Fábio Rodrigues Ferreira Seiva
@uenp.edu.br
Universidade Estadual do Norte do Paraná - UNEP/CLM
Scopus Publications
Scopus Publications
Juliana M.B. de Morais, Ellen M.S. Cruz, Virgínia M. Concato, Milena C. de Souza, Yasmin M. Santos, Débora H. Quadreli, Fabrício S.R. Inoue, Francielle B. Ferreira, Glaura S.A. Fernandes, Danielle L. Bidóia,et al.
Elsevier BV
Wesley Ladeira Caputo, Milena Cremer de Souza, Caroline Rodrigues Basso, Valber de Albuquerque Pedrosa, and Fábio Rodrigues Ferreira Seiva
MDPI AG
Background: Drug repurposing is a strategy that complements the conventional approach of developing new drugs. Hepatocellular carcinoma (HCC) is a highly prevalent type of liver cancer, necessitating an in-depth understanding of the underlying molecular alterations for improved treatment. Methods: We searched for a vast array of microarray experiments in addition to RNA-seq data. Through rigorous filtering processes, we have identified highly representative differentially expressed genes (DEGs) between tumor and non-tumor liver tissues and identified a distinct class of possible new candidate drugs. Results: Functional enrichment analysis revealed distinct biological processes associated with metal ions, including zinc, cadmium, and copper, potentially implicating chronic metal ion exposure in tumorigenesis. Conversely, up-regulated genes are associated with mitotic events and kinase activities, aligning with the relevance of kinases in HCC. To unravel the regulatory networks governing these DEGs, we employed topological analysis methods, identifying 25 hub genes and their regulatory transcription factors. In the pursuit of potential therapeutic options, we explored drug repurposing strategies based on computational approaches, analyzing their potential to reverse the expression patterns of key genes, including AURKA, CCNB1, CDK1, RRM2, and TOP2A. Potential therapeutic chemicals are alvocidib, AT-7519, kenpaullone, PHA-793887, JNJ-7706621, danusertibe, doxorubicin and analogues, mitoxantrone, podofilox, teniposide, and amonafide. Conclusion: This multi-omic study offers a comprehensive view of DEGs in HCC, shedding light on potential therapeutic targets and drug repurposing opportunities.
Fabiano Gonçalves Costa, Chayrra Chehade Gomes, Mateus Contar Adolfi, Mayra Costa da Cruz Gallo de Carvalho, Marco Antônio Zanoni, Fábio Rodrigues Ferreira Seiva, and Maria Inês Borella
Springer Science and Business Media LLC
Ellen Mayara Souza Cruz, Virginia Marcia Concato, Juliana Maria Bitencourt de Morais, Taylon Felipe Silva, Fabricio Seidy Ribeiro Inoue, Milena de Souza Cremer, Danielle Lazarin Bidóia, Rayanne Regina Beltrame Machado, Luiz Gustavo de Almeida Chuffa, Mário Sérgio Mantovani,et al.
Elsevier BV
M. Cucielo, R. C. Cesário, H. S. Silveira, L. B. Gaiotte, S. A. A. Dos Santos, D. A. P. de Campos Zuccari, F. Seiva, R. Reiter and L. G. de Almeida Chuffa
Ovarian cancer (OC) is the most lethal gynecologic malignancy, and melatonin has shown various antitumor properties. Herein, we investigated the influence of melatonin therapy on energy metabolism and mitochondrial integrity in SKOV-3 cells and tested whether its effects depended on MT1 receptor activation. SKOV-3 cells were exposed to different melatonin concentrations, and experimental groups were divided as to the presence of MT1 receptors (melatonin groups) or receptor absence by RNAi silencing (siRNA MT1+melatonin). Intracellular melatonin levels increased after treatment with melatonin independent of the MT1. The mitochondrial membrane potential of SKOV-3 cells decreased in the group treated with the highest melatonin concentration. Melatonin reduced cellular glucose consumption, while MT1 knockdown increased its consumption. Interconversion of lactate to pyruvate increased after treatment with melatonin and was remarkable in siRNA MT1 groups. Moreover, lactate dehydrogenase activity decreased with melatonin and increased after MT1 silencing at all concentrations. The UCSC XenaBrowser tool showed a positive correlation between the human ASMTL gene and the ATP synthase genes, succinate dehydrogenase gene (SDHD), and pyruvate dehydrogenase genes (PDHA and PDHB). We conclude that melatonin changes the glycolytic phenotype and mitochondrial integrity of SKOV-3 cells independent of the MT1 receptor, thus decreasing the survival advantage of OC cells.
Luiz Gustavo de Almeida Chuffa, Milena Cremer de Souza, Ellen Mayara Souza Cruz, Francielle Belinelli Ferreira, Juliana Maria Bitencourt de Morais, and Fábio Rodrigues Ferreira Seiva
Elsevier BV
Roberta Carvalho Cesário, Leticia Barbosa Gaiotte, Maira Smaniotto Cucielo, Henrique Spaulonci Silveira, Lucilene Delazari dos Santos, Debora Aparecida Pires de Campos Zuccari, Fábio Rodrigues Ferreira Seiva, Russel J. Reiter, and Luiz Gustavo de Almeida Chuffa
Elsevier BV
Dayane Priscila dos Santos, Diogo Farias Ribeiro, Giovanna Fachetti Frigoli, Rafaela Pires Erthal, Suellen Ribeiro da Silva Scarton, Glaucia Eloísa Munhoz de Lion Siervo, Fábio Rodrigues Ferreira Seiva, Larissa Staurengo-Ferrari, Waldiceu Aparecido Verri, Rafael Deminice,et al.
Springer Science and Business Media LLC
The hyperhomocysteinemia (HHcy) is toxic to the cells and associated with several diseases. Clinical studies have shown changes in plasma concentrations of Hcy after physical exercise. This study aimed to assess the effect of HHcy on testis, epididymis and sperm quality and to investigate whether voluntary exercise training protects this system against damage caused by HHcy in Swiss mice. In this study, 48 mice were randomly distributed in the control, HHcy, physical exercise, and HHcy combined with physical exercise groups. HHcy was induced by daily administration of dl-homocysteine thiolactone via gavage throughout the experimental period. Physical exercise was performed through voluntary running on the exercise wheels. The plasma concentrations of homocysteine (Hcy) and testosterone were determined. The testes and epididymis were used to assess the sperm count, histopathology, lipoperoxidation, cytokine levels, testicular cholesterol, myeloperoxidase, and catalase activity. Spermatozoa were analyzed for morphology, acrosome integrity, mitochondrial activity, and motility. In the testes, HHcy increased the number of abnormal seminiferous tubules, reduced the tubular diameter and the height of the germinal epithelium. In the epididymis, there was tissue remodeling in the head region. Ultimately, voluntary physical exercise training reduced plasma Hcy concentration but did not attenuate HHcy-induced testicular and epididymal disturbances.
Luiz Gustavo de Almeida Chuffa, Fábio Rodrigues Ferreira Seiva, Adriana Alonso Novais, Vinícius Augusto Simão, Virna Margarita Martín Giménez, Walter Manucha, Debora Aparecida Pires de Campos Zuccari, and Russel J. Reiter
MDPI AG
The use of nanosized particles has emerged to facilitate selective applications in medicine. Drug-delivery systems represent novel opportunities to provide stricter, focused, and fine-tuned therapy, enhancing the therapeutic efficacy of chemical agents at the molecular level while reducing their toxic effects. Melatonin (N-acetyl-5-methoxytriptamine) is a small indoleamine secreted essentially by the pineal gland during darkness, but also produced by most cells in a non-circadian manner from which it is not released into the blood. Although the therapeutic promise of melatonin is indisputable, aspects regarding optimal dosage, biotransformation and metabolism, route and time of administration, and targeted therapy remain to be examined for proper treatment results. Recently, prolonged release of melatonin has shown greater efficacy and safety when combined with a nanostructured formulation. This review summarizes the role of melatonin incorporated into different nanocarriers (e.g., lipid-based vesicles, polymeric vesicles, non-ionic surfactant-based vesicles, charge carriers in graphene, electro spun nanofibers, silica-based carriers, metallic and non-metallic nanocomposites) as drug delivery system platforms or multilevel determinations in various in vivo and in vitro experimental conditions. Melatonin incorporated into nanosized materials exhibits superior effectiveness in multiple diseases and pathological processes than does free melatonin; thus, such information has functional significance for clinical intervention.
Juliana Maria Bitencourt de Morais, Ellen Mayara Souza Cruz, Carlos Vinícius Dalto da Rosa, Roberta Carvalho Cesário, Jurandir Fernando Comar, Carolina Campos Lima Moreira, Luiz Gustavo de Almeida Chuffa, and Fábio Rodrigues Ferreira Seiva
Elsevier BV
AIMS
The present study investigated the potential effects of pterostilbene (PT) on glycemic and lipid profiles, fat storage, cardiovascular indices, and hepatic parameters of rats fed with sucrose solution.
MAIN METHODS
24 male Wistar rats received either drinking water or a 40% sucrose solution over a period of 140 days. After this period, animals were randomly allocated into four groups (n = 6): Control (C), C + Pterostilbene (PT), Sucrose (S), and S + PT. Pterostilbene (40 mg/kg) was given orally for 45 consecutive days.
KEY FINDINGS
Pterostilbene did not influence morphometric and nutritional parameters. The insulin sensitivity index TyG was elevated in the C + PT group (p < 0.01) and reduced in S + PT group (p < 0.05). Basal glucose levels were lower in the S + PT group (p < 0.05), and the glycemic response was improved with PT treatment in a glucose provocative test. Conversely, rats from the C + PT group showed impaired glucose disposal after during those tests. Lipid profile was partially improved by PT treatment. Hepatic oxidative stress in the S group was improved after PT treatment. In the C group, PT reduced SOD activity, glutathione levels, and increased catalase activity. Collagen content was reduced by PT treatment.
SIGNIFICANCE
PT effects depends on the type of diet the animals were submitted. In rats fed with sucrose-solution, PT confirmed its positive effects, improving glucose and lipid profile, and acting as a potent antioxidant. The effects of PT on rats that consumed a normal diet were very discrete or even undesirable. We suggest caution with indiscriminate consume of natural compounds by healthy subjects.
David Livingstone Alves Figueiredo, João Paulo Bianchi Ximenez, Fábio Rodrigues Ferreira Seiva, Carolina Panis, Rafael dos Santos Bezerra, Adriano Ferrasa, Alessandra Lourenço Cecchini, Alexandra Ivo de Medeiros, Ana Marisa Fusco Almeida, Anelisa Ramão,et al.
FapUNIFESP (SciELO)
Abstract Coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2), is the largest pandemic in modern history with very high infection rates and considerable mortality. The disease, which emerged in China’s Wuhan province, had its first reported case on December 29, 2019, and spread rapidly worldwide. On March 11, 2020, the World Health Organization (WHO) declared the COVID-19 outbreak a pandemic and global health emergency. Since the outbreak, efforts to develop COVID-19 vaccines, engineer new drugs, and evaluate existing ones for drug repurposing have been intensively undertaken to find ways to control this pandemic. COVID-19 therapeutic strategies aim to impair molecular pathways involved in the virus entrance and replication or interfere in the patients’ overreaction and immunopathology. Moreover, nanotechnology could be an approach to boost the activity of new drugs. Several COVID-19 vaccine candidates have received emergency-use or full authorization in one or more countries, and others are being developed and tested. This review assesses the different strategies currently proposed to control COVID-19 and the issues or limitations imposed on some approaches by the human and viral genetic variability.
Luiz Gustavo de Almeida Chuffa, Robson Francisco Carvalho, Luis Antônio Justulin, Sarah Santiloni Cury, Fábio Rodrigues Ferreira Seiva, Bruna Victorasso Jardim‐Perassi, Debora Aparecida Pires de Campos Zuccari, and Russel J. Reiter
Wiley
Melatonin is a ubiquitous molecule with a broad spectrum of functions including widespread anti‐cancer activities. Identifying how melatonin intervenes in complex molecular signaling at the gene level is essential to guide proper therapies. Using meta‐analysis approach, herein we examined the role of melatonin in regulating the expression of 46 microRNAs (miRNAs) and their target genes in breast, oral, gastric, colorectal, and prostate cancers, and glioblastoma. The deregulated miRNA‐associated target genes revealed their involvement in the regulation of cellular proliferation, differentiation, apoptosis, senescence, and autophagy. Melatonin changes the expression of miRNA‐associated genes in breast, gastric, and oral cancers. These genes are associated with cellular senescence, the hedgehog signaling pathway, cell proliferation, p53 signaling, and the hippo signaling pathway. Conversely, colorectal and prostate cancers as well as glioblastoma and oral carcinoma present a clear pattern of less pronounced changes in the expression of miRNA‐associated genes. Most notably, colorectal cancer displayed a unique molecular change in response to melatonin. Considering breast cancer network complexity, we compared the genes found during the meta‐analysis with RNA‐Seq data from breast cancer‐bearing mice treated with melatonin. Mechanistically, melatonin upregulated genes associated with immune responses and apoptotic processes, whereas it downregulated genes involved in cellular aggressiveness/metastasis (eg, mitosis, telomerase activity, and angiogenesis). We further characterized the expression profile of our gene subsets with human breast cancer and found eight upregulated genes and 16 downregulated genes that were appositively correlated with melatonin. Our results pose a multi‐dimension network of tumor‐associated genes regulated by miRNAs potentially targeted by melatonin.
Luiz Antonio Lupi, Maira Smaniotto Cucielo, Henrique Spaulonci Silveira, Letícia Barbosa Gaiotte, Roberta Carvalho Cesário, Fábio Rodrigues Ferreira Seiva, and Luiz Gustavo de Almeida Chuffa
Elsevier BV
Toll-like receptors (TLRs) are critical sensors related to inflammation and tumorigenesis. Among all subtypes, the TLR4 is a highly described transmembrane protein involved in the inflammatory process. The TLR4/myeloid differentiation factor 88 (MyD88) signaling pathway has been implicated in oncogenic events in several tissues and is associated with survival of patients. Through activation, TLR4 recruits adaptor proteins, i.e., MyD88 or TRIF, to triggers canonical and non-canonical signaling pathways that result in distinct immune responses. In most cancer cells, uncontrolled TLR4 signaling modifies the tumor microenvironment to proliferate and evade immune surveillance. By contrast, TLR4 activation can produce antitumor activities, thereby inhibiting tumor growth and enhancing the proper immune response. We review herein recent approaches on the role of the TLR4 signaling pathway and discuss potential candidates for gynecological cancer therapies; among these agents, natural and synthetic compounds have been tested both in vitro and in vivo. Since TLR4 ligands have been investigated as effective immune-adjuvants in the context of these aggressive malignancies, we described how TLR4 signaling controls part of the tumor-related inflammatory process and which are the new targeting molecules implicated in the regulation of tumorigenicity in ovarian, cervical, and endometrial cancers.
Ellen Mayara Souza Cruz, Juliana Maria Bitencourt de Morais, Carlos Vinícius Dalto da Rosa, Mellina da Silva Simões, Jurandir Fernando Comar, Luiz Gustavo de Almeida Chuffa, and Fábio Rodrigues Ferreira Seiva
The Company of Biologists
ABSTRACT As the number of overweight and obese people has risen in recent years, there has been a parallel increase in the number of people with metabolic syndrome, diabetes and non-alcoholic fatty liver disease. The consumption of artificially sweetened beverages contributes to these epidemics. This study investigated the long-term effects of ingestion of a 40% sucrose solution on serum and hepatic parameters in male Wistar rats (Rattus norvegicus). After 180 days, the glycemic response, lipid profile and hepatic oxidative stress were compared to those of rats maintained on water. Sucrose ingestion led to higher body weight, increased fat deposits, reduced voluntary food intake and reduced feeding efficiency. Rats that received sucrose solution showed early signs of glucose intolerance and insulin resistance, such as hyperinsulinemia. Serum triacylglycerol (TG), very-low density lipoprotein (VLDL), cholesterol, ALT and AST levels increased after sucrose consumption. Elevated malondialdehyde and superoxide dismutase (SOD) levels and reduced glutathione levels characterize the hepatic oxidative stress due to sucrose ingestion. Liver sample histology showed vacuolar traces and increased fibrotic tissue. Our data showed the harmful effects of chronic consumption of sucrose solution, which can cause alterations that are found frequently in obesity, glucose intolerance and non-alcoholic hepatic disease, characteristics of metabolic syndrome. Summary: Sucrose consumption in liquid form predisposes rats to obesity, alters glycemic and lipid profiles, and impairs hepatic oxidative metabolism; hence, we caution against excessive consumption of artificially-sweetened beverages.
Luiz Gustavo de Almeida Chuffa, Luiz Antonio Lupi, Maira Smaniotto Cucielo, Henrique Spaulonci Silveira, Russel J. Reiter, and Fábio Rodrigues Ferreira Seiva
MDPI AG
The development of the endometrium is a cyclic event tightly regulated by hormones and growth factors to coordinate the menstrual cycle while promoting a suitable microenvironment for embryo implantation during the “receptivity window”. Many women experience uterine failures that hamper the success of conception, such as endometrium thickness, endometriosis, luteal phase defects, endometrial polyps, adenomyosis, viral infection, and even endometrial cancer; most of these disturbances involve changes in endocrine components or cell damage. The emerging evidence has proven that circadian rhythm deregulation followed by low circulating melatonin is associated with low implantation rates and difficulties to maintain pregnancy. Given that melatonin is a circadian-regulating hormone also involved in the maintenance of uterine homeostasis through regulation of numerous pathways associated with uterine receptivity and gestation, the success of female reproduction may be dependent on the levels and activity of uterine and placental melatonin. Based on the fact that irregular production of maternal and placental melatonin is related to recurrent spontaneous abortion and maternal/fetal disturbances, melatonin replacement may offer an excellent opportunity to restore normal physiological function of the affected tissues. By alleviating oxidative damage in the placenta, melatonin favors nutrient transfer and improves vascular dynamics at the uterine–placental interface. This review focuses on the main in vivo and in vitro functions of melatonin on uterine physiological processes, such as decidualization and implantation, and also on the feto-maternal tissues, and reviews how exogenous melatonin functions from a mechanistic standpoint to preserve the organ health. New insights on the potential signaling pathways whereby melatonin resists preeclampsia and endometriosis are further emphasized in this review.
Carolina Ferreira Sampaio, Nicla Renata Lucchetta, Ana Paula Franco Punhagui, Philippe Rodrigues Banedetti, Nilton Syogo Arakawa, Fábio Rodrigues Ferreira Seiva, and Glaura Scantamburlo Alves Fernandes
Wiley
Bauhinia forficata is a medicinal plant that has flavonoid components with hypoglycemic, antioxidant, hepatoprotective, antibacterial, antiviral and anti‐inflammatory action. Aim of this study is to evaluate the action of B. forficata alcoholic extract in the male genital system of adult male Wistar rats. For that, 20 adult male Wistar rats were distributed into two experimental groups: the B. forficata group, receiving B. forficata alcoholic extract (0.1 ml/10 g body weight/day) on alternate days, and the control group, receiving just the vehicle for 30 days straight both via gavage. On the 31st day, the animals were euthanized, and the testis and epididymis were collected for histopathological, biochemical, morphometric, and sperm count analysis. Mass spectrometry identified new compounds in the extract: trans‐caffeic acid, liquiritigenin, gallocatechin, and 2,4,6‐trihydroxyphenanthren‐2‐glycoside. Biochemical analysis showed higher total cholesterol levels in the testis and lower malondialdehyde levels in the testis and epididymis, in the B. forficata group. The mast cell count showed a reduction in degranulated mast cells in the caput region of the epididymis, in the B. forficata group. The luminal compartment of the caput and the epithelial of the epididymis cauda were reduced, whereas the stromal region of the epididymis caput was increased in the B. forficata group, compared with the control group. The testicular tissue was less impaired, considering that all the histological analyses were similar to the control. We believe that B. forficata alcoholic extract in the male genital system showed antioxidant action, especially in the epididymal tissue.
Luiz Gustavo de Almeida Chuffa, Fábio Rodrigues Ferreira Seiva, Maira Smaniotto Cucielo, Henrique Spaulonci Silveira, Russel J. Reiter, and Luiz Antonio Lupi
Springer Science and Business Media LLC
Cancers of the reproductive organs have a strong association with mitochondrial defects, and a deeper understanding of the role of this organelle in preneoplastic–neoplastic changes is important to determine the appropriate therapeutic intervention. Mitochondria are involved in events during cancer development, including metabolic and oxidative status, acquisition of metastatic potential, resistance to chemotherapy, apoptosis, and others. Because of their origin from melatonin-producing bacteria, mitochondria are speculated to produce melatonin and its derivatives at high levels; in addition, exogenously administered melatonin accumulates in the mitochondria against a concentration gradient. Melatonin is transported into tumor cell by GLUT/SLC2A and/or by the PEPT1/2 transporters, and plays beneficial roles in mitochondrial homeostasis, such as influencing oxidative phosphorylation and electron flux, ATP synthesis, bioenergetics, calcium influx, and mitochondrial permeability transition pore. Moreover, melatonin promotes mitochondrial homeostasis by regulating nuclear DNA and mtDNA transcriptional activities. This review focuses on the main functions of melatonin on mitochondrial processes, and reviews from a mechanistic standpoint, how mitochondrial crosstalk evolved in ovarian, endometrial, cervical, breast, and prostate cancers relative to melatonin’s known actions. We put emphasis on signaling pathways whereby melatonin interferes within cancer-cell mitochondria after its administration. Depending on subtype and intratumor metabolic heterogeneity, melatonin seems to be helpful in promoting apoptosis, anti-proliferation, pro-oxidation, metabolic shifting, inhibiting neovasculogenesis and controlling inflammation, and restoration of chemosensitivity. This results in attenuation of development, progression, and metastatic potential of reproductive cancers, in addition to lowering the risk of recurrence and improving the life quality of patients.
Mariane S. Pinafo, Philippe R. Benedetti, Letícia B. Gaiotte, Fabiano G. Costa, João Paulo F. Schoffen, Glaura S.A. Fernandes, Luiz Gustavo A. Chuffa, and Fábio R.F. Seiva
Elsevier BV
Graphical abstract
Thais H.C. Patelli, Rafael Fagnani, Luis Fernando C. da Cunha Filho, Francisco A.A. Souza, Gabriele S. Wolf, Mauro J.L. Cardoso, Fábio Rodrigues F. Seiva, and Julio Matsuda
FapUNIFESP (SciELO)
RESUMO: Este estudo avaliou o status do cálcio sérico em 39 vacas com deslocamento de abomaso (DA), provenientes de 30 propriedades leiteiras selecionadas, na região de Campos Gerais no Paraná. O diagnóstico do deslocamento de abomaso foi realizado por percussão auscultatória, além dos sinais clínicos e informações da anamnese. Previamente ao procedimento cirúrgico, amostras de sangue foram coletadas para a mensuração dos níveis sanguíneos de cálcio, albumina, proteína e glicose. Como grupo controle, amostras de sangue foram coletadas de vacas hígidas que se encontravam em semelhante período de lactação. Das 39 vacas com deslocamento de abomaso, 35 apresentaram hipocalcemia e no grupo controle, apenas um animal. Concentrações sanguíneas de glicose e proteína foram inferiores nos animais com DA, quando comparados com animais do grupo controle.
Luiz Gustavo de Almeida Chuffa, Luiz Antonio Lupi-Júnior, Aline Balandis Costa, João Paulo de Arruda Amorim, and Fábio Rodrigues Ferreira Seiva
Elsevier BV
Sex steroids have been widely described to be associated with a number of human diseases, including hormone-dependent tumors. Several studies have been concerned about the factors regulating the availability of sex steroids and its importance in the pathophysiological aspects of the reproductive cancers in women. In premenopausal women, large fluctuations in the concentration of circulating estradiol (E2) and progesterone (P4) orchestrate many events across the menstrual cycle. After menopause, the levels of circulating E2 and P4 decline but remain at high concentration in the peripheral tissues. Notably, there is a strong relationship between circulating sex hormones and female reproductive cancers (e.g. ovarian, breast, and endometrial cancers). These hormones activate a number of specific signaling pathways after binding either to estrogen receptors (ERs), especially ERα, ERα36, and ERβ or progesterone receptors (PRs). Importantly, the course of the disease will depend on particular transactivation pathway. Identifying ER- or PR-positive tumors will benefit patients in terms of proper endocrine therapy. Based on hormonal responsiveness, effective prevention methods for ovarian, breast, and endometrial cancers represent a special opportunity for women at risk of malignancies. Hormone replacement therapy (HRT) might significantly increase the risk of these cancer types, and endocrine treatments targeting ER signaling may be helpful against E2-dependent tumors. This review will present the role of sex steroids and their receptors associated with the risk of developing female reproductive cancers, with emphasis on E2 levels in pre and postmenopausal women. In addition, new therapeutic strategies for improving the survival rate outcomes in women will be addressed.
Luiz Gustavo A. Chuffa, Luiz Antonio Lupi Júnior, Fábio R. F. Seiva, Marcelo Martinez, Raquel F. Domeniconi, Patricia Fernanda F. Pinheiro, Lucilene D. dos Santos, and Francisco Eduardo Martinez
American Chemical Society (ACS)
To obtain more information into the molecular mechanisms underlying ovarian cancer (OC), we proposed a comparative proteomic analysis in animals receiving long-term melatonin as therapy or only vehicle using multidimensional protein identification combined with mass spectrometry. To induce tumor, a single dose of 100 μg 7,12-dimethylbenz(a)anthracene (DMBA) dissolved in 10 μL of sesame oil was injected under the left ovarian bursa of 20 Fischer 344 rats. The right ovaries were injected with sesame oil only. After tumors were developed, half of the animals received intraperitoneal administration of melatonin (200 μg/100g body weight/day) for 60 days. Melatonin therapy promoted down-regulation in numerous proteins involved in OC signaling pathways. The most significant portion of these proteins are involved in several metabolic processes, mainly those associated with mitochondrial systems, generation of metabolites and energy, hypoxia-inducible factor-1 signaling, antigen processing and presentation, endoplasmic reticulum stress-associated pathways, and cancer-related proteoglycans. A small number of proteins that were overexpressed by melatonin therapy included ATP synthase subunit β, fatty acid-binding protein, and 10-kDa heat shock protein. Taken together, our findings suggest that melatonin therapy efficiently modulated important signaling pathways involved in OC, and these proteins might be further targets that should be explored in new therapeutic opportunities for OC.
M. A. Zanoni, F. G. Costa, S. de Carvalho, and F. R. F. Seiva
Wiley
The aim of this experiment was to compare the level of fish female stress during induced reproduction with pituitary extract by two different methods, natural and semiextruded. The reproductive efficiency was 62.5% in the seminatural treatment and 100% in the extruded. Obtained egg volume was 5200 ml and 4000 ml, for seminatural and extruded treatments respectively. The mean number of eggs was 46.7 for the seminatural and 52.0 and for the extruded treatment. The percentage of viable eggs was, respectively, 87.2% and 8.17% for the natural treatment and extruded semimethods. Blood samples were collected to quantify cortisol and glucose levels, as well as red cell series and lymphocyte count. Fishes submitted to induction procedures showed elevated cortisol and glucose levels, compared to the control animals. The results for haematocrit, haemoglobin concentration and red blood cell count showed no significant differences among groups. Significant differences found in the number of lymphocytes and monocytes suggest the general adaptation syndrome. Our results suggest the reproductive induction process with extrusion of gametes as a more stressful method than seminatural reproduction process.
Patrick Vianna Garcia, Fábio Rodrigues Ferreira Seiva, Amanda Pocol Carniato, Wilson de Mello Júnior, Nelson Duran, Alda Maria Macedo, Alexandre Gabarra de Oliveira, Rok Romih, Iseu da Silva Nunes, Odilon da Silva Nunes,et al.
Springer Science and Business Media LLC
BackgroundThe new modalities for treating patients with non-muscle invasive bladder cancer (NMIBC) for whom BCG (Bacillus Calmette-Guerin) has failed or is contraindicated are recently increasing due to the development of new drugs. Although agents like mitomycin C and BCG are routinely used, there is a need for more potent and/or less-toxic agents. In this scenario, a new perspective is represented by P-MAPA (Protein Aggregate Magnesium-Ammonium Phospholinoleate-Palmitoleate Anhydride), developed by Farmabrasilis (non-profit research network). This study detailed and characterized the mechanisms of action of P-MAPA based on activation of mediators of Toll-like Receptors (TLRs) 2 and 4 signaling pathways and p53 in regulating angiogenesis and apoptosis in an animal model of NMIBC, as well as, compared these mechanisms with BCG treatment.ResultsOur results demonstrated the activation of the immune system by BCG (MyD88-dependent pathway) resulted in increased inflammatory cytokines. However, P-MAPA intravesical immunotherapy led to distinct activation of TLRs 2 and 4-mediated innate immune system, resulting in increased interferons signaling pathway (TRIF-dependent pathway), which was more effective in the NMIBC treatment. Interferon signaling pathway activation induced by P-MAPA led to increase of iNOS protein levels, resulting in apoptosis and histopathological recovery. Additionally, P-MAPA immunotherapy increased wild-type p53 protein levels. The increased wild-type p53 protein levels were fundamental to NO-induced apoptosis and the up-regulation of BAX. Furthermore, interferon signaling pathway induction and increased p53 protein levels by P-MAPA led to important antitumor effects, not only suppressing abnormal cell proliferation, but also by preventing continuous expansion of tumor mass through suppression of angiogenesis, which was characterized by decreased VEGF and increased endostatin protein levels.ConclusionsThus, P-MAPA immunotherapy could be considered an important therapeutic strategy for NMIBC, as well as, opens a new perspective for treatment of patients that are refractory or resistant to BCG intravesical therapy.
Paula F. Martinez, Camila Bonomo, Daniele M. Guizoni, Silvio A. Oliveira Junior, Ricardo L. Damatto, Marcelo D.M. Cezar, Aline R.R. Lima, Luana U. Pagan, Fabio R. Seiva, Renata T. Bueno,et al.
S. Karger AG
Background/Aims: Although increased oxidative stress plays a role in heart failure (HF)-induced skeletal myopathy, signaling pathways involved in muscle changes and the role of antioxidant agents have been poorly addressed. We evaluated the effects of N-acetylcysteine (NAC) on intracellular signaling pathways potentially modulated by oxidative stress in soleus muscle from HF rats. Methods and Results: Four months after surgery, rats were assigned to Sham, myocardial infarction (MI)-C (without treatment), and MI-NAC (treated with N-acetylcysteine) groups. Two months later, echocardiogram showed left ventricular dysfunction in MI-C; NAC attenuated diastolic dysfunction. Oxidative stress was evaluated in serum and soleus muscle; malondialdehyde was higher in MI-C than Sham and did not differ between MI-C and MI-NAC. Oxidized glutathione concentration in soleus muscle was similar in Sham and MI-C, and lower in MI-NAC than MI-C (Sham 0.168 ± 0.056; MI-C 0.223 ± 0.073; MI-NAC 0.136 ± 0.023 nmol/mg tissue; p = 0.014). Western blot showed increased p-JNK and decreased p38, ERK1/2, and p-ERK1/2 in infarcted rats. NAC restored ERK1/2. NF-κB p65 subunit was reduced; p-Ser276 in p65 and IκB was increased; and p-Ser536 unchanged in MI-C compared to Sham. NAC did not modify NF-κB p65 subunit, but decreased p-Ser276 and p-Ser536. Conclusion: N-acetylcysteine modulates MAPK and NF-κB signaling pathways in soleus muscle of HF rats.
Luiz Gustavo A Chuffa, Beatriz A Fioruci-Fontanelli, Leonardo O Mendes, Fábio R Ferreira Seiva, Marcelo Martinez, Wagner J Fávaro, Raquel F Domeniconi, Patrícia FF Pinheiro, Lucilene Delazari dos Santos, and Francisco Eduardo Martinez
Springer Science and Business Media LLC
BackgroundToll-like receptors (TLRs) are effector molecules expressed on the surface of ovarian cancer (OC) cells, but the functions of the TLR2/TLR4 signaling pathways in these cells remain unclear. Melatonin (mel) acts as an anti-inflammatory factor and has been reported to modulate TLRs in some aggressive tumor cell types. Therefore, we investigated OC and the effect of long-term mel therapy on the signaling pathways mediated by TLR2 and TLR4 via myeloid differentiation factor 88 (MyD88) and toll-like receptor-associated activator of interferon (TRIF) in an ethanol-preferring rat model.MethodsTo induce OC, the left ovary of animals either consuming 10% (v/v) ethanol or not was injected directly under the bursa with a single dose of 100 μg of 7,12-dimethylbenz(a)anthracene (DMBA) dissolved in 10 μL of sesame oil. The right ovaries were used as sham-surgery controls. After developing OC, half of the animals received i.p. injections of mel (200 μg/100 g b.w./day) for 60 days.ResultsAlthough mel therapy was unable to reduce TLR2 levels, it was able to suppress the OC-associated increase in the levels of the following proteins: TLR4, MyD88, nuclear factor kappa B (NFkB p65), inhibitor of NFkB alpha (IkBα), IkB kinase alpha (IKK-α), TNF receptor-associated factor 6 (TRAF6), TRIF, interferon regulatory factor 3 (IRF3), interferon β (IFN-β), tumor necrosis factor alpha (TNF-α), and interleukin (IL)-6. In addition, mel significantly attenuated the expression of IkBα, NFkB p65, TRIF and IRF-3, which are involved in TLR4-mediated signaling in OC during ethanol intake.ConclusionCollectively, our results suggest that mel attenuates the TLR4-induced MyD88- and TRIF-dependent signaling pathways in ethanol-preferring rats with OC.