Publications by authors named "Joao Fernandes"

310 Publications

Metabolite profile of Nectandra oppositifolia Nees & Mart. and assessment of antitrypanosomal activity of bioactive compounds through efficiency analyses.

PLoS One 2021 25;16(2):e0247334. Epub 2021 Feb 25.

Center of Natural Sciences and Humanities, Federal University of ABC, Santo Andre, Sao Paulo, Brazil.

EtOH extracts from the leaves and twigs of Nectandra oppositifolia Nees & Mart. shown activity against amastigote forms of Trypanosoma cruzi. These extracts were subjected to successive liquid-liquid partitioning to afford bioactive CH2Cl2 fractions. UHPLC-TOF-HRMS/MS and molecular networking were used to obtain an overview of the phytochemical composition of these active fractions. Aiming to isolate the active compounds, both CH2Cl2 fractions were subjected to fractionation using medium pressure chromatography combined with semi-preparative HPLC-UV. Using this approach, twelve compounds (1-12) were isolated and identified by NMR and HRMS analysis. Several isolated compounds displayed activity against the amastigote forms of T. cruzi, especially ethyl protocatechuate (7) with EC50 value of 18.1 μM, similar to positive control benznidazole (18.7 μM). Considering the potential of compound 7, protocatechuic acid and its respective methyl (7a), n-propyl (7b), n-butyl (7c), n-pentyl (7d), and n-hexyl (7e) esters were tested. Regarding antitrypanosomal activity, protocatechuic acid and compound 7a were inactive, while 7b-7e exhibited EC50 values from 20.4 to 11.7 μM, without cytotoxicity to mammalian cells. These results suggest that lipophilicity and molecular complexity play an important role in the activity while efficiency analysis indicates that the natural compound 7 is a promising prototype for further modifications to obtain compounds effective against the intracellular forms of T. cruzi.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247334PLOS
February 2021

Octahedral ruthenium and magnesium naringenin 5-alkoxide complexes: NMR analysis of diastereoisomers and in-vivo antibacterial activity against Xylella fastidiosa.

Talanta 2021 Apr 31;225:122040. Epub 2020 Dec 31.

Centro APTA Citros Sylvio Moreira, Instituto Agronômico, CP 04, 13490-970, Cordeirópolis, SP, Brazil.

Although many copper-based antimicrobial compounds have been developed to control pathogenic bacteria and fungi in plants and applied for crop protection, there is evidence that several plant pathogens have developed resistance to copper-based antimicrobial compounds, including some Xanthomonas species. Xylella is a bacterial genus belonging to the Xanthomonas family; and X. fastidiosa, which is responsible for citrus variegated chlorosis (CVC) in sweet orange, may develop resistance to one or more copper-based antimicrobials. Because of the time required for the development and approval of new antimicrobials for commercial use, the discovery of novel bactericidal compounds is essential before the development of resistance to the antimicrobials currently in use becomes widespread. Here, we explored the antimicrobial potential of two newly synthesized antimicrobials complexes and one natural compound against X. fastidiosa. Several nuclear magnetic resonance (NMR) assays with high resolution and sensitivity were developed to identify new diastereoisomers in the context of octahedral ruthenium - [Ru(narin)(phen)]PFand magnesium naringenin 5-alkoxide - [Mg(narin)(phen)]OAc - complexes, obtained in the present work. The NMR assays proved to be powerful tools for the identification of isomers in metal complexes. Moreover, a protocol for the in-vivo determination of the effects of these complexes against X. fastidiosa was developed. The main trunks of X. fastidiosa infected plants were injected with the two complexes as well as with the limonoid azadirachtin using a syringe; the number of bacterial cells in the plants following treatment was estimated via real-time quantitative PCR (qPCR). Importantly, the administration of both complexes and of azadirachtin drastically reduced the number of X. fastidiosa cells in vivo.
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http://dx.doi.org/10.1016/j.talanta.2020.122040DOI Listing
April 2021

Repeat and Relapsing Peritonitis Microbiological Trends and Outcomes: A 21-Year Single-Center Experience.

Int J Nephrol 2021 30;2021:6662488. Epub 2021 Jan 30.

Nephrology Department, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal.

Peritonitis is a major peritoneal dialysis complication. Despite a high cure rate, relapsing and repeat peritonitis is associated with Tenckhoff catheter biofilm and multiple episodes of peritoneal damage. In relapsing peritonitis, prompt catheter removal is mandatory; otherwise, in repeat peritonitis, there is not a clear indication for catheter removal. It is questionable if the approach to removal should be different. There are few recent data on repeat and relapsing peritonitis microbiology and clinical outcomes since most studies are from the past decade. This study evaluates the microbiology, clinical outcomes, and impact of relapsing and repeat peritonitis on technique survival and the impact of catheter removal in development of further peritonitis episodes by the same microorganism. We developed a single-center retrospective study from 1998 to 2019 that compared repeat and relapsing peritonitis with a control group in terms of causative microorganisms, cure rate, catheter removal, and permanent and temporary transfer to hemodialysis. We also compared repeat and relapsing peritonitis clinical outcomes when Tenckhoff catheter was not removed. Comparing to the control group, the repeat/relapsing group had a higher cure rate (80.4% 74.5%, =0.01) and lower rate of hospitalization (10.9% versus 27.7%, =0.01). Technique survival was superior in the repeat/relapsing group (log rank = 4.5, =0.03). Gram-positive peritonitis was more common in the repeat/relapsing group especially (43.5% versus 21.3%, =0.01) and Gram-negatives in the control group (26.6% vs 9.0%, =0.02). When the Tenckhoff catheter was not removed after a repeat episode, 58.6% developed a new repeat/relapsing episode versus 60.0% in the relapsing group. Although repeat and relapsing peritonitis have a higher cure rate, it leads to further episodes of peritonitis and consequent morbidity. When Tenckhoff catheter was not removed, the probability of another peritonitis episode by the same microorganism is similar in repeat and relapsing peritonitis.
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http://dx.doi.org/10.1155/2021/6662488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867458PMC
January 2021

Looking Ahead: Health Impact Assessment of Front-Of-Pack Nutrition Labelling Schema as a Public Health Measure.

Int J Environ Res Public Health 2021 Feb 3;18(4). Epub 2021 Feb 3.

Direção-Geral da Saúde, Alameda Dom Afonso Henriques, 1000-123 Lisboa, Portugal.

This study aimed to describe the underlying process, used methods and major recommendations emerging from a comprehensive and prospective health impact assessment of the endorsement of a front-of-pack nutrition labelling (FOP-NL) system by the Portuguese health authorities. A mixed-methods approach was used to gather information on the impact of four FOP-NL schemes on consumers' selection of food products according to the perception of their nutritional quality, combining a systematic literature review, focus groups (FG), in-depth individual interviews, and an open-label crossover randomized controlled study. The relevance of FOP-NL as a public health promotion policy has emerged as a consensual idea among either FGs' participants (i.e., consumers and experts), or interviewed stakeholders. Although all of the evaluated FOP-NLs result better than no system on promoting the choice of the healthiest product, the effectiveness of easy-to-interpret FOP-NL among vulnerable groups raised concerns related to the need of integrating specific nutritional information to promote a better self-management of chronic diseases, and related to the level of literacy of consumers, which could impair the usage of FOP-NL. Educational campaigns addressing skills to use FOP-NL is recommended. Furthermore, a monitoring strategy should be considered to evaluate the long-term effectiveness of this policy in promoting healthier food choices, and in reducing diet-related non-communicable diseases burden.
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http://dx.doi.org/10.3390/ijerph18041422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913662PMC
February 2021

Septal curvature as a robust and reproducible marker for basal septal hypertrophy.

J Hypertens 2021 Jan 28. Epub 2021 Jan 28.

School of Biomedical Engineering and Imaging Sciences, Kings College London, London, UK Cardiovascular Ultrasound, GE Vingmed, Oslo, Norway Institute of Biomedical Research August Pi Sunyer (IDIBAPS), Barcelona Catalan Institution for Research and Advanced Studies (ICREA), Barcelona Hospital Clinic de Barcelona Barcelona Center for Maternal Fetal and Neonatal Medicine, Hospital Sant Joan de Déu, Barcelona, Spain.

Background: Basal septal hypertrophy (BSH) is an asymmetric, localized thickening of the upper interventricular septum and constitutes a marker of an early remodelling in patients with hypertension. This morphological trait has been extensively researched because of its prevalence in hypertension, yet its clinical and prognostic value for individual patients remains undetermined. One of the reasons is the lack of a reliable and reproducible metric to quantify the presence and the extent of BSH. This article proposes the use of the curvature of the left ventricular endocardium as a robust feature for BSH characterization, and as an objective criterion to quantify current subjective 'visual assessment' of the presence of sigmoidal septum. The proposed marker, called average septal curvature, is defined as the inverse of the radius adjacent to each point of the endocardial contour along the basal and mid inferoseptal segments of the left ventricle.

Method: Robustness and reproducibility were assessed on a cohort of 220 patients, including 161 hypertensive patients (32 with BSH) and 59 healthy controls.

Results: The results show that compared with the conventionally used wall thickness metrics, the new marker is more reproducible (relative standard deviation of errors of 7 vs. 13%, and 8 vs. 38% for intra-observer and inter-observer variability, respectively) and better correlates to the functional parameters related to BSH, with main difference (absolute rank correlation 0.417 vs. 0.341) in local deformation changes assessed by longitudinal strain.

Conclusion: Average septal curvature is a more precisely defined and reproducible metric than thickness ratios, it can be fully automated, and better infers the functional remodelling related to hypertension.
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http://dx.doi.org/10.1097/HJH.0000000000002813DOI Listing
January 2021

First Report of Root-Knot Nematode Infecting Sweetpotato in the State of Rio Grande do Norte, Brazil.

Plant Dis 2021 Jan 12. Epub 2021 Jan 12.

Sao Paulo State University Julio de Mesquita Filho - Jaboticabal Campus, 207340, Department of Agricultural Production Sciences, Jaboticabal, SP, Brazil;

The sweetpotato ( L., Convolvulaceae family) originated in Latin America and is currently cultivated worldwide. The storage roots, rich in calories, have made this crop one of the main caloric sources for low-income populations, especially in developing countries. Brazil annually produces about 805,000 tons, with the Northeast region responsible for 34% of this production (Albuquerque et al. 2020). In October 2019, sweetpotato plants cv. Campina, from a field in the region of Touros, state of Rio Grande do Norte (RN), Brazil (5°12'31"S 35°34'42"W), presented deformed storage roots, with galls, typical of root-knot nematodes. The roots were sent to the Nematology Laboratory (LabNema) where 14,032 eggs and 3,312 second-stage juveniles (J2s) of sp., in 10 g of roots, were recovered. The species of adults was identified through morphological, biochemical, and phylogenetic analysis. The perineal region of females (n = 10) presented an oval shape, with a high and semi-trapezoidal dorsal arch and streak-free perivulval region. The labial region of males (n=10) presented high and rounded head cap, labial region slightly set off from the body, without annulations. The morphological characters were compatible with the original description of (Yang and Eisenback 1983). The phenotype of esterase isoenzymes showed two major bands (VS1-S1) also characteristic of (Esbenshade and Triantaphyllou 1985). Sequences of 18S rDNA (~1200bp) of individual females (Holterman et al. 2006) obtained from sweetpotatoes before (SPme1 and 2) and after inoculation (SPme3 and 6), and from guava, used as species control, were submitted to Bayesian analysis. The sequences presented genetic diversity among them resulting from seven SNPs (Single Nucleotide Polymorphism) and 99.4 to 99.9% identity with sequences deposited in the NCBI GenBank (accession numbers MW209034-MW209039). The pathogenicity test was carried out under greenhouse conditions, in which 3,000 eggs and J2s from the original population isolated of were inoculated in sweetpotato seedlings cv. Campina (n = 6). After three months, the roots presented galls and deformations typical of root-knot nematodes, while non-inoculated plants did not present any symptoms. An average of 15,900 eggs and J2s of (RF = 5.3) were recovered from the roots, proving that sweetpotatoes were a host of this species. is known to cause great damage to sweetpotato (Ye et al. 2020). In Brazil, nematode had been reported once, isolated from a sweetpotato field in the Ceara state and the species suggested by the authors according to esterase electrophoresis was . Nonetheless, the authors did not present taxonomic, isoenzyme phenotypes and molecular species identification integratively, nor included pathogenicity tests (Silva et al. 2016). Therefore, it is the first time that , with reliable identification by different methods, including sequencing, was detected in commercial sweetpotato fields in the RN state and in Brazil. The local farmers reported that this nematode deforms the storage roots which make them useless for commercialization, resulting in minimal losses of 50% of production in the infested areas. Furthermore, as sweetpotatoes are vegetatively propagated, the spread of this nematode through planting material is favored. Considering the importance of this crop in Brazil, this report is essential for control measures of this pathogen to be taken in order to avoid its spread to other regions.
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http://dx.doi.org/10.1094/PDIS-11-20-2472-PDNDOI Listing
January 2021

A-family anti-inflammatory cyclopentenone prostaglandins: A novel class of non-statin inhibitors of HMG-CoA reductase.

Biochimie 2021 Mar 4;182:37-50. Epub 2021 Jan 4.

Laboratory of Cellular Physiology (FisCel), Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90050-170, Brazil. Electronic address:

Disruption of the intracellular lipid balance leading to cholesterol accumulation is one of the features of cells that participate in the development of atherosclerotic lesions. Evidence form our laboratory indicates that anti-inflammatory cyclopentenone prostaglandins (cyPGs) of A- and J-family deviate lipid metabolism from the synthesis of cholesterol and cholesteryl esters to the synthesis of phospholipids in foam-cell macrophages. cyPGs possessing an α,β-unsaturated cyclopentane ring are highly electrophilic substances able to promptly react with reactive cysteines of intracellular molecules through Michael addition. On the other hand, HMG-CoA reductase (HMGCR), the enzyme responsible for the rate-limiting step in cholesterol biosynthesis, presents critically reactive cysteines at the entry of catalytic domain, particularly Cys561, that could be target of cyPG inhibition. In the present study, we showed that cyPGs (but not other non-α,β-unsaturated PGs) physically interact with HMGCR, in a dithiothreitol- and β-mercaptoethanol-sensitive way, and block the activity of the catalytic subunit of the enzyme (IC for PGA = 0.17 μM). PGA inhibits HMGCR activity in cultured rat and human macrophages/macrophage-foam cells and leads to enhanced expression of HMGCR protein, as observed with statins. In cell culture models, PGA effectively inhibits the reductase at non-toxic doses (e.g., 1 μM) that block cell proliferation thus suggesting that part of the well-known antiproliferative effect of PGA may be due to its ability of blocking HMGCR activity, as cells cannot proliferate without a robust cholesterogenesis. Therefore, besides the powerfully anti-inflammatory and antiproliferative effects, the anticholesterogenic effects of PGA should be exploited in atherosclerosis therapeutics.
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http://dx.doi.org/10.1016/j.biochi.2020.12.019DOI Listing
March 2021

Effects of additives in wet brewery residue silage on lamb carcass traits and meat quality.

Trop Anim Health Prod 2021 Jan 7;53(1):85. Epub 2021 Jan 7.

Department of Animal Science, Universidade Federal Rural de Pernambuco, Recife, Brazil.

The objective was to evaluate the use of wet brewery residue (WBR) silage additives on carcass characteristics and sheep meat quality. Thirty-two Santa Inês male sheep uncastrated with initial body weight of 22.61 ± 7.2 kg were allocated to a completely randomized design with four treatments: (1) WBR silage without additive (WBRS), (2) WBR silage with milled corn (WBRS + MC), (3) WBR silage with wheat bran (WBRS + WB), and (4) WBR silage with cassava flour (WBRS + CF) and eight replicates. WBRS + WB resulted in lower cold carcass weight than WBRS + CF; however, this reduction was not sufficient to alter the carcass commercial yield or loin-eye area. The leg cut of animals fed WBRS + WB showed less value than those animals fed with WBRS + CS. The meat lightness of WBRS was higher that of WBRS + MC, WBRS + WB, and WBRS + CF. The cooking loss for WBRS + WB was less than those animals fed with WBRS + CS. However, meat protein, meat cholesterol, and shear force were similar among treatments (17.69%, 42.46 mg/100 g of meat, and 2.48 kgf/cm, respectively). The use of additives in wet brewery residue silage does not improve carcass characteristics or the quality of sheep meat, and it is therefore recommended to use WBR silage without additives.
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http://dx.doi.org/10.1007/s11250-020-02531-zDOI Listing
January 2021

Insecticidal activity of copper (II) complexes with flavanone derivatives.

Nat Prod Res 2021 Jan 6:1-4. Epub 2021 Jan 6.

Departamento de Química, Universidade Federal de São Carlos, São Carlos, Brazil.

In this work, we describe the insecticidal activity against of flavanone derivatives (naringin, naringenin and hesperidin) complexed to copper (II). For the assays, the compounds were incorporated into an artificial diet and offered to during its larval period. The duration of larval and pupal phases, the weight of pupae and the percentage of dead insects at the end of the larval phase were evaluated. Among the tested compounds, the free flavanones and and the complexes and showed a shortening of the larval phase when compared to the control. Complex showed the highest toxicity, with 96.66% larval mortality. This is the first report on the insecticidal activity of the Cu complexes of the flavanones naringin, naringenin and hesperidin.
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http://dx.doi.org/10.1080/14786419.2020.1868465DOI Listing
January 2021

Novel potent (dihydro)benzofuranyl piperazines as human histamine receptor ligands - Functional characterization and modeling studies on H and H receptors.

Bioorg Med Chem 2021 Jan 8;30:115924. Epub 2020 Dec 8.

Departamento de Ciências Farmacêuticas, Universidade Federal de São Paulo, Diadema, SP, Brazil. Electronic address:

Histamine acts through four different receptors (HR-HR), the HR and HR being the most explored in the last years as drug targets. The HR is a potential target to treat narcolepsy, Parkinson's disease, epilepsy, schizophrenia and several other CNS-related conditions, while HR blockade leads to anti-inflammatory and immunomodulatory effects. Our group has been exploring the dihydrobenzofuranyl-piperazines (LINS01 series) as human HR/HR ligands as potential drug candidates. In the present study, a set of 12 compounds were synthesized from adequate (dihydro)benzofuran synthons through simple reactions with corresponding piperazines, giving moderate to high yields. Four compounds (1b, 1f, 1g and 1h) showed high hHR affinity (pK > 7), compound 1h being the most potent (pK 8.4), and compound 1f showed the best efficiency (pKi 8.2, LE 0.53, LLE 5.85). BRET-based assays monitoring Gα activity indicated that the compounds are potent antagonists. Only one compound (2c, pK 7.1) presented high affinity for hHR. In contrast to what was observed for hHR, it showed partial agonist activity. Docking experiments indicated that bulky substituents occupy a hydrophobic pocket in hHR, while the N-allyl group forms favorable interactions with hydrophobic residues in the TM2, 3 and 7, increasing the selectivity towards hHR. Additionally, the importance of the indole NH in the interaction with Glu5.46 from hHR was confirmed by the modeling results, explaining the affinity and agonistic activity of compound 2c. The data reported in this work represent important findings for the rational design of future compounds for hHR and hHR.
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http://dx.doi.org/10.1016/j.bmc.2020.115924DOI Listing
January 2021

Severe hypoxemia due to intrapulmonary right-to-left shunt: AVM embolization through internal jugular access.

Porto Biomed J 2020 Jan-Feb;5(1):e44. Epub 2020 Jan 21.

Department of Anesthesiology.

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http://dx.doi.org/10.1097/j.pbj.0000000000000044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722397PMC
January 2020

The Novel HR Antagonist 1-[(5-Chloro-2,3-Dihydro-1-Benzofuran-2-Yl)Methyl]-4-Methyl-Piperazine (LINS01007) Attenuates Several Symptoms in Murine Allergic Asthma.

Cell Physiol Biochem 2020 Nov;54(6):1163-1176

Department of Pharmaceutical Sciences, Universidade Federal de São Paulo-campus Diadema, Diadema, Brazil,

Background/aims: Histamine is an important chemical transmitter involved in inflammatory processes, including asthma and other chronic inflammatory diseases. Its inflammatory effects involve mainly the histamine H receptor (HR), whose role in several studies has already been demonstrated. Our group have explored the effects of 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazines as antagonists of HR, and herein the compounds LINS01005 and LINS01007 were studied with more details, considering the different affinity profile on HR and the anti-inflammatory potential of both compounds.

Methods: We carried out a more focused evaluation of the modulatory effects of LINS01005 and LINS01007 in a murine asthma model. The compounds were given i.p. (1-7 mg/kg) to ovalbumin sensitized BALB/c male mice (12 weeks old) 30 min before the antigen challenging, and after 24 h the cell analysis from the bronchoalveolar lavage fluid (BALF) was performed. The lung tissue was used for evaluation by western blot (COX-2, 5-LO, NF-κB and STAT3 expressions) and histological analysis.

Results: Treatment with the more potent HR antagonist LINS01007 significantly decreased the total cell count and eosinophils in BALF at lower doses when compared to LINS01005. The expression of COX-2, 5-LO, NF-κB and STAT3 in lung tissue was significantly reduced after treatment with LINS01007. Morphophysiological changes such as mucus and collagen production and airway wall thickening were significantly reduced after treatment with LINS01007.

Conclusion: These results show important down regulatory effect of novel HR antagonist (LINS01007) on allergic lung inflammation.
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http://dx.doi.org/10.33594/000000307DOI Listing
November 2020

Relationship between polypharmacy, xerostomia, gustatory sensitivity, and swallowing complaints in the elderly: A multidisciplinary approach.

J Texture Stud 2020 Nov 15. Epub 2020 Nov 15.

Department of Pediatric Dentistry, University of Campinas, Piracicaba, Brazil.

Oral dysfunctions are common in the elderly but the literature lacks a multidisciplinary approach on the relationship between polypharmacy, saliva flow, xerostomia, taste, and swallowing complaints. This cross-sectional study included 204 non-institutionalized elderly (>60 years; 123 women/81 men), free of severe disabilities and non-alcohol/tobacco consumers, from whom specific pharmacological therapies were evaluated, as well xerostomia (Xerostomia Inventory-XI) and swallowing complaints (EAT-10 questionnaire), salivary flow rate and gustatory sensitivity. Statistical analysis included Chi-square, Mann-Whitney, Two-way ANCOVA, and linear multiple regression. Polypharmacy (≥5 drugs daily), hyposalivation, and severe taste dysfunction were found in 18, 46, and 10% of the participants, respectively. Polypharmacy was related with xerostomia (p = .041) and swallowing complaints (p < .001; power = 94%), but not with taste dysfunction. Dry mouth complaint and higher risk of swallowing disorders were found in 50 and 12% of the elderly, respectively, and angiotensin-converting enzyme (ACE) inhibitors users (n = 36) showed higher EAT-10 scores (p = .038). Regression models showed that stimulated salivary flow rate was dependent on gender and diuretic use, while xerostomia scores were dependent on the number of medications and unstimulated saliva flow (p < .001). In conclusion, the results draw attention to the high frequency of oral and maxillofacial dysfunctions found in non-institutionalized elderly, especially polypharmacy, xerostomia and swallowing complaints, and the side effects of drugs that can disturb the oral functions, the acceptance of food, and the adherence to oral therapies.
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http://dx.doi.org/10.1111/jtxs.12573DOI Listing
November 2020

Update of the Brazilian Guidelines for Valvular Heart Disease - 2020.

Arq Bras Cardiol 2020 10;115(4):720-775

Sociedade Campineira de Educação e Instrução Mantenedora da Pontifícia Universidade Católica de Campinas, Campinas, SP - Brasil.

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http://dx.doi.org/10.36660/abc.20201047DOI Listing
October 2020

COVID-19 myocarditis: a case report.

Einstein (Sao Paulo) 2020 23;18:eRC5876. Epub 2020 Oct 23.

Hospital Israelita Albert Einstein , São Paulo , SP , Brazil .

A male patient with flu-like symptoms and tomography and laboratory diagnosis of severe acute respiratory syndrome. He developed acute cardiac dysfunction during admission and was submitted to a cardiac magnetic resonance imaging examination, which confirmed acute myocarditis, indicating cardiac involvement by coronavirus disease 2019. A review and discussion about coronavirus disease 2019-related cardiac manifestations are reported, focusing on the imaging findings to make diagnosis.
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http://dx.doi.org/10.31744/einstein_journal/2020RC5876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575039PMC
October 2020

Potential insecticidal activity of aminonaphthoquinone Mannich bases derived from lawsone and their copper (II) complex derivatives.

Z Naturforsch C J Biosci 2020 Oct 12. Epub 2020 Oct 12.

Department of Chemistry, Natural Products Laboratory, Federal University of São Carlos (UFSCar), 13565-905, São Carlos, SP, Brazil.

The fall armyworm, Spodoptera frugiperda, is a polyphagous pest that causes important damage in different regions of America and mainly affects corn crops in both tropical and subtropical areas. Currently, control relies on both transgenic plants and/or chemical pesticides. In this work, we describe insecticidal activity against the fall armyworm from a series of Mannich bases (1-10), derived from 2-hydroxy-1,4-naphthoquinone (lawsone), substituted benzaldehydes, and two primary amines, and their Cu2+ complexes (11-20). The [Cu(L)2] complexes were more effective in larval mortality compared to the free Mannich bases. Among the tested compounds, complex 11 showed the highest toxicity, with 70.00% larval mortality.
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http://dx.doi.org/10.1515/znc-2020-0115DOI Listing
October 2020

Biochemical and morphological biomarker responses in the gills of a Neotropical fish exposed to a new flavonoid metal-insecticide.

Ecotoxicol Environ Saf 2021 Jan 16;208:111459. Epub 2020 Oct 16.

Postgraduate Program in Ecology and Natural Resources, Federal University of São Carlos, Rodovia Washington Luiz, Km 235, 13563-905 São Carlos, SP, Brazil; Department of Physiological Sciences, Federal University of São Carlos, Rodovia Washington, Luiz Km 235, 13563-905 São Carlos, SP, Brazil. Electronic address:

The flavonoid metal-insecticide [Mg(hesp)(phen)], denominated MgHP, has high potential for controlling agricultural pests. If applied in large scale, it may reach aquatic ecosystems and be harmful to the biota. This study evaluated the effects of MgHP in the gills of the Neotropical fish, Prochilodus lineatus by determining the activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione s-transferase (GST), and the levels of glutathione (GSH) and lipid peroxidation (LPO) after 24 and 96 h exposure to 0, 1, 10, 100 and 1000 μg L. The histopathological changes with emphases to mitochondria-rich cells (MRC) were evaluated as well. After 24 h exposure the enzyme activities and the GSH and LPO levels were unchanged however, after 96 h exposure to high MgHP concentration (1000 μg L), the GST activity and GSH levels increased. Oxidative stress measured as LPO levels did not occur after MgHP exposure in both periods. Gill tissue alterations increased after MgHP exposure to 10, 100 and 1000 μg L. Cellular atrophy, pillar cells changes, filament epithelium hyperplasia and hypertrophy, lamellar epithelium hyperplasia were the most frequent histopathology. MRC in the filament epithelium decreased after exposure to 24 h and increased after 96 h indicating possible transitory osmo-ionic disruption. P. lineatus exhibited high tolerance to MgHP. The increased GST activity and GSH levels after 96 h exposure suggested possible MgHP accumulation and concentration- and time-dependent response. Histopathology in the gills of exposed fish occurred at high MgHP concentrations. These results suggested that the MgHP into water, at high concentrations, affect the gills by changing GST activity, GSH levels and histology being useful biomarkers for MgHP water contamination.
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http://dx.doi.org/10.1016/j.ecoenv.2020.111459DOI Listing
January 2021

Vascular calcification by conventional X-ray and mortality in a cohort of predominantly African descent hemodialysis patients.

Int J Artif Organs 2020 Oct 16:391398820962805. Epub 2020 Oct 16.

Unit of Clinical Epidemiology and Evidence Based Medicine, Professor Edgard Santos University Hospital, Federal University of Bahia, Salvador, BA, Brazil.

Background/objective: There is a lack of studies describing the prevalence of vascular calcification (VC) and its association with mortality in maintenance hemodialysis (MHD) patients of African descent. We investigated if a VC score based on the number of calcified vascular beds was associated with mortality in MHD patients.

Methods: We analyzed data from 211 MHD patients enrolled from January 2010 to January 2011 in the prospective cohort study, "The Prospective Study of the Prognosis of Chronic Hemodialysis Patients (PROHEMO)," developed in Salvador, BA, Brazil. VC was evaluated using radiographs of the hands, abdomen, hip, and chest; the score was calculated by the number of calcified sites as 0 (absence of calcification), 1 (one calcified site), 2 (two sites), 3 (⩾3 sites). We used Cox's regression to estimate the hazard ratio (HR) and 95% confidence interval (CI) of associations between VC and mortality with adjustments for age and comorbidities.

Results: VC was detected in 114 (54.0%) patients; 37 (17.5%) with a VC score = 1; 21 (10%) with VC score = 2 and 56 (26.5%) with VC score = 3. Compared with VC score = 0, the adjusted hazard of death was 2.67 (95% CI: 1.12, 6.33) for patients with VC score = 1; HR = 2.89 (95% CI: 0.95, 7.63) for VC score = 2; and HR = 3.27 (95% CI: 1.47, 7.28) for VC score = 3.

Conclusion: The present study in an African descent MHD population provides support for the VC score based on conventional radiography as a prediction tool for the clinical practice. As shown, the VC score was monotonically and independently associated with mortality.
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http://dx.doi.org/10.1177/0391398820962805DOI Listing
October 2020

Multi-biomarkers approach to access the impact of novel metal-insecticide based on flavonoid hesperidin on fish.

Environ Pollut 2021 Jan 30;268(Pt B):115758. Epub 2020 Sep 30.

Postgraduate Program in Ecology and Natural Resources, Federal University of São Carlos, Washington Luiz Highway, km 235, 13565-905, São Carlos, SP, Brazil; Physiological Sciences Department, Federal University of São Carlos, Av. Washington Luiz Km 235, 13565-905, São Carlos, São Paulo, Brazil. Electronic address:

Aquatic ecosystem health is the main concern to increasing pesticides application to control agricultural pests as it is the ultimate receptor of such materials. This study evaluated the impact of new metal-insecticide, the [Mg(hesp)(phen)], referred as MgHP, on fish using physiological, genetic, biochemical, and morphological biomarkers. The fish, Prochilodus lineatus, was exposed to 0 (control), 1, 10, 100, 1000 μg L MgHP, for 24 and 96 h. MgHP was not lethal but caused genotoxicity, altered hematological variables and, the activity of antioxidant and biotransformation enzymes and histology of liver, depending on concentration and time exposure. Hematocrit and erythrocyte number (RBC) increased without change hemoglobin content resulting in changes in hematimetric indexes after 24 h; after 96 h, only RBC was changed. Erythrocyte nuclear abnormalities and crenate cells increased after 24 h but, not after 96 h. Erythrocytes and hepatocytes indicated instability in DNA integrity however, the absence of micronuclei suggested DNA damage repairment. After 24 h, the antioxidant defense system and the phase II biotransformation enzyme was responsiveness and catalase activity decreased at high MgHP concentrations; the antioxidant response was triggered after 96 h. Hepatocyte hypertrophy, intracellular cytoplasmic substances, cytoplasm degeneration, melanomacrophage and hyperemia increased in fish exposed from 10 μg L to higher MgHP concentrations; the organ alteration index increased as MgHP concentration increased showing dose-dependence. Most of hematological and genotoxic effects occurred after 24 h exposure evidencing potential recover capability of organism by activation of the antioxidant defense system and DNA repairment mechanisms. Nevertheless, the histopathological changes in the liver was maintained over time at high MgHP concentrations, a concentration usually no environmental relevant. In conclusion, this data reinforced the importance of continuing research on MgHP effects in other organisms considering the promising use of such compound to control the leaf-cutter ants and other insects.
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http://dx.doi.org/10.1016/j.envpol.2020.115758DOI Listing
January 2021

Total Parenteral Nutrition and Neuroleptic Malignant-Like Syndrome in Parkinson Disease.

Am J Ther 2020 Oct 1. Epub 2020 Oct 1.

Department of Pharmaceutical Sciences, Universidade Federal de São Paulo, Diadema-SP, Brazil.

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http://dx.doi.org/10.1097/MJT.0000000000001259DOI Listing
October 2020

First Report of Infecting in Brazil.

Plant Dis 2020 Sep 23. Epub 2020 Sep 23.

Sao Paulo State University Julio de Mesquita Filho - Jaboticabal Campus, 207340, Department of Agricultural Production Sciences, Jaboticabal, SP, Brazil;

C. Koch (Lamiaceae alt. Labiatae), commonly known as lamb's ear, is an important medicinal plant with anti-inflammatory, antitumor, anticancer, antispasmodic, sedative and diuretic properties (Asnaashari et al. 2010). This plant is widely consumed in Europe and Asia as aromatic teas. In Brazil, it is an unconventional food plant, nonetheless, its medicinal properties have been recognized as well as its production. In May 2019, in a Sao Paulo State municipality, Jaboticabal, (21°14'38.7"S 48°17'10.6"W), plants presented reduced growth and chlorotic leaves associated with root galls. In the phytopathological clinic, 7,983 eggs and juveniles of sp. were counted in 10 g of the plant roots. In 100 cm³ of soil surrounding the plant, 532 second-stage sp. juveniles (J2) were found. Morphological, enzymatic and molecular identification of the nematode species found were performed (Fig. S1). For morphological analysis, perineal pattern of females (n = 10) and labial region of males (n = 10) were analyzed. In the perineal region of females, a high and trapezoidal dorsal arch with thick striations was observed, whereas the males presented the trapezoidal labial region with the prominent labial disc in relation to the sub-median lips and transverse streaks in the head region, typical characteristics of (Kofoid and White, 1919) Chitwood 1949. (Netscher and Taylor 1974; Eisenback and Hirschmann 1981). The esterase enzyme profile, obtained individually from 8 females, was compatible with phenotype I1 [Rm (x100) = 46.25], also associated with (Esbenshade and Triantaphyllou 1985). Molecular analysis was realized (n = 3) by applying the primers Finc/Rinc (Zijlstra et al. 2000) in the DNA of individual females, which resulted in the amplification of an amplicon of 1200 bp specific for . Pathogenicity testing was conducted in a greenhouse by inoculation of 5,000 eggs and juveniles from the original population into seedlings (n = 4). After 90 days, the inoculated plants, unlike the non-inoculated ones, exhibited symptoms similar to those initially observed in the field. The nematodes were extracted from the roots of the inoculated plants, quantified, and the identity of was confirmed. The average reproductive factor obtained was 136.6, confirming the pathogenicity of to . Thus, this is the first report of associated with in Brazil and in the world. Lamb's ear is a horticultural plant, and its high reproductive factor to can also result in damage to the subsequent crops. In addition, Lamb's ear is propagated vegetatively and this favors the spread of nematodes to other areas. This new report is important in order to alert producers to realize the proper management of this nematode in .
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http://dx.doi.org/10.1094/PDIS-07-20-1628-PDNDOI Listing
September 2020

Assessment of the Physicochemical Properties and Stability for Pharmacokinetic Prediction of Pyrazinoic Acid Derivatives.

Curr Drug Metab 2020 ;21(9):714-721

Department of Natural Active Principles and Toxicology, Sao Paulo State University (UNESP), Araraquara, Sao Paulo, Brazil.

Background: Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis, which still has high prevalence worldwide. In addition, cases of drug resistance are frequently observed. In the search for new anti-TB drugs, compounds with antimycobacterial activity have been developed, such as derivatives of pyrazinoic acid, which is the main pyrazinamide metabolite. In a previous study, the compounds were evaluated and showed moderate antimycobacterial activity and no important cytotoxic profile; however, information about their pharmacokinetic profile is lacking.

Objective: The aim of this work was to perform physicochemical, permeability, and metabolic properties of four pyrazinoic acid esters.

Method: The compounds were analyzed for their chemical stability, n-octanol:water partition coefficient (logP) and apparent permeability (Papp) in monolayer of Caco-2 cells. The stability of the compounds in rat and human microsomes and in rat plasma was also evaluated.

Results: The compounds I, II and IV were found to be hydrophilic, while compound III was the most lipophilic (logP 1.59) compound. All compounds showed stability at the three evaluated pHs (1.2, 7.4 and 8.8). The apparent permeability measured suggests good intestinal absorption of the compounds. Additionally, the compounds showed metabolic stability under action of human and rat microsomal enzymes and stability in rat plasma for at least 6 hours.

Conclusion: The results bring favorable perspectives for the future development of the evaluated compounds and other pyrazinoic acid derivatives.
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http://dx.doi.org/10.2174/1389200221666200907145722DOI Listing
January 2020

Avocado kernels, an industrial residue: a source of compounds with insecticidal activity against silverleaf whitefly.

Environ Sci Pollut Res Int 2021 Jan 2;28(2):2260-2268. Epub 2020 Sep 2.

Department of Entomology and Acarology, "Luiz de Queiroz" College of Agriculture, University of São Paulo (ESALQ/USP), Piracicaba, São Paulo, 13418-900, Brazil.

Fruit processing waste, such as kernels (endocarp + seed) of avocado [Persea americana Mill. (Lauraceae)], could be used as raw material in the preparation of botanical insecticides. In light of this potential, this study assessed the insecticidal action of extracts and fractions from kernels of two avocado cultivars (Breda and Margarida) on Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae) biotype B, an important pest species in tropical conditions. Ethanolic and aqueous extracts prepared from kernels of P. americana, regardless of the plant cultivar used, caused promising insecticidal activity to whitefly nymphs. Based on yield in crude extracts [10.32 and 9.85% (w/w), respectively, for cultivars Breda and Margarida], on the bioassay results with crude extracts and on the chemical profiles, the ethanolic extract of kernels of P. americana cv. Breda was chose for the continuation of the study. Thus, the ethanolic extract of kernels of cv. Breda (LC = 197.84 ppm and LC = 567.19 ppm) was selected and subjected to fractionation by the liquid-liquid partition technique. The hexane and dichloromethane fractions of this extract caused significant mortality of nymphs. The analysis using the ultraviolet (UV) and hydrogen nuclear magnetic resonance (H NMR) showed the presence of long-chain aliphatic compounds (alkanols or acetogenins of Lauraceae), alkylfurans (or avocadofurans), and unsaturated fatty acids in these fractions, which are possibly related to bioactivity observed in B. tabaci, besides saccharides. The results show that kernels of P. americana are promising sources of compounds with insecticidal action for the control of B. tabaci biotype B, a great opportunity to transform environmental problems into eco-friendly solutions to agriculture.
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http://dx.doi.org/10.1007/s11356-020-10675-6DOI Listing
January 2021

Lycium barbarum polysaccharide fraction associated with photobiomodulation protects from epithelium thickness and collagen fragmentation in a model of cutaneous photodamage.

Lasers Med Sci 2020 Aug 22. Epub 2020 Aug 22.

Laboratory of Biology of Aging (LABEN), Department of Gerontology, Federal University of São Carlos, São Carlos, SP, CEP 13565-905, Brazil.

Ultraviolet radiation (UVR) is the major etiologic agent of cutaneous photoaging, and different strategies are used to prevent and treat this condition. The polysaccharide fraction (LBPF) isolated from Lycium Barbarum fruits (goji berry) contains several active ingredients with antioxidant, immune system modulation, and antitumor effects. In addition, the photobiomodulation (PBM) is widely applied in photoaging treatment. This study investigated the effects of LBPF and PBM against the UVR-induced photodamage in the skin of hairless mice. The mice were photoaged for 6 weeks in a chronic and cumulative exposure regimen using a 300-W incandescent lamp that simulates the UVR effects. From the third to the sixth week of photoaging induction, the animals received topical applications of LBPF and PBM, singly or combined, in different orders (first LBPF and then PBM and inversely), three times per week after each session of photoaging. After completion of experiments, the dorsal region skin was collected for the analysis of thickness, collagen content, and metalloproteinases (MMP) levels. A photoprotective potential against the increase of the epithelium thickness and the fragmentation of the collagen fibers was achieved in the skin of mice treated with LBPF or PBM singly, as well as their combination. All treatments maintained the skin collagen composition, except when PBM was applied after the LBPF. However, no treatment protected against the UVR-induced MMP increase. Taken together, we have shown that the LBPF and PBM promote a photoprotective effect in hairless mice skin against epidermal thickening and low collagen density. Both strategies, singly and combined, can be used to reduce the UVR-induced cutaneous photoaging.
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http://dx.doi.org/10.1007/s10103-020-03132-wDOI Listing
August 2020

Benzylidene-carbonyl compounds are active against itraconazole-susceptible and itraconazole-resistant Sporothrix brasiliensis.

Folia Microbiol (Praha) 2020 Dec 21;65(6):1033-1038. Epub 2020 Aug 21.

Department of Pharmaceutical Sciences, Institute of Environmental, Chemical and Pharmaceutical Sciences, Federal University of São Paulo (UNIFESP), Diadema, SP, 09913-030, Brazil.

We evaluated the antifungal activity of benzylidene-carbonyl compounds (LINS03) based on the structure of gibbilimbol from Piper malacophyllum Linn. Five analogues (1-5) were synthetized following a classic aldol condensation between an aromatic aldehyde and a ketone, under basic conditions. These were tested against itraconazole-susceptible (n = 3) and itraconazole-resistant (n = 5) isolates of Sporothrix brasiliensis by M38-A2 guidelines of CLSI. All of them were fungistatic (MIC ranged of 0.11-0.22 mg/mL (1); 0.08-0.17 mg/mL (2); 0.05-0.1 mg/mL (3); 0.04-0.33 mg/mL (4); and 0.04-0.3 mg/mL (5)), highlighting compounds 2 and 3. As fungicidal, compounds 1 and 2 were highlighted (MFC ranged of 0.22-0.89 mg/mL and 0.08-1.35 mg/mL, respectively), compared with the remaining (0.77-> 3.08 mg/mL (3); 0.08-> 2.6 mg/mL (4); and 0.59-> 2.37 mg/mL (5)). The inhibitory activity was related to the benzylidene-carbonyl, whereas the phenol group and the low chain homolog seems to contribute to some extent to the fungicidal effect. Compound 2 highlighted due to the considerable fungistatic and fungicidal activities, including itraconazole-resistant Sporothrix brasiliensis. These findings support the potential usefulness of benzylidene-carbonyl compounds as promising prototypes for the development of antifungal against sporotrichosis by Sporothrix brasiliensis, including against itraconazole-resistant isolates.
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http://dx.doi.org/10.1007/s12223-020-00814-4DOI Listing
December 2020

Impact of different front-of-pack nutrition labels on online food choices.

Appetite 2020 11 11;154:104795. Epub 2020 Aug 11.

Instituto de Saúde Ambiental, Faculdade de Medicina, Universidade de Lisboa. Avenida Professor Egas Moniz, 1649-028, Lisboa, Portugal; Direção-Geral da Saúde, Lisboa, Portugal. Alameda D, Afonso Henriques, 45, 1049-005, Lisboa, Portugal; Escola Superior de Enfermagem de Lisboa, Lisboa, Portugal, Avenida Professor Egas Moniz, 1649-028, Lisboa, Portugal. Electronic address:

Front-of-pack nutrition labels (FOP-NL) are efficient tools for increasing consumers' awareness of the nutritional quality of food products, prompting healthier food choices. The main goal of this study was to evaluate the impact of four FOP-NL schemes - Traffic Light label (TL), Guideline Daily Amounts (%GDA), Nutri-Score (NS) and Health Star Rating (HSR) - on consumers' selection of food products according to perceived nutritional quality. A cross-sectional open-label crossover randomized controlled study was carried out among Portuguese consumers. A web-based questionnaire was used to assess participants' a) preferences regarding FOP-NLs and b) capacity to select healthy products in a food selection task using the information from FOP-NL schemes. When performing the selection task, participants had the option to indicate that they could not decide simply based on the presented FOP-NL (requiring more information). Overall, 357 adults participated in the study. Regarding consumers' preferences, TL received the most favorable responses, while NS received the fewest. All FOP-NLs performed better than the no-nutritional label control condition in the food selection task. The highest proportion of correct choices was obtained for TL (72.3%), followed by HSR (70.9%), %GDA (70.0%) and NS (62.2%), though no significant differences were found among FOP-NLs. Percentages of respondents indicating not being able to answer due to lack of information affected the proportion of correct choices, with 10.3% for TL, 12.9% for %GDA, 14.6% for HSR, and 25.8% for NS, indicating they were unable to choose without additional information. Although no particular FOP-NL system stood out as the most significantly effective, TL was the most preferred by Portuguese adults. Long-term real-world evidence is necessary to assess the impact of FOP-NL systems on individuals' food choices.
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http://dx.doi.org/10.1016/j.appet.2020.104795DOI Listing
November 2020

Distribution of myocardial work in arterial hypertension: insights from non-invasive left ventricular pressure-strain relations.

Int J Cardiovasc Imaging 2021 Jan 12;37(1):145-154. Epub 2020 Aug 12.

Institute of Biomedical Research August Pi Sunyer (IDIBAPS), Carrer del Rosselló, 149, 08036, Barcelona, Spain.

A index of non-invasive myocardial work (MWI) can account for pressure during the assessment of cardiac function, potentially separating the influence of loading conditions from the influence of the underlying tissue remodelling. The aim is to assess LV function accounted for loading and explore hypertensive MWI distribution by comparing healthy individuals to hypertensive patients without and with localized basal septal hypertrophy (BSH). An echocardiogram was performed in 170 hypertensive patients and 20 healthy individuals. BSH was defined by a basal-to-mid septal wall thickness ratio ≥ 1.4. LV speckle-tracking was performed, and the MWI calculated globally and regionally for the apical, mid and basal regions. An apex-to-base gradient, seen in regional strain values, was preserved in the distribution of myocardial work, with the apical region compensating for the impairment of the basal segments. This functional redistribution was further pronounced in patients with localized BSH. In these patients, segmental MWI analysis revealed underlying impairment of regional work unrelated to acute loading conditions. Non-invasive MWI analysis offers the possibility to compare LV function regardless of blood pressure at the time of observation. Changes in MWI distribution can be seen in hypertension unrelated to the load-dependency of strain. Accentuated functional changes affirm the role of BSH as an echocardiographic marker in hypertension.
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http://dx.doi.org/10.1007/s10554-020-01969-4DOI Listing
January 2021

Head-to-Tail Cyclization after Interaction with Trypsin: A Scorpion Venom Peptide that Resembles Plant Cyclotides.

J Med Chem 2020 09 12;63(17):9500-9511. Epub 2020 Aug 12.

Neuropharma Lab, Departamento de Ciências Fisiológicas, Instituto de Ciências Biológicas, Universidade de Brası́lia, Brasília-DF 70910-900, Brazil.

Peptidase inhibitors (PIs) have been broadly studied due to their wide therapeutic potential for human diseases. A potent trypsin inhibitor from scorpion venom was characterized and named ToPI1, with 33 amino acid residues and three disulfide bonds. The X-ray structure of the ToPI1:trypsin complex, in association with the mass spectrometry data, indicate a sequential set of events: the complex formation with the inhibitor Lys in the trypsin S1 pocket, the inhibitor C-terminal residue Ser cleavage, and the cyclization of ToPI1 via a peptide bond between residues Ile and Lys. Kinetic and thermodynamic characterization of the complex was obtained. ToPI1 shares no sequence similarity with other PIs characterized to date and is the first PI with CS-α/β motif described from animal venoms. In its cyclic form, it shares structural similarities with plant cyclotides that also inhibit trypsin. These results bring new insights for studies with venom compounds, PIs, and drug design.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00686DOI Listing
September 2020

Coumaric acid derivatives as tyrosinase inhibitors: Efficacy studies through in silico, in vitro and ex vivo approaches.

Bioorg Chem 2020 10 21;103:104108. Epub 2020 Jul 21.

Department of Pharmaceutical Sciences, Institute of Environmental, Chemical and Pharmaceutical Sciences, Universidade Federal de São Paulo, Rua São Nicolau 210, 09913-030 Diadema-SP, Brazil. Electronic address:

p-Coumaric acid is a known inhibitor of tyrosinase, an enzyme involved in the initial steps of the melanin synthesis in human and other species. However, its low lipophilicity impairs its penetration through skin and efficacy as antimelanogenic agent indeed. Accordingly, this paper reports the assessment of several coumaric acid derivatives as tyrosinase inhibitors and antimelanogenic agents in in vitro, in silico and ex vivo assays. The compounds were designed with modifications in the aromatic and acid moieties of p-coumaric acid, being the coumarate esters the most promising derivatives. The compounds showed higher tyrosinase inhibitory activity (pIC 3.7-4.2) than the parent acid, being compounds 1d, 1e and 1f the most potent inhibitors. Docking analysis showed that these esters are competitive inhibitors per se, and act independently of a redox mechanism as suggested by DPPH assays. Moreover, the esters showed efficacy in reducing the melanin deposition in human skin fragments at 0.1% concentration, especially compound 1e. In summary, there is an important equilibria between tyrosinase affinity and lipophilicity that must be considered to get effective antimelanogenic agents with adequate permeability in the skin.
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http://dx.doi.org/10.1016/j.bioorg.2020.104108DOI Listing
October 2020

Coumaric acid analogues inhibit growth and melanin biosynthesis in Cryptococcus neoformans and potentialize amphotericin B antifungal activity.

Eur J Pharm Sci 2020 Oct 18;153:105473. Epub 2020 Jul 18.

Biological Sciences Department, Universidade Federal de São Paulo, Rua São Nicolau 210, 09913-030 Diadema, SP, Brazil. Electronic address:

Fungal infections are on the rise, since the imunocompromised population is increasing due to AIDS/HIV, organ transplant and chemotherapy. Many environmental and pathogenic fungi are able to accomplish melanin biosynthesis as a virulence factor to promote host invasion. Melanized cells are more resistant to radiation, oxidative and osmotic stresses; also melanin confers an advantage in vivo, since melanized cells are more resistant to phagocytic engulfment and oxidative stress caused by the host defense cells and by some antifungal drugs, such as fluconazole (FCZ) and amphotericin B (AmB). Brown, red or black melanin pigments can be produced by the polyketide pathway (DHN-melanin) or from dihydroxyphenols, such as L-DOPA (L-3,4-dihydroxyphenylalanine) and L-tyrosine by polyphenoloxidases. Among several pathogenic fungi, Cryptococcus neoformans is a melanized yeast that causes pneumonia and meningoencephalitis in immunocompromised patients. The knockout of the laccase genes or other interruptions on melanin biosynthetic pathway generates cryptococcal strains with attenuated virulence in an animal model. In this study 16 analogues of coumaric and cinnamic acid were evaluated as possible tyrosinase inhibitors. We have identified some valuable inhibitors of C. neoformans growth and melanin biosynthesis disruption agents. The results showed that coumaric acid derivatives (1a-c), the ketones (3a-b) and 2-allylphenol (7c) are significant inhibitors of tyrosinase and melanization of the fungus. Two analogues (1b and 3b) were selected as promising antimelanogenic agents to be combined with AmB, showing to promote 16-fold reduction in the AmB fungicidal concentration with no appreciable cytotoxicity to mammalian cells. The data suggest that inhibition of the melanin biosynthesis by these compounds may increase the susceptibility of the cells to the oxidative stress generated by AmB. In summary, our data show that C. neoformans can be a suitable model system to test novel inhibitors that target melanin biosynthesis, and novel compounds for adjunct therapy against C. neoformans were identified.
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http://dx.doi.org/10.1016/j.ejps.2020.105473DOI Listing
October 2020