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Microorganisms are remarkable producers of a wide diversity of natural products that significantly improve human health and well-being. Currently, these natural products comprise half of all the pharmaceuticals on the market. After the discovery of penicillin by Alexander Fleming 85 years ago, the search for and study of antibiotics began to gain relevance as drugs. Since then, antibiotics have played a valuable role in treating infectious diseases and have saved many human lives. New molecules with anticancer, hypocholesterolemic, and immunosuppressive activity have now been introduced to treat other relevant diseases. Smaller biotechnology companies and academic laboratories generate novel antibiotics and other secondary metabolites that big pharmaceutical companies no longer develop. The purpose of this review is to illustrate some of the recent developments and to show the potential that some modern technologies like metagenomics and genome mining offer for the discovery and development of new molecules, with different functions like therapeutic alternatives needed to overcome current severe problems, such as the SARS-CoV-2 pandemic, antibiotic resistance, and other emerging diseases. KEY POINTS: ⢠Novel alternatives for the treatment of infections caused by bacteria, fungi, and viruses. ⢠Second wave of efforts of microbial origin against SARS-CoV-2 and related variants. ⢠Microbial drugs used in clinical practice as hypocholesterolemic agents, immunosuppressants, and anticancer therapy.
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Produtos Biológicos , Tratamento Farmacológico da COVID-19 , Antibacterianos/metabolismo , Bactérias/metabolismo , Produtos Biológicos/uso terapêutico , Humanos , SARS-CoV-2RESUMO
Objective: To assess early care and education professionals' breastfeeding knowledge and practices before and after an e-learning program. Participants: Early care and education professionals from New Hampshire (U.S.A.) licensed child care programs were invited to complete a pre-assessment followed by a 90-minute e-learning breastfeeding program. Three months post-training, participants were invited to complete the post-assessment. Analysis: McNemar tests were used to assess changes from pre-post-assessment for dichotomous variables. McNemar-Bowker tests were used to determine differences from pre-post for variables with more than two categories. When the McNemar-Bowker test was significant, a multiple comparison correction (Bonferroni) was used. Results: 114 participants completed the e-learning program and pre-post assessment. Results showed significant improvement from pre-post in 10 of 15 breastfeeding knowledge questions related to health of baby, mother and child care centers, economics, and environmental impact. There were significant changes from pre-post in 24 of 50 breastfeeding practice questions in handling breast milk, promoting breastfeeding, and supporting mothers. Conclusions and Implications: This study indicates improvement in early care and education professionals' breastfeeding knowledge and practices; however, opportunities exist to design targeted initiatives to further strengthen practices that support breastfeeding families in the child care environment.
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Tolyporphins L-R (2-8) have been isolated from a mixed cyanobacterium-microbial culture. The structures of tolyporphins L and M have been revised to four constitutional isomers, isolated as two mixtures of dioxobacteriochlorins (2/3 and 4/5). In contrast, tolyporphin P (6) is a fully oxidized tetrapyrrole, while tolyporphins Q and R (7 and 8) are oxochlorins. X-ray structures are reported for the first time for tolyporphins A (1), R (8), and E (9), revealing unexpected stereochemical variation within the series.
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Cianobactérias/química , Porfirinas/química , Tetrapirróis/química , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Estrutura Molecular , Porfirinas/isolamento & purificação , Análise Espectral/métodos , Tetrapirróis/isolamento & purificaçãoRESUMO
In recent years, the number of pathogenic microorganisms resistant to antibiotics has increased alarmingly. For the next 10-20 years, health organizations forecast high human mortality caused by these microorganisms. Therefore, the search for new anti-infectives is quite necessary and urgent. Traditionally, antibiotic-producing microorganisms have been isolated from common soil samples. However, this source seems to be exhausted considering the very few examples of antibiotic-producing microorganisms reported recently. In this review, non-conventional sources of anti-infective producing microorganisms are presented as a possible way to look for new and more effective compounds. These sources included arid soils, caves, areas with high temperatures (hot springs), high salinity or oceans and seas. Finally, other non-conventional sources of antibiotics reviewed are animal and invertebrate venoms, among others.
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Anti-Infecciosos , Animais , Genômica , Humanos , Microbiota , Peçonhas/químicaRESUMO
Cryptorchidism (CPT), the most common male congenital abnormality, is variably associated with other male reproductive tract problems. We evaluated if cryptorchid rats develop enhanced testicular susceptibility to dibutyl phthalate (DBP) or acrylamide (AA) after extended exposure. Three studies with rats were performed: (1) in utero and postnatal exposure to DBP or AA; (2) establishment of CPT and orchiopexy; and (3) in utero and postnatal exposures to DBP or AA associated with CPT/orchiopexy. Seminiferous tubules were histologically scored according to the severity of lesions: (1) Rats exposed to DBP (score 1.5) or AA (score 1.1) presented mostly preserved spermatogenesis. Some seminiferous tubules showed vacuolated germinative epithelium, germ cell apoptosis, and a Sertoli cell-only (SCO) pattern. (2) CPT (score 3.3) resulted in decreased absolute testes weights, degenerated and SCO tubules, and spermatogenesis arrest that were reversed by orchiopexy (score 1.1). (3) Exposure to DBP or AA with CPT/orchiopexy led to atrophic testes, spermatogenesis arrest, germ cell exfoliation/multinucleation, and SCO tubules (both chemicals score 2.5). Exposure to chemicals such as DBP or AA prevented the recovery of cryptorchid testes by orchiopexy. The possible role of environmental contaminants should be considered when looking for factors that modulate human testicular disorders associated with CPT.
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Acrilamida/toxicidade , Criptorquidismo/cirurgia , Dibutilftalato/toxicidade , Testículo/efeitos dos fármacos , Animais , Criptorquidismo/patologia , Modelos Animais de Doenças , Feminino , Masculino , Troca Materno-Fetal , Orquidopexia , Gravidez , Ratos Sprague-Dawley , Testículo/patologiaRESUMO
We report the preparation and full characterization of a series of hydroxyl functionalized 1,2,3-triazolylidene-based PEPPSI complexes 2a-c and their catalytic application in the Suzuki cross coupling reaction of aryl chlorides/amides with boronic acids. Under basic reaction conditions, complexes 2a-c show a notable increase in their catalytic efficiency compared with two ether-wingtip functionalized PEPPSI analogues (3 and 4) and a commercially available NHC-Pd complex (5). The catalytic results suggest that deprotonation of the hydroxyl group in complexes 2a-c plays an important role in the overall process. Deprotonation of the alcohol moiety of complexes 2a-b with sodium tert-butoxide allows for the isolation of metallacycles 6a-b, which are proposed as the active species of cross coupling reactions.
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Previously, ferrocene incorporation into the principal structural component of biologically active molecules resulted in enhanced cytotoxic activity against hormone-dependent MCF-7 and T-47D and hormone-independent MDA-MB-231 breast-cancer cell lines. Here we explore 4 new ferrocene estrogen conjugates at position 16 of the estrogen hormone and compared them to the previously reported ferrocene estrogen conjugate 3-ferrocenyl-estra-1,3,5(10)-triene-17ß-ol. The ferrocene conjugate 16-ferrocenylidene-3-hydroxyestra-1,3,5(10)-trien-17-one was synthesized using estrone and ferrocene carboxaldehyde as starting materials in 86% yield. This ferrocene complex was used as the starting material for the synthesis of new ferrocene estrogen conjugates by a short linker group at position 16 of the estrogen hormone. The position and stereochemistry of the linker was verified by its crystal structure. The ferrocene redox behavior, in vitro studies on breast-cancer cell lines and docking studies on ERα are presented. The data suggest that the ferrocene conjugates presented, either at position 3 or 16 of the estrogen, could serve as vectors and can be recognized by ERα as a delivery mechanism into the cell. These new ferrocene hormone conjugates showed cytotoxic activity comparable to that of conventional therapeutic drugs such as tamoxifen and cisplatin.
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Antineoplásicos/síntese química , Neoplasias da Mama/tratamento farmacológico , Estrogênios/química , Compostos Ferrosos/síntese química , Metalocenos/síntese química , Aminoácidos/química , Antineoplásicos/metabolismo , Transporte Biológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Receptor alfa de Estrogênio/efeitos dos fármacos , Estrogênios/metabolismo , Feminino , Compostos Ferrosos/metabolismo , Humanos , Metalocenos/metabolismo , Simulação de Acoplamento Molecular/métodos , Estrutura Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Fermentative production of amino acids is an important goal of modern biotechnology. Through fermentation, micro-organisms growing on inexpensive carbon and nitrogen sources can produce a wide array of valuable products including amino acids. The amino acid market is $8 billion and mainly impacts the food, pharmaceutical and cosmetics industries. In terms of tons of amino acids produced per year by fermentation, L-glutamate is the most important amino acid produced (3.3 million), followed by L-lysine (2.2 million). The bacteria producing these amino acids are among the top fermentation organisms with respect to titers. Corynebacterium glutamicum is the best producer.The Journal of Antibiotics advance online publication, 1 November 2017; doi:10.1038/ja.2017.142.
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There is a renewed interest in better conceptualizing trajectories of attention-deficit/hyperactivity disorder (ADHD) from childhood to adulthood, driven by an increased recognition of long-term impairment and potential persistence beyond childhood and adolescence. This review addresses the following major issues relevant to the course of ADHD in light of current evidence from longitudinal studies: (1) conceptual and methodological issues related to measurement of persistence of ADHD, (2) estimates of persistence rate from childhood to adulthood and its predictors, (3) long-term negative outcomes of childhood ADHD and their early predictors, and (4) the recently proposed new adult-onset ADHD. Estimates of persistence vary widely in the literature, and diagnostic criteria, sample characteristics, and information source are the most important factors explaining variability among studies. Evidence indicates that ADHD severity, comorbid conduct disorder and major depressive disorder, and treatment for ADHD are the main predictors of ADHD persistence from childhood to adulthood. Comorbid conduct disorder and ADHD severity in childhood are the most important predictors of adverse outcomes in adulthood among children with ADHD. Three recent population studies suggested the existence of a significant proportion of individuals who report onset of ADHD symptoms and impairments after childhood. Finally, we highlight areas for improvement to increase our understanding of ADHD across the life span.
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Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/terapia , Transtorno da Conduta/epidemiologia , Transtorno Depressivo Maior/epidemiologia , Adolescente , Adulto , Fatores Etários , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Criança , Pré-Escolar , Comorbidade , Transtorno da Conduta/psicologia , Transtorno da Conduta/terapia , Transtorno Depressivo Maior/psicologia , Transtorno Depressivo Maior/terapia , Feminino , Humanos , Masculino , Índice de Gravidade de Doença , Adulto JovemRESUMO
Three complexes are reported from the initial use of dimethylarsinic acid (Me2AsO2H) in Mn(III/IV) cluster chemistry, [Mn4O4(O2AsMe2)6] (3; 2Mn(III), 2Mn(IV)), and [Mn16X4O8(O2CPh)16(Me2AsO2)24] (X = Ca(2+) (4) or Sr(2+) (5); 16Mn(III)). They were obtained from reactions with [Mn12O12(O2CR)16(H2O)4] (R = Me, Ph) either without (3) or with (4 and 5) the addition of X(2+) salts. Complex 3 contains a [Mn4O4](6+) cubane, whereas isostructural 4 and 5 contain a planar loop structure comprising four Mn4 asymmetric "butterfly" units linked by alternating anti,anti µ-O2AsMe2 and {X2(O2AsMe2)(O2CPh)2} units. Variable-temperature magnetic susceptibility (χM) data were collected on dried microcrystalline samples of 3-5 in the 5.0-300 K range in a 0.1 T (1000 G) direct-current (dc) magnetic field. Data for 3 were fit to the appropriate Van Vleck equation (using the [Formula: see text] = -2JSi·Sj convention) for a cubane of virtual C2v symmetry, giving J33 = 0.0(1) cm(-1), J34 = -3.4(4) cm(-1), J44 = -9.8(2) cm(-1), and g = 1.99(1), where the Jij subscripts refer to the oxidation states of the interacting Mn atoms. The ground state thus consists of two coupled Mn(IV) and two essentially noninteracting Mn(III). For 4 and 5, low-lying excited states from the high nuclearity and weak couplings prevent fits of dc magnetization data, but in-phase alternating current susceptibility χ'MT data down to 1.8 K indicate them to possess S = 4 ground states, if considered single Mn16 units. If instead they are treated as tetramers of weakly coupled Mn4 units, then each of the latter has an S = 2 ground state. Complexes 4 and 5 also exhibit very weak out-of-phase χâ³M signals characteristic of slow relaxation, and magnetization versus dc field scans on a single crystal of 4·15MeCN at T ≥ 0.04 K showed hysteresis loops but with unusual features suggesting the magnetization relaxation barrier consists of more than one contribution.
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A new ferrocene complex, 16-ferrocenylmethyl-3ß-hy-droxy-estra-1,3,5(10)-trien-17-one dimethyl sulfoxide monosolvate, [Fe(C5H5)(C24H27O2)]·C2H6OS, has been synthesized and structurally characterized by single-crystal X-ray diffraction techniques. The mol-ecule crystallizes in the space group P21 with one mol-ecule of dimethyl sulfoxide. A hydrogen bond links the phenol group and the dimethyl sulfoxide O atom, with an Oâ¯O distance of 2.655â (5)â Å. The ferrocene group is positioned in the ß face of the estrone moiety, with an O-C-C-C torsion angle of 44.1â (5)°, and the carbonyl bond length of the hormone moiety is 1.216â (5)â Å, typical of a C=O double bond. The average Fe-C bond length of the substituted Cp ring [Fe-C(Cp*)] is similar to that of the unsubstituted one [Fe-C(Cp)], i.e. 2.048â (3) versus 2.040â (12)â Å. The structure of the complex is compared with those of estrone and eth-oxy-methyl-estrone.
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Four new platinum(II) complexes, namely tetra-ethyl-ammonium tri-bromido-(2-methyl-1,3-benzo-thia-zole-κN)platinate(II), [NEt4][PtBr3(C8H7NS)] (1), tetra-ethyl-ammonium tri-bromido-(6-meth-oxy-2-methyl-1,3-benzo-thia-zole-κN)platinate(II), [NEt4][PtBr3(C9H9NOS)] (2), tetra-ethyl-ammonium tri-bromido-(2,5,6-trimethyl-1,3-benzo-thia-zole-κN)platinate(II), [NEt4][PtBr3(C10H11NS)] (3), and tetra-ethyl-ammonium tri-bromido-(2-methyl-5-nitro-1,3-benzo-thia-zole-κN)platinate(II), [NEt4][PtBr3(C8H6N2O2S)] (4), have been synthesized and structurally characterized by single-crystal X-ray diffraction techniques. These species are precursors of compounds with potential application in cancer chemotherapy. All four platinum(II) complexes adopt the expected square-planar coordination geometry, and the benzo-thia-zole ligand is engaged in bonding to the metal atom through the imine N atom (Pt-N). The Pt-N bond lengths are normal: 2.035â (5), 2.025â (4), 2.027â (5) and 2.041â (4)â Å for complexes 1, 2, 3 and 4, respectively. The benzo-thia-zole ligands are positioned out of the square plane, with dihedral angles ranging from 76.4â (4) to 88.1â (4)°. The NEt4 cation in 3 is disordered with 0.57/0.43 occupancies.
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Various methods are available for estimating usual dietary intake distributions. Hence, there is a need for simulation studies to compare them. The methods Iowa State University (ISU), National Cancer Institute (NCI), Multiple Source Method (MSM) and Statistical Program to Assess Dietary Exposure (SPADE) were previously compared in another study, but some results were inconclusive due to the small number of replications used in the simulation. Seeking to overcome this limitation, the present study used 1000 simulated samples for 12 different scenarios to compare the accuracy of estimates yielded by the aforementioned methods. The focus is on scenarios that exhibited the most uncertainty in the conclusions of the mentioned study above, i.e., scenarios with small sample sizes, skewed intake distributions, and large ratios of the between- and within-person variances. Bias was used as a measure of accuracy. For scenarios with small sample sizes (n = 150), the ISU, MSM and SPADE methods generally achieved more accurate estimates than the NCI method, particularly for the 10th and 90th percentiles. The differences between methods became smaller with larger sample sizes (n = 300 and n = 500). With few exceptions, the methods were found to perform similarly.
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Simulação por Computador , Dieta , Modelos Estatísticos , Avaliação Nutricional , Estado Nutricional , Recomendações Nutricionais , Humanos , Análise dos Mínimos Quadrados , Modelos Lineares , Reprodutibilidade dos TestesRESUMO
Six ferrocenecarboxylates with phenyl, 4-(1H-pyrrol-1-yl)phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl as pendant groups were synthesized and fully characterized by spectroscopic, electrochemical and X-ray diffraction methods. The anti-proliferative activity of these complexes were investigated in hormone dependent MCF-7 breast cancer and MCF-10A normal breast cell lines, to determine the role of the para substituent on the phenoxy pendant group. The 4-fluorophenyl ferrocenecarboxylate is inactive in both cell lines while 4-(1H-pyrrol-1-yl)phenyl ferrocenecarboxylate is highly cytotoxic in both cell lines. 4-chlorophenyl and 4-bromophenyl ferrocenecarboxylates have moderate to good anti-proliferative activity in MCF-7 and low anti-proliferative activity on normal breast cell line, MCF-10A whereas the 4-iodophenyl analog is highly toxic on normal breast cell line. The phenyl ferrocenecarboxylate has proliferative effects on MCF-7 and is inactive in MCF-10A. Docking studies between the complexes and the alpha-estrogen receptor (ERα) were performed to search for key interactions which may explain the anti-proliferative activity of 4-bromophenyl ferrocenecarboxylate. Docking studies suggest the anti-proliferative activity of these ferrocenecarboxylates is attributed to the cytotoxic effects of the ferrocene group and not to anti-estrogenic effects.
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INTRODUCTION: The majority of children presenting with paroxysmal supraventricular tachycardia (SVT) have either accessory-pathway-mediated tachycardia or AV node reentry tachycardia. The purpose of this study is to report an unusual mechanism of SVT found in children with structurally normal hearts. METHODS AND RESULTS: Records of all patients undergoing an electrophysiology study (EPS) at our institution between 2000 and 2004 were reviewed to identify those with nonautomatic focal atrial tachycardia (NAFAT). Five patients (three males) with an average age of 13.8 years (median 15 years, range 7-18 years) were identified. All presented with paroxysmal palpitations. They all had structurally normal hearts. At EPS, SVT was reproducibly induced with programmed atrial stimulation (single, double, or triple extrastimuli) in all patients. The average cycle length was 276 +/- 9 ms. Adenosine terminated SVT in 2. A 3-D electro-anatomical system mapping was used in all cases. The right atrium (RA) was mapped in all and the left in two. Foci were mapped to the posterior high RA, lateral RA, lower mid RA septum, inferior to the sinus node, and in the right and left posteroseptal areas. Average number of radiofrequency lesions placed was 8.6 +/- 5. The success rate was 80%; there was one late recurrence. No procedural complications were observed. CONCLUSIONS: NAFAT is a rare form of tachycardia that should be considered in the differential diagnosis of children presenting with SVT. It is amenable to mapping and radiofrequency ablation.
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Ablação por Cateter/métodos , Taquicardia Atrial Ectópica/diagnóstico , Taquicardia Atrial Ectópica/cirurgia , Adolescente , Criança , Feminino , Humanos , Masculino , Resultado do TratamentoRESUMO
Overproduction of microbial metabolites is related to developmental phases of microorganisms. Inducers, effectors, inhibitors and various signal molecules play a role in different types of overproduction. Biosynthesis of enzymes catalysing metabolic reactions in microbial cells is controlled by well-known positive and negative mechanisms, e.g. induction, nutritional regulation (carbon or nitrogen source regulation), feedback regulation, etc. The microbial production of primary metabolites contributes significantly to the quality of life. Fermentative production of these compounds is still an important goal of modern biotechnology. Through fermentation, microorganisms growing on inexpensive carbon and nitrogen sources produce valuable products such as amino acids, nucleotides, organic acids and vitamins which can be added to food to enhance its flavour, or increase its nutritive values. The contribution of microorganisms goes well beyond the food and health industries with the renewed interest in solvent fermentations. Microorganisms have the potential to provide many petroleum-derived products as well as the ethanol necessary for liquid fuel. Additional applications of primary metabolites lie in their impact as precursors of many pharmaceutical compounds. The roles of primary metabolites and the microbes which produce them will certainly increase in importance as time goes on. In the early years of fermentation processes, development of producing strains initially depended on classical strain breeding involving repeated random mutations, each followed by screening or selection. More recently, methods of molecular genetics have been used for the overproduction of primary metabolic products. The development of modern tools of molecular biology enabled more rational approaches for strain improvement. Techniques of transcriptome, proteome and metabolome analysis, as well as metabolic flux analysis. have recently been introduced in order to identify new and important target genes and to quantify metabolic activities necessary for further strain improvement.
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Bactérias/genética , Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica , Biotecnologia , Fermentação , Engenharia GenéticaRESUMO
El daño del nodo auriculoventricular (NAV) constituye una de las potenciales complicaciones de la ablación por radiofrecuencia de vías accesorias parahisianas. La crioterapia, con la potencial reversibilidad a temperaturas no extremas, puede constituir una alternativa en la ablación de estas vías. Un niño con preexcitación intermitente con una vía accesoria parahisiana y crisis de taquicardia paroxística supraventricular fue sometido a un estudio electrofisiológico y la crioablación permitió la eliminación de la vía accesoria con preservación de la integridad del NAV.
Reversible Damage of the Atrioventricular Node during Cryoablation of a para-Hissian Pathway in a Child with Intermittent Pre-excitation Syndrome Damage of the atrioventricular node (AVN) is one of the potential complications in radiofrequency ablation of para- Hissian accessory pathways. Cryotherapy, with reversibility potential at non extreme temperatures, may be an alternative in the ablation of these pathways. A child with intermittent pre-excitation syndrome, para-Hissian accessory pathway and a crisis of supraventricular paroxistic tachycardia was subjected to electrophysiological assessment, and cryoablation allowed removing the accessory pathway with preserved AVN integrity.
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OBJECTIVES: To determine if patients with cystic fibrosis (CF) have an altered pharmacokinetic profile of montelukast, we studied the single-dose pharmacokinetics in 12 patients with CF and 12 age- and gender-matched controls after they received a 10-mg oral dose. METHODS: Plasma samples were collected before dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, and 24 hours after drug administration. The specimens were analyzed by high-performance liquid chromatography (HPLC). RESULTS: The mean systemic clearance (mL/min) values (+/- SD) were not statistically different between the CF subjects (55.53 +/- 44.0 mL/min) and the controls (57.12 +/- 18.42 mL/min), nor were the results significantly different when normalized to body surface area or body weight. The mean value for elimination half-life, elimination rate constant, area under the plasma concentration versus time curve, and maximum concentration for controls was 2.37 +/- 0.38 hours, 0.30 +/- 0.05 hours(-1), 2,680.0 +/- 693.6 ng. min/mL, and 448.9 +/- 165.3 ng/mL; and for the CF patients it was 2.97 +/- 1.21 hours, 0.28 +/- 0.13 hrs(-1), 3976.1 +/- 2073.4 ng. min/mL, 606.7 +/- 237.8 ng/mL. There were no statistically significant differences (all P >.05) in the measured pharmacokinetic parameters between the CF and control subjects. CONCLUSIONS: We conclude that the dose of montelukast and the dosing interval does not need to be modified if the goal is to mimic the serum concentration used to treat asthma. The effectiveness of these concentrations for the inflammatory lung disease of patients with CF is unknown.