steroid 11β-hydroxylase (P-450(11β)) (1989) Journal of Biological Chemistry, 264 (35), pp. 20961-20967Spoudeas, H.A., Slater, J.D., Rumsby, G., Honour, J.W., Brook, C.G., Deoxycorticosterone, 11β-hydroxylase and the adrenal cortex (1993) Clin Endocrinol, 39, pp. 245-251. , OxfHague, W., Honour, J., Malignant hypertension in congenital adrenal hyperplasia due to 11β-hydroxylase deficiency (1983) Clin Endocrinol, 18, pp. 505-510. , OxfKrawczak, M., Cooper, D.N., The human gene mutation database (1997) Trends Genet, 13, pp. 121-122Chabre, O., Portrat-Doyen, S., Vivier, J., Morel, Y., Defaye, G., Two novel mutations in splice donor sites of CYP11B1 in congenital adrenal hyperplasia due to 11β-hydroxylase deficiency (2000) Endocrine Res, 26, pp. 797-801Curnow, K.M., Slutsker, L., Vitek, J., Cole, T., Speiser, P.W., New, M.I., White, P.C., Pascoe, L., Mutations in the CYP11B1 gene causing congenital adrenal hyperplasia and hypertension cluster in exons 6, 7, and 8 (1993) Proc Natl Acad Sci USA, 90, pp. 4552-4556Skinner, C.A., Rumsby, G., Honour, J.W., Single strand conformation polymorphism (SSCP) analysis for the detection of mutations in the CYP11B1 gene (1996) Journal of Clinical Endocrinology and Metabolism, 81 (6), pp. 2389-2393. , DOI 10.1210/jc.81.6.2389De Carvalho, C.E., Castro, M., Moreira, A.C., De Mello, M.P., CYP11B1 mutation and polymorphisms in congenital adrenal hyperplasia due to 11β-hydroxylase deficiency (1999) J Endocr Genet, 1, pp. 79-86Moreira, A.C., Elias, L.L.K., Pituitary-adrenal responses to corticotropin- releasing hormone in different degrees of adrenal 21-hydroxylase deficiency (1992) J Clin Endocrinol Metab, 74, pp. 198-203Mermejo, L.M., Elias, L.L.K., Marui, S., Moreira, A.C., Mendonca, B.B., De Castro, M., Refining hormonal diagnosis of type II 3β-hydroxysteroid dehydrogenase deficiency in patients with premature pubarche and hirsutism based on HSD3B2 genotyping (2005) Journal of Clinical Endocrinology and Metabolism, 90 (3), pp. 1287-1293. , DOI 10.1210/jc.2004-1552De-Araujo, M., Sanches, M.R., Suzuki, L.A., Guerra Jr., G., Farah, S.B., De-Mello, M.P., Molecular analysis of CYP21 and C4 genes in Brazilian families with the classical form of steroid 21-hydroxylase deficiency (1996) Brazilian Journal of Medical and Biological Research, 29 (1), pp. 1-13Soardi, F.C., Lemos-Marini, S.H.V., Coeli, F.B., Maturana, V.G., Silva, M.D., Bernardi, R.D., Justo, G.Z., De Mello, M.P., Heterozygosis for CYP21A2 mutation considered as 21-hydroxylase deficiency in neonatal screening (2008) Arq Bras Endocrinol Metab, 52, pp. 1388-1392White, P.C., Slutsker, L., Haplotype analysis of CYP11B2 (1995) Endocr Res, 21, pp. 437-442Ravichandran, K.G., Boddupalli, S.S., Hasemann, C.A., Peterson, J.A., Deisenhofer, J., Crystal structure of hemoprotein domain of P450BM-3, a prototype for microsomal P450's (1993) Science, 261 (5122), pp. 731-736Roumen, L., Sanders, M.P.A., Pieterse, K., Hilbers, P.A.J., Plate, R., Custers, E., De Gooyer, M., Hermans, J.J.R., Construction of 3D models of the CYP11B family as a tool to predict ligand binding characteristics (2007) Journal of Computer-Aided Molecular Design, 21 (8), pp. 455-471. , DOI 10.1007/s10822-007-9128-9Mount, S.M., A catalogue of splice junction sequences (1982) Nucleic Acids Res, 10, pp. 459-472Buratti, E., Chivers, M., Královicová, J., Romano, M., Baralle, M., Krainer, A.R., Vorechovsky, I., Aberrant 5′ splice sites in human disease genes: Mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization (2007) Nucleic Acids Res, 35, pp. 4250-426

Growth Inhibitory Activity Of A Novel Lectin From Cliona Varians Against K562 Human Erythroleukemia Cells

Purpose: In this study, the antitumoral potential of a novel lectin (CvL) purified from the marine sponge Cliona varians was studied in different cancer cell lines. Methods: CvL cytotoxicity was evaluated in mammalian tumor cells and in normal human peripheral blood lymphocytes by the MTT assay using the same range of concentrations (1-150 μg ml-1). The mechanisms involved in K562 cell death were investigated by confocal fluorescence microscopy, flow cytometry and immunoblot. Results: CvL inhibited the growth of human leukemia cells, with IC50 values of 70 and 100 μg ml-1 for K562 and JURKAT cells, respectively, but it was ineffective on blood lymphocytes and solid tumor cell lines. K562 cell death occurred 72 h after exposure to the lectin and with signs of apoptosis, as analyzed by DAPI and annexin V/PI staining. Investigation of the possible mediators of this process showed that cell death occurred via a caspase-independent pathway. Confocal fluorescence microscopy indicated a pivotal role for the lysosomal protease cathepsin B in mediating cell death. Accordingly, pre-incubation of K562 cells with the cathepsin inhibitor l-trans-epoxysuccinyl-l-leucylamido-(4-guanidino)butane (E-64) abolished CvL cytotoxic effect. Furthermore, we found upregulation of tumor necrosis factor receptor 1 (TNFR1) and down-modulation of p65 subunit of nuclear factor kappa B (NFκB) expression in CvL-treated cells. These effects were accompanied by increased levels of p21 and reduced expression of pRb, suggesting that CvL can induce cell cycle arrest. 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