Publications by authors named "M Castilho"

130 Publications

Synthesis and biological evaluation of thiazolidinedione derivatives with high ligand efficiency to PhzS.

J Enzyme Inhib Med Chem 2021 Dec;36(1):1217-1229

Programa de Pós-graduação em biotecnologia da, Universidade Estadual de Feira de Santana, Feira de Santana, Brazil.

The thiazolidinone ring is found in compounds that have widespan biology activity and there is mechanism-based evidence that compounds bearing this moiety inhibit PhzS (PzhS), a key enzyme in the biosynthesis of the virulence factor named pyocyanin. Ten novel thiazolidinone derivatives were synthesised and screened against PhzS, using two orthogonal assays. The biological results provided by these and 28 other compounds, whose synthesis had been described, suggest that the dihydroquinazoline ring, found in the previous hit (- Kd = 18 µM and LE = 0.20), is not required for PzhS inhibition, but unsubstituted nitrogen at the thiazolidinone ring is. The molecular simplification approach, pursued in this work, afforded an optimised lead compound (- 5-(2,4-dimethoxyphenyl)thiazolidine-2,4-dione) with 10-fold improvement in affinity (Kd= 1.68 µM) and more than 100% increase in LE (0.45), which follows the same inhibition mode as the original hit compound (competitive to NADH).Executive summaryPhzS is a key enzyme in the pyocyanin biosynthesis pathway in Orthogonal assays (TSA and FITC) show that fragment-like thiazolidinedione derivatives bind to PhzS with one-digit micromolar affinity.Fragment-like thiazolidinedione derivatives bind to the cofactor (NADH) binding site in PhzS.The molecular simplification optimised the ligand efficiency and affinity of the lead compound.
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http://dx.doi.org/10.1080/14756366.2021.1931165DOI Listing
December 2021

Zika Brazilian Cohorts (ZBC) Consortium: Protocol for an Individual Participant Data Meta-Analysis of Congenital Zika Syndrome after Maternal Exposure during Pregnancy.

Viruses 2021 04 16;13(4). Epub 2021 Apr 16.

Faculdade de Ciências Médicas, Universidade de Pernambuco, Recife 50100-130, Brazil.

Despite great advances in our knowledge of the consequences of Zika virus to human health, many questions remain unanswered, and results are often inconsistent. The small sample size of individual studies has limited inference about the spectrum of congenital Zika manifestations and the prognosis of affected children. The Brazilian Zika Cohorts Consortium addresses these limitations by bringing together and harmonizing epidemiological data from a series of prospective cohort studies of pregnant women with rash and of children with microcephaly and/or other manifestations of congenital Zika. The objective is to estimate the absolute risk of congenital Zika manifestations and to characterize the full spectrum and natural history of the manifestations of congenital Zika in children with and without microcephaly. This protocol describes the assembly of the Consortium and protocol for the Individual Participant Data Meta-analyses (IPD Meta-analyses). The findings will address knowledge gaps and inform public policies related to Zika virus. The large harmonized dataset and joint analyses will facilitate more precise estimates of the absolute risk of congenital Zika manifestations among Zika virus-infected pregnancies and more complete descriptions of its full spectrum, including rare manifestations. It will enable sensitivity analyses using different definitions of exposure and outcomes, and the investigation of the sources of heterogeneity between studies and regions.
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http://dx.doi.org/10.3390/v13040687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072625PMC
April 2021

Why Did ZIKV Perinatal Outcomes Differ in Distinct Regions of Brazil? An Exploratory Study of Two Cohorts.

Viruses 2021 04 23;13(5). Epub 2021 Apr 23.

Acute Febrile Illnesses Laboratory, National Institute of Infectious Diseases, Oswaldo Cruz Foundation (OCRUZ), Rio de Janeiro, RJ 21040-900, Brazil.

The Zika virus (ZIKV) epidemic in Brazil occurred in regions where dengue viruses (DENV) are historically endemic. We investigated the differences in adverse pregnancy/infant outcomes in two cohorts comprising 114 pregnant women with PCR-confirmed ZIKV infection in Rio de Janeiro, Southeastern Brazil ( = 50) and Manaus, in the north region of the country ( = 64). Prior exposure to DENV was evaluated through plaque reduction neutralizing antibody assays (PRNT 80) and DENV IgG serologies. Potential associations between pregnancy outcomes and Zika attack rates in the two cities were explored. Overall, 31 women (27%) had adverse pregnancy/infant outcomes, 27 in Rio (54%) and 4 in Manaus (6%), < 0.001. This included 4 pregnancy losses (13%) and 27 infants with abnormalities at birth (24%). A total of 93 women (82%) had evidence of prior DENV exposure, 45 in Rio (90%) and 48 in Manaus (75%). Zika attack rates differed; the rate in Rio was 10.28 cases/10,000 and in Manaus, 0.6 cases/10,000, < 0.001. Only Zika attack rates (Odds Ratio: 17.6, 95% Confidence Interval 5.6-55.9, < 0.001) and infection in the first trimester of pregnancy (OR: 4.26, 95% CI 1.4-12.9, = 0.011) were associated with adverse pregnancy and infant outcomes. Pre-existing immunity to DENV was not associated with outcomes (normal or abnormal) in patients with ZIKV infection during pregnancy.
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http://dx.doi.org/10.3390/v13050736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146858PMC
April 2021

5--methylcneorumchromone K Exerts Antinociceptive Effects in Mice via Interaction with GABAA Receptors.

Int J Mol Sci 2021 Mar 26;22(7). Epub 2021 Mar 26.

Laboratório de Farmacologia e Terapêutica Experimental, Faculdade de Farmácia, Universidade Federal da Bahia, Salvador CEP 40 170-115, Brazil.

The proper pharmacological control of pain is a continuous challenge for patients and health care providers. Even the most widely used medications for pain treatment are still ineffective or unsafe for some patients, especially for those who suffer from chronic pain. Substances containing the chromone scaffold have shown a variety of biological activities, including analgesic effects. This work presents for the first time the centrally mediated antinociceptive activity of 5-O-methylcneorumchromone K (5-CK). Cold plate and tail flick tests in mice showed that the 5-CK-induced antinociception was dose-dependent, longer-lasting, and more efficacious than that induced by morphine. The 5-CK-induced antinociception was not reversed by the opioid antagonist naloxone. Topological descriptors (fingerprints) were employed to narrow the antagonist selection to further investigate 5-CK's mechanism of action. Next, based on the results of fingerprints analysis, functional antagonist assays were conducted on nociceptive tests. The effect of 5-CK was completely reversed in both cold plate and tail-flick tests by GABA receptor antagonist bicuculline, but not by atropine or glibenclamide. Molecular docking studies suggest that 5-CK binds to the orthosteric binding site, with a similar binding profile to that observed for bicuculline and GABA. These results evidence that 5-CK has a centrally mediated antinociceptive effect, probably involving the activation of GABAergic pathways.
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http://dx.doi.org/10.3390/ijms22073413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037321PMC
March 2021

Biofabrication of a shape-stable auricular structure for the reconstruction of ear deformities.

Mater Today Bio 2021 Jan 21;9:100094. Epub 2021 Jan 21.

Department of Orthopaedics, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, 3584 CX, the Netherlands.

Bioengineering of the human auricle remains a significant challenge, where the complex and unique shape, the generation of high-quality neocartilage, and shape preservation are key factors. Future regenerative medicine-based approaches for auricular cartilage reconstruction will benefit from a smart combination of various strategies. Our approach to fabrication of an ear-shaped construct uses hybrid bioprinting techniques, a recently identified progenitor cell population, previously validated biomaterials, and a smart scaffold design. Specifically, we generated a 3D-printed polycaprolactone (PCL) scaffold via fused deposition modeling, photocrosslinked a human auricular cartilage progenitor cell-laden gelatin methacryloyl (gelMA) hydrogel within the scaffold, and cultured the bioengineered structure in chondrogenic media for 30 days. Our results show that the fabrication process maintains the viability and chondrogenic phenotype of the cells, that the compressive properties of the combined PCL and gelMA hybrid auricular constructs are similar to native auricular cartilage, and that biofabricated hybrid auricular structures exhibit excellent shape fidelity compared with the 3D digital model along with deposition of cartilage-like matrix in both peripheral and central areas of the auricular structure. Our strategy affords an anatomically enhanced auricular structure with appropriate mechanical properties, ensures adequate preservation of the auricular shape during a dynamic culture period, and enables chondrogenically potent progenitor cells to produce abundant cartilage-like matrix throughout the auricular construct. The combination of smart scaffold design with 3D bioprinting and cartilage progenitor cells holds promise for the development of clinically translatable regenerative medicine strategies for auricular reconstruction.
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http://dx.doi.org/10.1016/j.mtbio.2021.100094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903133PMC
January 2021