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1.
J Biomol Struct Dyn ; : 1-23, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38345036

RESUMO

Matrikines are biologically active peptides generated from fragments fragmentation of extracellular matrix components (ECM) that are functionally distinct from the original full-length molecule. The active matricryptic sites can be unmasked by ECM components enzymatic degradation or multimerization, heterotypic binding, adsorption to other molecules, cell-mediated mechanical forces, exposure to reactive oxygen species, ECM denaturation, and others. Laminin α1-derived peptide (SIKVAV) is a bioactive peptide derived from laminin-111 that participates in tumor development, cell proliferation, angiogenesis in various cell types. SIKVAV has also a potential pharmaceutical activity that may be used for tissue regeneration and bioengineering in Alzheimer's disease and muscular dystrophies. In this work, we made computational analyzes of SIKVAV regarding the ADMET panel, that stands for Administration, Distribution, Metabolism, Excretion, and Toxicity. Docking analyzes using the α3ß1 and α6ß1 integrin receptors were performed to fill in the gaps in the SIKVAV's signaling pathway and coupling tests showed that SIKVAV can interact with both receptors. Moreover, there is no indication of cytotoxicity, mutagenic or carcinogenic activity, skin or oral sensitivity. Our analysis suggests that SIKVAV has a high probability of interacting with peroxisome proliferator-activated receptor-gamma (NR-PPAR-γ), which has anti-inflammatory activity. The results of bioinformatics can help understand the participation of SIKVAV in homeostasis and influence the understanding of how this peptide can act as a biological asset in the control of dystrophies, neurodegenerative diseases, and tissue engineering.Communicated by Ramaswamy H. Sarma.

2.
Int J Mol Sci ; 24(11)2023 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-37298243

RESUMO

The term "liver disease" refers to any hepatic condition that leads to tissue damage or altered hepatic function and can be induced by virus infections, autoimmunity, inherited genetic mutations, high consumption of alcohol or drugs, fat accumulation, and cancer. Some types of liver diseases are becoming more frequent worldwide. This can be related to increasing rates of obesity in developed countries, diet changes, higher alcohol intake, and even the coronavirus disease 2019 (COVID-19) pandemic was associated with increased liver disease-related deaths. Although the liver can regenerate, in cases of chronic damage or extensive fibrosis, the recovery of tissue mass is impossible, and a liver transplant is indicated. Because of reduced organ availability, it is necessary to search for alternative bioengineered solutions aiming for a cure or increased life expectancy while a transplant is not possible. Therefore, several groups were studying the possibility of stem cells transplantation as a therapeutic alternative since it is a promising strategy in regenerative medicine for treating various diseases. At the same time, nanotechnological advances can contribute to specifically targeting transplanted cells to injured sites using magnetic nanoparticles. In this review, we summarize multiple magnetic nanostructure-based strategies that are promising for treating liver diseases.


Assuntos
COVID-19 , Hepatopatias , Nanoestruturas , Humanos , Medicina Regenerativa , Hepatócitos/transplante , COVID-19/terapia , Hepatopatias/terapia , Células-Tronco , Regeneração Hepática , Fenômenos Magnéticos
3.
Parasitology ; 149(12): 1526-1535, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35822537

RESUMO

This study focuses on the role of the population structure of Leishmania spp. on the adaptive capacity of the parasite. Herein, we investigate the contribution of subpopulations of the L. (V.) braziliensis Thor strain (Thor03, Thor10 and Thor22) in the profile of murine macrophages infection. Infection assays were performed with binary combinations of these subpopulations at stationary phases. The initial interaction time showed major effects on the combination assays, as demonstrated by the significant increase in the infection rate at 5 h. Based on the endocytic index (EI), Thor10 (EI = 563.6) and Thor03 (EI = 497) showed a higher infection load compared to Thor22 (EI = 227.3). However, the EI decreased in Thor03 after 48 h (EI = 447) and 72 h (EI = 388.3) of infection, and showed changes in the infection level in all Thor10/Thor22 combinations. Assays with CellTrace CFSE-labelled Thor22 promastigotes indicated an increase (~1.5 fold) in infection by this subpopulation in the presence of Thor10 when compared to the infection profile of Thor03/Thor22 combinations in the same proportions. In addition, the potential of these subpopulations, alone or in binary combinations, to modulate the expression of cytokines and nitric oxide (NO) in vitro was investigated. Lower NO and tumour necrosis factor-α production levels were observed for all Thor10/Thor22 combinations at 24 h compared to these subpopulations alone. In contrast, Thor03/Thor22 combination assays increased IL-10 production at this time. Collectively, these results provide in vitro evidence on the potential of L. (V.) braziliensis population structure to play a relevant role in a host infection by this parasite.


Assuntos
Leishmania braziliensis , Leishmania , Leishmaniose Cutânea , Camundongos , Animais , Leishmania/metabolismo , Macrófagos/parasitologia , Citocinas/metabolismo , Óxido Nítrico/metabolismo , Leishmaniose Cutânea/parasitologia
4.
Cells ; 10(10)2021 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-34685567

RESUMO

Mesenchymal stem cells (MSCs) are multipotent adult stem cells present in virtually all tissues; they have a potent self-renewal capacity and can differentiate into multiple cell types. They also affect the ambient tissue by the paracrine secretion of numerous factors in vivo, including the induction of other stem cells' differentiation. In vitro, the culture media supernatant is named secretome and contains soluble molecules and extracellular vesicles that retain potent biological function in tissue regeneration. MSCs are considered safe for human treatment; their use does not involve ethical issues, as embryonic stem cells do not require genetic manipulation as induced pluripotent stem cells, and after intravenous injection, they are mainly found in the lugs. Therefore, these cells are currently being tested in various preclinical and clinical trials for several diseases, including COVID-19. Several affected COVID-19 patients develop induced acute respiratory distress syndrome (ARDS) associated with an uncontrolled inflammatory response. This condition causes extensive damage to the lungs and may leave serious post-COVID-19 sequelae. As the disease may cause systemic alterations, such as thromboembolism and compromised renal and cardiac function, the intravenous injection of MSCs may be a therapeutic alternative against multiple pathological manifestations. In this work, we reviewed the literature about MSCs biology, focusing on their function in pulmonary regeneration and their use in COVID-19 treatment.


Assuntos
COVID-19/sangue , COVID-19/terapia , Pulmão/fisiologia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Regeneração/fisiologia , Animais , Diferenciação Celular , Terapia Baseada em Transplante de Células e Tecidos , Meios de Cultura , Vesículas Extracelulares , Humanos , Inflamação , Camundongos , Camundongos SCID , Fenótipo , Pneumonia/sangue , Pneumonia/imunologia , Pneumonia/terapia , Síndrome do Desconforto Respiratório , SARS-CoV-2 , Tromboembolia/sangue , Tromboembolia/imunologia , Tromboembolia/terapia , Tratamento Farmacológico da COVID-19
5.
Front Immunol ; 12: 780900, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35095855

RESUMO

Mesenchymal stem cells (MSCs) are multipotent adult stem cells present in virtually all tissues; they have potent self-renewal capacity and differentiate into multiple cell types. For many reasons, these cells are a promising therapeutic alternative to treat patients with severe COVID-19 and pulmonary post-COVID sequelae. These cells are not only essential for tissue regeneration; they can also alter the pulmonary environment through the paracrine secretion of several mediators. They can control or promote inflammation, induce other stem cells differentiation, restrain the virus load, and much more. In this work, we performed single-cell RNA-seq data analysis of MSCs in bronchoalveolar lavage samples from control individuals and COVID-19 patients with mild and severe clinical conditions. When we compared samples from mild cases with control individuals, most genes transcriptionally upregulated in COVID-19 were involved in cell proliferation. However, a new set of genes with distinct biological functions was upregulated when we compared severely affected with mild COVID-19 patients. In this analysis, the cells upregulated genes related to cell dispersion/migration and induced the γ-activated sequence (GAS) genes, probably triggered by IFNGR1 and IFNGR2. Then, IRF-1 was upregulated, one of the GAS target genes, leading to the interferon-stimulated response (ISR) and the overexpression of many signature target genes. The MSCs also upregulated genes involved in the mesenchymal-epithelial transition, virus control, cell chemotaxis, and used the cytoplasmic RNA danger sensors RIG-1, MDA5, and PKR. In a non-comparative analysis, we observed that MSCs from severe cases do not express many NF-κB upstream receptors, such as Toll-like (TLRs) TLR-3, -7, and -8; tumor necrosis factor (TNFR1 or TNFR2), RANK, CD40, and IL-1R1. Indeed, many NF-κB inhibitors were upregulated, including PPP2CB, OPTN, NFKBIA, and FHL2, suggesting that MSCs do not play a role in the "cytokine storm" observed. Therefore, lung MSCs in COVID-19 sense immune danger and act protectively in concert with the pulmonary environment, confirming their therapeutic potential in cell-based therapy for COVID-19. The transcription of MSCs senescence markers is discussed.


Assuntos
COVID-19/imunologia , Proliferação de Células/fisiologia , Inflamação/imunologia , Pulmão/imunologia , Células-Tronco Mesenquimais/imunologia , Regeneração/imunologia , Adulto , COVID-19/metabolismo , Diferenciação Celular/imunologia , Movimento Celular/imunologia , Citoplasma/imunologia , Transição Epitelial-Mesenquimal/imunologia , Humanos , Inflamação/metabolismo , Células-Tronco Mesenquimais/metabolismo , SARS-CoV-2/imunologia , Regulação para Cima/imunologia , Adulto Jovem
6.
Int J Mol Sci ; 21(15)2020 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-32751747

RESUMO

Induced pluripotent stem (iPS) cells are laboratory-produced cells that combine the biological advantages of somatic adult and stem cells for cell-based therapy. The reprogramming of cells, such as fibroblasts, to an embryonic stem cell-like state is done by the ectopic expression of transcription factors responsible for generating embryonic stem cell properties. These primary factors are octamer-binding transcription factor 4 (Oct3/4), sex-determining region Y-box 2 (Sox2), Krüppel-like factor 4 (Klf4), and the proto-oncogene protein homolog of avian myelocytomatosis (c-Myc). The somatic cells can be easily obtained from the patient who will be subjected to cellular therapy and be reprogrammed to acquire the necessary high plasticity of embryonic stem cells. These cells have no ethical limitations involved, as in the case of embryonic stem cells, and display minimal immunological rejection risks after transplant. Currently, several clinical trials are in progress, most of them in phase I or II. Still, some inherent risks, such as chromosomal instability, insertional tumors, and teratoma formation, must be overcome to reach full clinical translation. However, with the clinical trials and extensive basic research studying the biology of these cells, a promising future for human cell-based therapies using iPS cells seems to be increasingly clear and close.


Assuntos
Reprogramação Celular/genética , Células-Tronco Pluripotentes Induzidas/transplante , Distrofias Musculares/terapia , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Distrofias Musculares/genética , Distrofias Musculares/patologia , Proteínas de Transporte de Cátions Orgânicos/genética , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-myc/genética , Fatores de Transcrição SOXB1/genética
7.
J Leukoc Biol ; 107(4): 695-706, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32202341

RESUMO

In secondary lymphoid organs, pathogen-derived and endogenous danger molecules are recognized by pattern recognition receptors, leading to adaptive proinflammatory immune responses. This conceptual rule does not apply directly to the liver, as hepatic immune cells tolerate gut-derived bacterial molecules from the flora. Therefore, the recognition of danger and proinflammatory stimuli differs between the periphery and the liver. However, the tolerant nature of the liver must be overcome in the case of infections or cancer, for example. The central paradigm is the basis for danger recognition and the balance between inflammation and tolerance in the liver. Here, we observed functional integration, with activated peripheral T lymphocytes playing a role in the induction of a proinflammatory environment in the liver in the presence of Trypanosoma cruzi antigens. When only parasite extract was orally administered, it led to the up-regulation of hepatic tolerance markers, but oral treatment plus adoptively transferred activated splenic T lymphocytes led to a proinflammatory response. Moreover, treated/recipient mice showed increased levels of TNF, IFN-γ, IL-6, and CCL2 in the liver and increased numbers of effector and/or effector memory T lymphocytes and F4/80+ cells. There was a reduction in FoxP3+ Treg cells, NKT cells, and γδ T lymphocytes with increased liver damage in the presence of activated peripheral T cells. Our results show that the induction of a proinflammatory liver response against T. cruzi danger molecules is at least partially dependent on cooperation with activated peripheral T cells.


Assuntos
Antígenos de Protozoários/imunologia , Inflamação/patologia , Fígado/patologia , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Trypanosoma cruzi/imunologia , Transferência Adotiva , Animais , Antígeno B7-H1/metabolismo , Antígeno CTLA-4/metabolismo , Doença de Chagas/imunologia , Doença de Chagas/parasitologia , Citocinas/metabolismo , Linfócitos Intraepiteliais/imunologia , Células de Kupffer/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células T Matadoras Naturais/imunologia , Parasitos/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/parasitologia , Linfócitos T Reguladores/imunologia
8.
Eur J Cell Biol ; 99(1): 151060, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31812279

RESUMO

Trypanosoma cruzi causes Chagas disease, a neglected illness that affects millions of people worldwide, especially in Latin America. The balance between biochemical pathways triggered by the parasite and host cells response will ultimately define the progression of a life-threatening disease, justifying the efforts to understand cellular mechanisms for infection restrain. In this interaction, parasite and host cells are affected by different physiological responses as autophagy modulation, which could be under intense cellular stress, such as nutrient deprivation, hormone depletion, or infection. Autophagy is a constitutive pathway that leads to degradation of macromolecules and cellular structures and may induce cell death. In Trypanosoma cruzi infection, the relevance of host autophagy is controversial regarding in vitro parasite intracellular life cycle. In the present study, we evaluated host cell autophagy during T. cruzi infection in phagocytic and non-professional phagocytic cells. We described that the presence of the parasite increased the number of LC3 puncta, a marker for autophagy, in cardiac cells and peritoneal macrophages in vitro. The induction of host autophagy decreased infection in macrophages in early and late time-periods. We suggest that starved phagocytic cells reduced internalization, also confirmed by inert particles and dead trypomastigotes. Whereas, in cardiac cells, starvation-induced autophagy decreased lipid droplets and infection in later time-point, by reducing parasite differentiation/proliferation. In ATG5 knockout MEF cells, we confirmed our hypothesis of autophagy machinery activation during parasite internalization, increasing infection. Our data suggest that host autophagy downregulates T. cruzi infection through impairing parasite intracellular life cycle, reducing the infection in primary culture cells.


Assuntos
Autofagia , Doença de Chagas/metabolismo , Animais , Sobrevivência Celular , Células Cultivadas , Doença de Chagas/patologia , Gotículas Lipídicas/química , Gotículas Lipídicas/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Trypanosoma cruzi/isolamento & purificação , Trypanosoma cruzi/metabolismo
9.
Int J Mol Sci ; 20(21)2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31683627

RESUMO

Muscular dystrophies (MD) are a group of genetic diseases that lead to skeletal muscle wasting and may affect many organs (multisystem). Unfortunately, no curative therapies are available at present for MD patients, and current treatments mainly address the symptoms. Thus, stem-cell-based therapies may present hope for improvement of life quality and expectancy. Different stem cell types lead to skeletal muscle regeneration and they have potential to be used for cellular therapies, although with several limitations. In this review, we propose a combination of genetic, biochemical, and cell culture treatments to correct pathogenic genetic alterations and to increase proliferation, dispersion, fusion, and differentiation into new or hybrid myotubes. These boosted stem cells can also be injected into pretreate recipient muscles to improve engraftment. We believe that this combination of treatments targeting the limitations of stem-cell-based therapies may result in safer and more efficient therapies for MD patients. Matricryptins have also discussed.


Assuntos
Distrofias Musculares/terapia , Transplante de Células-Tronco/métodos , Células-Tronco/citologia , Animais , Técnicas de Cultura de Células/métodos , Diferenciação Celular , Humanos , Distrofias Musculares/fisiopatologia , Mioblastos Esqueléticos/citologia , Mioblastos Esqueléticos/transplante , Regeneração , Engenharia Tecidual/métodos
10.
Can J Gastroenterol Hepatol ; 2018: 2593745, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30065914

RESUMO

Background and Aims: Acute liver failure (ALF) is a severe syndrome with an elevated mortality rate, ranging from 40 to 80 %. Currently, liver transplantation is the only definitive treatment for these patients and new therapies aiming to treat ALF include artificial organs implant and stem cells therapy, for example. However, a major limitation of liver donors exists. Living donor liver transplantation (LDLT), split liver transplantation (SLT), and domino liver transplantation (DLT) are some of the available alternatives to treat ALF patients, but these do not reduce the number of patients on waiting lists. Herein, we discuss domino hepatocyte transplantation (DHT) using livers that would not meet transplantation criteria. Methods: We conducted a literature search on PubMed/Medline using acute liver failure, liver transplantation, hepatocyte transplantation, and domino liver transplantation as key words. Results: New sources of biochemically functional hepatocytes and therapeutic treatments, in parallel to organ transplantation, may improve liver injury recovery and decrease mortality rates. Moreover, the literature reports hepatocyte transplantation as a therapeutic alternative for organ shortage. However, a major challenge remains for a wide clinical application of hepatocytes therapy, i.e., the availability of sufficient amounts of cells for transplantation. Ideally, hepatocytes isolated from livers rejected for transplantation may be a promising alternative for this problem. Conclusion: Our review suggests that DHT may be an excellent strategy to increase cell supplies for hepatocyte transplantation.


Assuntos
Aloenxertos/provisão & distribuição , Terapia Baseada em Transplante de Células e Tecidos , Hepatócitos/transplante , Falência Hepática Aguda/cirurgia , Transplante de Fígado/métodos , Humanos , Falência Hepática Aguda/etiologia
11.
J Immunol ; 197(9): 3531-3544, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27707996

RESUMO

Duchenne muscular dystrophy (DMD) is a fatal X-linked disorder caused by mutations in the dystrophin gene that lead to degeneration of skeletal and cardiac muscles and to chronic inflammation. Despite the importance of γδ T cells in many diseases, this cellular subpopulation has not been described in DMD patients or in mdx mice, a widely used mouse model for studying DMD. Therefore, in this study, we aimed to evaluate the migration of γδ T cells to the cardiac muscle of mdx mice and to characterize their phenotype and functional activity. We observed no migration of γδ T cells to skeletal muscles, but these cells were found in the hearts of mdx mice during the study period, reaching a peak in 12-wk-old mice. These cells migrate primarily owing to CCL2 and CCL5 chemokines produced by cardiac tissue, and they are Vγ1+/CD27+ and thus produce high levels of IFN-γ. In vivo depletion of the γδ T cells revealed γδ T cell-dependent cardiac inflammatory immunoregulation, with increased numbers of CD3+CD4+, CD3+CD8+, and, in particular, F4/80+ cells in the heart and increased cardiac damage in mdx mice. We also observed in vitro that purified cardiac Γδ T cells are cytotoxic against adherent endomysial cardiac cells, mostly macrophages, but not against peritoneal cells, in a perforin/granzyme-dependent manner. Our present data indicate that γδ T cells exert protective effects on the hearts of mdx mice, possibly by selectively killing pathogenic macrophages, and this function may be important for the late onset of cardiac damage in DMD.


Assuntos
Cardiomiopatias/imunologia , Distrofina/metabolismo , Macrófagos/imunologia , Distrofia Muscular de Duchenne/imunologia , Miocárdio/imunologia , Linfócitos T/fisiologia , Animais , Cardiomiopatias/genética , Movimento Celular , Quimiocina CCL2/metabolismo , Quimiocina CCL5/metabolismo , Citotoxicidade Imunológica , Distrofina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Camundongos Knockout , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo
12.
Am J Pathol ; 179(4): 1894-904, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21819958

RESUMO

Although the roles of mast cells (MCs) are essential in many inflammatory and fibrotic diseases, their role in Trypanosoma cruzi-induced cardiomyopathy is unexplored. In this study, we treated infected CBA mice with cromolyn, an MC stabilizer, and observed much greater parasitemia and interferon-γ levels, higher mortality, myocarditis, and cardiac damage. Although these data show that MCs are important in controlling acute infection, we observed MC apoptosis in the cardiac tissue and peritoneal cavity of untreated mice. In the heart, pericardial mucosal MC die, perhaps because of reduced amounts of local stem cell factor. Using RT-PCR in purified cardiac MCs, we observed that infection induced transcription of P2X(7) receptor and Fas, two molecules reportedly involved in cell death and inflammatory regulation. In gld/gld mice (FasL(-/-)), apoptosis of cardiac, but not peritoneal, MCs was decreased. Conversely, infection of P2X(7)(-/-) mice led to reduced peritoneal, but not cardiac, MC death. These data illustrate the immunomodulatory role played by MCs in T. cruzi infection and the complexity of molecular interactions that control inflammatory pathways in different tissues and compartments.


Assuntos
Doença de Chagas/patologia , Doença de Chagas/parasitologia , Mastócitos/patologia , Mastócitos/parasitologia , Trypanosoma cruzi/fisiologia , Animais , Contagem de Células , Morte Celular/efeitos dos fármacos , Cromolina Sódica/farmacologia , Proteína Ligante Fas/metabolismo , Interleucina-3/metabolismo , Masculino , Mastócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Peritônio/efeitos dos fármacos , Peritônio/patologia , Receptores Purinérgicos P2X7/genética , Receptores Purinérgicos P2X7/metabolismo , Fator de Células-Tronco/metabolismo , Transcrição Gênica/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , Receptor fas/metabolismo
13.
Am J Pathol ; 176(6): 2891-900, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20413686

RESUMO

A deficiency of the dysferlin protein results in limb girdle muscular dystrophy type 2B and Miyoshi myopathy, with resulting plasma membrane abnormalities in myofibers. Many patients show muscle inflammation, but the molecular mechanisms that initiate and perpetuate this inflammation are not well understood. We previously showed abnormal activation of macrophages and hypothesized that activation of the inflammasome pathway may play a role in disease progression. To test this, we studied the inflammasome molecular platform in dysferlin-deficient human and mouse muscle. Consistent with our model, components of the NACHT, LRR and PYD-containing proteins (NALP)-3 inflammasome pathway were specifically up-regulated and activated in dysferlin-deficient but not in dystrophin-deficient and normal muscle. We demonstrate for the first time that normal primary skeletal muscle cells are capable of secreting IL-1beta in response to combined treatment with lipopolysaccharide and the P2X7 receptor agonist, benzylated ATP, suggesting that not only immune cells but also muscle cells can actively participate in inflammasome formation. In addition, we show that dysferlin-deficient primary muscle cells express toll-like receptors (TLRs; TLR-2 and TLR-4) and can efficiently produce IL-1beta in response to lipopolysaccharide and benzylated ATP. These data indicate that skeletal muscle is an active contributor of IL-1beta and strategies that interfere with this pathway may be therapeutically useful for patients with limb girdle muscular dystrophy type 2B.


Assuntos
Inflamação/metabolismo , Proteínas de Membrana , Proteínas Musculares , Músculo Esquelético/fisiologia , Músculo Esquelético/fisiopatologia , Distrofia Muscular do Cíngulo dos Membros , Trifosfato de Adenosina/química , Trifosfato de Adenosina/farmacologia , Adulto , Animais , Células Cultivadas , Progressão da Doença , Disferlina , Feminino , Humanos , Inflamação/genética , Inflamação/patologia , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/citologia , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/patologia , Distrofia Muscular do Cíngulo dos Membros/fisiopatologia , Mioblastos/citologia , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2X7 , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Regulação para Cima , Adulto Jovem
14.
Mem. Inst. Oswaldo Cruz ; 104(8): 1063-1071, Dec. 2009. ilus, tab
Artigo em Inglês | LILACS | ID: lil-538165

RESUMO

Trypanosoma cruzi infection induces diverse alterations in immunocompetent cells and organs, myocarditis and congestive heart failure. However, the physiological network of disturbances imposed by the infection has not been addressed thoroughly. Regarding myocarditis induced by the infection, we observed in our previous work that Fas-L-/- mice (gld/gld) have very mild inflammatory infiltration when compared to BALB/c mice. However, all mice from both lineages die in the early acute phase. Therefore, in this work we studied the physiological connection relating arterial pressure, renal function/damage and cardiac insufficiency as causes of death. Our results show that a broader set of dysfunctions that could be classified as a cardio/anaemic/renal syndrome is more likely responsible for cardiac failure and death in both lineages. However, gld/gld mice had very early glomerular deposition of IgM and a more intense renal inflammatory response with reduced renal filtration, which is probably responsible for the premature death in the absence of significant myocarditis in gld/gld.


Assuntos
Animais , Masculino , Camundongos , Injúria Renal Aguda , Doença de Chagas/fisiopatologia , Proteína Ligante Fas/metabolismo , Miocardite/fisiopatologia , Injúria Renal Aguda , Doença de Chagas/complicações , Camundongos Endogâmicos BALB C , Camundongos Mutantes , Miocardite/etiologia , Miocardite/metabolismo
15.
J Cardiovasc Pharmacol ; 53(2): 94-9, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19188841

RESUMO

The elucidation of the intricate molecular network of costimulus and regulatory pathways of the immune system led to the design of molecular therapies that specifically inactivate some cellular responses and ameliorate some autoimmune and inflammatory diseases. This innovative concept opens a new class of therapies, and one of the central components that could be targeted in future molecular therapies is the Fas-based pathway. Both soluble and membrane-bound Fas and Fas-L molecules exert a wide range of proinflammatory functions through the secretion of cytokines and chemokines, cellular chemotaxis, transcriptional regulation, cellular death, and others. Accordingly, many chronic inflammatory diseases, including myocarditis, are attenuated in mice lacking either molecule. Although it is tempting to speculate that the Fas/Fas-L pathway could be targeted for in vivo myocarditis therapy, the plurality of Fas/Fas-L functions can be an obstacle, leading to important side effects. In this review, we suggest that the injection of nonagonistic antibodies raised against the Fas molecule or the inactivation of downstream Fas-1,4,5-inositol triphosphate cascade are possible targets for myocarditis treatment.


Assuntos
Proteína Ligante Fas/fisiologia , Miocardite/terapia , Receptor fas/fisiologia , Animais , Anticorpos/uso terapêutico , Apoptose/fisiologia , Proteína Ligante Fas/imunologia , Miocardite/imunologia , Miocardite/metabolismo
16.
Mem Inst Oswaldo Cruz ; 104(8): 1063-71, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20140366

RESUMO

Trypanosoma cruzi infection induces diverse alterations in immunocompetent cells and organs, myocarditis and congestive heart failure. However, the physiological network of disturbances imposed by the infection has not been addressed thoroughly. Regarding myocarditis induced by the infection, we observed in our previous work that Fas-L-/- mice (gld/gld) have very mild inflammatory infiltration when compared to BALB/c mice. However, all mice from both lineages die in the early acute phase. Therefore, in this work we studied the physiological connection relating arterial pressure, renal function/damage and cardiac insufficiency as causes of death. Our results show that a broader set of dysfunctions that could be classified as a cardio/anaemic/renal syndrome is more likely responsible for cardiac failure and death in both lineages. However, gld/gld mice had very early glomerular deposition of IgM and a more intense renal inflammatory response with reduced renal filtration, which is probably responsible for the premature death in the absence of significant myocarditis in gld/gld.


Assuntos
Injúria Renal Aguda/fisiopatologia , Doença de Chagas/fisiopatologia , Proteína Ligante Fas/metabolismo , Miocardite/fisiopatologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/metabolismo , Animais , Doença de Chagas/complicações , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Mutantes , Miocardite/etiologia , Miocardite/metabolismo
17.
Muscle Nerve ; 37(5): 583-92, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18288709

RESUMO

Matrix metalloproteases (MMPs) are key regulatory molecules in the formation, remodeling, and degradation of extracellular matrix components in both physiological and pathological processes. Skeletal muscles of mdx dystrophic mice show distinct patterns of inflammation and regeneration, suggesting that factors within the microenvironment influence the adaptive responses of muscles with predominantly slow-twitch or fast-twitch fibers. This study aimed to verify the pattern of MMP activity in gastrocnemius, soleus, and diaphragm muscles and correlate it with the regenerative capability at distinct stages of the mdx myopathy. Marked inflammation and myonecrosis was associated with increased MMP-9 activity and TNF-alpha (tumor necrosis factor-alpha) production, whereas muscle regeneration, evidenced by NCAM (neural cell adhesion molecule) expression and MMP-2 activity, varied at different stages of the disease. Soleus muscles showed a high percentage of NCAM-positive myofibers in the early stages (2 weeks) of the disease, but they appeared in the gastrocnemius muscles at 12 weeks and in the diaphragm at 24 weeks. Increased MMP-2 activity in the diaphragm throughout all stages of the disease suggests important tissue remodeling, which is probably associated with persistent inflammation. The results indicate that the microenvironment of distinct skeletal muscle may influence a particular kinetic pattern of MMP activity, which ultimately favors persistent inflammation and myofiber regeneration at different stages of the myopathy in mdx mice.


Assuntos
Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Fibras Musculares Esqueléticas/fisiologia , Músculo Esquelético/fisiopatologia , Distrofia Muscular Animal/patologia , Regeneração/fisiologia , Fatores Etários , Animais , Antígenos Ly/metabolismo , Antígeno CD56/metabolismo , Regulação Enzimológica da Expressão Gênica , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Músculo Esquelético/enzimologia , Moléculas de Adesão de Célula Nervosa/metabolismo
18.
Am J Pathol ; 171(1): 79-86, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17591955

RESUMO

Fas/Fas ligand (Fas-L) engagement, a potent inducer of apoptosis, is also important for cellular activation, regulation of effector and chemotactic activity, and secretion of chemokines and cytokines. We evaluated the relevance of Fas/Fas-L in the regulation of myocarditis induced by Trypanosoma cruzi infection and observed that in Fas-L(-/-) mice (gld/gld), cardiac infiltration was significantly reduced, accordingly showing less cardiomyocyte destruction. Fluorescence-activated cell sorting analysis of cardiac inflammatory cells showed higher numbers of CD8(+) T cells in BALB/c compared with gld/gld mice but similar levels of lymphocyte function-associated antigen-1, intercellular adhesion molecule, CD2, and CD69 expression; MAC-1(+) myeloid cells and mast cells were increased in BALB/c mice, whereas gld/gld mice exhibited an enrichment of CD4(+/low) T cells. Intracellular labeling of cytokines revealed no clear cardiac skewing of Th1 or Th2 responses, but we found a higher number of interleukin-10(+) cells in gld/gld mice and a deficient expression of vascular cell adhesion molecule-1 on cardiac endothelial cells in gld/gld mice. Finally, we found a population of CD3(+) but CD4/CD8 double negative cardiac T cells in both groups of infected mice, but down-regulation of some adhesion molecules and surface receptors was only observed in gld/gld mice, indicating a targeted T-cell population mostly affected by the lack of Fas-L engagement. These results point to a role for myocarditis regulation by Fas/Fas-L beyond its possible direct relevance in cellular death.


Assuntos
Linfócitos T CD4-Positivos/fisiologia , Doença de Chagas/complicações , Proteína Ligante Fas/fisiologia , Inflamação/etiologia , Miocardite/metabolismo , Doença Aguda , Animais , Linfócitos T CD8-Positivos/fisiologia , Interleucina-10/análise , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Mutantes , Miocardite/etiologia , Miocardite/parasitologia
19.
J Antimicrob Chemother ; 56(6): 1034-41, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16269551

RESUMO

OBJECTIVES: Investigation of the mode of action of the naphthoimidazole N1, obtained from the reaction of beta-lapachone with benzaldehyde, which among 45 semi-synthetic derivatives of naphthoquinones isolated from Tabebuia sp. was one of the most active compounds against Trypanosoma cruzi trypomastigotes. METHODS: Quantification of the effect of N1 against the proliferative forms of T. cruzi, and investigation of potential targets in the parasite using electron microscopy and flow cytometry techniques. RESULTS: N1 presented the following order of activity: amastigotes > trypomastigotes > epimastigotes. The effect on intracellular forms was approximately 25 times higher than on macrophages and heart muscle cells. N1-treated parasites presented an abnormal chromatin condensation and mitochondrial damage. In epimastigotes, alterations of reservosomes were observed, and in trypomastigotes, a decrease in the electron density of acidocalcisomes was observed. In epimastigotes, the naphthoimidazole inhibited the activity of succinate cytochrome c reductase. Labelling with rhodamine 123 or Acridine Orange was decreased in both forms treated with N1. CONCLUSIONS: The results suggest that epimastigotes, reservosomes, mitochondrion, and nucleus contain N1 targets. In trypomastigotes, in which reservosomes are absent, the organelles affected by the compound were also the mitochondrion and nucleus, as well as acidocalcisomes, in which the decrease in electron density could be due to the use of polyphosphate as an alternative energy supply.


Assuntos
Organelas/efeitos dos fármacos , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Laranja de Acridina/metabolismo , Animais , Benzaldeídos/química , Células Cultivadas , Cromatina/efeitos dos fármacos , Grânulos Citoplasmáticos/efeitos dos fármacos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Imidazóis/toxicidade , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/parasitologia , Camundongos , Microscopia Eletrônica , Mitocôndrias/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/parasitologia , Naftoquinonas/síntese química , Naftoquinonas/química , Naftoquinonas/farmacologia , Naftoquinonas/toxicidade , Rodamina 123/metabolismo , Succinato Citocromo c Oxirredutase/antagonistas & inibidores , Tripanossomicidas/síntese química , Tripanossomicidas/isolamento & purificação , Tripanossomicidas/toxicidade , Trypanosoma cruzi/crescimento & desenvolvimento , Trypanosoma cruzi/ultraestrutura
20.
Mem. Inst. Oswaldo Cruz ; 99(7): 697-701, Nov. 2004. ilus, tab, graf
Artigo em Inglês | LILACS | ID: lil-391597

RESUMO

Primary cultures of cardiomyocytes represent a useful model for analyzing cardiac cell biology as well as pathogenesis of several cardiovascular disorders. Our aim was to standardize protocols for determining the damage of cardiac cells cultured in vitro by measuring the creatine kinase and its cardiac isotype and lactate dehydrogenase activities in the supernatants of mice cardiomyocytes submitted to different protocols of cell lysis. Our data showed that due to its higher specificity, the cardiac isotype creatine kinase was the most sensitive as compared to the others studied enzymatic markers, and can be used to monitor and evaluate cardiac damage in in vitro assays.


Assuntos
Animais , Camundongos , Doenças Cardiovasculares , Creatina Quinase , Isoenzimas , L-Lactato Desidrogenase , Miócitos Cardíacos , Biomarcadores , Doenças Cardiovasculares , Técnicas de Cultura de Células , Microscopia Eletrônica , Sensibilidade e Especificidade
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