Infection By Cytomegalovirus In Patients With Neonatal Cholestasis

Background - Neonatal cholestasis syndrome with an intra or extrahepatic origin has been associated to viral infections. The participation of the cytomegalovirus in the etiopathogenesis of neonatal hepatitis has been already known for some time, but only recently there have been indications that this virus may be one of the possible etiological factors for extrahepatic biliary atresia. Aims - To assess the prevalence of infection by cytomegalovirus in patients with intrahepatic cholestasis and extrahepatic cholestasis. To compare the clinical characteristics of the intrahepatic cholestasis and extrahepatic cholestasis groups with the cytomegalovirus serological results. Patients and Methods - This study consisted of 76 patients with neonatal cholestasis who were admitted between January 1980 and January 1999 when they underwent a cytomegalovirus serologic study using the ELISA method. A case note was kept on each patient with the following data: age of patient at admission, serologic result for cytomegalovirus, history of maternal infection, prematurity, fetal distress, birth weight, ponderal gain, choluria and fecal acholia. The final anatomic diagnosis of cholestasis was based on the results of an abdominal ultrasonography, a liver biopsy and its evolution. The patients were then divided into two groups: group I - intrahepatic cholestasis and group II - extrahepatic cholestasis. Each of these groups were then divided into two subgroups: subgroup A - positive serology (IgM) for cytomegalovirus and subgroup B - negative serology (IgM) for cytomegalovirus. Results - The frequency of positive serology (IgM) for cytomegalovirus was 29.4% in children with intrahepatic cholestasis and 28.5% in children with extrahepatic cholestasis. In comparison with group IIB, group IIA presented a higher rate of maternal infection history. The patients in group IIA demonstrated a delayed access to the service in comparison with group IA. The groups did not demonstrate any significant differences regarding the onset age of jaundice, choluria and fecal acholia, birth weight and ponderal gain. Conclusions - The positive (IgM) seroprevalence for cytomegalovirus in children with intrahepatic cholestasis and extrahepatic cholestasis is high. The history of maternal infection was more common in extrahepatic cholestasis patients with positive serology for cytomegalovirus. There was a delay in the referral of these patients which resulted in a late diagnosis and surgical treatment.392132136Balistreri, W.F., Grand, R., Hoofnagle, J.H., Suchy, F.J., Ryckman, F.C., Perlmutter, D.H., Sokol, R.J., Biliary atresia: Current concepts and research directions (1996) Hepatology, 23, pp. 1682-1692Boppana, S.B., Pass, R.F., Britt, W.J., Stagno, S., Alford, C.A., Symptomatic congenital cytomegalovirus infection: Neonatal morbidity and mortality (1992) Pediatr Infect Dis J, 11, pp. 93-99Chang, M.H., Huang, H.H., Huang, E.S., Kao, C.L., Hsu, H.Y., Lee, C.Y., Polymerase chain reaction to detect human cytomegalovirus in livers of infants with neonatal hepatitis (1992) Gastroenterology, 103, pp. 1022-1025Fischler, B., Ehrnst, A., Forsgren, M., Örvell, C., Nemeth, A., The viral association of neonatal cholestasis in Sweden: A possible link between cytomegalovirus infection and extrahepatic biliary atresia (1998) J Pediatr Gastroenterol Nutr, 27, pp. 57-64Fowler, K.B., Stagno, S., Pass, R.F., Maternal age and congenital cytomegalovirus infection: Screening of two diverse newborn populations, 1980-1990 (1993) J Infect Dis, 168, pp. 552-556Griffiths, P.D., Baboonian, C., A prospective study of primary cytomegalovirus infection during pregnancy: Final report (1984) Br J Obstet Gynaecol, 91, pp. 307-315Hanshaw, J.B., Congenital cytomegalovirus infection: A fifteen year perspective (1971) J Infect Dis, 123, pp. 555-561Jevon, G.P., Dimmick, J.E., Biliary atresia and cytomegalovirus infection: A DNA study (1999) Pediatr Dev Pathol, 2, pp. 11-14Kumar, M.L., Nankervis, G.A., Cooper, A.R., Gold, E., Postnatally acquired cytomegalovirus infections in infants of CMV excreting mothers (1984) J Pediatr, 104, pp. 669-673Leinikki, P., Granstrüm, M.L., Santavuori, P., Pettay, O., Epidemiology of cytomegalovirus infections during pregnancy and infancy: A prospective study (1978) Scand J Infect Dis, 10, pp. 165-171Leinikki, P., Heinonen, K., Pettay, O., Incidence of cytomegalovirus infections in early childhood (1972) Scand J Infect Dis, 4, pp. 1-5Levinsohn, E.M., Foy, H.M., Kenny, G.E., Wentworth, B.B., Grayston, J.T., Isolation of cytomegalovirus from a cohort of 100 infant throughout the first year of life (1969) Proc Soc Exp Biol Med, 132, pp. 957-962Machado, C.M., Fink, M.C.D.S., Vilas Boas, L.S., Sumita, L.M., Weinberg, A., Shiguematsu, K., Souza, I.C., Pannuti, C.S., Infecção perinatal pelo citomegalovirus em hospital público do municipio de São Paulo: Estudo prospectivo (1991) Rev Inst Med Trop São Paulo, 33, pp. 159-166Mediaris, D.N., Observations concerning human cytomegalovirus infection and disease (1964) Bull Johns Hopkins, 114, pp. 181-211Nankervis, G.A., Kumar, M.L., Cox, F.E., Gold, E., A prospective study of maternal cytomegalovirus infection and its effect on the fetus (1984) Am J Obstet Gynecol, 149, pp. 435-440Poley, J.R., Syndromes of neonatal cholestasis (1993) Pediatric Gastroenterology and Hepatology. 3. Ed., pp. 566-593. , Gracey M, Burke V, editors. Boston: Blackwell ScientificPrado, E.T.M.L., Araujo, M.F., Campos, J.V.M., Colestase neonatal prolongada: Estudo prospectivo (1999) Arq Gastroenterol, 36, pp. 185-194Reynolds, D.W., Stagno, S., Hosty, T.S., Tiller, M., Alford, C.A., Maternal cytomegalovirus excretion and perinatal infection (1973) N Engl J Med, 289, pp. 1-5Siegel, S., A prova de Kruskal-Wallis e o caso de duas amostras independentes (1975) Estatistica Não-paramétrica, pp. 107-124. , Siegel S, editor. São Paulo: McGraw-HillStagno, S., Pass, R.F., Dworsky, M.E., Henderson, R.E., Moore, E.G., Walton, P.D., Alford, C.A., Congenital cytomegalovirus infection: The relative importance of primary and recurrent maternal infection (1982) N Engl J Med, 306, pp. 945-949Stagno, S., Pass, R.F., Thomas, J.P., Navia, J.M., Dworsky, M.E., Defects of tooth structure in congenital cytomegalovirus infection (1982) Pediatrics, 69, pp. 646-648Stagno, S., Reynolds, D.W., Huang, E.S., Thames, S.D., Smith, R.J., Alford, C.A., Congenital cytomegalovirus infection: Occurrence in immune population (1977) N Engl J Med, 296, pp. 1254-1258Starr, J.G., Bart, R.D., Gold, E., Inapparent congenital cytomegalovirus infection: Clinical and epidemiologic characteristics in early infancy (1970) N Engl J Med, 282, pp. 1075-1078Tarr, P.I., Haas, J.E., Christie, D.L., Biliary atresia, cytomegalovirus and age at referral (1996) Pediatrics, 97, pp. 828-831Yamamoto, A.Y., Figueiredo, L.T.M., Mussi-Pinhata, M.M., Infecção perinatal por citomegalovirus: Muito freqüente mas pouco diagnosticada (1999) J Pediatr (Rio de Janeiro), 75, pp. 126-130Yamamoto, A.Y., Mussi-Pinhata, M.M., Pinto, P.C., Figueiredo, L.T., Jorge, S.M., Congenital cytomegalovirus infection in preterm and full-term newborn infants from a population with a high seroprevalence rate (2001) Pediatr Infect Dis J, 20, pp. 188-19

Correlation of mixed lymphocyte culture with chronic graft-versus-host disease following allogeneic stem cell transplantation

The purpose of the present study was to evaluate the mixed lymphocyte culture as a predictive assay of acute and chronic graft-versus-host disease (GVHD). We studied 153 patients who received a first bone marrow transplantation from human leukocyte antigen-identical siblings. Acute GVHD was observed in 26 of 128 (20.3%) patients evaluated and chronic GVHD occurred in 60 of 114 (52.6%). One-way mixed lymphocyte culture (MLC) assays were performed by the standard method. MLC results are reported as the relative response (RR) from donor against patient cells. The responses ranged from -47.0 to 40.7%, with a median of 0.5%. The Kaplan-Meier probability of developing GVHD was determined for patients with positive and negative MLC. There was no significant difference in incidence of acute GVHD between the groups studied. However, the incidence of chronic GVHD was higher in recipients with RR >4.5% than in those with RR 4.5%), 2.9 for those who received peripheral blood progenitor cells as a graft, and 2.2 for patients who developed previous acute GVHD. MLC was not useful for predicting acute GVHD, but MLC with RR >4.5% associated with other risk factors could predict the development of chronic GVHD, being of help for the prevention and/or treatment of this late complication.56757

Human herpesvirus infections of the central nervous system: laboratory diagnosis based on Dna detection by nested Pcr in plasma and cerebrospinal fluid samples

Infections of the central nervous systems (CNS) present a diagnostic problem for which an accurate laboratory diagnosis is essential. Invasive practices, such as cerebral biopsy, have been replaced by obtaining a polymerase chain reaction (PCR) diagnosis using cerebral spinal fluid (CSF) as a reference method. Tests on DNA extracted from plasma are noninvasive, thus avoiding all of the collateral effects and patient risks associated with CSF collection. This study aimed to determine whether plasma can replace CSF in nested PCR analysis for the detection of CNS human herpesvirus (HHV) diseases by analysing the proportion of patients whose CSF nested PCR results were positive for CNS HHV who also had the same organism identified by plasma nested PCR. In this study, CSF DNA was used as the "gold standard," and nested PCR was performed on both types of samples. Fifty-two patients with symptoms of nervous system infection were submitted to CSF and blood collection. For the eight HHV, one positive DNA result-in plasma and/or CSF nested PCR-was considered an active HHV infection, whereas the occurrence of two or more HHVs in the same sample was considered a coinfection. HHV infections were positively detected in 27/52 (51.9%) of the CSF and in 32/52 (61.5%) of the plasma, difference not significant, thus nested PCR can be performed on plasma instead of CSF. In conclusion, this findings suggest that plasma as a useful material for the diagnosis of cases where there is any difficulty to perform a CSF puncture.Infections of the central nervous systems (CNS) present a diagnostic problem for which an accurate laboratory diagnosis is essential. Invasive practices, such as cerebral biopsy, have been replaced by obtaining a polymerase chain reaction (PCR) diagnosis874648655sem informaçãosem informaçãoAbele, S.W., Puchhammer-Stöckl, E., Diagnosis of herpesvirus infections of the central nervous system (2002) J Clin Virol, 25, pp. S79-S85Altman, D.G., (1991) Practical statistics for medical research, pp. 410-411. , London: Chapman and hallBig, C., Reineck, L.A., Aronoff, D.M., Viral infections of the central nervous system: A case-based review (2009) J Clin Med Res, 7, pp. 142-146Boivin, G., Diagnosis of herpesvirus infections of the central nervous system (2004) Herpes, 11, pp. 48-56Calvario, A., Bozzi, A., Scarasciulli, M., Ventola, C., Stomati, D., Brancasi, B., Herpes consensus PCR test: A useful diagnostic approach to the screening of viral diseases of the central nervous system (2002) J Clin Virol, 25, pp. S71-S78Cassinotti, P., Siegl, G., A Nested-PCR assay for the simultaneous amplification of HSV-1, HSV-2, and HCMV genomes in patients with presumed herpetic CNS infections (1998) J Virol Methods, 71, pp. 105-114Chan, P.K., Ho-Keung, N.G., Cheung, J.L.K., Cheng, A.F., Survey for presence and distribuition of human herpesvirus 8 in healthy brain (2000) J Clin Microbiol, 38, pp. 2772-2773Cinque, P., Brytting, M., Vago, L., Castagna, A., Parravicini, C., Zanchetta, N., D'Arminio, M., Linde, A., Epstein-Barr virus DNA in cerebrospinal fluid from patients with Aids related primary lymphoma of the central nervous system (1993) Lancet, 342, pp. 398-401Danise, A., Cinque, P., Vergani, S., Candino, M., Racca, S., De Bona, A., Novati, R., Lazzarin, A., Use of polymerase chain reaction assays of aqueous humor in the differential diagnosis of retinitis in patients infected with human immunodeficiency virus (1997) Clin Infect Dis, 24, pp. 1100-1106Davies, N.W.S., Brown, L.J., Gonde, J., Irish, D., Robinson, R.O., Swan, A.V., Banatvala, J., Muir, P., Factors influencing PCR detection of viruses in cerebrospinal fluid of patients with suspected CNS infections (2005) J Neurol Neurosurg Psychiatry, 76, pp. 82-87DeBiasi, R., Kleinschmidt-Demasters, B., Weinberg, A., Tyler, K., Use of PCR for the diagnosis of herpesvirus infections of the central nervous system (2002) J Clin Virol, 25, pp. S5-S11Ehrnst, A., Barkholt, L., Lewensohhn-Fuchs, I., Ljungman, P., Teodosiu, O., Staland, A., Ringdén, O., Johansson, B., HCMV PCR monitoring in leukocytes of transplant patients (1995) Clin Diagn Virol, 3, pp. 139-153Fujimoto, H., Asaoka, K., Imaizumi, T., Ayabe, M., Shoji, H., Kaji, M., Epstein-Barr virus infections of the central nervous system (2003) Intern Med, 42, pp. 33-40Gilden, D., Mahalingam, R., Cohrs, R., Tyler, K., Herpesvirus infection of the nervous system (2007) Nat Clin Pract Neuro, 3, pp. 82-94Gregoire, S.M., Van Pesch, V., Goffete, S., Peeters, A., Sindic, C.J., Polymerase chain reaction analysis and oligoclonal antibody in the cerebrospinal fluid from 34 patients with Varicella-Zoster virus infection of the nervous system (2006) J Neurol Neurosurg Psychiatry, 77, pp. 938-942Imai, S., Usui, N., Sugiura, M., Osato, T., Sato, T., Tsutsumi, H., Tachi, N., Chiba, S., Epstein-Barr virus genomic sequences and specific antibodies in cerebrospinal fluid in children with neurologic complications of acute and reactivated EBV infections (1993) J Med Virol, 40, pp. 278-284Jeffery, K.J.M., Read, S.J., Peto, T.E.A., Mayon-White, R.T., Bangham, C.R.M., Diagnosis of viral infections of central nervous system: Clinical interpretation of PCR results (1997) Lancet, 249, pp. 313-317Juhl, D., Mosel, C., Nawroth, F., Funke, A.M., Dadgar, S.M., Hagenstrom, H., Kirchner, H., Hennig, H., Detection of herpes simplex virus DNA in plasma of patients with primary but not with recurrent infection: Implications for transfusion medicine (2010) Transfusion Med, 20, pp. 38-47Kaji, M., Shoji, H., Detection of Epstein-Barr virus genome in peripheral leucocytes and CSF by the polymerase chain reaction in two 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Withdrawal Of Maintenance Therapy For Cytomegalovirus Retinitis In Aids Patients Exhibiting Immunological Response To Haart

Background: Before the introduction of highly active antiretroviral therapy (HAART), CMV retinitis was a common complication in patients with advanced HIV disease and the therapy was well established; it consisted of an induction phase to control the infection with ganciclovir, followed by a lifelong maintenance phase to avoid or delay relapses. Methods: To determine the safety of CMV maintenance therapy withdrawal in patients with immune recovery after HAART, 35 patients with treated CMV retinitis, on maintenance therapy, with CD4+ cell count greater than 100 cells/mm3 for at least three months, but almost all patients presented these values for more than six months and viral load < 30000 copies/mL, were prospectively evaluated for the recurrence of CMV disease. Maintenance therapy was withdrawal at inclusion, and patients were monitored for at least 48 weeks by clinical and ophthalmologic evaluations, and by determination of CMV viremia markers (antigenemia-pp65), CD4+/CD8+ counts and plasma HIV RNA levels. Lymphoproliferative assays were performed on 26/35 patients. Results: From 35 patients included, only one had confirmed reactivation of CMV retinitis, at day 120 of follow-up. No patient returned positive antigenemia tests. No correlation between lymphoproliferative assays and CD4+ counts was observed. Conclusion: CMV retinitis maintenance therapy discontinuation is safe for those patients with quantitative immune recovery after HAART.494215219ACTG, Mortality in patients with the acquired immunodeficiency syndrome treated with either foscarnet or ganciclovir for cytomegalovirus retinitis. Studies of Ocular Complications of AIDS Research Group, in collaboration with the AIDS Clinical Trials Group. New Engl. J. Med, 326: 213-220, 1992BERENGUER, J., GONZALEZ, J., PULIDO, J., Discontinuation of secondary prophylaxis in patients with cytomegalovirus retinitis who have responded to highly active antiretroviral therapy (2002) Clin. infect. Dis, 34, pp. 394-397BONON, S.H., MENONI, S.M.F., ROSSI, C.L., Surveillance of cytomegalovirus infection in haematopoietic stem cell transplantation patients (2005) J. Infect, 50, pp. 130-137CASSOUX, N., BODAGHI, B., KATLAMA, C., LEHOANG, P., CMV retinitis in the era of HAART (1999) Ocul. Immunol. Inflamm, 7, pp. 231-235CURI, A.L., MURALHA, A., MURALHA, L., PAVESIO, C., Suspension of anticytomegalovirus maintenance therapy following immune recovery due to highly active antiretroviral therapy (2001) Brit. J. Ophthal, 85, pp. 471-473DEAYTON, J.WILSON, J.R.SABIN, P. et al. - Recovery of antibody responses to Cytomegalovirus (CMV) Glycoprotein B (gB) following Highly Active Antiretroviral Therapy (HAART). In: CONFERENCE ON RETROVIRUSES AND OPPORTUNISTIC INFECTIONS, 6., Chicago, 1999. p. 153DEAYTON, J.R., WILSON, P., SABIN, C., Changes in the natural history of cytomegalovirus retinitis following the introduction of highly active antiretroviral therapy (2000) Aids, 14, pp. 1163-1670DEGREZIA, M.G., ROBINSON, M., Ophthalmic manifestations of HIV: An update (2001) J. Ass. Nurses AIDS Care, 12, pp. 22-32FRANCISCI, D., TOSTI, A., PREZIOSI, R., Role of antigenemia assay in the early diagnosis and prediction of human cytomegalovirus organ involvement in AIDS patients (1995) Europ. J. clin. Microbiol. infect. Dis, 14, pp. 498-503GALLANT, J.E., MOORE, R.D., RICHMAN, D.D., KERULY, J., CHAISSON, R.E., Incidence and natural history of cytomegalovirus disease in patients with advanced human immunodeficiency virus disease treated with zidovudine. The Zidovudine Epidemiology Study Group (1992) J. infect. Dis, 166, pp. 1223-1227GERNA, G., PICCININI, G., GENINI, E., Declining levels of rescued lymphoproliferative response to human cytomegalovirus (HCMV) in AIDS patients with or without HCMV disease following long-term HAART (2001) J. acquir. immune Defic. Syndr, 28, pp. 320-331GOLDBERG, D.E., SMITHEN, L.M., ANGELILLI, A., FREEMAN, W.R., HIV-associated retinopathy in the HAART era (2005) Retina, 25, pp. 633-649HALWACHS, G., ZACH, G., POGGLITSCH, H., A rapid immunocytochemical assay for CMV detection in peripheral blood of organ-transplanted patients in clinical practice (1993) Transplantation, 56, pp. 338-342HENDERSON, H.W., MITCHELL, S.M., Treatment of immune recovery vitritis with local steroids (1999) Brit. J. Ophthal, 83, pp. 540-545HOOVER, D.R., PENG, Y., SAAH, A., Occurrence of cytomegalovirus retinitis after human immunodeficiency virus immunosuppression (1996) Arch. Ophthal, 114, pp. 821-827JABS, D.A., VAN NATTA, M.L., KEMPEN, M.L., Characteristics of patients with cytomegalovirus retinitis in the era of highly active antiretroviral therapy (2002) Amer. J. Ophthal, 133, pp. 48-61JACOBSON, M.A., Treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome (1997) New Engl. J. Med, 337, pp. 105-114JACOBSON, M.A., ZEGANS, M.A., PAVAN, M., Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy (1997) Lancet, 349, pp. 1443-1445JOUAN, M.SAVES, M.TUBIANA, M. et al. - A prospective multicentre study to evaluate the discontinuation of maintenance therapy for CMV Retinitis in HIV-patients receiving HAART. In: CONFERENCE ON RETROVIRUSES AND OPPORTUNISTIC INFECTIONS, 6., Chicago, 1999JOUAN, M., SAVES, M., TUBIANA, M., Discontinuation of maintenance therapy for cytomegalovirus retinitis in HIV-infected patients receiving highly active antiretroviral therapy (2001) Aids, 15, pp. 23-31KARAVELLAS, M.P., PLUMMER, M.P., MACDONALD, D.J., Incidence of immune recovery vitritis in cytomegalovirus retinitis patients following institution of successful highly active antiretroviral therapy (1999) J. infect. Dis, 179, pp. 697-700KEANE, N.M., PRICE, P., STONE, S.F., Assessment of immune function by lymphoproliferation underestimates lymphocyte functional capacity in HIV patients treated with highly active antiretroviral therapy (2000) AIDS Res. hum. Retroviruses, 16, pp. 1991-1996LI, T.S., TUBIANA, R., KATLAMA, C., Long-lasting recovery in CD4 T-cell function and viral-load reduction after highly active antiretroviral therapy in advanced HIV-1 disease (1998) Lancet, 351, pp. 1682-1686MACDONALD, J.C., KARAVELLAS, M.P., TORRIANI, F.J., Highly active antiretroviral therapy-related immune recovery in AIDS patients with cytomegalovirus retinitis (2000) Ophthalmology, 107, pp. 877-881MACDONALD, J.C., TORRIANI, F.J., MORSE, L.S., Lack of reactivation of cytomegalovirus (CMV) retinitis after stopping CMV maintenance therapy in AIDS patients with sustained elevations in CD4 T cells in response to highly active antiretroviral therapy (1998) J. infect. Dis, 177, pp. 1182-1187MARGOLIS, T.P., Discontinuation of anticytomegalovirus therapy in patients with HIV infection and cytomegalovirus retinitis (2000) Surv. Ophthal, 44, p. 455MITCHELL, S.M., MEMBREY, W.L., YOULE, M.S., Cytomegalovirus retinitis after the initiation of highly active antiretroviral therapy: A 2-year prospective study (1999) Brit. J. Ophthal, 83, pp. 652-655PANNUTI, C.S., KALLAS, E.G., MUCCIOLI, C., Cytomegalovirus antigenemia in acquired immunodeficiency syndrome patients with untreated cytomegalovirus retinitis (1996) Amer. J. Ophthal, 122, pp. 847-852PICCININI, G., COMOLLI, G., GENINI, G., Comparative analysis of human cytomegalovirus-specific CD4(+) T-cell frequency and lymphoproliferative response in human immunodeficiency virus-positive patients (2001) Clin. diagn. Lab. Immunol, 8, pp. 1225-1230POSTELMANS, L., GERARD, M., SOMMEREIJNS, B., CASPERS-VELU, L., Discontinuation of maintenance therapy for CMV retinitis in AIDS patients on highly active antiretroviral therapy (1999) Ocul. Immunol. 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Quercetin As An Inhibitor Of Snake Venom Secretory Phospholipase A2

As polyphenolic compounds isolated from plants extracts, flavonoids have been applied to various pharmaceutical uses in recent decades due to their anti-inflammatory, cancer preventive, and cardiovascular protective activities. In this study, we evaluated the effects of the flavonoid quercetin on Crotalus durissus terrificus secretory phospholipase A2 (sPLA2), an important protein involved in the release of arachidonic acid from phospholipid membranes. The protein was chemically modified by treatment with quercetin, which resulted in modifications in the secondary structure as evidenced through circular dichroism. In addition, quercetin was able to inhibit the enzymatic activity and some pharmacological activities of sPLA2, including its antibacterial activity, its ability to induce platelet aggregation, and its myotoxicity by approximately 40%, but was not able to reduce the inflammatory and neurotoxic activities of sPLA2. These results suggest the existence of two pharmacological sites in the protein, one that is correlated with the enzymatic site and another that is distinct from it. We also performed molecular docking to better understand the possible interactions between quercetin and sPLA2. Our docking data showed the existence of hydrogen-bonded, polar interactions and hydrophobic interactions, suggesting that other flavonoids with similar structures could bind to sPLA2. Further research is warranted to investigate the potential use of flavonoids as sPLA2 inhibitors. © 2010 Elsevier Ireland Ltd. All rights reserved.18901/02/15916Kini, R., Excitement ahead: Structure, function and mechanism of snake venom phospholipase A2 enzymes (2003) Toxicon, 42 (8), pp. 827-840Nevalainen, T., Graham, G., Scott, K., Antibacterial actions of secreted phospholipases A2. Review (2008) Biochim. Biophys. Acta, 1781 (12), pp. 1-9Burke, J., Dennis, E., Phospholipase A2 biochemistry (2009) Cardiovasc. 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Des., 21 (8), pp. 473-483Di Carlo, G., Mascolo, N., Izzo, A., Capasso, F., Flavonoids: Old and new aspects of a class of natural therapeutic drugs (1999) Life Sci., 65 (4), pp. 337-353Gil, B., Sanz, M., Terencio, M., Gunasegaran, R., Paya, M., Alcaraz, M., Morelloflavone, a novel biflavonoid inhibitor of human secretory phospholipase A(2) with anti-inflammatory activity (1997) Biochem. Pharmacol., 53, p. 733Lindahl, M., Tagesson, C., Flavonoids as phospholipase A2 inhibitors: Importance of their structure for selective inhibition of group II phospholipase A2 (1997) Inflammation, 21 (3), pp. 347-356Iglesias, C., Aparicio, R., Rodrigues-Simioni, L., Camargo, E., Antunes, E., Marangoni, S., De Oliveira Toyama, D., Toyama, M., Effects of morin on snake venom phospholipase A2 (PLA2) (2005) Toxicon, 46 (7), pp. 751-758Lindahl, M., Tagesson, C., Selective inhibition of group II phospholipase A2 by quercetin (1993) Inflammation, 17 (5), pp. 573-582Toyama, M.H., De Oliveira, D.G., Beriam, L.O.S., Novello, J.C., Rodrigues-Simioni, L., Marangoni, S., Structural, enzymatic and biological properties of new PLA2 isoform from Crotalus durissus terrificus venom (2003) Toxicon, 41 (8), pp. 1033-1038. , DOI 10.1016/S0041-0101(03)00085-0Zhao, H., Tang, L., Wang, X., Zhou, Y., Lin, Z., Structure of a snake venom phospholipase A2 modified by p-bromo-phenacyl-bromide (1998) Toxicon, 36 (6), pp. 875-886Laemmli, U., Cleavage of structural proteins during the assembly of the head of bacteriophage T4 (1970) Nature, 227 (5259), pp. 680-685Wen-Hwa, L., Toyama, M.H., Soares, A.M., Giglio, J.R., Marangoni, S., Polikarpov, I., Crystallization and preliminary X-ray diffraction studies of piratoxin III, a D-49 phospholipase A2 from the venom of Bothrops pirajai (1999) Acta Crystallographica Section D: Biological Crystallography, 55 (6), pp. 1229-1230. , DOI 10.1107/S0907444999004576Santi-Gadelha, T., Rocha, B., Oliveira, C., Aragão, K., Marinho, E., Gadelha, C., Toyama, M., Cavada, B., Purification of a PHA-like chitin-binding protein from Acacia farnesiana seeds: A time-dependent oligomerization protein (2008) Appl. 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Umbelliferone Induces Changes In The Structure And Pharmacological Activities Of Bn Iv, A Phospholipase A2 Isoform Isolated From Bothrops Neuwiedi

In this paper was demonstrated that umbelliferone induces changes in structure and pharmacological activities of Bn IV, a lysine 49 secretory phospholipase A2 (sPLA2) from Bothrops neuwiedi. Incubation of Bn IV with umbelliferone virtually abolished platelet aggregation, edema, and myotoxicity induced by native Bn IV. The amino acid sequence of Bn IV showed high sequence similarities with other Lys49 sPLA2s from B. jararacussu (BthTx-I), B. pirajai (PrTx-I), and B. neuwiedi pauloensis (Bn SP6 and Bn SP7). This sPLA2 also has a highly conserved C-terminal amino acid sequence, which has been shown as important for the pharmacological activities of Lys49 sPLA2. Sequencing of Bn IV previously treated with umbelliferone revealed modification of S(1) and S(20). Fluorescent spectral analysis and circular dichroism (CD) studies showed that umbelliferone modified the secondary structure of this protein. Moreover, the pharmacological activity of Bn IV is driven by synergism of the C-terminal region with the α-helix motifs, which are involved in substrate binding of the Asp49 and Lys49 residues of sPLA2 and have a direct effect on the Ca2+-independent membrane damage of some secretory snake venom PLA2. For Bn IV, these interactions are potentially important for triggering the pharmacological activity of this sPLA2. © 2011 Elsevier Ltd.576851860Chan, A.C., Pritchard, E.T., Gerrard, J.M., Man, R.Y., Choy, P.C., Biphasic modulation of platelet phospholipase A2 activity and platelet aggregation by mepacrine (quinacrine) (1982) Biochim. Biophys. 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Acta, 1474, pp. 56-60Toyama, M.H., Soares, A.M., Wen-Hwa, L., Polikarpov, I., Giglio, J.R., Marangoni, S., Amino acid sequence of piratoxin-II, a myotoxic lys49 phospholipase A(2) homologue from Bothrops pirajai venom (2000) Biochimie, 82 (3), pp. 245-250Toyama, M.H., de Oliveira, D.G., Beriam, L.O., Novello, J.C., Rodrigues-Simioni, L., Marangoni, S., Structural, enzymatic and biological properties of new PLA(2) isoform from Crotalus durissus terrificus venom (2003) Toxicon, 41, pp. 1033-1038Toyama, M.H., Toyama, D.O., Joazeiro, P.P., Carneiro, E.M., Beriam, L.O.S., Marangoni, S., Boschero, A.C., Biological and structural characterization of a new PLA(2) from the Crotalus durissus collilineatus venom (2005) Protein J., 24, pp. 103-112Toyama, D.O., Marangoni, S., Diz-Filho, E.B., Oliveira, S.C., Toyama, M.H., Effect of umbelliferone (7-hydroxycoumarin, 7-HOC) on the enzymatic, edematogenic and necrotic activities of secretory phospholipase A2 (sPLA2) isolated from Crotalus durissus collilineatus venom (2009) Toxicon, 53 (4), pp. 417-426Vincent, J.E., Zijlstra, F.J., Biphasic effects of phospholipase A2 on platelet aggregation. 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