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The development of new compounds to treat Chagas disease is imperative due to the adverse effects of current drugs and their low efficacy in the chronic phase. This study aims to investigate nitroisoxazole derivatives that produce oxidative stress while modifying the compounds' lipophilicity, affecting their ability to fight trypanosomes. The results indicate that these compounds are more effective against the epimastigote form of T. cruzi, with a 52 ± 4% trypanocidal effect for compound 9. However, they are less effective against the trypomastigote form, with a 15 ± 3% trypanocidal effect. Additionally, compound 11 interacts with a higher number of amino acid residues within the active site of the enzyme cruzipain. Furthermore, it was also found that the presence of a nitro group allows for the generation of free radicals; likewise, the large size of the compound enables increased interaction with aminoacidic residues in the active site of cruzipain, contributing to trypanocidal activity. This activity depends on the size and lipophilicity of the compounds. The study recommends exploring new compounds based on the nitroisoxazole skeleton, with larger substituents and lipophilicity to enhance their trypanocidal activity.
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Isoxazoles , Tripanocidas , Trypanosoma cruzi , Trypanosoma cruzi/efectos de los fármacos , Tripanocidas/farmacología , Tripanocidas/química , Tripanocidas/síntesis química , Isoxazoles/química , Isoxazoles/farmacología , Proteínas Protozoarias/metabolismo , Proteínas Protozoarias/química , Proteínas Protozoarias/antagonistas & inhibidores , Relación Estructura-Actividad , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , Cisteína Endopeptidasas/química , Cisteína Endopeptidasas/metabolismo , Animales , Dominio Catalítico , Estructura MolecularRESUMEN
BACKGROUND: Although the Ponseti method has been used with great success in a variety of nonidiopathic clubfoot deformities, the efficacy of this treatment in clubfeet associated with Down syndrome remains unreported. The purpose of this study is, therefore, to compare treatment characteristics and outcomes of clubfoot patients with Down syndrome to those with idiopathic clubfoot treated with the Ponseti method. METHODS: An Institutional Review Board-approved, retrospective review of prospectively gathered data were performed at a single pediatric hospital over an 18-year period. Patients with either idiopathic clubfeet or clubfeet associated with Down syndrome who were less than 1 year of age at the outset of treatment were treated by the Ponseti method, and had a minimum of 2 year's follow-up were included. Initial Dimeglio score, number of casts, need for heel cord tenotomy, recurrence, and need for further surgery were recorded. Outcomes were classified using the Richards classification system: "good" (plantigrade foot +/- heel cord tenotomy), "fair" (need for a limited procedure), or "poor" (need for a full posteromedial release). RESULTS: Twenty clubfeet in 13 patients with Down syndrome and 320 idiopathic clubfeet in 215 patients were identified. Average follow-up was 73 months for the Down syndrome cohort and 62 months for the idiopathic cohort. Down syndrome patients presented for treatment at a significantly older age (61 vs. 16 d, P =0.00) and with significantly lower average initial Dimeglio scores than the idiopathic cohort (11.3 vs. 13.4, P =0.02). Heel cord tenotomy was performed in 80% of the Down syndrome cohort and 79% of the idiopathic cohort ( P =1.00). Recurrence rates were higher in the Down syndrome cohort (60%) compared with the idiopathic group (37%), but this difference was not statistically significant ( P =0.06). Need for later surgical procedures was similar between the 2 cohorts, though recurrences in the Down syndrome group were significantly less likely to require intra-articular surgery (8.3% vs. 65.5%, P =0.00). Clinical outcomes were 95% "good," 0% "fair," and 5% "poor" in the Down syndrome cohort and 69% "good," 27% "fair," and 4% "poor" in the idiopathic cohort ( P =0.01). CONCLUSIONS: Despite the milder deformity and an older age at presentation, clubfeet associated with Down syndrome have similar rates of recurrence and may have better clinical outcomes when compared with their idiopathic counterparts. When deformities do relapse in Down syndrome patients, significantly less intra-articular surgery is required than for idiopathic clubfeet. LEVEL OF EVIDENCE: Level III.
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Pie Equinovaro , Síndrome de Down , Humanos , Niño , Lactante , Estudios de Seguimiento , Resultado del Tratamiento , Pie Equinovaro/cirugía , Pie Equinovaro/complicaciones , Síndrome de Down/complicaciones , Moldes Quirúrgicos , Estudios Retrospectivos , Tenotomía , RecurrenciaRESUMEN
3-formyl-2-quinolones have attracted the scientific community's attention because they are used as versatile building blocks in the synthesis of more complex compounds showing different and attractive biological activities. Using copper-catalyzed Chan-Lam coupling, we synthesized 32 new N-aryl-3-formyl-2-quinolone derivatives at 80 °C, in air and using inexpensive phenylboronic acids as arylating agents. 3-formyl-2-quinolones and substituted 3-formyl-2-quinolones can act as substrates, and among the products, the p-methyl derivative 9a was used as a substrate to obtain different derivatives such as alcohol, amine, nitrile, and chalcone.
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Aminas , Cobre , Cobre/química , CatálisisRESUMEN
The use of mobile health apps to improve diet and nutrition behaviors has increased in recent years. Several studies have described the benefits and advantages of this technology as a complement to interventions for improving nutrition behaviors and nutrition-related health outcomes, including obesity indices and clinical parameters. Few of these works have developed clinical mobile health apps for children, and although parents play a critical role in children's nutrition behaviors, work targeting parents is scarce. The work presented in this paper describes the development of the PersuHabit app, a stand-alone mobile health app targeting parents to promote the intake of fruits and vegetables (FVs) and reduce the intake of ultra-processed foods (UPF) in children aged 6 to 10 years. The paper also presents the execution of an exploratory pilot study to assess the feasibility, acceptability, and preliminary effects of the PersuHabit app. The results are presented and discussed, and actions for further improvement of the PersuHabit app are identified.
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Aplicaciones Móviles , Telemedicina , Niño , Estudios de Factibilidad , Conducta Alimentaria , Humanos , Padres , Proyectos Piloto , Telemedicina/métodosRESUMEN
N-Arylcytisine derivatives are quite rare. We report here a practical methodology to obtain these compounds. Using the copper-catalyzed Chan-Lam coupling, we synthesized new N-arylcytisine derivatives at room temperature, in air and using inexpensive phenylboronic acids. Cytisine and 3,5-dihalocytisines can act as substrates, and among the products, the p-Br-derivative 2r was used as a substrate to obtain biaryl derivatives under Pd-coupling conditions; ester 2j was converted into its acid and amide derivatives using classical carbodiimide conditions. This shows that the Chan-Lam cross-coupling reaction can be included as a versatile synthetic tool in the derivatization of natural products.
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Alcaloides/síntesis química , Amidas/síntesis química , Cobre/química , Azocinas/síntesis química , Catálisis , Estructura Molecular , Quinolizinas/síntesis químicaRESUMEN
Several antidepressants inhibit nicotinic acetylcholine receptors (nAChRs) in a non-competitive and voltage-dependent fashion. Here, we asked whether antidepressants with a different structure and pharmacological profile modulate the rat α7 nAChR through a similar mechanism by interacting within the ion-channel. We applied electrophysiological (recording of the ion current elicited by choline, ICh, which activates α7 nAChRs from rat CA1 hippocampal interneurons) and in silico approaches (homology modeling of the rat α7 nAChR, molecular docking, molecular dynamics simulations, and binding free energy calculations). The antidepressants inhibited ICh with the order: norfluoxetine ~ mirtazapine ~ imipramine < bupropion ~ fluoxetine ~ venlafaxine ~ escitalopram. The constructed homology model of the rat α7 nAChR resulted in the extracellular vestibule and the channel pore is highly negatively charged, which facilitates the permeation of cations and the entrance of the protonated form of antidepressants. Molecular docking and molecular dynamics simulations were carried out within the ion-channel of the α7 nAChR, revealing that the antidepressants adopt poses along the receptor channel, with slightly different binding-free energy values. Furthermore, the inhibition of ICh and free energy values for each antidepressant-receptor complex were highly correlated. Thus, the α7 nAChR is negatively modulated by a variety of antidepressants interacting in the ion-channel.
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Antidepresivos/química , Antidepresivos/farmacología , Canales Iónicos/metabolismo , Receptor Nicotínico de Acetilcolina alfa 7/química , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Animales , Antidepresivos/clasificación , Colina/farmacología , Interneuronas/efectos de los fármacos , Interneuronas/metabolismo , Activación del Canal Iónico/efectos de los fármacos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Ratas , Homología Estructural de Proteína , Relación Estructura-Actividad , TermodinámicaRESUMEN
BACKGROUND AND PURPOSE: Preclinical studies suggest that exercise can enhance cognition after cerebral ischemia but often use long training regiments and test cognition during or acutely after training. The cognitive changes may result from enhanced physical fitness and may only provide acute benefit. We sought to determine whether a short period of exercise after cerebral ischemia could improve cognitive outcomes when measured days after completion of exercise training in 2 cerebral ischemia models. METHODS: Focal or global cerebral ischemia was induced in Sprague-Dawley rats. Rats recovered (3-4 days) then were subject to no exercise (0 m/min), mild (6 m/min), moderate (10 m/min), or heavy (15-18 m/min) treadmill exercise (5-6 days). Cognition was tested 8 to 10 days after the last exercise session with hippocampal-dependent contextual fear conditioning. RESULTS: A short training period of moderate exercise enhanced cognitive function for a week after exercise completion in both models of cerebral ischemia. CONCLUSIONS: Utilization of this exercise paradigm can further the elucidation of exercise-mediated factors involved in cognitive recovery independent of changes in physical fitness.
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Cognición/fisiología , Modelos Animales de Enfermedad , Ataque Isquémico Transitorio/terapia , Condicionamiento Físico Animal/fisiología , Animales , Ataque Isquémico Transitorio/fisiopatología , Ataque Isquémico Transitorio/psicología , Masculino , Condicionamiento Físico Animal/métodos , Condicionamiento Físico Animal/psicología , Distribución Aleatoria , Ratas , Ratas Sprague-DawleyRESUMEN
Nicotinic acetylcholine receptors are a family of ligand-gated nonselective cationic channels that participate in fundamental physiological processes at both the central and the peripheral nervous system. The extent of calcium entry through ligand-gated ion channels defines their distinct functions. The α9α10 nicotinic cholinergic receptor, expressed in cochlear hair cells, is a peculiar member of the family as it shows differences in the extent of calcium permeability across species. In particular, mammalian α9α10 receptors are among the ligand-gated ion channels which exhibit the highest calcium selectivity. This acquired differential property provides the unique opportunity of studying how protein function was shaped along evolutionary history, by tracking its evolutionary record and experimentally defining the amino acid changes involved. We have applied a molecular evolution approach of ancestral sequence reconstruction, together with molecular dynamics simulations and an evolutionary-based mutagenesis strategy, in order to trace the molecular events that yielded a high calcium permeable nicotinic α9α10 mammalian receptor. Only three specific amino acid substitutions in the α9 subunit were directly involved. These are located at the extracellular vestibule and at the exit of the channel pore and not at the transmembrane region 2 of the protein as previously thought. Moreover, we show that these three critical substitutions only increase calcium permeability in the context of the mammalian but not the avian receptor, stressing the relevance of overall protein structure on defining functional properties. These results highlight the importance of tracking evolutionarily acquired changes in protein sequence underlying fundamental functional properties of ligand-gated ion channels.
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Calcio/metabolismo , Receptores Nicotínicos/genética , Acetilcolina/farmacología , Secuencia de Aminoácidos , Animales , Proteínas Aviares/química , Proteínas Aviares/genética , Proteínas Aviares/metabolismo , Señalización del Calcio , Membrana Celular/metabolismo , Células Cultivadas , Pollos , Evolución Molecular , Humanos , Simulación de Dinámica Molecular , Datos de Secuencia Molecular , Agonistas Nicotínicos/farmacología , Permeabilidad , Ratas , Receptores Nicotínicos/química , Receptores Nicotínicos/metabolismo , Xenopus laevisRESUMEN
BACKGROUND: Positive allosteric modulators (PAMs) facilitate endogenous neurotransmission and/or enhance the efficacy of agonists without directly acting on the orthosteric binding sites. In this regard, selective α7 nicotinic acetylcholine receptor type II PAMs display antinociceptive activity in rodent chronic inflammatory and neuropathic pain models. This study investigates whether 3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2), a new putative α7-selective type II PAM, attenuates experimental inflammatory and neuropathic pains in mice. METHODS: We tested the activity of PAM-2 after intraperitoneal administration in 3 pain assays: the carrageenan-induced inflammatory pain, the complete Freund adjuvant-induced inflammatory pain, and the chronic constriction injury-induced neuropathic pain in mice. We also tested whether PAM-2 enhanced the effects of the selective α7 agonist choline in the mouse carrageenan test given intrathecally. Because the experience of pain has both sensory and affective dimensions, we also evaluated the effects of PAM-2 on acetic acid-induced aversion by using the conditioned place aversion test. RESULTS: We observed that systemic administration of PAM-2 significantly reversed mechanical allodynia and thermal hyperalgesia in inflammatory and neuropathic pain models in a dose- and time-dependent manner without motor impairment. In addition, by attenuating the paw edema in inflammatory models, PAM-2 showed antiinflammatory properties. The antinociceptive effect of PAM-2 was inhibited by the selective competitive antagonist methyllycaconitine, indicating that the effect is mediated by α7 nicotinic acetylcholine receptors. Furthermore, PAM-2 enhanced the antiallodynic and antiinflammatory effects of choline, a selective α7 agonist, in the mouse carrageenan test. PAM-2 was also effective in reducing acetic acid-induced aversion in the conditioned place aversion assay. CONCLUSIONS: These findings suggest that the administration of PAM-2, a new α7-selective type II PAM, reduces the neuropathic and inflammatory pain sensory and affective behaviors in the mouse. Thus, this drug may have therapeutic applications in the treatment and management of chronic pain.
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Acrilamidas/uso terapéutico , Analgésicos/uso terapéutico , Antiinflamatorios/uso terapéutico , Furanos/uso terapéutico , Dolor/tratamiento farmacológico , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Receptor Nicotínico de Acetilcolina alfa 7/fisiología , Acrilamidas/farmacología , Regulación Alostérica/efectos de los fármacos , Regulación Alostérica/fisiología , Analgésicos/farmacología , Animales , Antiinflamatorios/farmacología , Furanos/farmacología , Masculino , Ratones , Ratones Endogámicos ICR , Dolor/patologíaRESUMEN
Purpose: Sepsis is a clinical syndrome defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis is a highly heterogeneous syndrome with distinct phenotypes that impact immune function and response to infection. To develop targeted therapeutics, immunophenotyping is needed to identify distinct functional phenotypes of immune cells. In this study, we utilized our Organ-on-Chip assay to categorize sepsis patients into distinct phenotypes using patient data, neutrophil functional analysis, and proteomics. Methods: Following informed consent, neutrophils and plasma were isolated from sepsis patients in the Temple University Hospital ICU (n=45) and healthy control donors (n=7). Human lung microvascular endothelial cells (HLMVEC) were cultured in the Organ-on-Chip and treated with buffer or cytomix ((TNF/IL-1ß/IFNγ). Neutrophil adhesion and migration across HLMVEC in the Organ-on-Chip were used to categorize functional neutrophil phenotypes. Quantitative label-free global proteomics was performed on neutrophils to identify differentially expressed proteins. Plasma levels of sepsis biomarkers and neutrophil extracellular traps (NETs) were determined by ELISA. Results: We identified three functional phenotypes in critically ill ICU sepsis patients based on ex vivo neutrophil adhesion and migration patterns. The phenotypes were classified as: Hyperimmune characterized by enhanced neutrophil adhesion and migration, Hypoimmune that was unresponsive to stimulation, and Hybrid with increased adhesion but blunted migration. These functional phenotypes were associated with distinct proteomic signatures and differentiated sepsis patients by important clinical parameters related to disease severity. The Hyperimmune group demonstrated higher oxygen requirements, increased mechanical ventilation, and longer ICU length of stay compared to the Hypoimmune and Hybrid groups. Patients with the Hyperimmune neutrophil phenotype had significantly increased circulating neutrophils and elevated plasma levels NETs. Conclusion: Neutrophils and NETs play a critical role in vascular barrier dysfunction in sepsis and elevated NETs may be a key biomarker identifying the Hyperimmune group. Our results establish significant associations between specific neutrophil functional phenotypes and disease severity and identify important functional parameters in sepsis pathophysiology that may provide a new approach to classify sepsis patients for specific therapeutic interventions.
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Neutrófilos , Sepsis , Humanos , Neutrófilos/metabolismo , Células Endoteliales , Proteómica , Biomarcadores/metabolismo , Fenotipo , Gravedad del PacienteRESUMEN
We report a nanohybrid material obtained by non-covalent functionalization of multi-walled carbon nanotubes (MWCNTs) with the new ligand (((1E,1'E)-(naphthalene-2,3-diylbis(azaneylylidene))bis(methaneylylidenedene)) bis(4-hydroxy-3,1-phenylene))diboronic acid (SB-dBA), rationally designed to mimic some recognition properties of biomolecules like concanavalin A, for the development of electrochemical biosensors based on the use of glycobiomolecules as biorecognition element. We present, as a proof-of-concept, a hydrogen peroxide biosensor obtained by anchoring horseradish peroxidase (HRP) at a glassy carbon electrode (GCE) modified with the nanohybrid prepared by sonication of 2.0 mg mL-1 MWCNTs and 0.50 mg mL-1 SB-dBA in N,N-dimethyl formamide (DMF) for 30 min. The hydrogen peroxide biosensing was performed at -0.050 V in the presence of 5.0 × 10-4 M hydroquinone. The analytical characteristics of the resulting biosensor are the following: linear range between 0.175 µM and 6.12 µM, detection limit of 58 nM, and reproducibility of 2.0 % using the same nanohybrid (6 biosensors), and 9.0 % using three different nanohybrids. The sensor was successfully used to quantify hydrogen peroxide in enriched milk and human blood serum samples and in a commercial disinfector.
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Técnicas Biosensibles , Nanotubos de Carbono , Humanos , Nanotubos de Carbono/química , Ácidos Borónicos , Peróxido de Hidrógeno/química , Bases de Schiff , Reproducibilidad de los Resultados , Técnicas Biosensibles/métodos , Peroxidasa de Rábano Silvestre/química , Electrodos , Técnicas ElectroquímicasRESUMEN
In this article, three unsymmetrical 7-(diethylamino)quinolone chalcones with D-π-A-D and D-π-A-π-D type push-pull molecular arrangements were synthesized via a Claisen-Schmidt reaction. Using 7-(diethylamino)quinolone and vanillin as electron donor (D) moieties, these were linked together through the α,ß-unsaturated carbonyl system acting as a linker and an electron acceptor (A). The photophysical properties were studied, revealing significant Stokes shifts and strong solvatofluorochromism caused by the ICT and TICT behavior produced by the push-pull effect. Moreover, quenching caused by the population of the TICT state in THF-H2O mixtures was observed, and the emission in the solid state evidenced a red shift compared to the emission in solution. These findings were corroborated by density functional theory (DFT) calculations employing the wb97xd/6-311G(d,p) method. The cytotoxic activity of the synthesized compounds was assessed on BHK-21, PC3, and LNCaP cell lines, revealing moderate activity across all compounds. Notably, compound 5b exhibited the highest activity against LNCaP cells, with an LC50 value of 10.89 µM. Furthermore, the compounds were evaluated for their potential as imaging agents in living prostate cells. The results demonstrated their favorable cell permeability and strong emission at 488 nm, positioning them as promising candidates for cancer cell imaging applications.
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Some synthetic 1-azabenzanthrones (7H-dibenzo[de,h]quinolin-7-ones) are weakly to moderately cytotoxic, suggesting that they might also show antiparasitic activity. We have now tested a small collection of these compounds in vitro against a chloroquine-resistant Plasmodium falciparum strain, comparing their cytotoxicity against normal human fibroblasts. Our results indicate that 5-methoxy-1-azabenzanthrone and its 2,3-dihydro analogue have low micromolar antiplasmodial activities and showed more than 10-fold selectivity against the parasite, indicating that the dihydro compound, in particular, might serve as a lead compound for further development.
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Antimaláricos/síntesis química , Compuestos Aza/química , Benzo(a)Antracenos/química , Antimaláricos/química , Antimaláricos/toxicidad , Benzo(a)Antracenos/síntesis química , Benzo(a)Antracenos/toxicidad , Línea Celular , Supervivencia Celular/efectos de los fármacos , Cloroquina/farmacología , Resistencia a Medicamentos/efectos de los fármacos , Humanos , Plasmodium falciparum/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
The quinuclidine scaffold has been extensively used for the development of nicotinic acetylcholine receptor (nAChR) agonists, with hydrophobic substituents at position 3 of the quinuclidine framework providing selectivity for α7 nAChRs. In this study, six new ligands (4-9) containing a 3-(pyridin-3-yloxy)quinuclidine moiety (ether quinuclidine) were synthesized to gain a better understanding of the structural-functional properties of ether quinuclidines. To evaluate the pharmacological activity of these ligands, two-electrode voltage-clamp and single-channel recordings were performed. Only ligand 4 activated α7 nAChR. Ligands 5 and 7 had no effects on α7 nAChR, but ligands 6, 8, and 9 potentiated the currents evoked by ACh. Ligand 6 was the most potent and efficacious of the potentiating ligands, with an estimated EC50 for potentiation of 12.6 ± 3.32 µM and a maximal potentiation of EC20 ACh responses of 850 ± 120%. Ligand 6 increased the maximal ACh responses without changing the kinetics of the current responses. At the single-channel level, the potentiation exerted by ligand 6 was evidenced in the low micromolar concentration range by the appearance of prolonged bursts of channel openings. Furthermore, computational studies revealed the preference of ligand 6 for an intersubunit site in the transmembrane domain and highlighted some putative key interactions that explain the different profiles of the synthesized ligands. Notably, Met276 in the 15' position of the transmembrane domain 2 almost abolished the effects of ligand 6 when mutated to Leu. We conclude that ligand 6 is a novel type I positive allosteric modulator (PAM-I) of α7 nAChR.
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Éter , Receptores Nicotínicos , Ligandos , Regulación Alostérica , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Agonistas Nicotínicos/farmacología , Agonistas Nicotínicos/química , Éteres de Etila , Éteres , Receptores Nicotínicos/metabolismoRESUMEN
Covering: up to the end of 2011. This review covers classical and modern structural modifications of the alkaloid, the more recent (since 2007) syntheses of cytisine and analogues, and the pharmacology of these compounds, with emphasis on their interactions with nicotinic receptors. 89 references are cited.
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Alcaloides/farmacología , Productos Biológicos/farmacología , Receptores Nicotínicos/efectos de los fármacos , Alcaloides/síntesis química , Alcaloides/química , Animales , Azocinas/síntesis química , Azocinas/química , Azocinas/farmacología , Humanos , Estructura Molecular , Quinolizinas/síntesis química , Quinolizinas/química , Quinolizinas/farmacología , RatasRESUMEN
In this study thirty-three novel indole derivatives were designed and synthesized based on the structure of deformylflustrabromine B (1), a metabolite isolated from the marine bryozoan Flustra foliacea L. The syntheses were carried out using standard methodologies and in good yields. The molecules were tested for their affinities for the α4ß2(∗), α3ß4(∗), α7(∗) and (α1)(2)ß1γδ nicotinic acetylcholine receptor (nAChR) subtypes. Binding assays showed that, among these ligands, compound 7c exhibited the highest affinity with K(i)=136.1, 93.9 and 862.4nM for the α4ß2(∗), α3ß4(∗), and α7(∗) nAChRs subtypes, respectively. These results indicated that the indole core might be a useful scaffold for the development of new potent and selective nAChR ligands.
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Indoles/síntesis química , Indoles/farmacología , Compuestos de Amonio Cuaternario/síntesis química , Compuestos de Amonio Cuaternario/farmacología , Receptores Nicotínicos/metabolismo , Animales , Briozoos/química , Bovinos , Indoles/química , Ligandos , Estructura Molecular , Compuestos de Amonio Cuaternario/química , Ratas , Relación Estructura-ActividadRESUMEN
High levels of resistance to the spinosad-based insecticidal protein bait GF-120 have been detected in some populations of melon fly, Zeugodacus cucurbitae (Coquillett) (Diptera: Tephritidae), in Hawaii in 2017. To provide cucurbit farmers in Hawaii with alternative insecticides, we field-tested the effectiveness of Agri-Mek SC (a.i., abamectin), Mustang Maxx (a.i., zeta-cypermethrin), and Malathion 5EC (a.i., malathion), added to a protein bait spray (Nu-Lure Insect Bait). The insecticide and protein bait combinations were applied to the roosting plants of Z. cucurbitae around the perimeter of the cucurbit fields at one-week intervals. When individually tested, all three insecticides in combination with protein bait significantly reduced or suppressed the numbers of female flies caught in torula yeast traps. A two-week rotation of weekly applications of the three insecticides and GF-120 significantly reduced Z. cucurbitae numbers on a commercial zucchini farm on Maui. The percentage of marketable fruits harvested increased from 51% to 98% after implementing the insecticide rotation. Our findings will be used to provide cucurbit farmers with additional products to control Z. cucurbitae. The future focus will be on educating cucurbit farmers to use the insecticide rotation strategy to prevent or delay resistance development.
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During sepsis, defined as life-threatening organ dysfunction due to dysregulated host response to infection, systemic inflammation activates endothelial cells and initiates a multifaceted cascade of pro-inflammatory signaling events, resulting in increased permeability and excessive recruitment of leukocytes. Vascular endothelial cells share many common properties but have organ-specific phenotypes with unique structure and function. Thus, therapies directed against endothelial cell phenotypes are needed to address organ-specific endothelial cell dysfunction. Omics allow for the study of expressed genes, proteins and/or metabolites in biological systems and provide insight on temporal and spatial evolution of signals during normal and diseased conditions. Proteomics quantifies protein expression, identifies protein-protein interactions and can reveal mechanistic changes in endothelial cells that would not be possible to study via reductionist methods alone. In this review, we provide an overview of how sepsis pathophysiology impacts omics with a focus on proteomic analysis of mouse endothelial cells during sepsis/inflammation and its relationship with the more clinically relevant omics of human endothelial cells. We discuss how omics has been used to define septic endotype signatures in different populations with a focus on proteomic analysis in organ-specific microvascular endothelial cells during sepsis or septic-like inflammation. We believe that studies defining septic endotypes based on proteomic expression in endothelial cell phenotypes are urgently needed to complement omic profiling of whole blood and better define sepsis subphenotypes. Lastly, we provide a discussion of how in silico modeling can be used to leverage the large volume of omics data to map response pathways in sepsis.
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Scurvy is a preventable condition caused by a severe vitamin C deficiency for prolonged periods. Most literature cases describe children with neurobehavioral disorders or extreme dietary restrictions. Vitamin C deficiency may be a rare clinical presentation in the developed world; hence, it is often overlooked and can lead to extensive workups when the history alone could have raised suspicion for the diagnosis. We report a previously healthy 29-month-old boy initially admitted to the hospital due to loss of ambulation over a three-week course. The patient had no history of fever, and the inflammatory parameters were normal. Blood workup, plain radiographs, and magnetic resonance imaging (MRI) of the right lower extremity were unremarkable. The patient was discharged home with antibiotics and anti-inflammatory medication but arrived a week later with worsening lower extremity weakness leading to complete loss of ambulation. Vitamin C deficiency was confirmed to be below normal levels (<0.4mg/dL), and a diagnosis of scurvy was confirmed and treated with oral ascorbic acid. Subsequently, his mother brought him to the orthopedic clinic with a positive Gower sign. CPK levels were normal. Within a month of ascorbic acid replacement, all symptoms disappeared. Our patient was a picky eater, which emphasizes the importance of early dietary screening to discover the underlying cause of symptoms. Vitamin C deficiency should be part of the differential diagnosis in patients with unremarkable laboratory workup for infection and other diseases presenting with a Gower sign.