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BACKGROUND: Long-term and high-intensity work can lead to considerable discomfort in people's cervical spines. OBJECTIVES: This study sought to explore the effect of mind-body exercise intervention on the cervical spine mobility of people with neck discomfort through meta-analysis. METHODS: This study's researchers were searched a total of five research databases for data retrieval: China National Knowledge Infrastructure (from 1979), Web of Science (from 1950), PubMed (from 1965), Cochrane (from 1991), and EBSCO (from 1949) (Date of retrieval: March 10, 2021). Two authors independently searched literature records, scanned titles, abstracts, and full texts, collected data, and assessed materials for risk of bias. Stata14.0 software was used for the data analysis (Registration number: INPLASY202140126). RESULTS: Four articles were finally included with a total of 208 participants, and their age range was 18-65 years old. (1) Mind-body exercise intervention had a significant improving effect on Cervical extension, effect size of [SMD = 0.51 (95% CI 0.13 to 0.88), p <0.01; I2 = 45.2%], there was moderate heterogeneity; Mind-body exercise intervention had a significant improving effect on Cervical flexion, effect size of [SMD = 0.61 (95% CI 0.32 to 0.90), p <0.01; I2 = 5.7%], no heterogeneity; (2) Mind-body exercise intervention was no effect on the other four cervical range of motions; (3) The difference in participant's neck discomfort was the source of heterogeneity, and all results had the potential risk of publication bias. CONCLUSION: This study showed that mind-body exercise had a positive effect on the extension and flexion of people with neck discomfort. However, further research and more reliable evidence were needed to prove that mind-body exercise could be used for the treatment of neck discomfort.
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Terapias Mente-Cuerpo/métodos , Movimiento/efectos de los fármacos , Dolor de Cuello/terapia , Adulto , Vértebras Cervicales/fisiopatología , China , Ejercicio Físico/fisiología , Terapia por Ejercicio/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Movimiento/fisiología , Cuello/fisiología , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Adjuvant tamoxifen therapy improves survival in breast cancer patients. Unfortunately, long-term treatment comes with side effects that impact health and quality of life, including hot flashes, changes in bone density, and fatigue. Partly due to a lack of proven animal models, the tissues and cells that mediate these negative side effects are unclear. Here, we show that mice undergoing tamoxifen treatment experience changes in temperature, bone, and movement. Single-cell RNA sequencing reveals that tamoxifen treatment induces widespread gene expression changes in the hypothalamus and preoptic area (hypothalamus-POA). These expression changes are dependent on estrogen receptor alpha (ERα), as conditional knockout of ERα in the hypothalamus-POA ablates or reverses tamoxifen-induced gene expression. Accordingly, ERα-deficient mice do not exhibit tamoxifen-induced changes in temperature, bone, or movement. These findings provide mechanistic insight into the effects of tamoxifen on the hypothalamus-POA and indicate that ERα mediates several physiological effects of tamoxifen treatment in mice.
Estrogen is a hormone often known for its role in female development and reproduction. Yet, it also has an impact on many biological processes such as immunity and the health of bones, the heart, or the brain. It usually works by attaching to receptor proteins in specific cells. For instance, estrogen-responsive cells are present in the hypothalamus, the brain area that controls energy levels as well as the body's temperature and internal clock. Breast cancer cells are also often sensitive to estrogen, with the hormone fuelling the growth of tumors. The drug tamoxifen blocks estrogen receptors, stopping cells from responding to the hormone. As such, it is often used to reduce the likelihood that estrogen-dependent breast cancer will come back after treatment. However, its use can induce hot flashes, changes in bone density, fatigue and other life-altering side effects. Here, Zhang et al. investigated how estrogen receptors in the hypothalamus and a related region known as the preoptic area could be responsible for these side effects in mice. When the rodents were given tamoxifen for 28 days, they experienced changes in temperature, bone density and movement similar to those found in humans. In fact, genetic analyses revealed that the drug altered the way genes were turned on and off in certain cells types in the hypothalamus. Crucially, mice whose hypothalamus and preoptic area lacked estrogen receptors did not experience these behavioral and biological alterations. The findings by Zhang et al. help to understand how the side effects of tamoxifen emerge, singling out estrogen receptors in particular brain regions. This result could help to develop new therapies so that breast cancer can be treated with a better quality of life.
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Antineoplásicos Hormonales/farmacología , Hipotálamo/metabolismo , Área Preóptica/metabolismo , Tamoxifeno/farmacología , Animales , Temperatura Corporal/efectos de los fármacos , Densidad Ósea/efectos de los fármacos , Receptor alfa de Estrógeno/deficiencia , Femenino , Regulación de la Expresión Génica , Ratones , Movimiento/efectos de los fármacosRESUMEN
Dietary supplements often contain additives not listed on the label, including α-ethyl homologs of amphetamine such as N,α-diethylphenethylamine (DEPEA). Here, we examined the neurochemical and cardiovascular effects of α-ethylphenethylamine (AEPEA), N-methyl-α-ethylphenethylamine (MEPEA), and DEPEA as compared with the effects of amphetamine. All drugs were tested in vitro using uptake inhibition and release assays for monoamine transporters. As expected, amphetamine acted as a potent and efficacious releasing agent at dopamine transporters (DAT) and norepinephrine transporters (NET) in vitro. AEPEA and MEPEA were also releasers at catecholamine transporters, with greater potency at NET than DAT. DEPEA displayed fully efficacious release at NET but weak partial release at DAT (i.e., 40% of maximal effect). In freely moving, conscious male rats fitted with biotelemetry transmitters for physiologic monitoring, amphetamine (0.1-3.0 mg/kg, s.c.) produced robust dose-related increases in blood pressure (BP), heart rate (HR), and motor activity. AEPEA (1-10 mg/kg, s.c.) produced significant increases in BP but not HR or activity, whereas DEPEA and MEPEA (1-10 mg/kg, s.c.) increased BP, HR, and activity. In general, the phenethylamine analogs were approximately 10-fold less potent than amphetamine. Our results show that α-ethylphenethylamine analogs are biologically active. Although less potent than amphetamine, they produce cardiovascular effects that could pose risks to humans. Given that MEPEA and DEPEA increased locomotor activity, these substances may also have significant abuse potential. SIGNIFICANCE STATEMENT: The α-ethyl homologs of amphetamine have significant cardiovascular, behavioral, and neurochemical effects in rats. Given that these compounds are often not listed on the ingredient labels of dietary supplements, these compounds could pose a risk to humans using these products.
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Presión Sanguínea/efectos de los fármacos , Butilaminas/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Metanfetamina/análogos & derivados , Movimiento/efectos de los fármacos , Fenetilaminas/farmacología , Animales , Proteínas de Transporte de Catecolaminas en la Membrana Plasmática/metabolismo , Suplementos Dietéticos/efectos adversos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Relación Dosis-Respuesta a Droga , Masculino , Metanfetamina/farmacología , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
In this study, we aim to assess the phytomedicinal potential of perillyl alcohol (PA), a dietary monoterpenoid, in a unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of Parkinson's disease (PD). We observed that PA supplementation alleviated behavioural abnormalities such as loss of coordination, reduced rearing and motor asymmetry in lesioned animals. We also observed that PA-treated animals exhibited reduced oxidative stress, DNA fragmentation and caspase 3 activity indicating alleviation of apoptotic cell death. We found reduced mRNA levels of pro-apoptotic regulator BAX and pro-inflammatory mediators IL18 and TNFα in PA-treated animals. Further, PA treatment successfully increased mRNA and protein levels of Bcl2, mitochondrial biogenesis regulator PGC1α and tyrosine hydroxylase (TH) in lesioned animals. We observed that PA treatment blocked BAX and Drp1 translocation to mitochondria, an event often associated with the inception of apoptosis. Further, 6-OHDA exposure reduced expression of electron transport chain complexes I and IV, thereby disturbing energy metabolism. Conversely, expression levels of both complexes were upregulated with PA treatment in lesioned rats. Finally, we found that protein levels of Nrf2, the transcription factor responsible for antioxidant gene expression, were markedly reduced in cytosolic and nuclear fraction on 6-OHDA exposure, and PA increased expression of Nrf2 in both fractions. We believe that our data hints towards PA having the ability to provide cytoprotection in a hemiparkinsonian rat model through alleviation of motor deficits, oxidative stress, mitochondrial dysfunction and apoptosis.
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Inhibidores Enzimáticos/farmacología , Mitocondrias/efectos de los fármacos , Monoterpenos/farmacología , Movimiento/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Trastornos Parkinsonianos/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Caspasa 3/efectos de los fármacos , Caspasa 3/metabolismo , Fragmentación del ADN/efectos de los fármacos , Dinaminas/efectos de los fármacos , Dinaminas/metabolismo , Complejo I de Transporte de Electrón/efectos de los fármacos , Complejo I de Transporte de Electrón/genética , Complejo I de Transporte de Electrón/metabolismo , Complejo IV de Transporte de Electrones/efectos de los fármacos , Complejo IV de Transporte de Electrones/genética , Complejo IV de Transporte de Electrones/metabolismo , Mitocondrias/metabolismo , Factor 2 Relacionado con NF-E2/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Oxidopamina/toxicidad , Trastornos Parkinsonianos/fisiopatología , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/efectos de los fármacos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Proteínas Proto-Oncogénicas c-bcl-2/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/genética , Ratas , Simpaticolíticos/toxicidad , Tirosina 3-Monooxigenasa/efectos de los fármacos , Tirosina 3-Monooxigenasa/genética , Proteína X Asociada a bcl-2/efectos de los fármacos , Proteína X Asociada a bcl-2/metabolismoRESUMEN
AIM: Study of the effect of taking a complex biologically active food supplement with calcium and vitamins D3 and B6 to the effectiveness and duration of medical rehabilitation effect at patients with osteoporosis and with a high risk of fractures. MATERIAL AND METHODS: We examined 119 men and women with osteoporosis and (or) with a high risk of fractures, beginning a course of medical rehabilitation. The 1st study group (SG1) included 41 patients who had already received antiresorptive therapy. In SG2 and SG3, 39 patients who did not receive pathogenetic therapy of osteoporosis were included by the randomization method. For patients SG1 and SG2, a complex biologically active food supplement Osteomed forte was prescribed to use within 12 months. The dynamics of tensodynamometry, stabilometry and functional tests were evaluated in 20 days, 6 and 12 months after the start of the study. RESULTS: The muscle strength indicators achieved during the 20-day training session compared to the initial level were maintained for 12 months in extensor and flexor of the back at patients within SG1 and SG2, as well as up to 6 months in the lateral flexor of the back at patients of SG1. At patients within SG3, the effect of medical rehabilitation completely regressed after 6 months. Higher stabilization parameters after 6 and 12 months in comparison with the initial level were observed only in patients within SG1 and SG2. The effect achieved during rehabilitation was supported for 12 months in the 'stand on one leg' test within SG1, comparing in contrast to SG3, where a deterioration in the average value of the test indicator was noted. CONCLUSION: Long-term use of food supplements containing calcium salts with vitamins D3 and B6can be recommended to maintain the effect of rehabilitation measures at patients with osteoporosis and with a high risk of fractures, more preferably in combination with antiresorptive therapy.
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Calcio/uso terapéutico , Movimiento/efectos de los fármacos , Fuerza Muscular/efectos de los fármacos , Osteoporosis/tratamiento farmacológico , Equilibrio Postural/efectos de los fármacos , Vitaminas/uso terapéutico , Femenino , Humanos , Masculino , Osteoporosis/rehabilitación , Resultado del TratamientoRESUMEN
Phosphatidylserine is one of the phospholipids present in cell membranes, especially in brain and nervous system. The phosphatidylserine content is reduced with aging and age-related decrease in phosphatidylserine is known to contribute to cognitive impairment and Alzheimer's disease in the elderly. In the present study, we examined the effect of supplementation with phosphatidylserine on the response to oxidative stress and aging using C. elegans as a model system. Dietary supplementation with phosphatidylserine significantly increased resistance to oxidative stress and extended lifespan accompanying reduced fertility as a trade-off. Age-related decline in motility was also delayed by supplementation with phosphatidylserine. The cellular levels of reactive oxygen species and the expression of stress-responsive genes were increased by phosphatidylserine treatment, suggesting a hormetic effect. The extension of lifespan by phosphatidylserine overlaps with reduced insulin/IGF-1-like signaling and requires DAF-16. The effect of phosphatidylserine on age-related diseases was examined using animal model of disease. Supplementation with phosphatidylserine significantly suppressed amyloid beta-induced toxicity in Alzheimer's disease model. Reduced survival in diabetes mellitus due to high-glucose diet was reversed by supplementation with phosphatidylserine. This study reports the anti-oxidative stress and anti-aging effect of phosphatidylserine for the first time at the organismal level and proposes possible underlying mechanisms.
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Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efectos de los fármacos , Suplementos Dietéticos , Factores de Transcripción Forkhead/metabolismo , Hormesis , Longevidad/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Fosfatidilserinas/administración & dosificación , Factores de Edad , Animales , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Factores de Transcripción Forkhead/genética , Movimiento/efectos de los fármacos , Fosfatidilserinas/metabolismoRESUMEN
BACKGROUND: Aging results in reductions in maximal muscular strength, speed, and power, which often lead to functional limitations highly predictive of disability, institutionalization, and mortality in elderly adults. This may be partially due to reduced nitric oxide (NO) bioavailability. We, therefore, hypothesized that dietary nitrate (NO3-), a source of NO via the NO3- â nitrite (NO2-) â NO enterosalivary pathway, could increase muscle contractile function in older subjects. METHODS: Twelve healthy older (age 71 ± 5 years) men and women were studied using a randomized, double-blind, placebo-controlled, crossover design. After fasting overnight, subjects were tested 2 hours after ingesting beetroot juice containing or devoid of 13.4 ± 1.6 mmol NO3-. Plasma NO3- and NO2- and breath NO were measured periodically, and muscle function was determined using isokinetic dynamometry. RESULTS: N O 3 - ingestion increased (p < .001) plasma NO3-, plasma NO2-, and breath NO by 1,051% ± 433%, 138% ± 149%, and 111% ± 115%, respectively. Maximal velocity of knee extension increased (p < .01) by 10.9% ± 12.1%. Maximal knee extensor power increased (p < .05) by 4.4% ± 7.8%. CONCLUSIONS: Acute dietary NO3- intake improves maximal knee extensor angular velocity and power in older individuals. These findings may have important implications for this population, in whom diminished muscle function can lead to functional limitations, dependence, and even premature death.
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Rodilla/fisiología , Fuerza Muscular/efectos de los fármacos , Nitratos/uso terapéutico , Anciano , Suplementos Dietéticos , Método Doble Ciego , Femenino , Humanos , Masculino , Movimiento/efectos de los fármacos , Contracción Muscular/efectos de los fármacos , Dinamómetro de Fuerza Muscular , Nitratos/administración & dosificación , Nitratos/sangreRESUMEN
Haloperidol (Hal) is an antipsychotic related to movement disorders. Magnesium (Mg) showed benefits on orofacial dyskinesia (OD), suggesting its involvement with N-methyl-D-aspartate receptors (NMDAR) since it acts blocking calcium channels. Comparisons between nifedipine (NIF; a calcium channel blocker) and Mg were performed to establish the Mg mechanism. Male rats concomitantly received Hal and Mg or NIF for 28 days, and OD behaviors were weekly assessed. Both Mg and NIF decreased Hal-induced OD. Hal increased Ca2+-ATPase activity in the striatum, and Mg reversed it. In the cortex, both Mg and NIF decreased such activity. Dopaminergic and glutamatergic immunoreactivity were modified by Hal and treatments: i) in the cortex: Hal reduced D1R and D2R, increasing NMDAR immunoreactivity. Mg and NIF reversed this Hal influence on D1R and NMDAR, while only Mg reversed Hal effects on D2R levels; ii) in the striatum: Hal decreased D2R and increased NMDAR while Mg and NIF decreased D1R and reversed the Hal-induced decreasing D2R levels. Only Mg reversed the Hal-induced increasing NMDAR levels; iii) in the substantia nigra (SN): while Hal increased D1R, D2R, and NMDAR, both Mg and NIF reversed this influence on D2R, but only Mg reversed the Hal-influence on D1R levels. Only NIF reversed the Hal effects on NMDAR immunoreactivity. These findings allow us to propose that Mg may be useful to minimize Hal-induced movement disturbances. Mg molecular mechanism seems to be involved with a calcium channel blocker because the NIF group showed less expressive effects than the Mg group.
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Discinesias/tratamiento farmacológico , Haloperidol/farmacología , Magnesio/farmacología , Animales , Antipsicóticos/farmacología , Encéfalo/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo L/metabolismo , Cuerpo Estriado/metabolismo , Haloperidol/efectos adversos , Magnesio/metabolismo , Masculino , Movimiento/efectos de los fármacos , Trastornos del Movimiento/tratamiento farmacológico , Neostriado/metabolismo , Nifedipino/farmacología , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Sustancia Negra/metabolismoRESUMEN
Clostridium perfringens is an anaerobic, Gram-positive bacterium that causes a range of diseases in humans and animals around the globe. The type IV pilus (TFP) system plays a key role in the colonization and invasion of host cells, biofilm formation and gliding motility, which is vital for C. perfringens infection. Therefore, targeting TFP function may be a promising strategy for the treatment of C. perfringens infection. Here, we investigated the potential inhibitory effects of tectorigenin (TE), an isoflavone extracted from the rhizome of the Chinese herb Belamcanda chinensis (L.) DC, on gliding motility, biofilm formation, adherence to cells and antibacterial activity of C. perfringens. Tectorigenin significantly inhibited gliding motility, biofilm formation and adherence to Caco-2 cells without observable antibacterial activity against C. perfringens. In addition, we also demonstrated that the inhibitory effect of TE on TFP function appears to be partially achieved by the suppression of TFP-associated genes. These findings demonstrate that TE may have the potential to be developed as a new anti-virulence drug for C. perfringens infection, particularly for the targeting of TFP.
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Antibacterianos/farmacología , Adhesión Bacteriana/efectos de los fármacos , Clostridium perfringens/efectos de los fármacos , Fimbrias Bacterianas/metabolismo , Isoflavonas/farmacología , Biopelículas/efectos de los fármacos , Células CACO-2 , Clostridium perfringens/genética , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Humanos , Movimiento/efectos de los fármacosRESUMEN
Glutamate dysfunction has been implicated in a number of substance of abuse studies, including cocaine and methamphetamine. Moreover, in attention-deficit/hyperactivity disorder (ADHD), it has been discovered that when the initiation of stimulant treatment occurs during adolescence, there is an increased risk of developing a substance use disorder later in life. The spontaneously hypertensive rat (SHR) serves as a phenotype for ADHD and studies have found increased cocaine self-administration in adult SHRs when treated with the stimulant methylphenidate (MPH) during adolescence. For this reason, we wanted to examine glutamate signaling in the pre-limbic frontal cortex, a region implicated in ADHD and drug addiction, in the SHR and its progenitor control strain, the Wistar Kyoto (WKY). We chronically implanted glutamate-selective microelectrode arrays (MEAs) into 8-week-old animals and treated with MPH (2 mg/kg, s.c.) for 11 days while measuring tonic and phasic extracellular glutamate concentrations. We observed that intermediate treatment with a clinically relevant dose of MPH increased tonic glutamate levels in the SHR but not the WKY compared to vehicle controls. After chronic treatment, both the SHR and WKY exhibited increased tonic glutamate levels; however, only the SHR was found to have decreased amplitudes of phasic glutamate signaling following chronic MPH administration. The findings from this study suggest that the MPH effects on extracellular glutamate levels in the SHR may potentiate the response for drug abuse later in life. Additionally, these data illuminate a pathway for investigating novel therapies for the treatment of ADHD and suggest that possibly targeting the group II metabotropic glutamate receptors may be a useful therapeutic avenue for adolescents diagnosed with ADHD.
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Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Estimulantes del Sistema Nervioso Central/administración & dosificación , Modelos Animales de Enfermedad , Lóbulo Frontal/metabolismo , Ácido Glutámico/metabolismo , Metilfenidato/administración & dosificación , Animales , Trastorno por Déficit de Atención con Hiperactividad/genética , Estimulantes del Sistema Nervioso Central/toxicidad , Esquema de Medicación , Electrodos Implantados , Lóbulo Frontal/efectos de los fármacos , Masculino , Metilfenidato/toxicidad , Movimiento/efectos de los fármacos , Movimiento/fisiología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Especificidad de la EspecieRESUMEN
There is a critical need for better analytical methods to study mitochondria in normal and diseased states. Mitochondrial image analysis is typically done on still images using slow manual methods or automated methods of limited types of features. MitoMo integrated software overcomes these bottlenecks by automating rapid unbiased quantitative analysis of mitochondrial morphology, texture, motion, and morphogenesis and advances machine-learning classification to predict cell health by combining features. Our pixel-based approach for motion analysis evaluates the magnitude and direction of motion of: (1) molecules within mitochondria, (2) individual mitochondria, and (3) distinct morphological classes of mitochondria. MitoMo allows analysis of mitochondrial morphogenesis in time-lapse videos to study early progression of cellular stress. Biological applications are presented including: (1) establishing normal phenotypes of mitochondria in different cell types; (2) quantifying stress-induced mitochondrial hyperfusion in cells treated with an environmental toxicant, (3) tracking morphogenesis in mitochondria undergoing swelling, and (4) evaluating early changes in cell health when morphological abnormalities are not apparent. MitoMo unlocks new information on mitochondrial phenotypes and dynamics by enabling deep analysis of mitochondrial features in any cell type and can be applied to a broad spectrum of research problems in cell biology, drug testing, toxicology, and medicine.
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Biología Computacional/métodos , Aprendizaje Automático , Mitocondrias/metabolismo , Células A549 , Humanos , Mitocondrias/efectos de los fármacos , Movimiento/efectos de los fármacos , Fenotipo , Selenio/farmacología , Estrés Fisiológico , Aprendizaje Automático SupervisadoRESUMEN
OBJECTIVES: The aim of this study was to investigate the expression of the mammalian Mg2+ transporter solute carrier family 41, member 1 (SLC41A1) in the striatum (STR) of a 6-hydroxydopamine (6-OHDA)-induced rat model, and its response to magnesium before the degenerative process commenced. MATERIALS AND METHODS: A unilateral parkinsonian rat model was induced by injection of 6-OHDA into the right medial forebrain bundle. Some rats received MgSO4 (90 mg/kg/day, intraperitoneal injection) for 7 or 14 days starting from the day following the 6-OHDA injection. The extent of dopamine depletion was determined by assessing the numbers of tyrosine hydroxylase (TH)-immunoreactive neurons in the substantia nigra pars compacta (SNc) and the apomorphine (APO)-induced rotational behavior. The mRNA and protein expression of SLC41A1 in STR were evaluated by real-time RT-PCR and western blotting respectively. RESULTS: APO-induced rotations increased significantly in the 6-OHDA lesioned rats compared with the controls, with MgSO4 administration significantly improving the behavior. The numbers of TH-immunoreactive neurons in SNc were significantly lower in the lesioned side than in the unlesioned side. Administration of MgSO4 for 14 days partly ameliorated the loss of TH-positive neurons. The mRNA and protein expressions of SLC41A1 in the lesioned STR were lower in the 6-OHDA lesioned rats than in the controls at both 7 and 14 days post-lesion induction. MgSO4 supplementation partly reversed the mRNA and protein expressions of SLC41A1. CONCLUSION: The regulation of SLC41A1 expression is responsive to magnesium in a 6-OHDA-induced rat model, wherein 6-OHDA may alter magnesium transport in the brain.
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Proteínas de Transporte de Catión/metabolismo , Cuerpo Estriado/metabolismo , Trastornos Parkinsonianos/metabolismo , Animales , Antiparkinsonianos/farmacología , Apomorfina/farmacología , Cuerpo Estriado/efectos de los fármacos , Agonistas de Dopamina/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Expresión Génica , Magnesio/metabolismo , Sulfato de Magnesio/farmacología , Masculino , Movimiento/efectos de los fármacos , Oxidopamina , Trastornos Parkinsonianos/tratamiento farmacológico , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Schistosomiasis is a tropical disease caused by a flatworm trematode parasite that infects over 200 million people worldwide. Treatment and control of the disease rely on just one drug, praziquantel. The possibility of drug resistance coupled with praziquantel's variable efficacy encourages the identification of new drugs and drug targets. Disruption of neuromuscular homeostasis in parasitic worms is a validated strategy for drug development. In schistosomes, however, much remains to be understood about the organization of the nervous system, its component neurotransmitters and potential for drug discovery. Using synapsin as a neuronal marker, we map the central and peripheral nervous systems in the Schistosoma mansoni adult and schistosomulum (post-infective larva). We discover the widespread presence of octopamine (OA), a tyrosine-derived and invertebrate-specific neurotransmitter involved in neuromuscular coordination. OA labeling facilitated the discovery of two pairs of ganglia in the brain of the adult schistosome, rather than the one pair thus far reported for this and other trematodes. In quantitative phenotypic assays, OA and the structurally related tyrosine-derived phenolamine and catecholamine neurotransmitters differentially modulated schistosomulum motility and length. Similarly, from a screen of 28 drug agonists and antagonists of tyrosine-derivative signaling, certain drugs that act on OA and dopamine receptors induced robust and sometimes complex concentration-dependent effects on schistosome motility and length; in some cases, these effects occurred at concentrations achievable in vivo The present data advance our knowledge of the organization of the nervous system in this globally important pathogen and identify a number of drugs that interfere with tyrosine-derivative signaling, one or more of which might provide the basis for a new chemotherapeutic approach to treat schistosomiasis.This article has an associated First Person interview with the first author of the paper.
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Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Octopamina/metabolismo , Schistosoma mansoni/metabolismo , Transducción de Señal , Bibliotecas de Moléculas Pequeñas/análisis , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Especificidad de Anticuerpos/inmunología , Antiparasitarios/agonistas , Antiparasitarios/antagonistas & inhibidores , Biomarcadores/metabolismo , Femenino , Movimiento/efectos de los fármacos , Red Nerviosa/efectos de los fármacos , Red Nerviosa/metabolismo , Sistema Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Octopamina/química , Ovario/efectos de los fármacos , Ovario/metabolismo , Parásitos/efectos de los fármacos , Parásitos/metabolismo , Proteínas Protozoarias/metabolismo , Schistosoma mansoni/anatomía & histología , Schistosoma mansoni/efectos de los fármacos , Schistosoma mansoni/embriología , Transducción de Señal/efectos de los fármacos , Caracoles/parasitología , Tirosina/metabolismoRESUMEN
The present investigation for the first time explains the anti biofilm and anti virulence potential of Kaffir lime oil (KLO) and its major constituent, Citronellal (3,7-dimethyloct-6-enal) against Xanthomonas oryzae pv. oryzae, causal organism of bacterial blight disease of rice. KLO at 500â¯ppm showed potential activity against X. oryzae pv. oryzae. Among the major components identified, citronellal (CIT) at 75⯵M concentration was found to significantly inhibit biofilm along with the swimming and swarming potential of X. oryzae pv. oryzae. In contrary, CIT did not affect the metabolic status and growth kinetics of the bacterial cells. Gene expression analysis showed down regulation in motA, cheD, cheY, flgF, gumC, xylanase, endogluconase, cellulose, cellobiosidase, virulence and rpfF transcript levels by citronellal treatment. However, an insignificant effect of 75⯵M CIT treatment was observed on motB, flgE, pilA, estY, pglA, protease and lytic genes expression. Finally, the observations recorded were in confirmity with the virulence leaf clip test as lesion length was significantly decreased (39%) in CIT treatment as compared to the control leaves inoculated with only X. oryzae pv. oryzae. Overall, the findings obtained advocate the use of CIT for promising anti biofilm and anti virulence activity which in turn can be used for managing the blight disease in rice.
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Aldehídos/farmacología , Biopelículas/crecimiento & desarrollo , Citrus/química , Monoterpenos/farmacología , Aceites Volátiles/farmacología , Oryza/microbiología , Aceites de Plantas/farmacología , Xanthomonas/efectos de los fármacos , Monoterpenos Acíclicos , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Movimiento/efectos de los fármacos , Enfermedades de las Plantas/microbiología , Hojas de la Planta/microbiología , Factores de Virulencia/genética , Xanthomonas/genética , Xanthomonas/patogenicidadRESUMEN
Quorum-sensing (QS) is known to play an essential role in regulation of virulence factors and toxins during Pseudomonas aeruginosa infection which may frequently cause antibiotic resistance and hostile outcomes of inflammatory injury. Therefore, it is an urgent need to search for a novel agent with low risk of resistance development that can target QS and inflammatory damage prevention as well. Andrographis paniculata, a herbaceous plant under the family Acanthaceae, native to Asian countries and also cultivated in Scandinavia and some parts of Europe, has a strong traditional usage with its known antibacterial, anti-inflammatory, antipyretic, antiviral and antioxidant properties. In this study, three different solvent extracts (viz., chloroform, methanol and aqueous) of A. paniculata were examined for their anti-QS and anti-inflammatory activities. Study was carried out to assess the effect on some selected QS-regulatory genes at transcriptional level using Real Time-PCR. In addition, ability to attenuate MAPK pathways upon P. aeruginosa infection was performed to check its potential anti-inflammatory activity. Chloroform and methanol extracts showed significant reduction (pâ¯<â¯0.05) of the QS-controlled extracellular virulence factors in P. aeruginosa including the expression of pyocyanin, elastase, total protease, rhamnolipid and hemolysin without affecting bacterial viability. They also significantly (pâ¯<â¯0.05) reduced swarming motility and biofilm formation of P. aeruginosa. The chloroform extract, which was found to be more effective, decreased expression of lasI, lasR, rhlI and rhlR by 61%, 75%, 41%, and 44%, respectively. Moreover, chloroform extract decreased activation of p-p38 and p-ERK1/2 expression levels in MAPK signal pathways in P. aeruginosa infected macrophage cells. As the present study demonstrates that A. paniculata extracts inhibit QS in P. aeruginosa and exhibit anti-inflammatory activities, therefore it represents itself as a prospective therapeutic agent against P. aeruginosa infection.
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Andrographis/metabolismo , Antibacterianos/farmacología , Biopelículas/crecimiento & desarrollo , Extractos Vegetales/farmacología , Pseudomonas aeruginosa/patogenicidad , Percepción de Quorum/efectos de los fármacos , Factores de Virulencia/biosíntesis , Animales , Células Cultivadas , Macrófagos/inmunología , Ratones , Pruebas de Sensibilidad Microbiana , Movimiento/efectos de los fármacos , Estudios Prospectivos , Pseudomonas aeruginosa/efectos de los fármacosRESUMEN
UNLABELLED: Long-term treatment of Parkinson's disease with l-DOPA almost always leads to the development of involuntary movements termed l-DOPA-induced dyskinesia. Whereas hyperdopaminergic signaling in the basal ganglia is thought to cause dyskinesia, alterations in primary motor cortex (M1) activity are also prominent during dyskinesia, suggesting that the cortex may represent a therapeutic target. The present study used the rat unilateral 6-hydroxydopamine lesion model of Parkinson's disease to characterize in vivo changes in GABA and glutamate neurotransmission within M1 and determine their contribution to behavioral output. 6-Hydroxydopamine lesion led to parkinsonian motor impairment that was partially reversed by l-DOPA. Among sham-lesioned rats, l-DOPA did not change glutamate or GABA efflux. Likewise, 6-hydroxydopamine lesion did not impact GABA or glutamate among rats chronically treated with saline. However, we observed an interaction of lesion and treatment whereby, among lesioned rats, l-DOPA given acutely (1 d) or chronically (14-16 d) reduced glutamate efflux and enhanced GABA efflux. Site-specific microinjections into M1 demonstrated that l-DOPA-induced dyskinesia was reduced by M1 infusion of a D1 antagonist, an AMPA antagonist, or a GABAA agonist. Overall, the present study demonstrates that l-DOPA-induced dyskinesia is associated with increased M1 inhibition and that exogenously enhancing M1 inhibition may attenuate dyskinesia, findings that are in agreement with functional imaging and transcranial magnetic stimulation studies in human Parkinson's disease patients. Together, our study suggests that increasing M1 inhibitory tone is an endogenous compensatory response designed to limit dyskinesia severity and that potentiating this response is a viable therapeutic strategy. SIGNIFICANCE STATEMENT: Most Parkinson's disease patients will receive l-DOPA and eventually develop hyperkinetic involuntary movements termed dyskinesia. Such symptoms can be as debilitating as the disease itself. Although dyskinesia is associated with dynamic changes in primary motor cortex physiology, to date, there are no published studies investigating in vivo neurotransmitter release in M1 during dyskinesia. In parkinsonian rats, l-DOPA administration reduced M1 glutamate efflux and enhanced GABA efflux, coincident with the emergence of dyskinetic behaviors. Dyskinesia could be reduced by local M1 modulation of D1, AMPA, and GABAA receptors, providing preclinical support for the notion that exogenously blunting M1 signaling (pharmacologically or with cortical stimulation) is a therapeutic approach to the treatment of debilitating dyskinesias.
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Ácido Glutámico/metabolismo , Corteza Motora/metabolismo , Transducción de Señal/efectos de los fármacos , Discinesia Tardía/patología , Ácido gamma-Aminobutírico/metabolismo , Animales , Antiparkinsonianos/efectos adversos , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Fármacos actuantes sobre Aminoácidos Excitadores/farmacología , GABAérgicos/farmacología , Levodopa/efectos adversos , Masculino , Corteza Motora/efectos de los fármacos , Movimiento/efectos de los fármacos , Oxidopamina/toxicidad , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/tratamiento farmacológico , Desempeño Psicomotor/efectos de los fármacos , Desempeño Psicomotor/fisiología , Ratas , Ratas Sprague-Dawley , Simpaticolíticos/toxicidad , Discinesia Tardía/inducido químicamenteRESUMEN
BACKGROUND/AIMS: Motility is a feature of many pathogens that contributes to the migration and dispersion of the infectious agent. Whether gentamycin has a post-antibiotic effect (PAE) on the swarming and swimming motility of Escherichia coli (E. coli) remains unknown. In this study, we aimed to examine whether short-term pretreatment of sub-inhibitory concentrations of gentamycin alter motility of E. coli and the mechanisms involved therein. METHODS: After exposure to sub-inhibitory concentrations (0.8 µg/ml) of gentamicin, the swarming and swimming motility of E. coli was tested in semi-solid media. Real-time PCR was used to detect the gene expression of succinate dehydrogenase (SDH). The production of SDH and fumarate by E. coli pretreated with or without gentamycin was measured. Fumarate was added to swarming agar to determine whether fumarate could restore the swarming motility of E. coli. RESULTS: After pretreatment of E. coli with sub-inhibitory concentrations of gentamycin, swarming motility was repressed in the absence of growth inhibition. The expression of all four subunits of SDH was down-regulated, and the intracellular concentration of SDH and fumarate, produced by E. coli, were both decreased. Supplementary fumarate could restore the swarming motility inhibited by gentamycin. A selective inhibitor of SDH (propanedioic acid) could strongly repress the swarming motility. CONCLUSION: Sub-inhibitory concentrations of gentamycin inhibits the swarming motility of E. coli. This effect is mediated by a reduction in cellular fumarate caused by down-regulation of SDH. Gentamycin may be advantageous for treatment of E. coli infections.
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Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Escherichia coli/efectos de los fármacos , Flavoproteínas/antagonistas & inhibidores , Regulación Bacteriana de la Expresión Génica , Gentamicinas/farmacología , Subunidades de Proteína/antagonistas & inhibidores , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Escherichia coli/enzimología , Escherichia coli/genética , Escherichia coli/crecimiento & desarrollo , Flavoproteínas/genética , Flavoproteínas/metabolismo , Fumaratos/metabolismo , Malonatos/farmacología , Pruebas de Sensibilidad Microbiana , Movimiento/efectos de los fármacos , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , Transducción de Señal , Ácido Succínico/metabolismo , Factores de TiempoRESUMEN
BACKGROUND: Antiepileptic drugs (AEDs) decrease the occurrence of epileptic seizures and modulate cortical excitability through several mechanisms that likely interact. The modulation of brain excitability by AEDs is believed to reflect their antiepileptic action(s) and could be used as a surrogate marker of their efficacy. Transcranial magnetic stimulation (TMS) is one of the best noninvasive methods to study cortical excitability in human subjects. Specific TMS parameters can be used to quantify the various mechanisms of action of AEDs. A new AED called retigabine increases potassium efflux by changing the conformation of KCNQ 2-5 potassium channels, which leads to neuronal hyperpolarisation and a decrease in excitability. HYPOTHESIS: The purpose of this study is to investigate the effect of retigabine on cortical excitability. Based on the known mechanisms of action of retigabine, we hypothesized that the oral intake of retigabine would increase the resting motor threshold (RMT). METHODS: Fifteen healthy individuals participated in a placebo-controlled, double-blind, randomised, clinical trial (RCT). The primary outcome measure was the RMT quantified before and after oral intake of retigabine. Several secondary TMS outcome measures were acquired. RESULTS: The mean RMT, active motor threshold (AMT) and intensity to obtain a 1mV peak-to-peak amplitude potential (SI1mV) were significantly increased after retigabine intake compared to placebo (RMT: P=0.039; AMT: P=0.014; SI1mV: P=0.019). No significant differences were found for short-interval intracortical inhibition/intracortical facilitation (SICI/ICF), long-interval intracortical inhibition (LICI) or short-interval intracortical facilitation (SICF). CONCLUSION: A single dose of retigabine increased the RMT, AMT and S1mV in healthy individuals. No modulating intracortical facilitation or inhibition was observed. This study provides the first in vivo demonstration of the modulating effects of retigabine on the excitability of the human brain, and the results are consistent with the data showing that retigabine hyperpolarizes neurons mainly by increasing potassium conductance.
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Anticonvulsivantes/farmacología , Carbamatos/farmacología , Corteza Motora/efectos de los fármacos , Corteza Motora/fisiología , Fenilendiaminas/farmacología , Estimulación Magnética Transcraneal , Adulto , Análisis de Varianza , Estudios Cruzados , Método Doble Ciego , Electromiografía , Femenino , Humanos , Masculino , Movimiento/efectos de los fármacos , Movimiento/fisiología , Músculo Esquelético/fisiología , DescansoRESUMEN
Mechanisms that could mitigate the effects of hypoxia on neuronal signaling are incompletely understood. We show that axonal performance of a locust visual interneuron varied depending on oxygen availability. To induce hypoxia, tracheae supplying the thoracic nervous system were surgically lesioned and action potentials in the axon of the descending contralateral movement detector (DCMD) neuron passing through this region were monitored extracellularly. The conduction velocity and fidelity of action potentials decreased throughout a 45-min experiment in hypoxic preparations, whereas conduction reliability remained constant when the tracheae were left intact. The reduction in conduction velocity was exacerbated for action potentials firing at high instantaneous frequencies. Bath application of octopamine mitigated the loss of conduction velocity and fidelity. Action potential conduction was more vulnerable in portions of the axon passing through the mesothoracic ganglion than in the connectives between ganglia, indicating that hypoxic modulation of the extracellular environment of the neuropil has an important role to play. In intact locusts, octopamine and its antagonist, epinastine, had effects on the entry to, and recovery from, anoxic coma consistent with octopamine increasing overall neural performance during hypoxia. These effects could have functional relevance for the animal during periods of environmental or activity-induced hypoxia.
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Agonistas alfa-Adrenérgicos/farmacología , Hipoxia/patología , Fibras Nerviosas Amielínicas/efectos de los fármacos , Conducción Nerviosa/efectos de los fármacos , Octopamina/farmacología , Potenciales de Acción/efectos de los fármacos , Agonistas alfa-Adrenérgicos/uso terapéutico , Animales , Inhibidores Enzimáticos/farmacología , Lateralidad Funcional/efectos de los fármacos , Saltamontes , Oxigenoterapia Hiperbárica/métodos , Masculino , Movimiento/efectos de los fármacos , Fibras Nerviosas Amielínicas/fisiología , Octopamina/uso terapéutico , Técnicas de Placa-Clamp , Estimulación Luminosa , Azida Sódica/farmacología , Nervios Torácicos/patología , Factores de TiempoRESUMEN
Entomopathogenic nematodes (EPNs) play a role in indirect defense of plants under attack by root herbivores. Several investigations have shown that EPNs are attracted or repelled by various volatile compounds (VOCs) released from insect damaged plant roots. We hypothesized that the directional responses of EPNs to the VOCs would be affected by foraging strategy and would vary among species, VOC type, and VOC concentrations. We tested the chemotactic responses of four commercial EPN species (Steinernema feltiae, S. carpocapsae, S. kraussei, and Heterorhabditis bacteriophora) to seven compounds released from insect (Melolontha hippocastani)-damaged (decanal, nonanal, octanal, undecane, 6-methyl-5-hepten-2-one, and 1,2,4-trimethylbenzene) and undamaged (2-ethyl-1-hexanol) potato tubers. Our results suggest that EPNs are able to distinguish herbivore-induced VOCs from those that are typical for healthy potato tubers. In our investigation, nonanal, octanal, and decanal had a greater influence on the movement of EPNs than other tested synthetic volatiles. Decanal was an attractant for H. bacteriophora and S. kraussei at both tested concentrations (as a pure compound and at a concentration of 0.03 ppm). The results suggest that the susceptibility to perception of chemical stimuli from the environment is a species-specific characteristic that prevails over the influence of the foraging strategy.