Nem de Oliveira Souza I, Frost PS, França JV, Nascimento-Viana JB, Neris RLS, Freitas L, Pinheiro DJLL, Nogueira CO, Neves G, Chimelli L, De Felice FG, Cavalheiro ÉA, Ferreira ST, Assunção-Miranda I, Figueiredo CP, Da Poian AT, Clarke JR. Acute and chronic neurological consequences of early-life Zika virus infection in mice. Sci Transl Med. 2018 Jun 6;10(444):eaar2749.
DOI: 10.1126/scitranslmed.aar2749
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Although congenital Zika virus (ZIKV) exposure has been associated with microcephaly and other neurodevelopmental disorders, long-term consequences of perinatal infection are largely unknown. We evaluated short- and long-term neuropathological and behavioral consequences of neonatal ZIKV infection in mice. ZIKV showed brain tropism, causing postnatal-onset microcephaly and several behavioral deficits in adulthood. During the acute phase of infection, mice developed frequent seizures, which were reduced by tumor necrosis factor–α (TNF-α) inhibition. During adulthood, ZIKV replication persisted in neonatally infected mice, and the animals showed increased susceptibility to chemically induced seizures, neurodegeneration, and brain calcifications. Altogether, the results show that neonatal ZIKV infection has long-term neuropathological and behavioral complications in mice and suggest that early inhibition of TNF-α–mediated neuroinflammation might be an effective therapeutic strategy to prevent the development of chronic neurological abnormalities.
Barboza RS, Valente LMM, Wolff T, Assunção-Miranda I, Neris RLS, Guimarães-Andrade IP, Gomes M. Antiviral Activity of Faramea hyacinthina and Faramea truncata Leaves on Dengue Virus Type-2 and Their Major Compounds. Chem Biodivers. 2018 Feb;15(2).
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The defatted fractions of the Faramea hyacinthina and F. truncata (Rubiaceae) leaf MeOH extracts showed in vitro non-cytotoxic and anti-dengue virus serotype 2 (DENV2) activity in human hepatocarcinoma cell lineage (HepG2). Submitting these fractions to the developed RP-SPE method allowed isolating the antiviral flavanone (2S)-isosakuranetin-7-O-β-d-apiofuranosyl-(1→6)-β-d-glucopyranoside (1) from both species and yielded less active sub-fractions. The new diastereoisomeric epimer pair (2S) + (2R) of 5,3′,5′-trihydroxyflavanone-7-O-β-d-apiofuranosyl-(1→6)-β-d-glucopyranoside (2a/2b) from F. hyacinthina; the known narigenin-7-O-β-d-apiofuranosyl-(1→6)-β-d-glucopyranoside (3) from both species; rutin (4) and quercetin-4′-β-d-O-glucopyranosyl-3-O-rutinoside (5) from F. hyacinthina, and kaempferol-3-O-rutinoside (6), erythroxyloside A (7) and asperuloside (8) from F. truncata have been isolated from these sub-fractions. Compounds 4 – 8 are reported for the first time in Faramea spp.
Posso SV, Quesnot N, Moraes JA, Brito-Gitirana L, Kennedy-Feitosa E, Barroso MV, Porto LC, Lanzetti M, Valença SS. AT-RVD1 repairs mouse lung after cigarette smoke-induced emphysema via downregulation of oxidative stress by NRF2/KEAP1 pathway. Int Immunopharmacol. 2018 Mar;56:330-338.
DOI: 10.1016/j.intimp.2018.01.045
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Long-term exposure to cigarette smoke (CS) results in alveolar parenchyma destruction due to chronic inflammatory response and the imbalance between oxidants and antioxidants, and proteases and antiproteases. Emphysema is the main symptom of chronic obstructive pulmonary disease. Current treatment focuses on relieving respiratory symptoms, and inflammation resolution failure is an important pathophysiological element of the disease. Specialized pro-resolving mediators (SPMs) synthesized endogenously during resolution processes demonstrated beneficial effects in murine models of airway inflammation. Here, we aimed to test the SPM AT-RvD1 in a murine model of CS-induced emphysema. AT-RvD1 restored elastic fibers and lung morphology, with reduction in MMP-3, neutrophils, and myeloperoxidase activity and increases in macrophages and IL-10 levels. AT-RvD1 also decreased levels of oxidative stress markers and ROS via upregulation of the Nrf2/Keap1 pathway. Therefore, we suggest that AT-RvD1 causes pro-resolutive action in our murine model of CS-induced emphysema by upregulation of the Nrf2/Keap1 pathway.
Melo AC, Cattani-Cavalieri I, Barroso MV, Quesnot N, Gitirana LB, Lanzetti M, Valença SS. Atorvastatin dose-dependently promotes mouse lung repair after emphysema induced by elastase. Biomed Pharmacother. 2018 Jun;102:160-168.
DOI: 10.1016/j.biopha.2018.03.067
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Emphysema results in a proteinase – antiproteinase imbalance, inflammation and oxidative stress. Our objective was to investigate whether atorvastatin could repair mouse lungs after elastase-induced emphysema. Vehicle (50 μL) or porcine pancreatic elastase (PPE) was administered on day 1, 3, 5 and 7 at 0.6 U intranasally. Male mice were divided into a control group (sham), PPE 32d (sacrificed 24 h after 32 days), PPE 64d (sacrificed 24 h after 64 days), and atorvastatin 1, 5 and 20 mg treated from day 33 until day 64 and sacrificed 24 h later (A1 mg, A5 mg and A20 mg, respectively). Treatment with atorvastatin was performed via inhalation for 10 min once a day. We observed that emphysema at day 32 was similar to emphysema at day 64. The mean airspace chord length (Lm) indicated a recovery of pulmonary morphology in groups A5 mg and A20 mg, as well as recovery of collagen and elastic fibers in comparison to the PPE group. Bronchoalveolar lavage fluid (BALF) leukocytes were reduced in all atorvastatin-treated groups. However, tissue macrophages were reduced only in the A20 mg group compared with the PPE group, while tissue neutrophils were reduced in the A5 mg and A20 mg groups. The redox balance was restored mainly in the A20 mg group compared with the PPE group. Finally, atorvastatin at doses of 5 and 20 mg reduced nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and matrix metalloproteinase-12 (MMP-12) compared with the PPE group. In conclusion, atorvastatin was able to induce lung tissue repair in emphysematous mice.
de Mattos Barbosa MG, de Andrade Silva BJ, Assis TQ, da Silva Prata RB, Ferreira H, Andrade PR, da Paixão de Oliveira JA, Sperandio da Silva GM, da Costa Nery JA, Sarno EN, Pinheiro RO. Autophagy Impairment Is Associated With Increased Inflammasome Activation and Reversal Reaction Development in Multibacillary Leprosy. Front Immunol. 2018 Jun 4;9:1223.
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Leprosy reactions are responsible for incapacities in leprosy and represent the major cause of permanent neuropathy. The identification of biomarkers able to identify patients more prone to develop reaction could contribute to adequate clinical management and the prevention of disability. Reversal reaction may occur in unstable borderline patients and also in lepromatous patients. To identify biomarker signature profiles related with the reversal reaction onset, multibacillary patients were recruited and classified accordingly the occurrence or not of reversal reaction during or after multidrugtherapy. Analysis of skin lesion cells at diagnosis of multibacillary leprosy demonstrated that in the group that developed reaction (T1R) in the future there was a downregulation of autophagy associated with the overexpression of TLR2 and MLST8. The autophagy impairment in T1R group was associated with increased expression of NLRP3, caspase-1 (p10) and IL-1β production. In addition, analysis of IL-1β production in serum from multibacillary patients demonstrated that patients who developed reversal reaction have significantly increased concentrations of IL-1β at diagnosis, suggesting that the pattern of innate immune responses could predict the reactional episode outcome. In vitro analysis demonstrated that the blockade of autophagy with 3-methyladenine (3-MA) in Mycobacterium leprae-stimulated human primary monocytes increased the assembly of NLRP3 specks assembly, and it was associated with an increase of IL-1β and IL-6 production. Together, our data suggest an important role for autophagy in multibacillary leprosy patients to avoid exacerbated inflammasome activation and the onset of reversal reaction.
Siqueira MDS, Ribeiro RM, Travassos LH. Autophagy and Its Interaction With Intracellular Bacterial Pathogens. Front Immunol. 2018 May 23;9:935.
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Cellular responses to stress can be defined by the overwhelming number of changes that cells go through upon contact with and stressful conditions such as infection and modifications in nutritional status. One of the main cellular responses to stress is autophagy. Much progress has been made in the understanding of the mechanisms involved in the induction of autophagy during infection by intracellular bacteria. This review aims to discuss recent findings on the role of autophagy as a cellular response to intracellular bacterial pathogens such as, Streptococcus pyogenes, Mycobacterium tuberculosis, Shigella flexneri, Salmonella typhimurium, Listeria monocytogenes, and Legionella pneumophila, how the autophagic machinery senses these bacteria directly or indirectly (through the detection of bacteria-induced nutritional stress), and how some of these bacterial pathogens manage to escape from autophagy.
Linhares-Lacerda L, Granato A, Gomes-Neto JF, Conde L, Freire-de-Lima L, de Freitas EO, Freire-de-Lima CG, Coutinho Barroso SP, Jorge de Alcântara Guerra R, Pedrosa RC, Savino W, Morrot A. Circulating Plasma MicroRNA-208a as Potential Biomarker of Chronic Indeterminate Phase of Chagas Disease. Front Microbiol. 2018 Mar 6;9:269.
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Chagas cardiomyopathy is the most severe clinical manifestation of chronic Chagas disease. The disease affects most of the Latin American countries, being considered one of the leading causes of morbidity and death in the continent. The pathogenesis of Chagas cardiomyopathy is very complex, with mechanisms involving parasite-dependent cytopathy, immune-mediated myocardial damage and neurogenic disturbances. These pathological changes eventually result in cardiac myocyte hypertrophy, arrhythmias, congestive heart failure and stroke during chronic infection phase. Herein, we show that miR-208a, a microRNA that is a key factor in promoting cardiovascular dysfunction during cardiac hypertrophy processes of heart failure, has its circulating levels increased during chronic indeterminate phase when compared to cardiac (CARD) clinical forms in patients with Chagas disease. In contrast, we have not found altered serum levels of miR-34a, a microRNA known to promote pro-apoptotic role in myocardial infarction during degenerative process of cardiac injuries thus indicating intrinsic differences in the nature of the mechanisms underlying the heart failure triggered by Trypanosoma cruzi infection. Our findings support that the chronic indeterminate phase is a progressive phase involved in the genesis of chagasic cardiopathy and point out the use of plasma levels of miR-208a as candidate biomarker in risk-prediction score for the clinical prognosis of Chagas disease.
