Sheilla Andrade de Oliveira
@fiocruz.br
Pesquisadora em Saúde/ Departamento de Imunologia
INSTITUTO DE PESQUISAS AGGEU MAGALHÃES/ FIOCRUZ-PE
Scopus Publications
Scholar Citations
Scholar h-index
Scholar i10-index
Scopus Publications
Carine Machado Azevedo, Cássio Santana Meira, Jaqueline Wang da Silva, Danielle Maria Nascimento Moura, Sheilla Andrade de Oliveira, Cícero Jádson da Costa, Emanuelle de Souza Santos, and Milena Botelho Pereira Soares
MDPI AG
It is estimated that 250 million people worldwide are affected by schistosomiasis. Disease transmission is related to the poor sanitation and hygiene habits that affect residents of impoverished regions in tropical and subtropical countries. The main species responsible for causing disease in humans are Schistosoma Mansoni, S. japonicum, and S. haematobium, each with different geographic distributions. Praziquantel is the drug predominantly used to treat this disease, which offers low effectiveness against immature and juvenile parasite forms. In addition, reports of drug resistance prompt the development of novel therapeutic approaches. Natural products represent an important source of new compounds, especially those obtained from plant sources. This review compiles data from several in vitro and in vivo studies evaluating various compounds and essential oils derived from plants with cercaricidal and molluscicidal activities against both juvenile and adult forms of the parasite. Finally, this review provides an important discussion on recent advances in molecular and computational tools deemed fundamental for more rapid and effective screening of new compounds, allowing for the optimization of time and resources.
Camilla Almeida Menezes, Langia Colli Montresor, Soraya Torres Gaze Jangola, Aline Carvalho de Mattos, Ana Lúcia Coutinho Domingues, Arnaldo Maldonado Júnior, Clélia Christina Mello Silva, Constança Simões Barbosa, Cristiane Lafetá Furtado de Mendonça, Cristiano Lara Massara,et al.
Frontiers Media SA
The World Health Organization (WHO) recognizes schistosomiasis as one of the Neglected Tropical Diseases targeted for global elimination in the 2030 Agenda of the Sustainable Development Goals. In Brazil, schistosomiasis mansoni is considered a public health problem, particularly prevalent among vulnerable populations living in areas with poor environmental and sanitary conditions. In 2022, the WHO published a Guideline encompassing recommendations to assist national programs in endemic countries in achieving morbidity control, eliminating schistosomiasis as a public health problem, and advancing towards interrupting transmission. The perspectives presented here, collectively prepared by members of the Oswaldo Cruz Foundation’s (Fiocruz) Schistosomiasis Translational Program (FioSchisto), along with invited experts, examine the feasibility of the WHO recommendations for the Brazilian settings, providing appropriate recommendations for public health policies applicable to the epidemiological reality of Brazil, and suggests future research to address relevant issues. In Brazil, the provision of safe water and sanitation should be the key action to achieve schistosomiasis elimination goals. The agencies involved in measures implementation should act together with the Primary Care teams for planning, executing, monitoring, and evaluating actions in priority municipalities based on their epidemiological indicators. Host snails control should prioritize judicious ecological interventions at breeding sites. The Information, Education, and Communication (IEC) strategy should be associated with water and sanitation and other control actions, actively involving school community. To identify infected carriers, FioSchisto recommends a two-stage approach of immunological and molecular tests to verify transmission interruption during the intervention and beyond. Praziquantel administration should be done under medical supervision at the Primary Care level. MDA should be considered in exceptional settings, as a measure of initial attack strategy in locations presenting high endemicity, always integrated with water and sanitation, IEC, and snail control. To assist decision-making, as well as the monitoring and evaluation of strategic actions, there is a need for an Information System. FioSchisto considers this systematization essential to make investments in strategic research to support the improvement of schistosomiasis control actions. Efforts toward schistosomiasis elimination in Brazil will succeed with a paradigm shift from the vertical prescriptive framework to a community-centered approach involving intersectoral and interdisciplinary collaboration.
Cleonilde Maria do Nascimento, Sheilla Andrade de Oliveira, Otacílio Antunes Santana, and Helotonio Carvalho
International Society of Global Health
Background
Lockdowns have been fundamental to decreasing disease transmission during the COVID-19 pandemic even after vaccines were available. We aimed to evaluate and compare changes in air quality during the first year of the pandemic in different cities around the world, investigate how these changes correlate with changes in mobility, and analyse how lockdowns affected air pollutants' annual means.
Methods
We compared the concentrations of NO2, PM2.5, and PM10 in 42 cities around the world in the first months of the pandemic in 2020 to data from 2016-2019 and correlated them with changes in mobility using Human Development Indexes (HDIs). Cities with the highest decreases in air pollutants during this period were evaluated for the whole year 2020. We calculated the annual means for these cities and compared them to the new World Health Organization (WHO) Air Quality Guidelines. A Student's t-test (95% confidence interval) was used to evaluate significant changes.
Results
Highest decreases in NO2, PM2.5, and PM10 were between -50 and -70%. Cities evaluated for the whole year 2020 generally showed a recovery in air pollution levels after the initial months of the pandemic, except for London. These changes positively correlated with year-long mobility indexes for NO2 and PM2.5 for some cities. The highest reductions in air pollutants' annual means were from -20 to -35%. In general, decreases were higher for NO2, compared to PM2.5 and PM10. All analysed cities showed annual means incompliant with the new WHO Air Quality Guidelines for NO2 of 10 μg/m3, with values 1.7 and 4.3 times higher. For PM2.5, all cities showed values 1.3 to 7.6 times higher than the WHO Guidelines of 5 μg/m3, except for New Delhi, with a value 18 times higher. For PM10, only New York complied with the new guidelines of 15 μg/m3 and all the other cities were 1.1 to 4.2 times higher, except for New Delhi, which was 11 times higher.
Conclusions
These data show that even during a pandemic that highly affected mobility and economic activities and decreased air pollution around the world, complying with the new WHO Guidelines will demand a global strategical effort in the way we generate energy, move in and around the cities, and manufacture products.
Carlos André Laranjeira Miranda Filho, Míria de Oliveira Barbosa, Arsênio Rodrigues Oliveira, Aline Ferreira Pinto, Daniel Lopes Araújo, Jéssica Paula Lucena, Roni Evêncio de Araújo, Sheilla Andrade de Oliveira, and Ana Cristina Lima Leite
Springer Science and Business Media LLC
Débora Elienai de Oliveira Miranda, Kamila Gaudêncio da Silva Sales, Luciana Aguiar Figueredo, Sheilla Andrade de Oliveira, Amanda Vasconcelos do Nascimento, Diego José Lira Torres, Petra Sumova, Petr Volf, Sinval Pinto Brandão-Filho, Suênia da Cunha Gonçalves de Albuquerque,et al.
Elsevier BV
Cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis is the most widespread clinical form of leishmaniasis in the Americas. Migonemyia migonei is a widely distributed phlebotomine sand fly species in Brazil and has been implicated as a vector for L. (V.) braziliensis. In the present study, we investigated the effects of salivary gland homogenates (SGH) of Mg. migonei on the course of L. (V.) braziliensis infection in BALB/c mice. Mice were separated into four groups (six mice per group): CRTL (uninfected mice); SGH (mice inoculated with Mg. migonei SGH); SGH+LEISH (mice inoculated with Mg. migonei SGH plus L. (V.) braziliensis promastigotes); LEISH (mice inoculated with L. (V.) braziliensis promastigotes). Mice were followed up for 8 weeks and the cellular immune response was evaluated by flow cytometry at the end of the experiment. Analysis of cytokine production by splenic cells stimulated with 0.5 SGH, 0.25 SGH of Mg. migonei or L. (V.) braziliensis soluble antigen stimulation (LSA) demonstrated that upon stimulation with SGH 0.25, the production of IL-17A and TNF was not sustained in the SGH group, with decreasing levels of these cytokines after 5 days compared to 3 days of incubation. Analyzing the production of cytokines after LSA stimulation, we observed lower levels of IL-17A in the SGH group after 5 days compared to 3 days. The same was observed for IFN-γ in the SGH group. Yet, the levels of TNF were significantly higher in the LEISH group after 5 days compared to 3 days. Among SGH+LEISH and LEISH mice, three animals in each group developed skin lesions on the tail, the mean lesion size was significantly higher in the LEISH group. Our study suggests that Mg. migonei SGH may modulate BALB/c immune response, as reflected by the low production or early decrease of pro-inflammatory cytokines in splenic cell cultures following stimulation with L. (V.) braziliensis antigen. Our data also suggest that Mg. migonei saliva may reduce the lesion size in BALB/c mice, but further research with a larger sample size is needed to confirm this hypothesis.
Carlos André Laranjeira Miranda Filho, Miria de Oliveira Barbosa, Arsênio Rodrigues Oliveira, Edna Farias Santiago, Veruska Cintia Alexandrino de Souza, Jéssica Paula Lucena, Camila Juliet Barbosa Fernandes, Ignes Regina dos Santos, Renata Lins Carneiro Leão, Fabio André Brayner dos Santos,et al.
Elsevier BV
Schistosomicidal activity of six phthalimido-thiazoles derivatives with substitutions at the position three of the thiazole ring were analyzed in an experimental model. The substituents biphenyl (2i) and 2- naphthyl (2j) at a concentration of 80 µg/mL caused 100% mortality of the parasite in culture after 24 hours and 48 hours respectively. An evaluation of ultrastructural parasites showed damage in the tegument, formation of bubbles and partial destruction of the tubercles. The in vivo anti-parasitic activity with the derivate 2i was performed by administering it orally and intraperitoneally in a 400mg/kg/5days regimen. Decreases in the number of eggs in the gut (45.1%) and a reduction of the percentage of mature (23.7%) and increased unviable (53.8%) eggs were observed. Our results also showed a reduction in the number of recovered worms after treatment with 2i (oral administration: 81, 25%). The results demonstrated that the prototypes which were tested had a significant anti-schistosomal effect against S. mansoni, suggesting that these derivatives are promising candidates for further research into the chemotherapy of schistosomiasis.
Carlos G. Piscoya Roncal, Adriano A. Mendes, Maria T.C. Muniz, Sheilla A. de Oliveira, Leonidas M. do Valle Neto, Nathália A. de Vasconcellos Piscoya, Gustavo H.B. Góes, Dario C. Sobral Filho, and Mardi Gomberg-Maitland
Elsevier BV
Highlights • The PHC registry equation accurately predicted survival in Sch-PAH patients.• Sch-PAH survival cannot be safely predicted using only validated clinical variables only.• Survival studies in endemic regions of Schistosomiasis are needed to establish the real prognosis of Sch-PAH in the world.
Veruska Cintia Alexandrino de Souza, Danielle Maria Nascimento Moura, Maria Carolina Accioly Brelaz de Castro, Patrícia Torres Bozza, Ligia de Almeida Paiva, Camila Juliet Barbosa Fernandes, Renata Lins Carneiro Leão, Jéssica Paula Lucena, Roni Evencio de Araujo, Alex José de Melo Silva,et al.
Springer Science and Business Media LLC
Liver diseases are a major health problem worldwide leading to high mortality rates and causing a considerable economic burden in many countries. Cellular therapies as potential treatments for liver diseases have proven beneficial in most of the conditions. In recent years, studies involving therapy with bone marrow cells have been implemented to promote liver regeneration and to reduce hepatic fibrosis, however identifying the cell population present in the bone marrow that is responsible for hepatic improvement after therapy is still necessary. The aim of the present study was the evaluation of the therapeutic efficacy of monocytes obtained from bone marrow in fibrosis resulting from S. mansoni infection in C57BL/6 mice. Monocytes were isolated by immunomagnetic separation and administered to the infected animals. The effects of treatment were evaluated through morphometric, biochemical, immunological and molecular analyzes. Monocyte therapy promoted reduction of liver fibrosis induced by S. mansoni infection, associated with a decrease in production of inflammatory and pro-fibrogenic mediators. In addition, monocyte infusion caused downregulation of factors associated with the M1 activation profile, as well as upregulation of M2reg markers. The findings altogether reinforce the hypothesis that the predominance of M2reg macrophages, producers of immunosuppressive cytokines, may favor the improvement of hepatic fibrosis in a preclinical model, through fibrous tissue remodeling, modulation of the inflammatory response and fibrogenesis.
Miria de Oliveira Barbosa, Sheilla Andrade de Oliveira, Carlos André Laranjeira Miranda Filho, Arsênio Rodrigues Oliveira, Camila Juliet Barbosa Fernandes, Jéssica Paula Lucena, Fabiano Amaro de Sousa, Mabilly Cox Holanda de Barros Dias, Fábio André Brayner, Luiz Carlos Alves,et al.
Elsevier BV
Abstract Schistosomiasis is a major public health problem worldwide, especially in poor communities. Praziquantel is currently the only drug available to treat schistosomiasis and it shows low efficacy against schistosomula and juveniles stages of Schistosoma mansoni, allowing lower cure rate in areas with high endemicity. There is an urgent need to identify new antischistosomal drugs. Previous works identified phthalimido‐thiazoles as privileged structures acting as schistossomicidal agent. In this way, a phthalimido‐thiosemicarbazide intermediate and eight phthalimido‐thiazoles derivatives were evaluated concerning the in vitro antischistosomal activity compounds in adult phase of Schistosoma mansoni and examined alterations on the tegumental surface. The results revealed that compounds 2f, 2 l and 2 m caused significant mortality in adult worms at concentrations range of 20 &mgr;g/mL to 100 &mgr;g/mL. These compounds were also selected in view to verify the activity against the schistosomula. Compound 2 m promoted 100% of mortality of larval forms until doses of 2.5 &mgr;g/mL within 48 h. In addition, when compound 2 m was administered orally at dose of 200 mg/kg for 5 consecutive days to the infected mouse with adult schistosomes, a reduction in the parasite burden was observed. Furthermore, scanning electron microscopy revealed that compound 2 m kill the parasite by tegumental damage and bubbles generation. Graphical abstract Figure. No Caption available.
Lindomar José Pena, Klarissa Miranda Guarines, Anna Jéssica Duarte Silva, Lígia Rosa Sales Leal, Daniele Mendes Félix, Adalúcia Silva, Sheilla Andrade de Oliveira, Constância Flávia Junqueira Ayres, Abelardo Silva Júnior, and Antonio Carlos de Freitas
Microbiology Society
The emergence and rapid spread of Zika virus (ZIKV) in the Americas has prompted the development of in vitro and in vivo models to understand several aspects of ZIKV biology and boost the development of vaccines and antivirals. In vitro model studies include reverse genetics systems, two-dimensional (2D) cell models, such as primary cells and cell lines, and ex vivo three-dimensional (3D) models derived from skin, brain and placenta. While these models are cost-effective and allow rigorous control of experimental variables, they do not always recapitulate in vivo scenarios. Thus, a number of in vivo models have been developed, including mosquitoes (Aedes sp. and Culex sp.), embryonated chicken eggs, immunocompetent and immunodeficient mice strains, hamsters, guinea pigs, conventional swine and non-human primates. In this review, we summarize the main research systems that have been developed in recent years and discuss their advantages, limitations and main applications.
Sheilla Andrade de Oliveira, Miria de Oliveira Barbosa, Carlos André Laranjeira Miranda Filho, Arsênio Rodrigues Oliveira, Fabiano Amaro de Sousa, Edna de Farias Santiago, Gevanio Bezerra de Oliveira Filho, Paulo André Teixeira de Moraes Gomes, Juliana Maria da Conceição, Fábio André Brayner,et al.
Springer Science and Business Media LLC
AbstractPhthalimide, 1,3-thiazole, and thiazolidinone cores are considered privileged scaffolds and represent an attractive starting point to design new bioactive compounds for neglected tropical disease (NTD). Schistosomiasis is a NTD, caused by Schistosoma worms which praziquantel (PZQ) is the only drug used to treat humans, but the decrease in the effect after treatment has been reported. Recently, some phthalimide-thiazole derivatives exhibited in vitro antischistosomal activity against adult worms with significant ultrastructural changes and a lower cytotoxic effect on splenocytes. This new biological phthalimido-thiazole profile has motivated us to evaluate a new generation of such molecules in immature and adult worms. Thus, a phthalimido-thiazolidinone derivative, (3c), and three phthalimido-thiazoles (6c, 7a, and 7h) were evaluated concerning their in vitro activity on schistosomulae and adult worms. The results showed that these compounds brought a significant reduction on the mortality, inhibited oviposition, and then induced mortality in immature and adult worms alike. According to scanning electron microscopy, the tegument was the principal target for 7a and 7h and revealed gradual damage to the tegument surface, inducing destruction and decomposition of the tegument in the same areas and exposition of subtegumental tissue and of muscle tissue. Furthermore, they caused less toxicity in splenocytes than PZQ. Compounds 7a and 7h revealed to possess promising activity against larval forms. According to the present study, the privileged structure phthalimido-thiazoles act as a molecular framework that has antischistosomal activity and most form the basis to the next pre-clinical tests.
Graphical abstract
Veruska Cintia Alexandrino de Souza, Thiago Almeida Pereira, Valéria Wanderley Teixeira, Helotonio Carvalho, Maria Carolina Accioly Brelaz de Castro, Carolline Guimarães D’assunção, Andréia Ferreira de Barros, Camila Lima Carvalho, Virgínia Maria Barros de Lorena, Vláudia Maria Assis Costa,et al.
Baishideng Publishing Group Inc.
AIM To evaluate the therapeutic effects of bone marrow-derived CD11b+CD14+ monocytes in a murine model of chronic liver damage. METHODS Chronic liver damage was induced in C57BL/6 mice by administration of carbon tetrachloride and ethanol for 6 mo. Bone marrow-derived monocytes isolated by immunomagnetic separation were used for therapy. The cell transplantation effects were evaluated by morphometry, biochemical assessment, immunohistochemistry and enzyme-linked immunosorbent assay. RESULTS CD11b+CD14+ monocyte therapy significantly reduced liver fibrosis and increased hepatic glutathione levels. Levels of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-6 and IL-1β, in addition to pro-fibrotic factors, such as IL-13, transforming growth factor-β1 and tissue inhibitor of metalloproteinase-1 also decreased, while IL-10 and matrix metalloproteinase-9 increased in the monocyte-treated group. CD11b+CD14+ monocyte transplantation caused significant changes in the hepatic expression of α-smooth muscle actin and osteopontin. CONCLUSION Monocyte therapy is capable of bringing about improvement of liver fibrosis by reducing oxidative stress and inflammation, as well as increasing anti-fibrogenic factors.
Anekécia Lauro da Silva, Jamerson Ferreira de Oliveira, Willams Leal Silva, Aracelly França Luis, Edna de Farias Santiago, Antônio Sérgio Alves de Almeida Júnior, Tiago Bento de Oliveira, Veruska Cíntia Alexandrino de Souza, Andréia Ferreira de Barros, Ivan da Rocha Pitta,et al.
Elsevier BV
Praziquantel has been the drug most widely used therapy against different forms of schistosomiasis around the world. However, this treatment has shown ineffective in humans and in experimental models of Schistosoma mansoni. New therapeutic alternatives have been tested, including the imidazolidine derivative LPSF/PT-09, which has shown high therapeutic potential in vitro. In this work, we tested the schistosomal activity of this derivative in doses of 250mg/kg and 200mg/kg in mice experimentally infected with a high parasite load of S. mansoni. Parasitological evaluations related to the number of S. mansoni worms and their oviposition were performed during the acute phase of the disease and have demonstrated moderate effectiveness of 30-54,4%. However, LPSF/PT-09 did not influence oviposition of the parasites or the embryonic development of the eggs. The results obtained in this model showed that the imidazolidine derivative LPSF/PT-09 presented significant antischistosomal activity in vivo, posing as a potential candidate for this class of drugs. However, a better understanding of the pharmacokinetics and pharmacodynamics of the imidazolidine derivative LPSF/PT-09 is needed.
Fabrício Souza Silva, Pedro Modesto Nascimento Menezes, Pedro Guilherme Souza de Sá, André Luís de Santana Oliveira, Eric Alencar Araújo Souza, Vinicius Martins Bamberg, Henrique Ribeiro de Oliveira, Sheilla Andrade de Oliveira, Roni Evêncio e Araújo, Ana Paula Trovatti Uetanabaro,et al.
Hindawi Limited
The aim of this study was to evaluate crude extracts and fractions from leaves and stems ofLippia thymoidesand to validate their use in folk medicine.In vitroantioxidant and antimicrobial activities andin vivowound healing in rats, baker yeast-induced fever in young rats, and acute oral toxicity in mice assays were realized. The crude extracts and their dichloromethane and ethyl acetate fractions had potent radical-scavenging activity against the DPPH but were not effective in theβ-carotene bleaching method. The dichloromethane fraction from the leaves extract showed the broadest spectrum of activity againstS. aureus,B. cereus, andC. parapsilosis. The animals treated with crude extracts showed no difference in wound healing when compared with the negative control group. The crude extract from leaves (1200 mg/kg) has equal efficacy in reducing temperature in rats with hyperpyrexia compared to dipyrone (240 mg/kg) and is better than paracetamol (150 mg/kg). In acute toxicity test, crude extract of leaves fromLippia thymoidesexhibited no mortality and behavioral changes and no adverse effects in male and female mice. This work validates the popular use ofLippia thymoidesfor treating the wound and fever, providing a source for biologically active substances.
Andreia Ferreira Barros, Sheilla Andrade Oliveira, Camila Lima Carvalho, Fabiana Leticia Silva, Veruska Cintia Alexandrino de Souza, Anekecia Lauro da Silva, Roni Evencio de Araujo, Bruno Solano F Souza, Milena Botelho Pereira Soares, Vlaudia MA Costa,et al.
FapUNIFESP (SciELO)
Undernourished mice infected (UI) submitted to low and long-lasting infections by Schistosoma mansoni are unable to develop the hepatic periportal fibrosis that is equivalent to Symmers’ fibrosis in humans. In this report, the effects of the host’s nutritional status on parasite (worm load, egg viability and maturation) and host (growth curves, biology, collagen synthesis and characteristics of the immunological response) were studied and these are considered as interdependent factors influencing the amount and distribution of fibrous tissue in hepatic periovular granulomas and portal spaces. The nutritional status of the host influenced the low body weight and low parasite burden detected in UI mice as well as the number, viability and maturation of released eggs. The reduced oviposition and increased number of degenerated or dead eggs were associated with low protein synthesis detected in deficient hosts, which likely induced the observed decrease in transformation growth factor (TGF)-β1 and liver collagen. Despite the reduced number of mature eggs in UI mice, the activation of TGF-β1 and hepatic stellate cells occurred regardless of the unviability of most miracidia, due to stimulation by fibrogenic proteins and eggshell glycoproteins. However, changes in the repair mechanisms influenced by the nutritional status in deficient animals may account for the decreased liver collagen detected in the present study.
Edna de Farias Santiago, Sheilla Andrade de Oliveira, Gevânio Bezerra de Oliveira Filho, Diogo Rodrigo Magalhaes Moreira, Paulo André Teixeira Gomes, Anekécia Lauro da Silva, Andréia Ferreira de Barros, Aline Caroline da Silva, Thiago André Ramos dos Santos, Valéria Rêgo Alves Pereira,et al.
American Society for Microbiology
ABSTRACTSchistosomiasis is a chronic and debilitating disease caused by a trematode of the genusSchistosomaand affects over 207 million people. Chemotherapy is the only immediate recourse for minimizing the prevalence of this disease and involves predominately the administration of a single drug, praziquantel (PZQ). Although PZQ has proven efficacy, there is a recognized need to develop new drugs as schistosomicides since studies have shown that repeated use of this drug in areas of endemicity may cause a temporary reduction in susceptibility in isolates ofSchistosoma mansoni. Hydrazones, thiosemicarbazones, phthalimides, and thiazoles are thus regarded as privileged structures used for a broad spectrum of activities and are potential candidates for sources of new drug prototypes. The present study determined thein vitroschistosomicidal activity of 10 molecules containing these structures. During the assays, parameters such motility and mortality, oviposition, morphological changes in the tegument, cytotoxicity, and immunomodulatory activity caused by these compounds were evaluated. The results showed that compounds formed of thiazole and phthalimide led to higher mortality of worms, with a significant decline in motility, inhibition of pairing and oviposition, and a mortality rate of 100% starting from 144 h of exposure. These compounds also stimulated the production of nitric oxide and tumor necrosis factor alpha (TNF-α), thereby demonstrating the presence of immunomodulatory activity. The phthalyl thiazole LpQM-45 caused significant ultrastructural alterations, with destruction of the tegument in both male and female worms. According to the present study, phthalyl thiazole compounds possess antischistosomal activities and should form the basis for future experimental and clinical trials.
Bruno Solano de Freitas Souza, Ramon Campos Nascimento, Sheilla Andrade de Oliveira, Juliana Fraga Vasconcelos, Carla Martins Kaneto, Lian Felipe Paiva Pontes de Carvalho, Ricardo Ribeiro-dos-Santos, Milena Botelho Pereira Soares, and Luiz Antonio Rodrigues de Freitas
Elsevier BV
BACKGROUND AIMS
Acute liver failure (ALF), although rare, remains a rapidly progressive and frequently fatal condition. Acetaminophen (APAP) poisoning induces a massive hepatic necrosis and often leads to death as a result of cerebral edema. Cell-based therapies are currently being investigated for liver injuries. We evaluated the therapeutic potential of transplantation of bone marrow mononuclear cells (BMC) in a mouse model of acute liver injury.
METHODS
ALF was induced in C57Bl/6 mice submitted to an alcoholic diet followed by fasting and injection of APAP. Mice were transplanted with 10(7) BMC obtained from enhanced green fluorescent protein (GFP) transgenic mice.
RESULTS
BMC transplantation caused a significant reduction in APAP-induced mortality. However, no significant differences in serum aminotransferase concentrations, extension of liver necrosis, number of inflammatory cells and levels of cytokines in the liver were found when BMC- and saline-injected groups were compared. Moreover, recruitment of transplanted cells to the liver was very low and no donor-derived hepatocytes were observed. Mice submitted to BMC therapy had some protection against disruption of the blood-brain barrier, despite their hyperammonemia, and serum metalloproteinase (MMP)-9 activity similar to the saline-injected group. Tumor necrosis factor (TNF)-α concentrations were decreased in the serum of BMC-treated mice. This reduction was associated with an early increase in interleukin (IL)-10 mRNA expression in the spleen and bone marrow after BMC treatment.
CONCLUSIONS
BMC transplantation protects mice submitted to high doses of APAP and is a potential candidate for ALF treatment, probably via an immunomodulatory effect on TNF-α production.
Sheilla Andrade de Oliveira, Bruno Solano de Freitas Souza, Elton Pereira Sá Barreto, Carla Martins Kaneto, Hélio Almeida Neto, Carine Machado Azevedo, Elisalva Teixeira Guimarães, Luiz Antonio Rodrigues de Freitas, Ricardo Ribeiro-Dos-Santos, and Milena Botelho Pereira Soares
Elsevier BV
BACKGROUND AIMS
Cirrhosis, end-stage liver disease, is caused by different mechanisms of injury, associated with persistent inflammation. Galectin-3 is an important regulator of fibrosis that links chronic inflammation to fibrogenesis. We investigated the role of bone marrow cell (BMC) transplantation in chronic inflammation and hepatic fibrosis.
METHODS
Liver cirrhosis was induced by administration of carbon tetrachloride and ethanol to wild-type C57BL/6 or bone marrow chimeric mice. Bone marrow chimeras were generated by lethal irradiation and transplantation with BMC obtained from green fluorescent protein (GFP(+) )donors. Wild-type cirrhotic mice were transplanted with BMC without irradiation. Livers from chimeras and cirrhotic transplanted mice were obtained for evaluation of inflammation, fibrosis and regulatory factors [galectin-3, matrix metallopeptidase (MMP)-9, tissue inhibitor of metalloproteinase (TIMP)-1 and transforming growth factor (TGF)-β].
RESULTS
The development of cirrhosis was associated with increased expression of galectin-3 by F4/80(+) cells and intense migration of BMC to the liver. Furthermore, when transplanted after the establishment of cirrhosis, BMC also migrated to the liver and localized within the fibrous septa. Two months after BMC therapy, cirrhotic mice had a significant reduction in liver fibrosis and expression of type I collagen. We did not find any difference in levels of TGF-β, TIMP-1 and MMP-9 between saline and BMC groups. However, the numbers of inflammatory cells, phagocytes and galectin-3(+) cells were markedly lower in the livers of cirrhotic mice treated with BMC.
CONCLUSIONS
Our results demonstrate an important role for BMC in the regulation of liver fibrosis and that transplantation of BMC can accelerate fibrosis regression through modulatory mechanisms.
Eridan M Coutinho, Sheilla A de Oliveira, Andréia F de Barros, Fabiana L Silva, and Renata P Ramos
FapUNIFESP (SciELO)
This paper deals with current knowledge of the interrelationships between Schistosoma infection and malnutrition. It emphasizes the relevance of these investigations in the face of dynamic and evolving changes occurring in population diets and changes in the epidemiological patterns of schistosomiasis in endemic countries. The paper further discusses the basis for continuing the studies on this subject and the reasons why it represents a misunderstood association. This review also focuses on the cellular and humoral immune responses in the undernourished mouse model infected with Schistosoma mansoni, with updated information on the immune response in wild-type and iNOS knockout mice concerning soluble egg antigen specific antibodies and kinetics of IFN-gamma, IL-4, IL-10 and IL-13 cytokines, in the chronic phase of Manson's schistosomiasis. There is indication that schistosome-infected undernourished mice are able to develop a humoral immune response, but antibody titres are much lower than in the control animals. Cytokine production (IFN-gamma, IL-4, IL-10) is lower in the undernourished mice, but as infection progresses to the chronic phase its kinetics run an antagonistic course when compared to that of well-nourished animals. Marked variation in the secretion of IL-13 (a fibrogenic cytokine) could explain why undernourished mice do not develop liver "pipe-stem" fibrosis described in previous papers on well-nourished animals.
Andre Castro Lyra, Milena Botelho Pereira Soares, Luiz Flavio Maia da Silva, Eduardo Lorens Braga, Sheilla A. Oliveira, Marcos Fraga Fortes, Andre Goyanna Pinheiro Silva, Daniele Brustolim, Bernd Genser, Ricardo Ribeiro dos Santos,et al.
Ovid Technologies (Wolters Kluwer Health)
Aim This randomized controlled study evaluated the effect of autologous infusion of bone marrow cells (BMC) in patients with hepatic cirrhosis. Methods Thirty patients on the liver transplant waiting list were randomly assigned to receive BMC therapy or no treatment. They were followed up for 1 year. The study was nonblinded. Autologous mononuclear-enriched BMC were infused into the hepatic artery; liver function scores/tests were chosen as endpoints to assess efficacy. Statistical analysis calculated mean relative changes (RC) from baseline and fitted a random-effects model. Results Mean age, baseline model for end-stage liver disease, and Child–Pugh score were similar in both groups. Child–Pugh score improved in the first 90 days in the cell therapy group compared with controls (P = 0.017, BMC group RC = −8%, controls RC = +5%). The model for end-stage liver disease score remained stable in the treated patients (RC −2 to +6%), whereas it increased during follow-up in the control group (RC +6 to +18%). Albumin levels improved in the treatment arm, whereas they remained stable among controls in the first 90 days (P = 0.034; BMC group RC = +16%, control group RC = +2%). Bilirubin levels increased among controls, whereas they decreased in the therapy arm during the first 60 days; INR RC differences between groups reached up to 10%. The changes observed did not persist beyond 90 days. Conclusion Transplantation of autologous BMC into the hepatic artery improved liver function in patients with advanced cirrhosis in the first 90 days. However, larger studies are necessary to define the role of BMC therapy in cirrhotic patients. Repeated autologous BMC infusions or combination therapy with granulocyte-colony-stimulating factor might improve or sustain the treatment response.
Bruno Solano de Freitas Souza, Renata Campos Nogueira, Sheilla Andrade de Oliveira, Luiz Antonio Rodrigues de Freitas, Luiz Guilherme Costa Lyra, Ricardo Ribeiro dos Santos, Andre Castro Lyra, and Milena Botelho Pereira Soares
SAGE Publications
Liver failure is one of the main causes of death worldwide and is a growing health problem. Since the discovery of stem cell populations capable of differentiating into specialized cell types, including hepatocytes, the possibility of their utilization in the regeneration of the damaged liver has been a focus of intense investigation. A variety of cell types were tested both in vitro and in vivo, but the definition of a more suitable cell preparation for therapeutic use in each type of liver lesions is yet to be determined. Here we review the protocols described for differentiation of stem cells into hepatocytes, the results of cell therapy in animal models of liver diseases, as well as the available data of the clinical trials in patients with advanced chronic liver disease.
Sheilla Andrade Oliveira, Bruno Solano Freitas Souza, Carla Adriana Guimarães-Ferreira, Elton Sá Barreto, Siane Campos Souza, Luiz Antonio Rodrigues Freitas, Ricardo Ribeiro-dos-Santos, and Milena Botelho Pereira Soares
Baishideng Publishing Group Inc.
AIM
To investigate the potential of bone marrow mononuclear cells (BM-MCs) in the regeneration of hepatic lesions induced by Schistosoma mansoni (S.mansoni) chronic infection.
METHODS
Female mice chronically infected with S.mansoni were treated with BM-MCs obtained from male green fluorescent protein (GFP) transgenic mice by intravenous or intralobular injections. Control mice received injections of saline in similar conditions. Enzyme-linked immunosorbent assay (ELISA) assay for transforming growth factor-beta (TGF-beta), polymerase chain reaction (PCR) for GFP DNA, immunofluorescence and morphometric studies were performed.
RESULTS
Transplanted GFP(+) cells migrated to granuloma areas and reduced the percentage of liver fibrosis. The presence of donor-derived cells was confirmed by fluorescence in situ hybridization (FISH) analysis for detection of cells bearing Y chromosome and by PCR analysis for detection of GFP DNA. The levels of TGF-beta, a cytokine associated with fibrosis deposition, in liver fragments of mice submitted to therapy were reduced. The number of oval cells in liver sections of S.mansoni-infected mice increased 3-4 fold after transplantation. A partial recovery in albumin expression, which is decreased upon infection with S.mansoni, was found in livers of infected mice after cellular therapy.
CONCLUSION
In conclusion, transplanted BMCs migrate to and reduce the damage of chronic fibrotic liver lesions caused by S.mansoni.
Andre Castro Lyra
Baishideng Publishing Group Inc.
AIM
To evaluate the safety and feasibility of bone marrow cell (BMC) transplantation in patients with chronic liver disease on the waiting list for liver transplantation.
METHODS
Ten patients (eight males) with chronic liver disease were enrolled to receive infusion of autologous bone marrow-derived cells. Seven patients were classified as Child-Pugh B and three as Child-Pugh C. Baseline assessment included complete clinical and laboratory evaluation and abdominal MRI. Approximately 50 mL of bone marrow aspirate was prepared by centrifugation in a ficoll-hypaque gradient. At least of 100 millions of mononuclear-enriched BMCs were infused into the hepatic artery using the routine technique for arterial chemoembolization for liver tumors. Patients were followed up for adverse events up to 4 mo.
RESULTS
The median age of the patients was 52 years (range 24-70 years). All patients were discharged 48 h after BMC infusion. Two patients complained of mild pain at the bone marrow needle puncture site. No other complications or specific side effects related to the procedure were observed. Bilirubin levels were lower at 1 (2.19 +/- 0.9) and 4 mo (2.10 +/- 1.0) after cell transplantation that baseline levels (2.78 +/- 1.2). Albumin levels 4 mo after BMC infusion (3.73 +/- 0.5) were higher than baseline levels (3.47 +/- 0.5). International normalized ratio (INR) decreased from 1.48 (SD = 0.23) to 1.43 (SD = 0.23) one month after cell transplantation.
CONCLUSION
BMC infusion into hepatic artery of patients with advanced chronic liver disease is safe and feasible. In addition, a decrease in mean serum bilirubin and INR levels and an increase in albumin levels are observed. Our data warrant further studies in order to evaluate the effect of BMC transplantation in patients with advanced chronic liver disease.
Eridan M. Coutinho, Fabiana L. Silva, Andreia F. Barros, Roni E. Araújo, Sheilla A. Oliveira, Carlos F. Luna, Aryon A. Barbosa, and Zilton A. Andrade
Elsevier BV
The mouse model of schistosomal periportal fibrosis (Symmers' "pipestem" fibrosis), that develops in 30-50% of the infected animals, is not reproduced in undernourished mice. Host nutritional status is likely to be a variable that may influence the outcome and progression of infection, since it interferes with the dynamics of connective tissue changes occurring in chronic hepatic schistosomiasis. Re-infections increase the occurrence of periportal liver fibrosis in well-nourished animals, but it is not known how undernourished mice would behave being repeatedly re-infected. So, 21-day-old male albino Swiss mice were individually exposed to 30 cercariae (percutaneous route) of the BH strain of Schistosoma mansoni, 4 weeks after being on a low-protein diet. Control animals were fed on a commercial balanced chow for mice. The nutritional status was evaluated by body weight gain and measurement of food intake. Mice were divided into four groups: A1 (undernourished, single infected), A2 (well-nourished, single infected), B1 (undernourished, re-infected), B2 (well-nourished, re-infected). The primary infection was performed 4 weeks after ingesting the respective diet. Re-infections started 45 days later, with exposure to 15 cercariae, at 15 day intervals. Mice were sacrificed 18 weeks after the primary exposure. The livers were submitted to morphological (gross and microscopic pathology), morphometric (percentage of fibrosis; granuloma size; volume and numerical densities) by using semi-automatic morphometry, and biochemical (quantification of collagen as hydroxyproline) studies. Worm burdens and hepatic egg counting were also recorded. Values for body weight gains were always lower in undernourished mice, the effects of re-infection being minimal on this regard. Liver and spleen weights were higher in well-nourished mice (either single infected or re-infected) and mainly related to the type of ingested diet. A greater number of re-infected well-nourished mice developed periportal fibrosis, but undernourished re-infected animals did not reproduce this lesion. The percentage of fibrosis and hepatic collagen content were higher in well-nourished mice, but differences between single infected and re-infected groups were not statistically significant.
S. A. Oliveira, L. M. Silva, A. A. Barbosa J�nior, R. Ribeiro-dos-Santos, E. M. Coutinho, Z. A. Andrade, and M. B. P. Soares
Springer Science and Business Media LLC
We previously demonstrated that mice subjected to a hypoproteinic diet showed milder chronic lesions on infection with Schistosoma mansoni than normally fed mice. Here we compare the immune response of well-nourished and undernourished mice with chronic S. mansoni infection. The proliferative response and cytokine (IFN-γ and IL-5) production of splenocytes from undernourished mice against the soluble egg antigen (SEA) of S. mansoni or concanavalin A was similar to that of well-nourished mice. The levels of SEA-specific IgG1, IgG2b and IgG3 antibodies were significantly higher in the sera of well-nourished mice in comparison with undernourished mice. Undernourished animals also exhibited diminished periovular granuloma size compared to well-nourished infected controls. Our results support the importance of host nutritional status in the humoral immune response of mice and its effects on the development of periovular granulomas in malnourished animals infected with S. mansoni.