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1.
Int J Mol Sci ; 24(13)2023 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-37446227

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive, relentless, and deadly disease. Little is known about its pathogenetic mechanisms; therefore, developing efficient pharmacological therapies is challenging. This work aimed to apply a therapeutic alternative using immunomodulatory peptides in a chronic pulmonary fibrosis murine model. BALB/c mice were intratracheally instilled with bleomycin (BLM) and followed for 30 days. The mice were treated with the immune modulatory peptides ToAP3 and ToAP4 every three days, starting on the 5th day post-BLM instillation. ELISA, qPCR, morphology, and respiratory function analyses were performed. The treatment with both peptides delayed the inflammatory process observed in the non-treated group, which showed a fibrotic process with alterations in the production of collagen I, III, and IV that were associated with significant alterations in their ventilatory mechanics. The ToAP3 and ToAP4 treatments, by lung gene modulation patterns, indicated that distinct mechanisms determine the action of peptides. Both peptides controlled the experimental IPF, maintaining the tissue characteristics and standard function properties and regulating fibrotic-associated cytokine production. Data obtained in this work show that the immune response regulation by ToAP3 and ToAP4 can control the alterations that cause the fibrotic process after BLM instillation, making both peptides potential therapeutic alternatives and/or adjuvants for IPF.


Assuntos
Fibrose Pulmonar Idiopática , Pulmão , Camundongos , Animais , Pulmão/patologia , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/patologia , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Bleomicina , Colágeno Tipo I , Camundongos Endogâmicos C57BL
2.
Nanomaterials (Basel) ; 12(10)2022 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-35630905

RESUMO

Diets rich in omega-3 or -6 fatty acids will produce different profiles for cell membranes phospholipid constitutions. Omegas 3 and 6 are part of the diet and can modulate the inflammatory profile. We evaluated the effects of the oral absorption of fish oil, when associated with a lipid nanoemulsion in an experimental pulmonary inflammatory model. Pulmonary fibrosis is a disease associated with excessive extracellular matrix deposition. We determined to investigate the morphophysiological mechanisms in mice that were pretreated after induction with bleomycin (BLM). The pretreatment was for 21 days with saline solution, sunflower oil (SO), fish oil (FO), and fish oil nanoemulsion (NEW3). The animals received a daily dose of 50 mg/Kg of docosahexaenoic acid DHA and 10 mg/Kg eicosapentaenoic (EPA) (100 mg/Kg), represented by a daily dose of 40 µL of NEW3. The blank group was treated with the same amount daily (40 µL) during the 21 days of pretreatment. The animals were treated with SO and FO, 100 mg/Kg (containing 58 mg/Kg of polyunsaturated fats/higher% linoleic acid) and 100 mg/Kg (50 mg/Kg of DHA and 10 mg/Kg EPA), respectively. A single dose of 5 mg/mL (50 µL) bleomycin sulfate, by the intratracheal surgical method in BALB/cAnNTac (BALB/c). NEW3 significantly reduced fibrotic progression, which can be evidenced by the protection from loss of body mass, increase in respiratory incursions per minute, decreased spacing of alveolar septa, decreased severity of fibrosis, and changes in the respiratory system. NEW3 attenuated the inflammatory changes developed in the experimental model of pulmonary fibrosis, while group SO showed a significant increase in inflammatory changes. This concluded that the presented results demonstrated that is possible to positively modulate the immune and inflamamtory response to an external agressor, by changing the nutitional intake of specific fatty acids, such as omega-3 placed in fish oil. Moreover, these benefits can be improved by the nanoencapsulation of fish oil in lipid nanoemulsions.

3.
Biomed Pharmacother ; 118: 109152, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31376652

RESUMO

Antimicrobial peptides (AMPs) are small molecules with microbicidal and immunoregulatory activities. In this study we evaluated the anti-inflammatory and antimicrobial activities of peptides ToAP3 and ToAP4, AMPs from the venom of the Brazilian scorpion Tityus obscurus. To test the peptides' activity, murine bone marrow-derived macrophages (BMDMs) or dendritic cells (BMDCs) were stimulated with peptides plus LPS to analyze their ability to modulate cytokine release as well as phenotypic markers. For antimicrobial analysis, we evaluated the indirect activity against macrophage-internalized Cryptococcus neoformans and direct activity against Mycobacterium massiliense. Our data demonstrate that they were able to reduce TNF-α and IL-1ß transcript levels and protein levels for BMDM and BMDC. Furthermore, the reduction of TNF-α secretion, before LPS- inflammatory stimuli, is associated with peptide interaction with TLR-4. ToAP4 increased MHC-II expression in BMDC, while ToAP3 decreased co-stimulatory molecules such as CD80 and CD86. Although these peptides were able to modulate the production of cytokines and molecules associated with antigen presentation, they did not increase the ability of clearance of C. neoformans by macrophages. In antimicrobial analysis, only ToAP3 showed potent action against bacteria. Altogether, these results demonstrate a promising target for the development of new immunomodulatory and anti-bacterial therapies.


Assuntos
Anti-Infecciosos/farmacologia , Citocinas/metabolismo , Peptídeos/farmacologia , Venenos de Escorpião/química , Escorpiões , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Anti-Infecciosos/isolamento & purificação , Anti-Inflamatórios não Esteroides/isolamento & purificação , Anti-Inflamatórios não Esteroides/farmacologia , Linhagem Celular , Cryptococcus neoformans/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Imunidade Inata/efeitos dos fármacos , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Testes de Sensibilidade Microbiana , Mycobacterium abscessus/efeitos dos fármacos , Peptídeos/isolamento & purificação , Receptor 4 Toll-Like/genética
4.
PLoS One ; 11(3): e0149729, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26930596

RESUMO

Mycobacterium abscessus subsp. massiliense, a rapidly growing mycobacteria (RGM) that is becoming increasingly important among human infectious diseases, is virulent and pathogenic and presents intrinsic resistance to several antimicrobial drugs that might hamper their elimination. Therefore, the identification of new drugs to improve the current treatment or lower the risk of inducing resistance is urgently needed. Wasp venom primarily comprises peptides that are responsible for most of the biological activities in this poison. Here, a novel peptide Polydim-I, from Polybia dimorpha Neotropical wasp, was explored as an antimycobacterial agent. Polydim-I provoked cell wall disruption and exhibited non-cytotoxicity towards mammalian cells. Polydim-I treatment of macrophages infected with different M. abscessus subsp. massiliense strains reduced 40 to 50% of the bacterial load. Additionally, the Polydim-I treatment of highly susceptible mice intravenously infected with M. abscessus subsp. massiliense induced 0.8 to 1 log reduction of the bacterial load in the lungs, spleen, and liver. In conclusion, this is the first study to show the therapeutic potential of a peptide derived from wasp venom in treating mycobacteria infections. Polydim-I acts on the M. abscessus subsp. massiliense cell wall and reduce 40-90% of the bacterial load both in vitro and in vivo. The presented results encourage further studies on the use of Polydim-I as one of the components for M. abscessus subsp. massiliense treatment.


Assuntos
Antibacterianos/farmacologia , Infecções por Mycobacterium/tratamento farmacológico , Mycobacterium/efeitos dos fármacos , Peptídeos/farmacologia , Vespas/metabolismo , Sequência de Aminoácidos , Animais , Antibacterianos/química , Linhagem Celular , Células Cultivadas , Cromatografia Líquida de Alta Pressão/métodos , Feminino , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Proteínas de Insetos/química , Proteínas de Insetos/farmacologia , Interferon gama/deficiência , Interferon gama/genética , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Camundongos Endogâmicos BALB C , Camundongos Knockout , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Dados de Sequência Molecular , Mycobacterium/fisiologia , Mycobacterium/ultraestrutura , Infecções por Mycobacterium/genética , Infecções por Mycobacterium/microbiologia , Peptídeos/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Venenos de Vespas/metabolismo
5.
Mycopathologia ; 175(5-6): 463-75, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23179449

RESUMO

Chromoblastomycosis (CBM) is a chronic subcutaneous mycosis, caused by several dimorphic, pigmented dematiaceous fungi. Patients with the disease are still considered a therapeutic challenge, mainly due to its recalcitrant nature. There is no "gold standard" treatment for this neglected mycosis, but rather there are several treatment options. Chemotherapy alternatives include 5-flucytosine, itraconazole, terbinafine, fluconazole, thiabendazole, ketoconazole and amphotericin B, although the healing of severe cases is still uncommon. However, several studies have reported the DNA vaccine to be promising in the treatment for fungal infections; this vaccine allows the host to restore depressed cellular immunity, minimizing the toxic effects from conventional antifungal therapies. This work was therefore carried out aiming to establish a suitable model for experimental CBM, suggesting also new therapies, including DNA-hsp65 vaccine. By analyzing the morphometrical and histopathological aspects and by quantifying the fungal burden, the results showed the establishment of a chronic, although transitory, experimental CBM model with lesions similar to those presented in humans. A treatment regimen using intralesional itraconazole or amphotericin B was effective in treating experimental CBM, as was a therapy using naked DNA-hsp65 vaccine. It has also been shown that chemotherapy associated with DNA-hsp65 vaccine is promising in the treatment for CBM.


Assuntos
Proteínas de Bactérias/imunologia , Chaperonina 60/imunologia , Cromoblastomicose/terapia , Fatores Imunológicos/administração & dosagem , Vacinas de DNA/administração & dosagem , Animais , Antifúngicos/uso terapêutico , Proteínas de Bactérias/genética , Chaperonina 60/genética , Cromoblastomicose/microbiologia , Cromoblastomicose/patologia , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Histocitoquímica , Fatores Imunológicos/genética , Masculino , Ratos Wistar , Resultado do Tratamento , Vacinas de DNA/genética
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