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1.
Mol Biol (Mosk) ; 53(4): 531-540, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31397430

RESUMO

The phenomenon of bacterial persistence, also known as non-inherited antibiotic tolerance in a part of bacterial populations, was described more than 70 years ago. This type of tolerance contributes to the chronization of infectious diseases, including tuberculosis. Currently, the emergence of persistent cells in bacterial populations is associated with the functioning of some stress-induced molecular triggers, including toxin-antitoxin systems. In the presented review, genetic and metabolic peculiarities of persistent cells are considered and the mechanisms of their occurrence are discussed. The hypothesis of the origin of persister cells based on bistability, arising due to the non-linear properties of a coupled transcription-translation system, was proposed. Within this hypothesis, the phenomenon of the bacterial persistence of modern cells is considered as a result of the genetic fixation of the phenotypic multiplicity that emerged in primitive cells in the process of neutrally coupled co-evolution (genetic drift of multiple neutrally coupled mutations). Our hypothesis explains the properties of persister cells, as well as their origin and "ineradicable" nature.


Assuntos
Antibacterianos/farmacologia , Archaea/efeitos dos fármacos , Bactérias/efeitos dos fármacos , Tolerância a Medicamentos , Archaea/citologia , Bactérias/citologia , Sistemas Toxina-Antitoxina
2.
Arch Endocrinol Metab ; 63(4): 376-384, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365624

RESUMO

OBJECTIVE: To test the influence of oral fructose and glucose dose-response solutions in blood glucose (BG), glucagon, triglycerides, uricaemia, and malondialdehyde in postprandial states in type 1 diabetes mellitus (T1DM) patients. SUBJECTS AND METHODS: The study had a simple-blind, randomized, two-way crossover design in which T1DM patients were selected to receive fructose and glucose solutions (75g of sugars dissolved in 200 mL of mineral-water) in two separate study days, with 2-7 weeks washout period. In each day, blood samples were drawn after 8h fasting and at 180 min postprandial to obtain glucose, glucagon, triglycerides, uric acid, lactate, and malondialdehyde levels. RESULTS: Sixteen T1DM patients (seven men) were evaluated, with a mean age of 25.19 ± 8.8 years, a mean duration of disease of 14.88 ± 4.73 years, and glycated hemoglobin of 8.13 ± 1.84%. Fructose resulted in lower postprandial BG levels than glucose (4.4 ± 5.5 mmol/L; and 12.9 ± 4.1 mmol/L, respectively; p < 0.01). Uric acid levels increased after fructose (26.1 ± 49.9 µmol/L; p < 0.01) and reduced after glucose (-13.6 ± 9.5 µmol/L; p < 0.01). The malondialdehyde increased after fructose (1.4 ± 1.6 µmol/L; p < 0.01) and did not change after glucose solution (-0.2 ± 1.6 µmol/L; p = 0.40). Other variables did not change. CONCLUSIONS: Fructose and glucose had similar sweetness, flavor and aftertaste characteristics and did not change triglycerides, lactate or glucagon levels. Although fructose resulted in lower postprandial BG than glucose, it increased uric acid and malondialdehyde levels in T1DM patients. Therefore it should be used with caution. ClinicalTrials.gov registration: NCT01713023.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Frutose/metabolismo , Glucose/metabolismo , Período Pós-Prandial/efeitos dos fármacos , Edulcorantes/metabolismo , Adolescente , Adulto , Glicemia/análise , Glicemia/efeitos dos fármacos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Tolerância a Medicamentos , Feminino , Frutose/farmacologia , Glucose/farmacologia , Humanos , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Projetos Piloto , Método Simples-Cego , Soluções/farmacologia , Edulcorantes/farmacologia , Paladar/efeitos dos fármacos , Triglicerídeos/sangue , Ácido Úrico/sangue , Adulto Jovem
3.
JAMA ; 322(4): 315-325, 2019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31334793

RESUMO

Importance: Patients with active rheumatoid arthritis (RA) despite treatment with biologic disease-modifying antirheumatic drug (bDMARD) therapy need treatment options. Objective: To evaluate the effects of filgotinib vs placebo on the signs and symptoms of RA in a treatment-refractory population. Design, Setting, and Participants: A 24-week, randomized, placebo-controlled, multinational phase 3 trial conducted from July 2016 to June 2018 at 114 sites internationally, randomizing 449 adult patients (and treating 448) with moderately to severely active RA and inadequate response/intolerance to 1 or more prior bDMARDs. Interventions: Filgotinib, 200 mg (n = 148); filgotinib, 100 mg (n = 153); or placebo (n = 148) once daily; patients continued concomitant stable conventional synthetic DMARDs (csDMARDs). Main Outcomes and Measures: The primary end point was the proportion of patients who achieved 20% improvement in the American College of Rheumatology criteria (ACR20) at week 12. Secondary outcomes included week 12 assessments of low disease activity (disease activity score in 28 joints-C-reactive protein [DAS28-CRP] ≤3.2) and change in Health Assessment Questionnaire-Disability Index, 36-Item Short-Form Health Survey Physical Component, and Functional Assessment of Chronic Illness Therapy-Fatigue scores, as well as week 24 assessment of remission (DAS28-CRP <2.6) and adverse events. Results: Among 448 patients who were treated (mean [SD] age, 56 [12] years; 360 women [80.4%]; mean [SD] DAS28-CRP score, 5.9 [0.96]; 105 [23.4%] with ≥3 prior bDMARDs), 381 (85%) completed the study. At week 12, more patients receiving filgotinib, 200 mg (66.0%) or 100 mg (57.5%), achieved ACR20 response (placebo, 31.1%; difference vs placebo: 34.9% [95% CI, 23.5%-46.3%] and 26.4% [95% CI, 15.0%-37.9%], respectively; both P < .001), including among patients with prior exposure to 3 or more bDMARDs (70.3%, 58.8%, and 17.6%, respectively; difference vs placebo: 52.6% [95% CI, 30.3%-75.0%] for filgotinib, 200 mg, and 41.2% [95% CI, 17.3%-65.0%] for filgotinib, 100 mg; both P < .001). The most common adverse events were nasopharyngitis (10.2%) for filgotinib, 200 mg; headache, nasopharyngitis, and upper respiratory infection (5.9% each) for filgotinib, 100 mg; and RA (6.1%) for placebo. Four uncomplicated herpes zoster cases and 1 retinal vein occlusion were reported with filgotinib; there were no opportunistic infections, active tuberculosis, malignancies, gastrointestinal perforations, or deaths. Conclusions and Relevance: Among patients with active RA who had an inadequate response or intolerance to 1 or more bDMARDs, filgotinib, 100 mg daily or 200 mg daily, compared with placebo resulted in a significantly greater proportion achieving a clinical response at week 12. However, further research is needed to assess longer-term efficacy and safety. Trial Registration: ClinicalTrials.gov Identifier: NCT02873936.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Janus Quinase 1/antagonistas & inibidores , Piridinas/uso terapêutico , Triazóis/uso terapêutico , Adulto , Idoso , Antirreumáticos/efeitos adversos , Biomarcadores/sangue , Proteína C-Reativa/análise , Relação Dose-Resposta a Droga , Método Duplo-Cego , Tolerância a Medicamentos , Feminino , Testes Hematológicos , Humanos , Infecção/etiologia , Masculino , Pessoa de Meia-Idade , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Indução de Remissão , Índice de Gravidade de Doença , Triazóis/administração & dosagem , Triazóis/efeitos adversos
4.
Br J Anaesth ; 123(2): e226-e238, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31253357

RESUMO

BACKGROUND: The long-term use of opioid analgesics is limited by the development of unwanted side-effects, such as tolerance. The molecular mechanisms of morphine anti-nociceptive tolerance are still unclear. The mitochondrial calcium uniporter (MCU) is involved in painful hyperalgesia, but the role of MCU in morphine tolerance has not been uncharacterised. METHODS: Rats received intrathecal injection of morphine for 7 days to induce morphine tolerance. The mechanical withdrawal threshold was measured using von Frey filaments, and thermal latency using the hotplate test. The effects of an MCU inhibitor, antisense oligodeoxynucleotide against cyclic adenosine monophosphate response element (CRE)-binding protein (CREB) or cytoplasmic polyadenylation element-binding protein 1 (CPEB1) in morphine tolerance were examined. RESULTS: Spinal morphine tolerance was associated with an increased expression of neuronal MCU, phospho-CREB (pCREB), and CPEB1 in the spinal cord dorsal horn. MCU inhibition increased the mechanical threshold and thermal latency, and reduced the accumulation of mitochondrial calcium in morphine tolerance. Intrathecal antisense oligodeoxynucleotide against CREB or CPEB1 restored the anti-nociceptive effects of morphine compared with mismatch oligodeoxynucleotide in von Frey test and hotplate test. Chromatin immunoprecipitation with quantitative PCR assay showed that CREB knockdown reduced the interaction of pCREB with the ccdc109a gene (encoding MCU expression) promoter and decreased the MCU mRNA transcription. RNA immunoprecipitation assay suggested that CPEB1 binds to the MCU mRNA 3' untranslated region. CPEB1 knockdown decreased the expression of MCU protein. CONCLUSIONS: These findings suggest that spinal MCU is regulated by pCREB and CPEB1 in morphine tolerance, and that inhibition of MCU, pCREB, or CPEB1 may be useful in preventing the development of opioid tolerance.


Assuntos
Proteína de Ligação a CREB/genética , Canais de Cálcio/metabolismo , Tolerância a Medicamentos/genética , Morfina/farmacologia , Proteínas de Ligação a RNA/genética , Corno Dorsal da Medula Espinal/metabolismo , Analgésicos Opioides/farmacologia , Animais , Masculino , Modelos Animais , Reação em Cadeia da Polimerase , Ratos , Ratos Sprague-Dawley
5.
Environ Sci Pollut Res Int ; 26(23): 23788-23797, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31209746

RESUMO

Lead (Pb) is known for its low mobility and persistence in soils. The main aim of the present study was to explore potential of different fungal strains to promote phytoextraction of Pb-contaminated soils. Five non-pathogenic fungal strains (Trichoderma harzianum, Penicillium simplicissimum, Aspergillus flavus, Aspergillus niger, and Mucor spp.) were tested for their ability to modify soil properties (pH and organic matter) and to increase Pb phytoavailability at varying concentrations. Lead tolerance of fungal strains followed the decreasing order as A. niger > T. harzianum > A. flavus > Mucor sp. > P. simplicissimum. Lead solubility induced by A. flavus and Mucor spp. was increased by 1.6- and 1.8-fold, respectively, as compared to the control soil (Pb added, without fungi). A. flavus and Mucor spp. lowered the soil pH by - 0.14 and - 0.13 units, in soils spiked with 2000 mg Pb kg-1. The maximum increase in the percentage of organic matter (OM) recorded was 1.7-fold for A. flavus at 500 mg Pb kg-1 soil. Plant growth-promoting assays confirmed the beneficial role of these fungal strains. Significantly high production of IAA (249 µg mL-1) and siderophores (61%) was observed with A. niger, and phosphate solubilization with P. simplicissimum (58 µg mL-1). Based on the results in Pb-contaminated soils, Pelargonium hortorum L. inoculated with Mucor spp. showed the potential to enhance phytoextraction of Pb by promoting Pb phytoavailability in soil and improving plant biomass production through plant growth-promoting activities.


Assuntos
Biodegradação Ambiental , Chumbo/metabolismo , Microbiologia do Solo , Poluentes do Solo/metabolismo , Adaptação Fisiológica/fisiologia , Aspergillus , Biomassa , Tolerância a Medicamentos , Fungos/metabolismo , Chumbo/análise , Desenvolvimento Vegetal , Solo/química , Poluentes do Solo/análise , Trichoderma
6.
Environ Pollut ; 252(Pt B): 941-949, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31252132

RESUMO

The accumulation of bound and conjugated polyamines (PAs) is an important protective trait in plants under adverse environmental conditions. However, their role in plant responses to aluminum (Al) stress remains largely unknown. In this study, we showed that Al treatment increased bound putrescine (Put) levels in the wheat root tips of Al-tolerant Xi Aimai-1, with little effect on its bound spermidine and conjugated PAs or that of Al-sensitive Yangmai-5. Terminating bound Put increments with a synthesis inhibitor (Phenanthroline, o-phen) exacerbated Al-induced root inhibition and callose production. However, it had no significant effect on Al uptake or distribution under Al stress. Instead, Al-induced reactive oxygen species (ROS) production and thus, oxidative damage, was greatly exacerbated by o-phen in the roots of Xi Aimai-1. Application of o-phen barely affected the two ROS generating enzymes (plasma membrane NADPH oxidase and cell wall-bound polyamine oxidase) in wheat roots. However, exogenous o-phen significantly reduced antioxidant enzyme (superoxide dismutase, ascorbate peroxidase, and catalase) activity, which positively correlated with the level of bound Put in Xi Aimai-1. These results clearly suggest that bound Put accumulation works to protect against Al-induced oxidative damage, possibly by maintaining antioxidant capacity in wheat.


Assuntos
Alumínio/toxicidade , Antioxidantes/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Putrescina/metabolismo , Poluentes do Solo/toxicidade , Triticum , Tolerância a Medicamentos , Oxirredução , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/enzimologia , Triticum/efeitos dos fármacos , Triticum/enzimologia
7.
Environ Sci Pollut Res Int ; 26(24): 24445-24461, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31228071

RESUMO

The study of the soil microbial community represents an important step in better understanding the environmental context. Therefore, biological characterisation and physicochemical integration are keys when defining contaminated sites. Fungi play a fundamental role in the soil, by providing and supporting ecological services for ecosystems and human wellbeing. In this research, 52 soil fungal taxa were isolated from in situ pilot reactors installed to a contaminated site in Czech Republic with a high concentration of hexachlorocyclohexane (HCH). Among the identified isolates, 12 strains were selected to evaluate their tolerance to different isomers of HCH by using specific indices (Rt:Rc; T.I.) and to test their potential in xenobiotic biotransformation. Most of the selected taxa was not significantly affected by exposure to HCH, underlining the elevated tolerance of all the tested fungal taxa, and different metabolic intermediates of HCH dechlorination were observed. The oxidative stress responses to HCH for two selected species, Penicillium simplicissimum and Trichoderma harzianum, were investigated in order to explore their toxic responses and to evaluate their potential functioning in bioremediation of contaminated environments. This research suggests that the isolated fungal species may provide opportunities for new eco-friendly, integrated and cost-effective solutions for environmental management and remediation, considering their efficient adaptation to stressful conditions.


Assuntos
Biotransformação , Fungos/metabolismo , Hexaclorocicloexano/metabolismo , Microbiologia do Solo , Poluentes do Solo/metabolismo , Biodegradação Ambiental , República Tcheca , Tolerância a Medicamentos , Ecossistema , Hexaclorocicloexano/análise , Isomerismo , Estresse Oxidativo , Penicillium/metabolismo , Solo , Poluentes do Solo/análise , Trichoderma/metabolismo
8.
Ecotoxicol Environ Saf ; 180: 333-347, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31102841

RESUMO

Arsenic (As) recognized as a group I human carcinogen additionally poses a threat to plants which limit growth, metabolic activity, and productivity. Melatonin (MEL) is a naturally occurring compound in plants that have been recognized to mediate numerous morphological, physiological and molecular processes. Conversely, the role of MEL in inducing As-tolerance remains inexpressible and the plausible mechanisms in inducing As tolerance have remained largely unknown. The present investigation was designed to understand the protective role of MEL concentrations in rosemary herbs cultivated under As contamination. Arsenic evoked a deleterious decline on herb productivity, photosynthetic pigment, ion concentration, water status, ascorbic acid, essential oil (EO) yield and induced malformation of the chloroplast. Alternatively, increased organic osmolytes, oxidative impairment criteria, additionally antioxidant enzymes, phenol, flavonoid, anthocyanin, and EO%. Exogenous application of MEL with or without As, considerably increased growth, photosynthetic pigment, ion concentration, organic osmolytes as well as EO yield regarding polluted or non-polluted treatment respectively. Moreover, MEL treatment stabilized the cell membrane integrity, suppressed oxidative impairment criteria, and enhanced antioxidant capacity, additionally upregulation antioxidant enzymes. Plant treated with As showed a significant increase in As contamination and a bioconcentration factor in both root and shoot system. MEL supplementation under normal or As concentration, reduced As accumulation and bioconcentration factors, in either shoot or root systems. Additionally As decrease transfer factor, however, supplementation of MEL further decreased it. Application of 50 µM MEL might help the herbs to withstand As stress by strengthening their antioxidant machinery and osmoregulation capacity.


Assuntos
Antioxidantes/metabolismo , Arsênico/toxicidade , Cloroplastos/ultraestrutura , Melatonina/farmacologia , Rosmarinus/efeitos dos fármacos , Poluentes do Solo/toxicidade , Arsênico/metabolismo , Tolerância a Medicamentos , Estresse Oxidativo/efeitos dos fármacos , Fotossíntese/efeitos dos fármacos , Rosmarinus/metabolismo , Poluentes do Solo/metabolismo
9.
World J Microbiol Biotechnol ; 35(5): 77, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31069553

RESUMO

Ethylene is a volatile alkene which is used in large commercial scale as a precursor in plastic industry, and is currently derived from petroleum refinement. As an alternative production strategy, photoautotrophic cyanobacteria Synechocystis sp. PCC 6803 and Synechococcus elongatus PCC 7942 have been previously evaluated as potential biotechnological hosts for producing ethylene directly from CO2, by the over-expression of ethylene forming enzyme (efe) from Pseudomonas syringae. This work addresses various open questions related to the use of Synechococcus as the engineering target, and demonstrates long-term ethylene production at rates reaching 140 µL L-1 h-1 OD750-1 without loss of host vitality or capacity to produce ethylene. The results imply that the genetic instability observed earlier may be associated with the expression strategies, rather than efe over-expression, ethylene toxicity or the depletion of 2-oxoglutarate-derived cellular precursors in Synechococcus. In context with literature, this study underlines the critical differences in expression system design in the alternative hosts, and confirms Synechococcus as a suitable parallel host for further engineering.


Assuntos
Etilenos/biossíntese , Engenharia Metabólica/métodos , Fotossíntese/fisiologia , Synechococcus/genética , Synechococcus/metabolismo , Biotecnologia , Dióxido de Carbono/metabolismo , Clonagem Molecular , Tolerância a Medicamentos , Escherichia coli/genética , Etilenos/toxicidade , Regulação Bacteriana da Expressão Gênica , Genes Bacterianos/genética , Instabilidade Genômica , Ácidos Cetoglutáricos/metabolismo , Liases/genética , Liases/metabolismo , Pseudomonas syringae/genética , Pseudomonas syringae/metabolismo , Synechococcus/efeitos dos fármacos , Synechococcus/crescimento & desenvolvimento , Transformação Genética
10.
Ecotoxicol Environ Saf ; 180: 491-500, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31121556

RESUMO

Ammonia, one of the major limiting environment factors in aquaculture, may pose a threat to the shrimp growth, reproduction and survival. In this study, to understand molecular differences of transcriptomic and metabolomic responses and investigate the tolerance mechanisms underlying ammonia stress in Litopenaeus vannamei, ammonia-tolerant family (LV-AT) and ammonia-sensitive family (LV-AS) of these two extreme families were exposed to high-concentration (NH4Cl, 46 mg/L) ammonia for 24 h. The comparative transcriptome analysis between ammonia-treated and control (LV-C) groups revealed involvement of immune defense, cytoskeleton remodeling, antioxidative system and metabolic pathway in ammonia-stress response of L. vannamei. Likewise, metabolomics analysis showed that ammonia exposure could disturb amino acid metabolism, nucleotide metabolism and lipid metabolism, with metabolism related-genes changed according to RNA-seq analysis. The comparison of metabolite and transcript profiles between LV-AT and LV-AS indicated that LV-AT used the enhanced glycolysis and tricarboxylic acid (TCA) cycle strategies for energy supply and ammonia excretion to adapt high-concentration ammonia. Furthermore, some of genes involved in the detoxification and ammonia excretion were highly expressed in LV-AT. We speculate that the higher ability of ammonia excretion and detoxification and the accelerated energy metabolism for energy supplies might be the adaptive strategies for LV-AT relative to LV-AS after ammonia stress. Collectively, the combination of transcriptomics and metabolomics results will greatly contribute to incrementally understand the stress responses on ammonia exposure to L. vannamei and supply molecular level support for evaluating the environmental effects of ammonia on aquatic organisms. The results further constitute new sights on the potential molecular mechanisms of ammonia adaptive strategies in shrimps at the transcriptomics and metabolomics levels.


Assuntos
Amônia/toxicidade , Metabolismo Energético/efeitos dos fármacos , Penaeidae/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Tolerância a Medicamentos , Perfilação da Expressão Gênica , Metabolômica , Penaeidae/genética , Penaeidae/metabolismo
11.
World J Microbiol Biotechnol ; 35(6): 81, 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31134389

RESUMO

TiO2 nanoparticles (TiO2NPs) is one of the most widely used nanomaterials. Arbuscular mycorrhizal fungi (AMF) are an important and widely distributed group of soil microorganisms, which promote the absorption of nutrients by host plants and increase their tolerance to contaminants. However, the effects and mechanisms of AMF on plant TiO2NPs tolerance in wetland habitats are not clear. In this experiment, under the conditions of three soil moisture contents (drought 50%, normal 70% and flooding 100%) and four TiO2NPs concentrations (0, 100, 200 and 500 mg kg-1), the effects of Funneliformis mosseae on the growth, antioxidant enzyme activities, osmotic substances and the absorption and accumulation of Ti in the Phragmites australis (reed) seedlings were studied. The results showed that the inoculation of F. mosseae under three moisture content conditions significantly increased the plant nutrition and root activities of reeds. Compared with the non-inoculated control, inoculation with F. mosseae increased the activities of antioxidant enzymes, the contents of chlorophyll, proline, soluble protein, and free amino acids, and significantly reduced the contents of malondialdehyde (MDA) and reactive oxygen species (ROS) of leaves. The accumulating ability of inoculated reeds to Ti was significantly higher than that of non-inoculated controls (P < 0.05), and inoculation of F. mosseae changed the distribution of Ti in reeds, increased the accumulation of Ti in roots. It's confirmed that inoculation of F. mosseae under three water conditions could improve the plant growth and nutrition, the activities of antioxidant enzymes, and enhance the reeds tolerance to TiO2NPs in this study.


Assuntos
Glomeromycota/fisiologia , Nanopartículas/toxicidade , Poaceae/efeitos dos fármacos , Poaceae/microbiologia , Plântula/crescimento & desenvolvimento , Estresse Fisiológico , Titânio/toxicidade , Água/metabolismo , Aminoácidos/metabolismo , Antioxidantes/metabolismo , Clorofila/metabolismo , Secas , Tolerância a Medicamentos , Malondialdeído/metabolismo , Osmose , Desenvolvimento Vegetal , Folhas de Planta/metabolismo , Proteínas de Plantas/metabolismo , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/metabolismo , Raízes de Plantas/microbiologia , Poaceae/crescimento & desenvolvimento , Prolina/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Plântula/efeitos dos fármacos , Plântula/microbiologia , Microbiologia do Solo , Áreas Alagadas
12.
Life Sci ; 229: 251-260, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31112711

RESUMO

AIMS: Cardiovascular diseases may originate from suboptimal intrauterine environments. We aimed to examine the effects of prenatal androgen exposure (PAE) on heart basal hemodynamic parameters and tolerance to ischemia/reperfusion (I/R) injury, in PAE adult females and males. MAIN METHODS: Pregnant Wistar rats in the experimental group (n = 8) received 5 mg of testosterone (s.c. injection) on the 20th day of pregnancy, while controls received solvent. The hearts of adult female and male offspring were isolated and perfused in a Langendorff apparatus, values of left ventricular systolic pressure(LVSP), left ventricular developed pressure(LVDP), rate pressure product(RPP) and peak rates of positive and negative changes in left ventricular pressure(±dp/dt) were recorded using a power lab system. KEY FINDINGS: At baseline, PAE adult males demonstrated significant higher values of LVSP, LVDP, RPP and ±â€¯dp/dt, compared to controls and PAE adult females (p < 0.05), while PAE adult females showed no significant differences compared to controls. In PAE adult males, LVSP, LVDP, RPP and ±â€¯dp/dt had significant decreasing trends per phases after I/R, compared to their controls and PAE females, while these decreasing trends were not statistically significant in PAE adult female rats vs. their controls. SIGNIFICANCE: The impact of prenatal androgen exposure on adulthood cardiac function and tolerance to I/R is gender dependent, which may be partly explained by different cardiac effects of hyperandrogenism in males versus females. After prenatal androgen exposure, the baseline hemodynamic parameters of the hearts of adult males are increased; although they had less tolerance to I/R, findings however not observed in females.


Assuntos
Androgênios/administração & dosagem , Tolerância a Medicamentos , Coração/fisiologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Animais , Pressão Sanguínea , Feminino , Coração/efeitos dos fármacos , Hemodinâmica , Masculino , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Gravidez , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Ratos , Ratos Wistar
14.
Clin Exp Rheumatol ; 37(5): 756-761, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30943139

RESUMO

OBJECTIVES: To compare different methods of antidrug antibody (ADA) against adalimumab detection in ankylosing spondylitis (AS) patients and the impact of ADA on adalimumab drug levels and mean ASDAS-CRP. METHODS: We used the acid-dissociation-radioimmunoassay (ARIA), antidrug-binding-test (ABT) and a bridging Enzyme-linked Immunosorbent Assay (ELISA) to detect ADA at 4, 12 and 24 weeks of treatment. Patients were divided into groups; all assays negative (All-neg), only ARIA positive (ARIA-only-pos), ARIA and ABT positive, bridging ELISA negative (ARIA/ABT-double-pos) and all assays positive (All-pos). RESULTS: Eighty-three consecutive AS patient were included. At week 4, 18% compared to 11% and 0% of the patients tested positive for ADA in the ARIA, ABT and bridging ELISA, respectively. At week 12 and 24, cumulative 52% and 69% patients tested positive in the ARIA, compared to 27% and 30% patients in the ABT and 2% patients in the bridging ELISA. Adalimumab levels between All-neg and ARIA-only-pos were 9.1 (5.5-12.5) and 8.5 (5.7-12.3). Drug levels differed between ARIA/ABT-double-pos (2.7 (1.3-4.4)) and All-neg (9.1 (5.5-12.5)). All-pos patients had undetectable drug levels. Mean ASDAS-CRP at week 24 differs between All-neg (1.9 (±1.2)), and All-pos (3.8 (±1.9)) and ARIA/ABT-double-pos (2.0 (±1.1)) and All-pos. CONCLUSIONS: The majority of AS patients had detectable ADA against adalimumab in the ARIA. The ARIA detects more ADA compared to the less drug tolerant ABT and bridging ELISA. The clinical relevance depends on the impact on the bio-availability of the drug. A drug level measurement therefore helps to interpret ADA data regardless of type of assay used.


Assuntos
Adalimumab/imunologia , Anticorpos Monoclonais Humanizados/imunologia , Artrite Reumatoide , Espondilite Anquilosante , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Tolerância a Medicamentos , Ensaio de Imunoadsorção Enzimática , Humanos , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/imunologia
15.
Malar J ; 18(1): 112, 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940139

RESUMO

BACKGROUND: Physiological characteristics (age and blood feeding status) of malaria vectors can influence their susceptibility to the current vector control tools that target their feeding and resting behaviour. To ensure the sustainability of the current and future vector control tools an understanding of how physiological characteristics may contribute to insecticide tolerance in the field is fundamental for shaping resistance management strategies and vector control tools. The aim of this study was to determine whether blood meal and mosquito age affect pyrethroid tolerance in field-collected Anopheles gambiae from western Kenya. METHODS: Wild mosquito larvae were reared to adulthood alongside the pyrethroid-susceptible Kisumu strain. Adult females from the two populations were monitored for deltamethrin resistance when they were young at 2-5 days old and older 14-16 days old and whether fed or unfed for each age group. Metabolic assays were also performed to determine the level of detoxification enzymes. Mosquito specimens were further identified to species level using the polymerase chain reaction (PCR) method. RESULTS: Anopheles gambiae sensu stricto was the predominant species comprising 96% of specimens and 2.75% Anopheles arabiensis. Bioassay results showed reduced pyrethroid induced mortality with younger mosquitoes compared to older ones (mortality rates 83% vs. 98%), independently of their feeding status. Reduced mortality was recorded with younger females of which were fed compared to their unfed counterparts of the same age with a mortality rate of 35.5% vs. 83%. Older blood-fed females showed reduced susceptibility after exposure when compared to unfed females of the same age (mortality rates 86% vs. 98%). For the Kisumu susceptible population, mortality was straight 100% regardless of age and blood feeding status. Blood feeding status and mosquito age had an effect on enzyme levels in both populations, with blood fed individuals showing higher enzyme elevations compared to their unfed counterparts (P < 0.0001). The interaction between mosquito age and blood fed status had significant effect on mosquito mortality. CONCLUSION: The results showed that mosquito age and blood feeding status confers increased tolerance to insecticides as blood feeding may be playing an important role in the toxicity of deltamethrin, allowing mosquitoes to rest on insecticide-treated materials despite treatment. These may have implications for the sustained efficacy of indoor residual spraying and insecticide-treated nets based control programmes that target indoor resting female mosquitoes of various gonotrophic status.


Assuntos
Anopheles/efeitos dos fármacos , Anopheles/fisiologia , Tolerância a Medicamentos , Inseticidas/farmacologia , Piretrinas/farmacologia , Fatores Etários , Animais , Anopheles/classificação , Anopheles/genética , Comportamento Alimentar , Feminino , Técnicas de Genotipagem , Quênia , Nitrilos/farmacologia , Reação em Cadeia da Polimerase
16.
Drug Des Devel Ther ; 13: 949-964, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30962677

RESUMO

Background: Aprocitentan is an orally active, dual endothelin (ET) receptor antagonist developed for the treatment of hypertension in which, despite available treatments, a medical need exists for drugs with a new mechanism of action. Subjects and methods: In this study, the single- and multiple-dose tolerability, safety, pharmacokinetics (PK), and pharmacodynamics of up to 600 mg (single doses) and 100 mg once a day (qd; multiple doses) of aprocitentan were investigated in healthy male and female subjects. The effect of age on the tolerability and PK parameters was investigated at a dose of 100 mg qd. Results: Aprocitentan was well tolerated across all doses. No serious adverse events (AEs) occurred. The most frequently reported AE was headache. Small increases in body weight were recorded in subjects receiving 100 mg qd. Plasma concentration-time profiles of aprocitentan were similar after single- and multiple-dose administration, and support a qd dosing regimen based on a half-life of 44 hours. After multiple doses, PK was dose proportional. Accumulation at steady state, reached by Day 8, was 3-fold. Only minor differences in exposure between healthy females and males, healthy elderly and adult subjects, and fed and fasted conditions were observed. Plasma ET-1 concentrations, reflecting ETB receptor antagonism, significantly increased with doses ≥25 mg. Time-matched analysis of electrocardiogram (ECG) parameters did not suggest drug-induced ECG effects. Exposure-response analysis indicated no QTc prolongations at plasma levels up to 10 µg/mL. Conclusion: Aprocitentan was well tolerated in healthy subjects with a PK profile favorable for qd dosing.


Assuntos
Antagonistas dos Receptores de Endotelina/efeitos adversos , Antagonistas dos Receptores de Endotelina/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Receptores de Endotelina/metabolismo , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Tolerância a Medicamentos , Antagonistas dos Receptores de Endotelina/administração & dosagem , Antagonistas dos Receptores de Endotelina/sangue , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Pirimidinas/administração & dosagem , Pirimidinas/sangue , Sulfonamidas/administração & dosagem , Sulfonamidas/sangue , Adulto Jovem
17.
Drug Des Devel Ther ; 13: 1011-1022, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30992659

RESUMO

Background: KM-819 is a novel FAS-associated factor 1 (FAF1) inhibitor, and a neuroprotective agent, under clinical development for the treatment of Parkinson's disease as a disease-modifying drug. Methods: This first-in-human, single and multiple ascending dose study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of KM-819 in healthy volunteers. Additionally, the effect of age on safety and pharmacokinetics were assessed. The starting dose was determined considering the no observed adverse effect level based on preclinical studies, and the dose escalations in subsequent cohorts were decided based on safety, tolerability, and pharmacokinetic data from previous dose cohorts. Results: After a single dose, the KM-819 plasma exposure showed a less than dose-proportional increase across a dose range of 10-400 mg. After repeated dosing, KM-819 plasma exposure increased in an approximately dose-proportional manner across the evaluated dose range (30-400 mg once daily for 7 days). The mean elimination half-life was 1.8 to 4.8 h with the lower KM-819 doses (≤30 mg), which increased to around 9 h with the higher doses (100-400 mg). When administered to the elderly population, KM-819 plasma exposure increased to 102% after a 200 mg once-daily dosing for 7 days. No clear treatment-related effects on the estimated pharmacodynamic variables were observed. Single or multiple doses of KM-819 were generally well tolerated. Conclusion: The data from this study can be used to guide rational drug dosing and choose therapeutic regimens in subsequent clinical studies.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/farmacocinética , Doença de Parkinson/tratamento farmacológico , Administração Oral , Adulto , Relação Dose-Resposta a Droga , Esquema de Medicação , Tolerância a Medicamentos , Voluntários Saudáveis , Humanos , Masculino , Fármacos Neuroprotetores/administração & dosagem
18.
Chemosphere ; 228: 183-194, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31029964

RESUMO

Saxifraga stellaris var. alpigena grows as one of the very few higher plants in the copper rich area of the "blue creek" in Austria. Two endophytes were isolated from it: Mortierella sp. (fungus), and Stenotrophomonas maltophilia (bacterium). Both microbes were practically inseparable due to resistance of the bacteria to the antibiotics tested. On PDA media, the fungus showed higher tolerance to copper than the bacterium, which disappeared from both the media and the surface of the fungus in the presence of 150 µM of Cu. However, at this Cu concentration, the bacteria were still detectable inside the mycelium and reappeared on the outside when transferred to media of lower Cu concentration. Microscopic studies of in vitro cultivated plants showed that the fungus was present in both, the roots and shoots of the plant. The effects of endophytes on plant performance were assessed in rhizoboxes filled with Cu-rich substratum; plants inoculated with both microbes showed better growth, survival and photosynthesis performance than the non-inoculated controls. The results of this study prove the beneficial influence of the isolated endophytes on the Cu tolerance of S. stellaris, and indicate the ecological potential of applying microbial consortia to plants under extreme environmental conditions.


Assuntos
Cobre/toxicidade , Tolerância a Medicamentos , Endófitos/fisiologia , Saxifragaceae/microbiologia , Simbiose , Áustria , Bactérias , Ecologia , Fungos , Raízes de Plantas/microbiologia , Brotos de Planta/microbiologia , Poluentes do Solo
19.
Eur J Pharmacol ; 852: 265-273, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-30959048

RESUMO

Oxycodone, a widely prescribed and very potent oral opioid analgesic agent, is highly addictive and has many side effects, including troublesome constipation. Our studies in mice indicated that pretreatment of naltrindole did not significantly affect the analgesic efficacy of oxycodone but attenuated the tolerance and withdrawal induced by chronic oxycodone administration. Naltrindole also attenuated the oxycodone-induced rewarding and re-instatement behaviors, as shown by the conditioned place preference test. Further, oxycodone-induced decrease in intestinal transit (i.e., constipation) was reduced by naltrindole. However, naltrindole did not block the respiratory depression produced by oxycodone. Taken together, these data suggest that naltrindole can attenuate some major side effects while retaining the analgesic efficacy of oxycodone in mice. Naltrindole and oxycodone may have the potential to be a potent analgesic combination with much lower levels of oxycodone's side effects of addictive liability and constipation.


Assuntos
Constipação Intestinal/tratamento farmacológico , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/farmacologia , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Oxicodona/efeitos adversos , Receptores Opioides delta/antagonistas & inibidores , Analgésicos/efeitos adversos , Animais , Constipação Intestinal/induzido quimicamente , Tolerância a Medicamentos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Naltrexona/farmacologia , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/complicações , Transtornos Relacionados ao Uso de Opioides/etiologia , Insuficiência Respiratória/complicações
20.
Ecotoxicol Environ Saf ; 178: 1-8, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-30980963

RESUMO

The aim of this study was to investigate whether the cadmium tolerance developed in the beet armyworm Spodoptera exigua selected for over 150 generations may be related to synthesis of the stress proteins metallothioneins (Mts) and 70 kDa heat shock proteins (HSP70). To achieve this, six S. exigua strains (control, k), 150-generation Cd exposure strain (cd), and four 18-generation Cd exposure strains differing in Cd concentration (cd44, cd22, cd11, cd5) were reared. Stress protein level was measured in the midgut of the 5th larval stage after 1-6, 12 and 18 generations. Cd contents was measured in the pupae. Unlike Cd concentration, which depended on metal contents in food but was not generation-dependent, the pattern of Mts and HSP70 concentrations changed in experimental strains from generation to generation. Stress protein levels in the insects exposed to the highest Cd concentration (the same as in the 150-generation Cd exposure strain), initially higher than in the control strain, after the 12th generation did not differ from the level measured in the control strains. It seems therefore that stress proteins play a protective role in insects of lower tolerance to cadmium. The tolerance developed during multigenerational exposure probably relies on mechanisms other than Mt and HSP70 synthesis.


Assuntos
Cádmio/toxicidade , Tolerância a Medicamentos , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico/metabolismo , Metalotioneína/metabolismo , Poluentes do Solo/toxicidade , Spodoptera/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Beta vulgaris/crescimento & desenvolvimento , Cádmio/metabolismo , Larva/efeitos dos fármacos , Larva/metabolismo , Modelos Teóricos , Pupa/efeitos dos fármacos , Pupa/metabolismo , Poluentes do Solo/metabolismo , Spodoptera/metabolismo
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