NATHALIA MONTOURO PINHEIRO MENEGASSO
Projetos de Pesquisa
Unidades Organizacionais
LIM/20 - Laboratório de Terapêutica Experimental, Hospital das Clínicas, Faculdade de Medicina
11 resultados
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- Effects of Eugenol and Dehydrodieugenol B from Nectandra leucantha against Lipopolysaccharide (LPS)-Induced Experimental Acute Lung Inflammation(2021) I, Marcia Bittencourt-Mernak; PINHEIRO, Nathalia M.; SILVA, Rafael C. da; PONCI, Vitor; BANZATO, Rosana; PINHEIRO, Aruana J. M. C. R.; OLIVO, Clarice R.; TIBERIO, Iolanda F. L. C.; LIMA NETO, Lidio G.; SANTANA, Fernanda P. R.; LAGO, Joao H. G.; PRADO, Carla M.Acute lung injury (ALI) is an important public health problem. The present work investigated whether dehydrodieugenol B treatment, a compound isolated from Brazilian plant Nectandra leucantha (Lauraceae), modulates experimental ALI and compared the observed effects to eugenol. Effects of dehydrodieugenol B in vitro in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells were evaluated. The lung and systemic inflammatory profile, lung function, and possible mechanisms involved in BALB/C male mice (6-8 weeks) with ALI induced by LPS instillation (5 mg/kg) was assayed. Dehydrodieugenol B did not affect the cell viability and inhibited the increase in NO release and IL-1 beta and IL-6 gene expression induced by LPS. In vivo, both compounds reduced lung edema, inflammatory cells, and the IL-6 and IL-1 beta levels in bronchoalveolar lavage fluid, as well as reduced inflammatory cell infiltration and those positive to iNOS, MMP-9, and TIMP-1, and reduced the collagen content and the 8-isoprostane expression in lung tissue. Eugenol and dehydrodieugenol B also inhibited the phosphorylation of Jc-Jun-NH2 terminal Kinase (JNK), a signaling protein involved in the MAPKinase pathway. There was no effect of these compounds in lung function. Therefore, eugenol and dehydrodieugenol B ameliorates several features of experimental ALI and could be considered as a pharmacological tool to ameliorate acute lung inflammation.
- Evidences of Herbal Medicine-Derived Natural Products Effects in Inflammatory Lung Diseases(2016) SANTANA, Fernanda Paula R.; PINHEIRO, Nathalia M.; MERNAK, Marcia Isabel B.; RIGHETTI, Renato F.; MARTINS, Milton A.; LAGO, Joao H. G.; LOPES, Fernanda D. T. Q. dos Santos; TIBERIO, Iolanda F. L. C.; PRADO, Carla M.Pulmonary inflammation is a hallmark of many respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory syndrome distress (ARDS). Most of these diseases are treated with anti-inflammatory therapy in order to prevent or to reduce the pulmonary inflammation. Herbal medicine-derived natural products have been used in folk medicine and scientific studies to evaluate the value of these compounds have grown in recent years. Many substances derived from plants have the biological effects in vitro and in vivo, such as flavonoids, alkaloids, and terpenoids. Among the biological activities of natural products derived from plants can be pointed out the anti-inflammatory, antiviral, antiplatelet, antitumor anti-allergic activities, and antioxidant. Although many reports have evaluated the effects of these compounds in experimental models, studies evaluating clinical trials are scarce in the literature. This review aims to emphasize the effects of these different natural products in pulmonary diseases in experimental models and in humans and pointing out some possible mechanisms of action.
- Structurally Related Monoterpenes p-Cymene, Carvacrol and Thymol Isolated from Essential Oil from Leaves of Lippia sidoides Cham. (Verbenaceae) Protect Mice against Elastase-Induced Emphysema(2016) GAMES, Ellen; GUERREIRO, Marina; SANTANA, Fernanda R.; PINHEIRO, Nathalia M.; OLIVEIRA, Emerson A. de; LOPES, Fernanda D. T. Q. S.; OLIVO, Clarice R.; TIBERIO, Iolanda F. L. C.; MARTINS, Milton A.; LAGO, Joao Henrique G.; PRADO, Carla M.Background: Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow obstruction and inflammation. Natural products, such as monoterpenes, displayed anti-inflammatory and anti-oxidant activities and can be used as a source of new compounds to COPD treatment. Our aim was to evaluate, in an elastase-induced pulmonary emphysema in mice, the effects of and underlying mechanisms of three related natural monoterpenes (p-cymene, carvacrol and thymol) isolated from essential oil from leaves Lippia sidoides Cham. (Verbenaceae). Methods: Mices received porcine pancreatic elastase (PPE) and were treated with p-cymene, carvacrol, thymol or vehicle 30 min later and again on 7th, 14th and 28th days. Lung inflammatory profile and histological sections were evaluated. Results: In the elastase-instilled animals, the tested monoterpenes reduced alveolar enlargement, macrophages and the levels of IL-1 beta, IL-6, IL-8 and IL-17 in bronchoalveolar lavage fluid (BALF), and collagen fibers, MMP-9 and p-65-NF-kappa B-positive cells in lung parenchyma (p < 0.05). All treatments attenuated levels of 8-iso-PGF2 alpha but only thymol was able to reduced exhaled nitric oxide (p < 0.05). Conclusion: Monoterpenes p-cymene, carvacrol and thymol reduced lung emphysema and inflammation in mice. No significant differences among the three monoterpenes treatments were found, suggesting that the presence of hydroxyl group in the molecular structure of thymol and carvacrol do not play a central role in the anti-inflammatory effects.
- Prophylactic and therapeutic treatment with the flavonone sakuranetin ameliorates LPS-induced acute lung injury(2017) BITTENCOURT-MERNAK, Marcia Isabel; PINHEIRO, Nathalia M.; SANTANA, Fernanda P. R.; GUERREIRO, Marina P.; SARAIVA-ROMANHOLO, Beatriz M.; GRECCO, Simone S.; CAPERUTO, Luciana C.; FELIZARDO, Raphael J. F.; CAMARA, Niels O. S.; TIBERIO, Iolanda F. L. C.; MARTINS, Mlton A.; LAGO, Joao Henrique G.; PRADO, Carla M.Sakuranetin is the main isolate flavonoid from Baccharis retusa (Asteraceae) leaves and exhibits anti-inflammatory and antioxidative activities. Acute respiratory distress syndrome is an acute failure of the respiratory system for which effective treatment is urgently necessary. This study investigated the preventive and therapeutic effects of sakuranetin on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. Animals were treated with intranasal sakuranetin 30 min before or 6 h after instillation of LPS. Twenty-four hours after ALI was induced, lung function, inflammation, macrophages population markers, collagen fiber deposition, the extent of oxidative stress, and the expression of matrix metalloprotease-9 (MMP-9), tissue inhibitor of MMP- 9 (TIMP-1) and NF-kB were evaluated. The animals began to show lung alterations 6 h after LPS instillation, and these changes persisted until 24 h after LPS administration. Preventive and therapeutic treatment with sakuranetin reduced the neutrophils in the peripheral blood and in the bronchial alveolar lavage. Sakuranetin treatment also reduced macrophage populations, particularly that of M1-like macrophages. In addition, sakurnaetin treatment reduced keratinocyte-derived chemokines (IL-8 homolog) and NF-kB levels, collagen fiber formation, MMM-9 and TIMP-1-positive cells, and oxidative stress in lung tissues compared with LPS animals treated with vehicle. Finally, sakuranetin treatment also reduced total protein, and the levels of TNF-alpha and IL-1 beta in the lung. This study shows that sakuranetin prevented and reduced pulmonary inflammation induced by LPS. Because sakuranetin modulates oxidative stress, the NF-kB pathway, and lung function, it may constitute a novel therapeutic candidate to prevent and treat ALI.
- Lung Edema and Mortality Induced by Intestinal Ischemia and Reperfusion Is Regulated by VAChT Levels in Female Mice(2021) SANTANA, Fernanda P. R.; RICARDO-DA-SILVA, Fernanda Y.; FANTOZZI, Evelyn T.; PINHEIRO, Nathalia M.; TIBERIO, Iolanda F. L. C.; MOREIRA, Luiz Felipe Pinho; PRADO, Marco Antonio M.; PRADO, Vania F.; TAVARES-DE-LIMA, Wothan; PRADO, Carla Maximo; BREITHAUPT-FALOPPA, Ana CristinaAcute lung injury induced by intestinal ischemia/reperfusion (I/R) is a relevant clinical condition. Acetylcholine (ACh) and the alpha 7 nicotinic ACh receptor (nAChR alpha-7) are involved in the control of inflammation. Mice with reduced levels of the vesicular ACh transporter (VAChT), a protein responsible for controlling ACh release, were used to test the involvement of cholinergic signaling in lung inflammation due to intestinal I/R. Female mice with reduced levels of VAChT (VAChT-KDHOM) or wild-type littermate controls (WT) were submitted to intestinal I/R followed by 2 h of reperfusion. Mortality, vascular permeability, and recruitment of inflammatory cells into the lung were investigated. Parts of mice were submitted to ovariectomy (OVx) to study the effect of sex hormones or treated with PNU-282,987 (nAChR alpha-7 agonist). A total of 43.4% of VAChT-KDHOM-I/R mice died in the reperfusion period compared to 5.2% of WT I/R mice. The I/R increased lung inflammation in both genotypes. In VAChT-KDHOM mice, I/R increased vascular permeability and decreased the release of cytokines in the lung compared to WT I/R mice. Ovariectomy reduced lung inflammation and permeability compared to non-OVx, but it did not avoid mortality in VAChT-KDHOM-I/R mice. PNU treatment reduced lung permeability, increased the release of proinflammatory cytokines and the myeloperoxidase activity in the lungs, and prevented the increased mortality observed in VAChT-KDHOM mice. Cholinergic signaling is an important component of the lung protector response against intestinal I/R injury. Decreased cholinergic signaling seems to increase pulmonary edema and dysfunctional cytokine release that increased mortality, which can be prevented by increasing activation of nAChR alpha-7.
- Vesicular acetylcholine transport deficiency potentiates some inflammatory responses induced by diesel exhaust particles(2019) SANTANA, Fernanda P. R.; PINHEIRO, Nathalia M.; BITTENCOURT-MERNAK, Marcia I.; PERINI, Adenir; YOSHIZAKI, Kelly; MACCHIONE, Mariangela; SALDIVA, Paulo H. N.; MARTINS, Milton A.; TIBERIO, Iolanda F. L. C.; PRADO, Marco Antonio M.; PRADO, Vania F.; PRADO, Carla M.Endogenous acetylcholine (ACh), which depends of the levels of vesicular ACh transport (VAChT) to be released, is the central mediator of the cholinergic anti-inflammatory system. ACh controls the release of cytokine in different models of inflammation. Diesel exhaust particles (DEP) are one of the major environmental pollutants produced in large quantity by automotive engines in urban center. DEP bind the lung parenchyma and induce inflammation. We evaluated whether cholinergic dysfunction worsens DEP-induced lung inflammation. Male mice with decreased ACh release due to reduced expression of VAChT (VAChT-KD mice) were submitted to DEP exposure for 30 days (3 mg/mL of DEP, once a day, five days a week) or saline. Pulmonary function and inflammation as well as extracellular matrix fiber deposition were evaluated. Additionally, airway and nasal epithelial mucus production were quantified. We found that DEP instillation worsened lung function and increased lung inflammation. Higher levels of mononuclear cells were observed in the peripheral blood of both wild-type (WT) and VAChT-KD mice. Also, both wild-type (WT) and VAChT-KD mice showed an increase in macrophages in bronchoalveolar lavage fluid (BALF) as well as increased expression of IL-4, IL-6, IL-13, TNF-alpha, and NF-kappa B in lung cells. The collagen fiber content in alveolar septa was also increased in both genotypes. On the other hand, we observed that granulocytes were increased only in VAChT-KD peripheral blood. Likewise, increased BALF lymphocytes and neutrophils as well as increased elastic fibers in alveolar septa, airway neutral mucus, and nasal epithelia acid mucus were observed only in VAChT-KD mice. The cytokines IL-4 and TNF-alpha were also higher in VAChT-KD mice compared with WT mice. In conclusion, decreased ability to release ACh exacerbates some of the lung alterations induced by DEP in mice, suggesting that VAChT-KD animals are more vulnerable to the effects of DEP in the lung.
- A flavanone from Baccharis retusa (Asteraceae) prevents elastase-induced emphysema in mice by regulating NF-kappa B, oxidative stress and metalloproteinases (vol 16, 79, 2015)(2015) TAGUCHI, Laura; PINHEIRO, Nathalia M.; OLIVO, Clarice R.; CHOQUETA-TOLEDO, Alessandra; GRECCO, Simone S.; LOPES, Fernanda D. T. Q. S.; CAPERUTO, Luciana C.; MARTINS, Milton A.; TIBERIO, Iolanda F. L. C.; CAMARA, Niels O.; LAGO, Joao Henrique G.; PRADO, Carla M.
- A flavanone from Baccharis retusa (Asteraceae) prevents elastase-induced emphysema in mice by regulating NF-kappa B, oxidative stress and metalloproteinases(2015) TAGUCHI, Laura; PINHEIRO, Nathalia M.; OLIVO, Clarice R.; CHOQUETA-TOLEDO, Alessandra; GRECCO, Simone S.; LOPES, Fernanda D. T. Q. S.; CAPERUTO, Luciana C.; MARTINS, Milton A.; TIBERIO, Iolanda F. L. C.; CAMARA, Niels O.; LAGO, Joao Henrique G.; PRADO, Carla M.Background: Pulmonary emphysema is characterized by irreversible airflow obstruction, inflammation, oxidative stress imbalance and lung remodeling, resulting in reduced lung function and a lower quality of life. Flavonoids are plant compounds with potential anti-inflammatory and antioxidant effects that have been used in folk medicine. Our aim was to determine whether treatment with sakuranetin, a flavonoid extracted from the aerial parts of Baccharis retusa, interferes with the development of lung emphysema. Methods: Intranasal saline or elastase was administered to mice; the animals were then treated with sakuranetin or vehicle 2 h later and again on days 7, 14 and 28. We evaluated lung function and the inflammatory profile in bronchoalveolar lavage fluid (BALF). The lungs were removed to evaluate alveolar enlargement, extracellular matrix fibers and the expression of MMP-9, MMP-12, TIMP-1, 8-iso-PGF-2 and p65-NF-kappa B in the fixed tissues as well as to evaluate cytokine levels and p65-NF-kappa B protein expression. Results: In the elastase-treated animals, sakuranetin treatment reduced the alveolar enlargement, collagen and elastic fiber deposition and the number of MMP-9- and MMP-12-positive cells but increased TIMP-1 expression. In addition, sakuranetin treatment decreased the inflammation and the levels of TNF-alpha, IL-1 beta and M-CSF in the BALF as well as the levels of NF-kappa B and 8-iso-PGF-2 alpha in the lungs of the elastase-treated animals. However, this treatment did not affect the changes in lung function. Conclusion: These data emphasize the importance of oxidative stress and metalloproteinase imbalance in the development of emphysema and suggest that sakuranetin is a potent candidate that should be further investigated as an emphysema treatment. This compound may be useful for counteracting lung remodeling and oxidative stress and thus attenuating the development of emphysema.
- Effects of VAChT reduction and alpha 7nAChR stimulation by PNU-282987 in lung inflammation in a model of chronic allergic airway inflammation(2020) PINHEIRO, Nathalia M.; MIRANDA, Claudia J. C. P.; SANTANA, Fernanda R.; BITTENCOURT-MERNAK, Marcia; ARANTES-COSTA, Fernanda M.; OLIVO, Clarice; PERINI, Adenir; FESTA, Sergio; CAPERUTO, Luciana C.; TIBERIO, Iolanda F. L. C.; PRADO, Marco Antonio M.; MARTINS, Milton A.; PRADO, Vania F.; PRADO, Carla M.The cholinergic anti-inflammatory pathway has been shown to regulate lung inflammation and cytokine release in acute models of inflammation, mainly via alpha 7 nicotinic receptor (alpha 7nAChR). We aimed to evaluate the role of endogenous acetylcholine in chronic allergic airway inflammation in mice and the effects of therapeutic nAChR stimulation in this model. We first evaluated lung inflammation and remodeling on knock-down mice with 65% of vesicular acetylcholine transport (VAChT) gene reduction (KDVAChT) and wild-type(WT) controls that were subcutaneously sensitized and then inhaled with ovalbumin(OVA). We then evaluated the effects of PNU282987(0.5-to-2mg/kg),( alpha 7nAChR agonist) treatment in BALB/c male mice intraperitoneal sensitized and then inhaled with OVA. Another OVA-sensitized-group was treated with PNU-282987 plus Methyllycaconitine (MLA,1 mg/kg, alpha 7nAChR antagonist) to confirm that the effects observed by PNU were due to alpha 7nAChR. We showed that KDVAChT-OVA mice exhibit exacerbated airway inflammation when compared to WT-OVA mice. In BALB/c, PNU-282987 treatment reduced the number of eosinophils in the blood, BAL fluid, and around airways, and also decreased pulmonary levels of IL-4,IL-13,IL-17, and IgE in the serum of OVA-exposed mice. MLA pretreatment abolished all the effects of PNU-282987. Additionally, we showed that PNU-282987 inhibited STAT3phosphorylation and reduced SOCS3 expression in the lung. These data indicate that endogenous cholinergic tone is important to control allergic airway inflammation in a murine model. Moreover, alpha 7nAChR is involved in the control of eosinophilic inflammation and airway remodeling, possibly via inhibition of STAT3/SOCS3 pathways. Together these data suggest that cholinergic anti-inflammatory system mainly alpha 7nAChR should be further considered as a therapeutic target in asthma.
- Pulmonary Inflammation Is Regulated by the Levels of the Vesicular Acetylcholine Transporter(2015) PINHEIRO, Nathalia M.; MIRANDA, Claudia J. C. P.; PERINI, Adenir; CAMARA, Niels O. S.; COSTA, Soraia K. P.; ALONSO-VALE, Maria Isabel C.; CAPERUTO, Luciana C.; TIBERIO, Iolanda F. L. C.; PRADO, Marco Antonio M.; MARTINS, Milton A.; PRADO, Vania F.; PRADO, Carla M.Acetylcholine (ACh) plays a crucial role in physiological responses of both the central and the peripheral nervous system. Moreover, ACh was described as an anti-inflammatory mediator involved in the suppression of exacerbated innate response and cytokine release in various organs. However, the specific contributions of endogenous release ACh for inflammatory responses in the lung are not well understood. To address this question we have used mice with reduced levels of the vesicular acetylcholine transporter (VAChT), a protein required for ACh storage in secretory vesicles. VAChT deficiency induced airway inflammation with enhanced TNF-alpha and IL-4 content, but not IL-6, IL-13 and IL-10 quantified by ELISA. Mice with decreased levels of VAChT presented increased collagen and elastic fibers deposition in airway walls which was consistent with an increase in inflammatory cells positive to MMP-9 and TIMP-1 in the lung. In vivo lung function evaluation showed airway hyperresponsiveness to methacholine in mutant mice. The expression of nuclear factor-kappa B (p65-NF-kappa B) in lung of VAChT-deficient mice were higher than in wild-type mice, whereas a decreased expression of janus-kinase 2 (JAK2) was observed in the lung of mutant animals. Our findings show the first evidence that cholinergic deficiency impaired lung function and produce local inflammation. Our data supports the notion that cholinergic system modulates airway inflammation by modulation of JAK2 and NF-kappa B pathway. We proposed that intact cholinergic pathway is necessary to maintain the lung homeostasis.