RESUMO
As the most abundant pollinator insect in crops, Apis mellifera is a sentinel species of the pollinator communities. In these ecosystems, honey bees of different ages and developmental stages are exposed to diverse agrochemicals. However, most toxicological studies analyse the immediate effects during exposure. Late effects during adulthood after early exposure to pollutants during larval development are poorly studied in bees. The herbicide glyphosate (GLY) is the most applied pesticide worldwide. GLY has been detected in honey and beebread from hives near treated crops. Alterations in growth, morphogenesis or organogenesis during pre-imaginal development could induce late adverse effects after the emergence. Previous studies have demonstrated that GLY alters honey bee development, immediately affecting survival, growth and metabolism, followed by late teratogenic effects. The present study aims to determine the late impact on the behaviour and physiology of adult bees after pre-imaginal exposure to GLY. For that, we reared brood in vitro or in the hive with sub-chronic exposure to the herbicide with the average detected concentration in hives. Then, all newly emerged bees were reared in an incubator until maturity and tested when they became nurse-aged bees. Three behavioural responses were assessed as markers of cognitive and physiological impairment. Our results show i) decreased sensitivity to sucrose regardless of the rearing procedure, ii) increased choice latency and locomotor alterations during chemotaxis and iii) impaired associative learning. These late toxicity signs could indicate adverse effects on task performance and colony efficiency.
Assuntos
Comportamento Animal , Glicina , Glifosato , Herbicidas , Larva , Animais , Abelhas/efeitos dos fármacos , Abelhas/fisiologia , Glicina/análogos & derivados , Glicina/toxicidade , Herbicidas/toxicidade , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Comportamento Animal/efeitos dos fármacosRESUMO
OBJECTIVE: To explore the association between serum levels and food intake of Vitamin D (VD) among healthy women in mid-pregnancy and preeclampsia. STUDY DESIGN: In a Brazilian multicentre cohort of healthy nulliparous pregnant women from five maternity centres we developed a nested case-control analysis comparing cases with and without preeclampsia. Women were enrolled and followed during prenatal care, including only singleton pregnancies, without any fetal malformations or previous chronic maternal disease. We matched 87 cases of preeclampsia to eligible controls randomly selected in a 1:1 ratio, by age and region. MAIN OUTCOME MEASURES: Blood samples from these were collected, and a 24-hour recall of food intake was obtained in mid-pregnancy, between 19 and 21 weeks. VD serum levels (25-hydroxyvitamin D) were measured by liquid chromatography-tandem mass spectrometry and were categorized as deficient, insufficient, and sufficient. The dietary intake of VD was estimated with the 24-hour diet recall applied at the same time and from supplementation. Maternal characteristics and VD levels were compared between cases and controls with OR and respective 95 %CI. Multivariate analysis using the Path method was used to assess relationships among VD, PE, BMI, skin colour/ethnicity, and diet. RESULTS: The maternal characteristics of both groups were similar, except for the higher occurrence of obesity among women with preeclampsia (OR 3.47, 95 %CI 1.48-8.65). Dietary intake of VD was similar in both groups, and most of the women in both groups consumed insufficient VD (82.2 vs 79.3 % in the groups with and without PE). CONCLUSIONS: Levels and dietary intake of VD were not associated with PE in this Brazilian sample of healthy pregnant women; however, BMI and skin colour/ethnicity were associated with PE.
Assuntos
Pré-Eclâmpsia , Segundo Trimestre da Gravidez , Vitamina D , Humanos , Feminino , Gravidez , Pré-Eclâmpsia/sangue , Adulto , Brasil/epidemiologia , Vitamina D/sangue , Vitamina D/análogos & derivados , Vitamina D/administração & dosagem , Estudos de Casos e Controles , Segundo Trimestre da Gravidez/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/epidemiologia , Adulto JovemRESUMO
There is evidence that astrocytes modulate synaptic transmission in the nucleus tractus solitarius (NTS) interacting with glutamatergic and purinergic mechanisms. Here, using in situ working heart-brainstem preparations, we evaluated the involvement of astrocyte and glutamatergic/purinergic neurotransmission in the processing of autonomic and respiratory pathways in the NTS of control and rats exposed to sustained hypoxia (SH). Baseline autonomic and respiratory activities and the responses to chemoreflex activation (KCN) were evaluated before and after microinjections of fluorocitrate (FCt, an astrocyte metabolic inhibitor), kynurenic acid, and pyridoxalphosphate-6-azophenyl-2',4'-disulfonate (PPADS) (nonselective antagonists of glutamatergic and purinergic receptors) into the rostral aspect of the caudal commissural NTS. FCt had no effects on the baseline parameters evaluated but reduced the bradycardic response to chemoreflex activation in SH rats. FCt combined with kynurenic acid and PPADS in control rats reduced the baseline duration of expiration, which was attenuated after SH. FCt produced a large increase in PN frequency discharge in control rats, which was reduced after SH, indicating a reduction in the astrocyte modulation after SH. The data show that 1) the bradycardic component of the peripheral chemoreflex is reduced in SH rats after astrocytes inhibition, 2) the inhibition of astrocytes in the presence of double antagonists in the NTS affects the modulation of baseline duration of expiration in control but not in SH rats, and 3) the autonomic and respiratory responses to chemoreflex activation are mediated by glutamatergic and purinergic receptors in the rostral aspect of the caudal commissural NTS.NEW & NOTEWORTHY Our findings indicate that the neurotransmission of autonomic and respiratory components of the peripheral chemoreflex in the nucleus tractus solitarius (NTS) is mediated by glutamatergic and purinergic mechanisms and reveal a selective involvement of NTS astrocytes in controlling the chemoreflex parasympathetic response in rats exposed to sustained hypoxia (SH) and the baseline duration of expiration mainly in control rats, indicating a selective role for astrocytes modulation in the NTS of control and SH rats.
Assuntos
Astrócitos , Ácido Glutâmico , Hipóxia , Receptores Purinérgicos , Núcleo Solitário , Transmissão Sináptica , Animais , Núcleo Solitário/metabolismo , Núcleo Solitário/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Hipóxia/fisiopatologia , Hipóxia/metabolismo , Masculino , Ácido Glutâmico/metabolismo , Receptores Purinérgicos/metabolismo , Ratos , Ratos Wistar , Ácido Cinurênico/farmacologia , Células Quimiorreceptoras/metabolismo , Células Quimiorreceptoras/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Fosfato de Piridoxal/análogos & derivados , Fosfato de Piridoxal/farmacologia , Citratos/farmacologia , Fatores de TempoRESUMO
The oxidation of proteins and, in particular, of tryptophan (Trp) residues leads to chemical modifications that can affect the structure and function. The oxidative damage to proteins in photochemical processes is relevant in the skin and eyes and is related to a series of pathologies triggered by exposure to electromagnetic radiation. In this work, we studied the photosensitized formation of N-formylkynurenine (NFKyn) from Trp in different reaction systems. We used two substrates: free Trp and a peptide of nine amino acid residues, with Trp being the only oxidizable residue. Two different photosensitizers were employed: Rose Bengal (RB) and pterin (Ptr). The former is a typical type II photosensitizer [acts by producing singlet oxygen (1O2)]. Ptr is the parent compound of oxidized or aromatic pterins, natural photosensitizers that accumulate in human skin under certain pathological conditions and act mainly through type I mechanisms (generation of radicals). Experimental data were collected in steady photolysis, and the irradiated solutions were analyzed by chromatography (HPLC). Results indicate that the reaction of Trp with 1O2 initiates the process leading to NFKyn, but different competitive pathways take place depending on the photosensitizer and the substrate. In Ptr-photosensitization, a type I mechanism is involved in secondary reactions accelerating the formation of NFKyn when free Trp is the substrate.
Assuntos
Cinurenina , Oxirredução , Fármacos Fotossensibilizantes , Rosa Bengala , Triptofano , Triptofano/química , Cinurenina/química , Cinurenina/análogos & derivados , Cinurenina/metabolismo , Fármacos Fotossensibilizantes/química , Rosa Bengala/química , Peptídeos/química , Oxigênio Singlete/química , Pterinas/química , Cromatografia Líquida de Alta Pressão , Fotólise , HumanosRESUMO
The study investigated guanidinoacetic acid (GAA) supplementation with varying dietary digestible arginine (Arg) and glycine+serine (Gly+Ser) concentrations in the starter phase, exploring respective carry-over effects on growth performance, blood chemistry, incidence of pectoral myopathies and proximate composition in broilers. A total of 2,800 one-day-old male broiler chicks were distributed in a central composite design with 2 factors and double experimental mesh, represented by supplementation or omission of 0.6 g per kg of GAA, with a central point represented by 107% of Arg and 147% of Gly+Ser, 4 factorial points (combinations of Arg/Gly+Ser concentrations: 96.4/132.5%; 117.6/132.5%; 96.4/161.5%, and 117.6/132.5%), and 4 axial points (combinations of axial points estimated for Arg and Gly+Ser, with the central points of 92/147%; 122/147%; 107/126.5, and 107/167.5%), totaling 18 treatments, 4 repetitions to factorial and axial points, 24 replicates to the central point, and 25 birds per pen. Feed conversion ratio (FCR) from d 1 to 10 had a linear response (P = 0.009) for the decreasing Arg content and a quadratic response (P = 0.047) for Gly+Ser concentrations. Broilers supplemented GAA had lower FCR compared with nonsupplemented groups from d 1 to 10 (P = 0.048) and d 1 to 42 (P = 0.026). Aspartate aminotransferase (AST) exhibited increasing and decreasing linear effects as a function of Arg (P = 0.008) and Gly+Ser (P = 0.020) concentrations, respectively. Guanidinoacetic acid decreased serum AST (P = 0.028). Guanidinoacetic acid reduced moderate + severe (P = 0.039) and mild (P = 0.015) Wooden Breast scores. The occurrence of normal White Striping increased (P = 0.002), while severe score was reduced (P = 0.029) with GAA supplementation. In conclusion, increased digestible Arg:Lys and 14% and 6% above the recommendations (107% and 147%), respectively, provided improved FCR during the starter phase. Dietary GAA supplementation (0.6 g per kg) improved FCR, reduced severity of breast myopathies and appears to have reduced muscle damage in broilers fed plant-based diets.
Assuntos
Ração Animal , Fenômenos Fisiológicos da Nutrição Animal , Arginina , Galinhas , Dieta , Suplementos Nutricionais , Glicina , Serina , Animais , Galinhas/fisiologia , Galinhas/crescimento & desenvolvimento , Glicina/análogos & derivados , Glicina/administração & dosagem , Glicina/farmacologia , Ração Animal/análise , Arginina/administração & dosagem , Arginina/farmacologia , Suplementos Nutricionais/análise , Dieta/veterinária , Masculino , Fenômenos Fisiológicos da Nutrição Animal/efeitos dos fármacos , Serina/administração & dosagem , Serina/farmacologia , Distribuição Aleatória , Músculos PeitoraisRESUMO
BACKGROUND: Neuropeptide Y (NPY) Y2 receptor (Y2) antagonist BIIE0246 can both inhibit and facilitate nociception. The authors hypothesized that Y2 function depends on inflammation or nerve injury status. METHODS: The authors implemented a battery of behavioral tests in mice of both sexes that received (1) no injury; (2) an incision model of postoperative pain; (3) a spared nerve injury model of neuropathic pain; and (4) a latent sensitization model of chronic postsurgical pain. In addition to Y2 gene expression assays, spinal Y2 G-protein coupling was studied with guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding assays. RESULTS: The authors report that intrathecal BIIE0246 increased mechanical and cold hypersensitivity, produced behavioral signs of spontaneous nociception and itch, and produced conditioned place aversion and preference in normal, uninjured mice. BIIE0246 did not change heat hypersensitivity or motor coordination. Conditional (sensory neuron-specific) Y2 deletion prevented BIIE0246-induced mechanical and cold hypersensitivity, nocifensive behaviors, and aversion. Both conditional deletion and pharmacologic blockade of Y2 reduced mechanical and thermal hypersensitivity after incision or nerve injury. SNI did not change the sensitivity of Y2 G-protein coupling with the Y2 agonist peptide YY (3-36) (PYY3-36), but increased the population of Y2 that effectively coupled G-proteins. Intrathecal PYY3-36 failed to reduce spared nerve injury- or incision-induced hypersensitivity in C57BL/6N mice. Incision did not change Npy2r gene expression in dorsal root ganglion. CONCLUSIONS: The authors conclude that Y2 at central terminals of primary afferent neurons provides tonic inhibition of mechanical and cold nociception and itch. This switches to the promotion of mechanical and thermal hyperalgesia in models of acute and chronic postsurgical and neuropathic pain, perhaps due to an increase in the population of Y2 that effectively couples to G-proteins. These results support the development of Y2 antagonists for the treatment of chronic postsurgical and neuropathic pain.
Assuntos
Hiperalgesia , Neuralgia , Nociceptividade , Dor Pós-Operatória , Prurido , Receptores de Neuropeptídeo Y , Células Receptoras Sensoriais , Animais , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Receptores de Neuropeptídeo Y/metabolismo , Prurido/metabolismo , Camundongos , Neuralgia/metabolismo , Masculino , Nociceptividade/efeitos dos fármacos , Nociceptividade/fisiologia , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Feminino , Dor Pós-Operatória/metabolismo , Hiperalgesia/metabolismo , Camundongos Endogâmicos C57BL , Arginina/análogos & derivados , BenzazepinasRESUMO
The crystallographic structure of the FolB enzyme from Mycobacterium tuberculosis (MtFolB), complexed with its inhibitor 8-mercaptoguanine (8-MG), was elucidated at a resolution of 1.95 Å. A novel series of S8-functionalized 8-MG derivatives were synthesised and evaluated as in vitro inhibitors of dihydroneopterin aldolase (DHNA, EC 4.1.2.25) activity of MtFolB. These compounds exhibited IC50 values in the submicromolar range. Evaluation of the activity for five compounds indicated their inhibition mode and inhibition constants. Molecular docking analyses were performed to determine the enzyme-inhibitor intermolecular interactions and ligand conformations upon complex formation. The inhibitory activities of all compounds against the M. tuberculosis H37Rv strain were evaluated. Compound 3e exhibited a minimum inhibitory concentration in the micromolar range. Finally, Compound 3e showed no apparent toxicity in both HepG2 and Vero cells. The findings presented herein will advance the quest for novel, specific inhibitors targeting MtFolB, an attractive molecular target for TB drug development.
Assuntos
Aldeído Liases , Antituberculosos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Antituberculosos/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Relação Estrutura-Atividade , Aldeído Liases/antagonistas & inibidores , Aldeído Liases/metabolismo , Aldeído Liases/química , Células Vero , Estrutura Molecular , Cristalografia por Raios X , Chlorocebus aethiops , Animais , Guanina/farmacologia , Guanina/química , Guanina/análogos & derivados , Guanina/síntese química , Simulação de Acoplamento Molecular , Células Hep G2 , Modelos MolecularesRESUMO
Women with deep infiltrating endometriosis (DIE) can benefit from the use of progestins. Our aim is to explore if levonorgestrel-releasing intrauterine system (LNG-IUS) non inferior to dienogest (DNG) in improving deep endometriosis women's quality of life (QoL). This randomized open-label clinical trial included forty women with DIE assessed using clinical history and physical examination, transvaginal ultrasonography and magnetic resonance of the pelvis without any previous surgical treatment, with two treatments arms. The two groups underwent a 3-month washout of hormonal treatments, and then received either DNG or LNG-IUS for 6 months. QoL was assessed prior to and 6 months after the intervention, using the SF36 and the EHP30. DNG and LNG-IUS showed an increase on all domains of the SF36 (p < .001). There was no difference between treatments on the improvement observed (p > .05 for all domains). DNG and LNG-IUS, also, showed improvement on all domains of EHP30 (p < .001), except "relationship with children" and "feelings about pregnancy." However, there was no statistical difference between treatments for all sections scores (p > .05). The treatment of deep endometriosis symptoms using either DNG or LNG-IUS in women with no prior surgical treatment is associated with improvement in QoL.Trial Registration Number: This trial is registered on "The Brazilian Registry of Clinical Trials (ReBECID: RBR-8fjx2jp)," that is part of Primary Registries in the WHO Registry Network, under the title: "Dienogest versus Levonorgestrel IUS on deep endometriosis patient´s QoL without surgery" on June 14, 2021; https://ensaiosclinicos.gov.br/rg/RBR-8fjx2jp.
Assuntos
Endometriose , Dispositivos Intrauterinos Medicados , Levanogestrel , Nandrolona , Qualidade de Vida , Humanos , Feminino , Endometriose/tratamento farmacológico , Endometriose/psicologia , Levanogestrel/uso terapêutico , Levanogestrel/administração & dosagem , Nandrolona/análogos & derivados , Nandrolona/uso terapêutico , Adulto , Resultado do TratamentoRESUMO
This study evaluated the use of the GnRH agonist hormone, deslorelin, to control the follicular population before initiating multiple ovulation and embryo transfer (MOET) treatment. Twenty-four cross-bred Santa Inês ewes, aged between 2 and 4 years, were randomly assigned to either a control group (n = 11) or a treated group (n = 13). All ewes received an intravaginal device containing 60 mg of medroxyprogesterone acetate on day 0, and a new device on day 7, which remained in place until day 14. Additionally, the ewes were administered 125 µg of cloprostenol on day 7. The superovulatory treatment involved administering 200 mg of pFSH, divided into eight decreasing doses at 12-h intervals starting on day 12. On day 14, 300 IU of eCG was administered. In the deslorelin group, three doses of 100 µg of deslorelin were administered starting on day 3 after the insertion of the vaginal device, with subsequent doses given at 72-h and 144-h intervals. Natural mating was performed 36 h after the removal of the progesterone implant using males with proven fertility. Embryo collection took place on the 6th day after mating, and the recovered structures were quantified and evaluated for quality and developmental stage. Transrectal ultrasonography was conducted on days 12, 16 and 21 to evaluate the ovaries, specifically to assess the ovarian follicular population and the presence of the corpus luteum. Ewes in the control group had higher embryo recovery rates (p < .01) compared to the treated group (5.2 ± 0.8 vs. 1.1 ± 0.8), with differences observed primarily in the number of morulae. The number of corpus luteum observed during the laparotomy on day 21 was significantly higher (p < .01) in the control group (10.44 vs. 4.5 corpus luteum per ewe). Yet, the treated group had a significantly higher number of follicles (p < .05) on the first day of pFSH application (5.5 vs. 3.0 follicles per ewe). In conclusion, although the inclusion of deslorelin in the superovulation protocol resulted in increased synchronization of oestrus and follicle number, it did not lead to an increase in the number of corpus luteum or harvested embryos.
Assuntos
Transferência Embrionária , Hormônio Foliculoestimulante , Superovulação , Pamoato de Triptorrelina , Animais , Feminino , Pamoato de Triptorrelina/análogos & derivados , Pamoato de Triptorrelina/farmacologia , Pamoato de Triptorrelina/administração & dosagem , Superovulação/efeitos dos fármacos , Hormônio Foliculoestimulante/farmacologia , Hormônio Foliculoestimulante/administração & dosagem , Transferência Embrionária/veterinária , Cloprostenol/farmacologia , Cloprostenol/administração & dosagem , Gravidez , Ovário/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Carneiro Doméstico , Ovinos/fisiologia , Hormônio Liberador de Gonadotropina/farmacologia , Hormônio Liberador de Gonadotropina/administração & dosagem , Acetato de Medroxiprogesterona/farmacologia , Acetato de Medroxiprogesterona/administração & dosagemRESUMO
The objective of this exploratory study was to assess the changes on lipidome and metabolome profiling of Longissimus lumborum bull muscle with different ultimate pH (pHu) and aging periods. The bull muscles classified as normal, intermediate, or high pHu were collected from a Brazilian commercial slaughterhouse, cut into steaks, individually vacuum-packaged, and aged for 3 days (3-d) or 21 days (21-d) at 2 °C. Muscle extracts were analyzed for the profiles of both lipids, by mass spectrometry (via direct flow-injection), and metabolites, by nuclear magnetic resonance, with downstream multivariate data analysis. As major results, pairwise comparisons identified C12:0 and C14:0 acylcarnitines as potential biomarkers of the intermediate pHu-muscle, which are related to lipid catabolism for alternative energy metabolism and indicate less protein breakage postmortem. Interestingly, the concentration of arginine at early postmortem aging (3-d) may influence the previously reported improved tenderness in normal and high pHu-muscles. Moreover, upregulation of fumarate, formate, and acetate with increased pHu muscle at 21-d aging indicate more intense tricarboxylic acid cycle, amino acid degradation, and pyruvate oxidation by reactive oxygen species, respectively. These three compounds (fumarate, formate, and acetate) discriminated statistically the muscle with high pHu at 21-d aging. The normal pHu-muscle showed higher concentrations of glycogenolysis and glycolysis metabolites, including glucose, mannose, and pyruvate. Hence, our results enhance knowledge of postmortem biochemical changes of beef within different pHu groups aged up to 21 days, which is essential to understand the mechanisms underpinning bull meat quality changes.
Assuntos
Metaboloma , Músculo Esquelético , Carne Vermelha , Animais , Bovinos , Carne Vermelha/análise , Músculo Esquelético/química , Músculo Esquelético/metabolismo , Concentração de Íons de Hidrogênio , Masculino , Lipidômica/métodos , Mudanças Depois da Morte , Brasil , Manipulação de Alimentos/métodos , Formiatos , Carnitina/análogos & derivados , Carnitina/metabolismo , Carnitina/análiseRESUMO
Background: HER-2 positive (+) breast cancer (BC) accounts for 20-25% of BC, it is more aggressive, and it has a lower survival rate. Since the approval of trastuzumab in 1998, other HER-2-targeted therapies such as pertuzumab and trastuzumab emtansine (TDM1) have been introduced, improving patient survival. However, cardiotoxicity is an adverse effect of these treatments. Objective: To estimate the incidence of cardiotoxicity with trastuzumab, trastuzumab/pertuzumab, and TDM1 in women with HER-2 + BC treated over a 6-year period at the Hospital de Clínicas and the Hospital Departamental de Soriano. Material and methods: Observational, descriptive, and retrospective study which included patients with HER-2 + BC treated with trastuzumab, trastuzumab/pertuzumab, or TDM1. Results: 81 patients were included, with a cardiotoxicity incidence of 23.4%. Cardiotoxicity was determined by a > 10% decrease in left ventricular ejection fraction (LVEF) (57.9%) and a LVEF < 50% evident during treatment (42.1%). Only 1 patient presented symptomatic heart failure. 63.1% of those who discontinued treatment due to cardiotoxicity managed to resume it. No relationship was evident between cardiovascular history or the administration regimen and the development of cardiotoxicity. Conclusion: The study showed a cardiotoxicity incidence similar to the international one. Most did not present cardiac toxicity, and if they did, it was asymptomatic and reversible.
Introducción: el cáncer de mama (CM) HER-2 positivo (+) representa el 20-25% de los CM, es más agresivo y tiene menor sobrevida. Desde la aprobación del trastuzumab en 1998, se han introducido otras terapias dirigidas al HER-2 como pertuzumab y trastuzumab emtansina (TDM1), con lo cual ha mejorado la supervivencia de las pacientes. Sin embargo, la cardiotoxicidad representa un efecto adverso de estos tratamientos. Objetivo: estimar la incidencia de cardiotoxicidad con trastuzumab, trastuzumab/pertuzumab y TDM1 en mujeres con CM HER-2 +, tratadas en un periodo de 6 años en el Hospital de Clínicas y el Hospital Departamental de Soriano. Material y métodos: estudio observacional, descriptivo y retrospectivo que incluyó pacientes con CM HER-2 +, tratadas con trastuzumab, trastuzumab/pertuzumab o TDM1. Resultados: se incluyeron 81 pacientes. La incidencia de cardiotoxicidad fue del 23.4%. La cardiotoxicidad se determinó por una disminución > 10% de la fracción de ejección del venticulo izquierdo (FEVI) (57.9%) y por una FEVI < 50%, evidenciada durante el tratamiento (42.1%). Únicamente una paciente presentó insuficiencia cardiaca sintomática. El 63.1% de quienes suspendieron el tratamiento por cardiotoxicidad logró reanudarlo. No se evidenció una relación entre los antecedentes cardiovasculares ni con el esquema de administración y el desarrollo de cardiotoxicidad. Conclusión: el estudio mostró una incidencia de cardiotoxicidad similar a la internacional. La mayoría no tuvo toxicidad cardiaca y si la hubo fue asintomática y reversible.
Assuntos
Ado-Trastuzumab Emtansina , Anticorpos Monoclonais Humanizados , Neoplasias da Mama , Cardiotoxicidade , Receptor ErbB-2 , Trastuzumab , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Estudos Retrospectivos , Cardiotoxicidade/etiologia , Pessoa de Meia-Idade , Receptor ErbB-2/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Idoso , Adulto , Ado-Trastuzumab Emtansina/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Incidência , Maitansina/análogos & derivados , Maitansina/efeitos adversosRESUMO
American Tegumentary Leishmaniasis (ATL) is a disease of high severity and incidence in Brazil, in addition to being a worldwide concern in public health. Leishmania amazonensis is one of the etiological agents of ATL, and the inefficiency of control measures, associated with the high toxicity of the treatment and the lack of effective immunoprophylactic strategies, makes the development of vaccines indispensable and imminent. In this light, the present study proposes to elaborate a chimeric protein (rChiP), based on the fusion of multiple epitopes of CD4+/CD8+ T cells, identified in the immunoproteome of the parasites L. amazonensis and L. braziliensis. The designed chimeric protein was tested in the L. amazonensis murine model of infection using the following formulations: 25 µg of the rChiP in saline (rChiP group) and 25 µg of the rChiP plus 25 µg of MPLA-PHAD® (rChiP+MPLA group). After completing immunization, CD4+ and CD8+ T cells, stimulated with SLa-Antigen or rChiP, showed an increased production of nitric oxide and intracytoplasmic pro-inflammatory cytokines, in addition to the generation of central and effector memory T cells. rChiP and rChiP+MPLA formulations were able to promote an effective protection against L. amazonensis infection determined by a reduction in the development of skin lesions and lower parasitic burden. Reduction in the development of skin lesions and lower parasitic burden in the vaccinated groups were associated with an increase of nitrite, CD4+/CD8+IFN-γ+TNF-α+ and CD4+/CD8+CD44highCD62Lhigh/low T cells, IgGTotal, IgG2a, and lower rates of IgG1 and CD4+/CD8+IL-10+. This data suggests that proposed formulations could be considered potential tools to prevent ATL.
Assuntos
Adjuvantes Imunológicos , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Epitopos de Linfócito T , Memória Imunológica , Vacinas contra Leishmaniose , Leishmaniose Cutânea , Animais , Leishmaniose Cutânea/prevenção & controle , Leishmaniose Cutânea/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD4-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Camundongos , Vacinas contra Leishmaniose/imunologia , Feminino , Adjuvantes Imunológicos/administração & dosagem , Camundongos Endogâmicos BALB C , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/genética , Leishmania braziliensis/imunologia , Lipídeo A/análogos & derivados , Lipídeo A/imunologia , Anticorpos Antiprotozoários/imunologia , Citocinas/metabolismo , Citocinas/imunologia , Modelos Animais de Doenças , Antígenos de Protozoários/imunologiaRESUMO
Many bacterial polysaccharide vaccines, including the typhoid Vi polysaccharide (ViPS) and tetravalent meningococcal polysaccharide conjugate (MCV4) vaccines, do not incorporate adjuvants and are not highly immunogenic, particularly in infants. I found that endotoxin, a TLR4 ligand in ViPS, contributes to the immunogenicity of typhoid vaccines. Because endotoxin is pyrogenic, and its levels are highly variable in vaccines, I developed monophosphoryl lipid A, a nontoxic TLR4 ligand-based adjuvant named Turbo. Admixing Turbo with ViPS and MCV4 vaccines improved their immunogenicity across all ages and eliminated booster requirement. To understand the characteristics of this adjuvanticity, I compared Turbo with alum. Unlike alum, which polarizes the response toward the IgG1 isotype, Turbo promoted Ab class switching to all IgG isotypes with affinity maturation; the magnitude of this IgG response is durable and accompanied by the presence of long-lived plasma cells in the mouse bone marrow. In striking contrast with the pathways employed by alum, Turbo adjuvanticity is independent of NLPR3, pyroptotic cell death effector Gasdermin D, and canonical and noncanonical inflammasome activation mediated by Caspase-1 and Caspase-11, respectively. Turbo adjuvanticity is primarily dependent on the MyD88 axis and is lost in mice deficient in costimulatory molecules CD86 and CD40, indicating that Turbo adjuvanticity includes activation of these pathways. Because Turbo formulations containing either monophosphoryl lipid A or TLR2 ligands, Pam2CysSerLys4, and Pam3CysSerLys4 help generate Ab response of all IgG isotypes, as an adjuvant Turbo can improve the immunogenicity of glycoconjugate vaccines against a wide range of bacterial pathogens whose elimination requires appropriate IgG isotypes.
Assuntos
Adjuvantes Imunológicos , Lipídeo A , Animais , Camundongos , Adjuvantes Imunológicos/administração & dosagem , Lipídeo A/análogos & derivados , Lipídeo A/imunologia , Polissacarídeos Bacterianos/imunologia , Imunoglobulina G/imunologia , Imunoglobulina G/sangue , Camundongos Endogâmicos C57BL , Adjuvantes de Vacinas , Vacinas Meningocócicas/imunologia , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/imunologia , Vacinas Tíficas-Paratíficas/imunologia , Vacinas Tíficas-Paratíficas/administração & dosagem , Anticorpos Antibacterianos/imunologia , Anticorpos Antibacterianos/sangue , Feminino , Ligantes , Glicoconjugados/imunologia , Humanos , Vacinas Conjugadas/imunologia , Compostos de Alúmen/administração & dosagem , Camundongos KnockoutRESUMO
AIMS: It is well established that intracellular cAMP contributes to the relaxation of vas deferens smooth muscle. In many tissues, intracellular cAMP is actively transported to the extracellular space, where it exerts regulatory functions, via its metabolite adenosine. These actions take place through the cAMP conversion to adenosine by ectoenzymes, a process called "extracellular cAMP-adenosine pathway". Herein, we investigated whether, in addition to ATP, extracellular cAMP might be an alternative source of adenosine, influencing the contraction of vas deferens smooth muscle. MAIN METHODS: The effects of cAMP, 8-Br-cAMP and adenosine were analyzed in the isometric contractions of rat vas deferens. cAMP efflux was analyzed by measuring extracellular cAMP levels after exposure of vas deferens segments to isoproterenol and forskolin in the presence or absence of MK-571, an inhibitor of MRP/ABCC transporters. KEY FINDINGS: While 8-Br-cAMP, a cell-permeable cAMP analog, induced relaxation of KCl-precontracted vas deferens, the non-permeant cAMP increased the KCl-induced contractile response, which was mimicked by adenosine, but prevented by inhibitors of ecto-5'-nucleotidase or A1 receptors. Our results also showed that isoproterenol and forskolin increases cAMP efflux via an MRP/ABCC transporter-dependent mechanism, since it is inhibited by MK-571. SIGNIFICANCE: Our data show that activation of ß-adrenoceptors and adenylyl cyclase increases cAMP efflux from vas deferens tissue, which modulates the vas deferens contractile response via activation of adenosine A1 receptors. Assuming that inhibition of vas deferens contractility has been proposed as a strategy for male contraception, the extracellular cAMP-adenosine pathway emerges as a potential pharmacological target that should be considered in studies of male fertility.
Assuntos
5'-Nucleotidase , AMP Cíclico , Contração Muscular , Ratos Wistar , Receptor A1 de Adenosina , Ducto Deferente , Masculino , Animais , Ducto Deferente/efeitos dos fármacos , Ducto Deferente/metabolismo , AMP Cíclico/metabolismo , 5'-Nucleotidase/metabolismo , Receptor A1 de Adenosina/metabolismo , Receptor A1 de Adenosina/efeitos dos fármacos , Ratos , Contração Muscular/efeitos dos fármacos , Adenosina/farmacologia , Adenosina/análogos & derivados , Adenosina/metabolismo , Isoproterenol/farmacologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Colforsina/farmacologiaRESUMO
Strain T-12T, an orange, Gram-stain-negative, non-motile, rod-shaped strain, was isolated in November 2013 from water samples collected from an Atlantic salmon (Salmo salar) fry culturing system at a fish farm in Chile. Phylogenetic analysis based on 16S rRNA sequences (1394 bp) revealed that strain T-12T belonged to the genus Flavobacterium, showing close relationships to Flavobacterium bernardetii F-372T (99.48â%) and Flavobacterium terrigena DS-20T (98.50â%). The genome size of strain T-12T was 3.28 Mb, with a G+C content of 31.1âmol%. Genome comparisons aligned strain T-12T with Flavobacterium bernardetii F-372T (GCA_011305415) and Flavobacterium terrigena DSM 17934T (GCA_900108955). The highest digital DNA-DNA hybridization (dDDH) values were 42.6â% with F. bernardetii F-372T (GCA_011305415) and 33.9â% with F. terrigena DSM 17934T (GCA_900108955). Pairwise average nucleotide identity (ANI) calculations were below the species cutoff, with the best results with F. bernardetii F-372T being: ANIb, 90.33â%; ANIm, 91.85â%; and TETRA, 0.997â%. These dDDH and ANI results confirm that strain T-12T represents a new species. The major fatty acids were iso-C15â:â0 and C15â:â1ω6Ñ. Detected polar lipids included phospholipids (n=2), aminophospholipid (n=1), aminolipid (n=1) and unidentified lipids (n=2). The predominant respiratory quinone was menaquinone MK7 (80â%) followed by MK-6 (20â%). Phenotypic, chemotaxonomic, and genomic data support the classification of strain T-12T (=CECT 30410T=RGM 3222T) as representing a novel species of Flavobacterium, for which the name Flavobacterium facile sp. nov. is proposed.
Assuntos
Técnicas de Tipagem Bacteriana , Composição de Bases , DNA Bacteriano , Ácidos Graxos , Flavobacterium , Hibridização de Ácido Nucleico , Filogenia , RNA Ribossômico 16S , Salmo salar , Análise de Sequência de DNA , Vitamina K 2 , Animais , Flavobacterium/genética , Flavobacterium/isolamento & purificação , Flavobacterium/classificação , RNA Ribossômico 16S/genética , Ácidos Graxos/análise , Salmo salar/microbiologia , DNA Bacteriano/genética , Chile , Vitamina K 2/análogos & derivados , Vitamina K 2/análise , Microbiologia da Água , Fosfolipídeos/análiseRESUMO
This review highlights the nutritional content, phytochemical compounds, and biological properties of three unconventional food plants consumed in the Amazon: ora-pro-nóbis (Pereskia aculeata Mill.), taioba (Xanthosoma sagittifolium), and vitória-régia (Victoria amazonica). These plants show significant nutritional, functional, and economic potential, which can enhance the intake of daily nutrients, energy, and bioactive compounds. Ora-pro-nóbis is a rich source of caftaric acid, quercetin, and isorhamnetin; taioba contains syringic acid, caffeic acid, and quercetin; and vitória-régia shows cinnamic acid, caffeic acid, and sinapic acid in its composition. These compounds confer antioxidant, anticancer, antimicrobial, anti-inflammatory, analgesic, and antiproliferative properties on these plants. These unconventional plants can be exploited by the food industry as food and supplements and therapeutic plants to develop valuable products for food, cosmetics, pharmaceutical, and medical applications.
Assuntos
Antioxidantes , Valor Nutritivo , Fenóis , Plantas Comestíveis , Plantas Comestíveis/química , Antioxidantes/farmacologia , Antioxidantes/análise , Fenóis/análise , Extratos Vegetais/farmacologia , Quercetina/farmacologia , Quercetina/análise , Quercetina/análogos & derivados , Ácidos Cumáricos/análise , Ácidos Cafeicos/farmacologia , Humanos , Cinamatos/análise , Cinamatos/farmacologia , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/farmacologia , Animais , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/farmacologia , Ácido Gálico/análogos & derivadosRESUMO
To analyze the mechanism of copper accumulation in the marine alga Ulva compressa, it was cultivated with 10 µM of copper, with 10 µM of copper and increasing concentrations of a sulfide donor (NaHS) for 0 to 7 days, and with 10 µM of copper and a concentration of the sulfide acceptor (hypotaurine) for 5 days. The level of intracellular copper was determined as well as the level of glutathione (GSH) and phytochelatins (PCs) and the expression of metallothioneins (UcMTs). The level of intracellular copper in the algae treated with copper increased at day 1, slightly increased until day 5 and remained unchanged until day 7. The level of copper in the algae cultivated with copper and 100 or 200 µM of NaHS continuously increased until day 7 and the copper level was higher in the algae cultivated with 200 µM of NaHS compared to 100 µM of NaHS. In contrast, the level of intracellular copper decreased in the algae treated with copper and hypotaurine. The level of intracellular copper did not correlate with the level of GSH or with the expression of UcMTs, and PCs were not detected in response to copper, or copper and NaHS. Algae treated with copper and with copper and 200 µM of NaHS for 5 days were visualized by TEM and the elemental composition of electrondense particles was analyzed by EDXS. The algae treated with copper showed electrondense particles containing copper and sulfur, but not nitrogen, and they were mainly located in the chloroplast, but also in the cytoplasm. The algae treated with copper and NaHS showed a higher level of electrondense particles containing copper and sulfur, but not nitrogen, and they were located in the chloroplast, and in the cytoplasm. Thus, copper is accumulated as copper sulfide insoluble particles, and not bound to GSH, PCs or UcMTs, in the marine alga U. compressa.
Assuntos
Cobre , Glutationa , Metalotioneína , Fitoquelatinas , Sulfetos , Ulva , Cobre/metabolismo , Ulva/metabolismo , Ulva/efeitos dos fármacos , Fitoquelatinas/metabolismo , Glutationa/metabolismo , Metalotioneína/metabolismo , Sulfetos/metabolismo , Taurina/análogos & derivadosRESUMO
Although the disease caused by chikungunya virus (CHIKV) is of great interest to public health organizations around the world, there are still no authorized antivirals for its treatment. Previously, dihalogenated anti-CHIKV compounds derived from L-tyrosine (dH-Y) were identified as being effective against in vitro infection by this virus, so the objective of this study was to determine the mechanisms of its antiviral action. Six dH-Y compounds (C1 to C6) dihalogenated with bromine or chlorine and modified in their amino groups were evaluated by different in vitro antiviral strategies and in silico tools. When the cells were exposed before infection, all compounds decreased the expression of viral proteins; only C4, C5 and C6 inhibited the genome; and C1, C2 and C3 inhibited infectious viral particles (IVPs). Furthermore, C1 and C3 reduce adhesion, while C2 and C3 reduce internalization, which could be related to the in silico interaction with the fusion peptide of the E1 viral protein. Only C3, C4, C5 and C6 inhibited IVPs when the cells were exposed after infection, and their effect occurred in late stages after viral translation and replication, such as assembly, and not during budding. In summary, the structural changes of these compounds determine their mechanism of action. Additionally, C3 was the only compound that inhibited CHIKV infection at different stages of the replicative cycle, making it a compound of interest for conversion as a potential drug.
Assuntos
Antivirais , Febre de Chikungunya , Vírus Chikungunya , Tirosina , Replicação Viral , Vírus Chikungunya/efeitos dos fármacos , Vírus Chikungunya/fisiologia , Tirosina/farmacologia , Tirosina/análogos & derivados , Tirosina/metabolismo , Tirosina/química , Antivirais/farmacologia , Antivirais/química , Febre de Chikungunya/tratamento farmacológico , Febre de Chikungunya/virologia , Animais , Replicação Viral/efeitos dos fármacos , Chlorocebus aethiops , Células Vero , Humanos , Internalização do Vírus/efeitos dos fármacos , Proteínas Virais/metabolismoRESUMO
The variation in light within the environment triggers morphophysiological changes in plants and can lead to distinct responses in sun-exposed or shaded plants to glyphosate. The response of Urochloa genotypes subjected to desiccation with 2160, 1622.4, 1080, 524.4, 273.6, and 0.0 g ha-1 of glyphosate was evaluated in full sun and shade conditions. Cayana grass, mulato II grass, and sabiá grass - hybrids recently launched on the market, in addition to palisade grass and congo grass were evaluated. Under full sun, we achieved control of congo grass using 1080 g ha-1 of glyphosate, while the other grasses required 2160 g ha-1. In the low-light environment, sabiá grass was effectively controlled with 524.4 g ha-1 of glyphosate, but the other grasses needed 273.6 g ha-1. In shading, compared to full sun, the savings with glyphosate were 75 and 76% for the control of congo grass and sabiá grass, respectively, and 87% for palisade grass, mulato II grass and cayana grass. Increasing glyphosate doses leads to a decline in the quantum efficiency of photosystem II and in the electron transport rate, especially in the shade. Urochloa genotypes are more sensitive to glyphosate in the shade, which must be considered when determining the herbicide dose.
Assuntos
Glicina , Glifosato , Herbicidas , Poaceae , Glicina/análogos & derivados , Glicina/farmacologia , Herbicidas/farmacologia , Poaceae/efeitos dos fármacos , Poaceae/efeitos da radiação , Poaceae/genética , Poaceae/metabolismo , Luz , Luz SolarRESUMO
Uncontrolled use of pesticides has caused a dramatic reduction in the number of pollinators, including bees. Studies on the effects of pesticides on bees have reported effects on both metabolic and neurological levels under chronic exposure. In this study, variations in the differential expression of head and thorax-abdomen proteins in Africanized A. mellifera bees treated acutely with sublethal doses of glyphosate and imidacloprid were studied using a proteomic approach. A total of 92 proteins were detected, 49 of which were differentially expressed compared to those in the control group (47 downregulated and 2 upregulated). Protein interaction networks with differential protein expression ratios suggested that acute exposure of A. mellifera to sublethal doses of glyphosate could cause head damage, which is mainly associated with behavior and metabolism. Simultaneously, imidacloprid can cause damage associated with metabolism as well as, neuronal damage, cellular stress, and impairment of the detoxification system. Regarding the thorax-abdomen fractions, glyphosate could lead to cytoskeleton reorganization and a reduction in defense mechanisms, whereas imidacloprid could affect the coordination and impairment of the oxidative stress response.