SERGIO PAULO BYDLOWSKI
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Clínica Médica, Faculdade de Medicina - Docente
LIM/19 - Laboratório de Histocompatibilidade e Imunidade Celular, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/19 - Laboratório de Histocompatibilidade e Imunidade Celular, Hospital das Clínicas, Faculdade de Medicina - Líder
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- Effects of Oxysterols on Immune Cells and Related Diseases(2022) FREITAS, Fabio Alessandro de; LEVY, Debora; REICHERT, Cadiele Oliana; CUNHA-NETO, Edecio; KALIL, Jorge; BYDLOWSKI, Sergio PauloOxysterols are the products of cholesterol oxidation. They have a wide range of effects on several cells, organs, and systems in the body. Oxysterols also have an influence on the physiology of the immune system, from immune cell maturation and migration to innate and humoral immune responses. In this regard, oxysterols have been involved in several diseases that have an immune component, from autoimmune and neurodegenerative diseases to inflammatory diseases, atherosclerosis, and cancer. Here, we review data on the participation of oxysterols, mainly 25-hydroxycholesterol and 7 alpha,25-dihydroxycholesterol, in the immune system and related diseases. The effects of these oxysterols and main oxysterol receptors, LXR and EBI2, in cells of the immune system (B cells, T cells, macrophages, dendritic cells, oligodendrocytes, and astrocytes), and in immune-related diseases, such as neurodegenerative diseases, intestinal diseases, cancer, respiratory diseases, and atherosclerosis, are discussed.
- Paraoxonases (PON) 1, 2, and 3 Polymorphisms and PON-1 Activities in Patients with Sickle Cell Disease(2019) REICHERT, Cadiele Oliana; MACEDO, Carolina Garcia de; LEVY, Debora; SINI, Bruno Carnevale; MONTEIRO, Andreia Moreira; GIDLUND, Magnus; MASELLI, Luciana Morganti Ferreira; GUALANDRO, Sandra Fatima Menosi; BYDLOWSKI, Sergio Paulo(1) Background: Oxidative stress, chronic inflammation, vasoocclusion, and free iron are all features present in sickle cell disease. Paraoxonases (PON) are a family (PON-1, PON-2, PON-3) of antioxidant enzymes with anti-inflammatory action. Here, for the first time, we described PON-1 activities and PON-1, PON-2, PON-3 polymorphisms in patients with sickle cell disease, homozygous for HbSS, compared with healthy controls. (2) Methods: The groups were matched for age and gender. PON-1 activities (arylesterase and paraoxonase) were determined by enzymatic hydrolysis of phenylcetate and paraoxon, respectively. Polymorphisms were determined by Restriction Fragment Length Polymorphism- Polymerase Chain Reaction (RFLP-PCR). (3) Results: Plasma cholesterol and fractions, ApoA1 and ApoB levels were all decreased in sickle cell disease patients, while anti-oxidized low-density lipoprotein (LDL) antibodies and C-reactive protein were increased. Serum arylesterase activity was lower in sickle cell disease patients when compared with healthy controls. In patients, paraoxonase activity was higher in those with PON-1 RR Q192R polymorphism. In these patients, the increase of serum iron and ferritin levels and transferrin saturation were less pronounced than those observed in patients with QQ or QR polymorphism. No differences were observed with PON-1 L55M, and PON-2 and PON-3 polymorphisms. Multivariate regression analysis showed that transferrin and ferritin concentrations correlated with arylesterase and paraoxonase activities. (4) Conclusions: Both transferrin and ferritin were the main predictors of decreased arylesterase and paraoxonase activities in patients with sickle cell disease. LDL oxidation increased, and RR PON-1 Q192R polymorphism is likely to be a protective factor against oxidative damage in these patients.
conferenceObject POTENTIAL IMMUNOLOGICAL MARKERS FOR DIAGNOSIS OF HUMAN STRONGYLOIDIASIS USING HETEROLOGOUS ANTIGENS(2017) GRYSCHEK, Ronaldo; CORRAL, Marcelo; PAULA, Fabiana; MEISEL, Dirce; CASTILHO, Vera; GONCALVES, Elenice; LEVY, Debora; BYDLOWSKI, Sergio; CHIEFFI, Pedro Paulo; CASTRO-BORGES, WilliambookPart Farmacogenética nas doenças hematológicas(2016) BYDLOWSKI, Sérgio Paulo; LEVY, Debora- Synergistic anti-tumor effects of the combination of a benzofuroxan derivate and sorafenib on NCI-H460 human large cell lung carcinoma cells(2014) TEIXEIRA, Sarah Fernandes; AZEVEDO, Ricardo Alexandre de; SALOMON, Maria Alejandra Clavijo; JORGE, Salomao Doria; LEVY, Debora; BYDLOWSKI, Sergio Paulo; RODRIGUES, Cecilia Pessoa; PIZZO, Celia Regina; BARBUTO, Jose Alexandre Marzagao; FERREIRA, Adilson KleberLung cancer is the most frequent and lethal human cancer in the world. Because is still an unsolved health issue, new compounds or therapeutic strategies are urgently needed. Furoxans are presented as potentials candidates for lung cancer treatment. Accordingly, we evaluated the efficacy of a benzofuroxan derivative, BFD-22, alone and combined with sorafenib against NCI-H460 cell line. We showed that BFD-22 has cytotoxic effects on the NCI-H460 cells. Importantly, the Combination Index (CI) evaluation revels that BFD-22 combined with sorafenib has a stronger cytotoxic effect. In addition, the combination induces apoptosis through extrinsic pathway, leading to TRAIL-R1/DR4-triggered apoptosis. Furthermore, BFD-22 combined with sorafenib increases ROS production and simultaneously reduces perlecan expression in the NCI-H460 cells. In accordance, tumor cells were arrested in the S-phase, and these anti-proliferative effects also inhibit cell migration. This is the first study reporting an advantage of BFD-22 combined with sorafenib as a new therapeutic strategy in the fight against lung cancer.
- Short-term effects of 7-ketocholesterol on human adipose tissue mesenchymal stem cells in vitro(2014) LEVY, Debora; RUIZ, Jorge Luis Maria; CELESTINO, Andrea Turbuck; SILVA, Suelen Feitoza; FERREIRA, Adilson Kleber; ISAAC, Cesar; BYDLOWSKI, Sergio PauloOxysterols comprise a very heterogeneous group derived from cholesterol through enzymatic and nonenzymatic oxidation. Among them, 7-ketocholesterol (7-KC) is one of the most important. It has potent effects in cell death processes, including cytoxicity and apoptosis induction. Mesenchymal stem cells (MSCs) are multipotent cells characterized by self-renewal and cellular differentiation capabilities. Very little is known about the effects of oxysterols in MSCs. Here, we describe the short-term cytotoxic effect of 7-ketocholesterol on MSCs derived from human adipose tissue. MSCs were isolated from adipose tissue obtained from two young, healthy women. After 24 h incubation with 7-KC, mitochondrial hyperpolarization was observed, followed by a slight increase in the level of apoptosis and changes in actin organization. Finally, the IC50 of 7-KC was higher in these cells than has been observed or described in other normal or cancer cell lines.
- LIMD2 Regulates Key Steps of Metastasis Cascade in Papillary Thyroid Cancer Cells via MAPK Crosstalk(2020) ARALDI, Rodrigo Pinheiro; MELO, Thatiana Correa de; LEVY, Debora; SOUZA, Dener Madeiro de; MAURICIO, Beatriz; COLOZZA-GAMA, Gabriel Avelar; BYDLOWSKI, Sergio Paulo; PENG, Hongzhuang; III, Frank J. Rauscher; CERUTTI, Janete MariaAlthough papillary thyroid carcinoma (PTC) has a good prognosis, 20-90% of patients show metastasis to regional lymph nodes and 10-15% of patients show metastasis to distant sites. Metastatic disease represents the main clinical challenge that impacts survival rate. We previously showed that LIMD2 was a novel metastasis-associated gene. In this study, to interrogate the role of LIMD2 in cancer invasion and metastasis, we used CRISPR-mediated knockout (KO) of LIMD2 in PTC cells (BCPAP and TPC1). Western blot and high-content screening (HCS) analysis confirmed functional KO of LIMD2. LIMD2 KO reduced in vitro invasion and migration. Ultrastructural analyses showed that cell polarity and mitochondria function and morphology were restored in LIMD2 KO cells. To unveil the signals supervising these phenotypic changes, we employed phospho-protein array. Several members of the MAPK superfamily showed robust reduction in phosphorylation. A Venn diagram displayed the overlap of kinases with reduced phosphorylation in both cell lines and showed that they were able to initiate or sustain the epithelial-mesenchymal transition (EMT) and DNA damage checkpoint. Flow cytometry and HCS validation analyses further corroborated the phospho-protein array data. Collectively, our findings show that LIMD2 enhances phosphorylation of kinases associated with EMT and invasion. Through cooperation with different kinases, it contributes to the increased genomic instability that ultimately promotes PTC progression.
- Beneficial effects of IL-4 and IL-6 on rat neonatal target cardiac cells(2020) ZOGBI, Camila; OLIVEIRA, Nathalia C.; LEVY, Debora; BYDLOWSKI, Sergio P.; BASSANEZE, Vinicius; NERI, Elida A.; KRIEGER, Jose E.The nature of the early post-natal immune response in rodents appears to influence cardiac regeneration even though the underlying molecules remain poorly understood. Consistent with this idea, we show now significant changes in the expression of immune and cell movement gene pathways in heart samples from 1- and 7-day-old rats with ventricle resection. We then tested whether conditioned media from adult M2 anti-inflammatory macrophages target neonatal cardiac cells to a pro-regenerative like phenotype compared to the M1 pro-inflammatory macrophages. We found that M2 compared to M1 macrophage-conditioned media upregulates neonatal cardiomyocyte proliferation, suppresses myofibroblast-induced differentiation and stimulates endothelial cell tube formation. Using a cytokine array, we selected four candidate cytokine molecules uniquely expressed in M2 macrophage-conditioned media and showed that two of them (IL-4 and IL-6) induce endothelial cell proliferation whilst IL-4 promotes proliferation in neonatal cardiomyocytes and prevents myofibroblast-induced collagen type I secretion. Altogether, we provided evidence that adult M2 macrophage-conditioned media displays a paracrine beneficial pro-regenerative response in target cardiac cells and that IL-4 and IL-6 recapitulate, at least in part, these pleiotropic effects. Further characterization of macrophage immune phenotypes and their secreted molecules may give rise to novel therapeutic approaches for post-natal cardiac repair.
conferenceObject PARAOXONASE 3 POLYMORPHISMS ARE NOT ASSOCIATED WITH PROGRESSION FREE SURVIVAL AND OVERALL SURVIVAL IN DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS(2012) BYDLOWSKI, Sergio; SINI, Bruno; FLORES, Milagros; CHAVES, Denise; MASELLI, Luciana; PEREIRA, Juliana; LEVY, DeboraBackground: Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive lymphoma. It is a heterogeneous disease. Approximately 40% of the patients respond well to chemotherapy based on rituximab-CHOP (R-CHOP). The prognosis for the other 60% is poor and only half of the patients survive 5 years after the onset of the disease. The paraoxonase (PON) gene family is composed of three members (PON1, PON2, PON3). All the three proteins have been shown to exhibit antioxidant and anti-inflammatory properties. Evidences exist indicating that the PON family plays an important role in a variety of human illnesses such as cardiovascular disease, diabetes mellitus, metabolic syndrome, obesity, non-alcoloholic steatohepatitis and several mental disorders. However, their role inDLBCL is still unknown. Methods: 106 DLBCL patients treated with R-CHOP or CHOP were studied. Control group included 130 healthy blood donors. Blood was drawn and DNA extracted by conventional methods. Polymorphisms of PON3 were performed by real time polymerase chain reaction using TaqMan system. Results: Forty-six (43.4%) patients were in stage III-IV and 42 (39.6%) had more than 2 factors established by the International Prognostic Index (IPI). Seventy-nine (74.5%) achieved complete response (IC95%: 77-93%); 6 (5.6%) had partial response (RD) and 21 (19.9%) patients had refractory disease. Eighteen (16.9%) patients died in a follow up median of 29.6 months (5.5 to 72.7). Polymorphisms frequencies in control group were:76% and 24%, respectively, for the alleles PON3-10340T and PON3-10340G; 8% and 92%, respectively, for the alleles PON3-2115A and PON3-2115T; and 4% and 96%, respectively, for the alleles PON3-45486A and PON3-45486C. The frequencies in the group of patients were: 76% and 24% for the alleles PON3-10340T and PON3-10340G, respectively; 9% and 91% for the alleles PON3-2115A and PON3-2115T, respectively; and 1% and 99% for the alleles PON3-45486A and PON3-45486C, respectively. Fisher exact test showed no significant difference between groups. The overall response and progression-free survival of patients with DLBCL were not related to PON3 polymorphisms. Conclusion: The present data shows that PON3 polymorphisms do not play a role in diffuse large B-cell lymphoma.- Azidothymidine is Effective Against Human Multiple Myeloma: A New Use for an Old Drug?(2013) PEREIRA, Juliana; LEVY, Debora; RUIZ, Jorge L. M.; BROCARDO, Graciela A.; FERREIRA, Kleber A.; COSTA, Renata O.; QUEIROZ, Rodrigo G.; MARIA, Durvanei A.; HALLACK NETO, Abrahao E.; CHAMONE, Dalton A. F.; BYDLOWSKI, Sergio P.Azidothymidine (AZT) is an antiretroviral drug that affects cell proliferation, apoptosis, and the NF-kappa B pathway. As multiple myeloma (MM) presents with constitutive activation of NF-kappa B, we analyzed the effect of AZT on human MM cell lines. We evaluated the cytotoxic effect of AZT in human MM cell lines sensitive (8226/S) or resistant to doxorubicin (8226/DX5) and human T cell lymphoblast-like cells, uterine sarcoma cells, and HUVEC using MTT assay. Cytotoxicity was also evaluated in vivo in nude mice xenografted with 8226/S tumor. The effect of AZT on the expression of genes involved in cell proliferation, apoptosis, angiogenesis, and the NF-kappa B pathway was analyzed in the xenografts using real-time polymerase chain reaction. AZT was effective against both 8226/S and 8226/DX5 cells in a dose and time-dependent manner (p = 0.02) in vitro and promoted cell cycle arrest in S phase in these cells. The tumor volume was lower in mice treated with AZT compared to untreated mice (p = 0.0003). AZT down-regulated the pro-proliferative genes encoding AKT1, MYC, STAT1, MAPK8, MAPK9, CCL-3, Bcl-3, and cyclin D2; pro-angiogenenic genes encoding VEGF and IL8; and genes involved in cell adhesion (ICAM1 and FN1) and the NF-kappa B pathway. AZT up-regulated the expression of tumor suppressor gene FOXP1 and the pro-apoptotic genes encoding BID, Bcl-10, and caspase-8. Thus, we demonstrated the cytotoxic effect of AZT in human MM cell lines for the first time. Our data may provide the rationale for future clinical trials of AZT for treating MM.