RESUMEN
Stroke is a condition with few medical treatments available. Semaglutide, a novel Glucagon-like peptide-1 (GLP-1) analogue, has been brought to the market as a treatment for diabetes. We tested the protective effects of semaglutide against middle cerebral artery occlusion injury in rats. Animals were treated with 10â¯nmol/kg bw ip. starting 2â¯h after surgery and every second day for either 1, 7, 14 or 21 days. Semaglutide-treated animals showed significantly reduced scores of neurological impairments in several motor and grip strength tasks. The cerebral infarction size was also reduced, and the loss of neurons in the hippocampal areas CA1, CA3 and the dentate gyrus was much reduced. Chronic inflammation as seen in levels of activated microglia and in the activity of the p38 MAPK - MKK - c-Jun- NF-κB p65 inflammation signaling pathway was reduced. In addition, improved growth factor signaling as shown in levels of activated ERK1 and IRS-1, and a reduction in the apoptosis signaling pathway C-raf, ERK2, Bcl-2/BAX and Caspase-3 was observed. Neurogenesis had also been normalized by the drug treatment as seen in increased neurogenesis (DCX-positive cells) in the dentate gyrus and a normalization of biomarkers for neurogenesis. In conclusion, semaglutide is a promising candidate for re-purposing as a stroke treatment.
Asunto(s)
Apoptosis/efectos de los fármacos , Encéfalo/efectos de los fármacos , Péptidos Similares al Glucagón/farmacología , Hipocampo/efectos de los fármacos , Hipoglucemiantes/farmacología , Infarto de la Arteria Cerebral Media/patología , Neurogénesis/efectos de los fármacos , Animales , Encéfalo/inmunología , Encéfalo/patología , Modelos Animales de Enfermedad , Proteína Doblecortina , Péptido 1 Similar al Glucagón/análogos & derivados , Hipocampo/citología , Infarto de la Arteria Cerebral Media/inmunología , Infarto de la Arteria Cerebral Media/fisiopatología , Inflamación/inmunología , Proteínas Sustrato del Receptor de Insulina/efectos de los fármacos , Proteínas Sustrato del Receptor de Insulina/metabolismo , Microglía/efectos de los fármacos , Microglía/inmunología , Proteína Quinasa 3 Activada por Mitógenos/efectos de los fármacos , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/efectos de los fármacos , Quinasas de Proteína Quinasa Activadas por Mitógenos/inmunología , Actividad Motora/efectos de los fármacos , Neuronas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-jun/efectos de los fármacos , Proteínas Proto-Oncogénicas c-jun/inmunología , Ratas , Accidente Cerebrovascular/inmunología , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/fisiopatología , Factor de Transcripción ReIA/efectos de los fármacos , Factor de Transcripción ReIA/inmunología , Proteínas Quinasas p38 Activadas por Mitógenos/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/inmunologíaRESUMEN
Type 2 diabetes mellitus (T2DM) is a risk factors for developing Parkinson's disease (PD). Insulin desensitization is observed in the brains of PD patients, which may be an underlying mechanism that promotes neurodegeneration. Incretin hormones are growth factors that can re-sensitize insulin signalling. We have previously shown that analogues of the incretins GLP-1 or GIP have neuroprotective effects in the MPTP mouse model of PD. Novel dual GLP-1/GIP receptor agonists have been developed as treatments for T2DM. We have tested 3 novel dual receptor agonists DA-JC1, DA-JC4 and DA-CH5 in comparison with the GLP-1 analogue liraglutide (all drugs at 25â¯nmol/kg ip once-daily for 6 days) in the MPTP mouse model of PD (4â¯×â¯25â¯mg/kg ip). In the Rotarod and grip strength assessment, DA-CH5 performed best in reversing the MPTP-induced motor impairment. Dopamine synthesis as indicated by levels of tyrosine hydroxylase was much reduced by MPTP in the substantia nigra and striatum, and DA-CH5 was the best drug to reverse this. Pro-inflammatory cytokines were best reduced by DA-CH5, while expression levels of the neuroprotective growth factor Glial-Derived Neurotrophic Factor (GDNF) was most increased by DA-JC4. Synapses were protected best by DA-JC4 and DA-CH5. Both DA-JC1 and liraglutide showed inferior effects. These results show that a combination of GLP-1 and GIP receptor activation is more efficient compared to single GLP-1 receptor activation. We conclude that dual agonists are a promising novel treatment for PD. The GLP-1 mimetic exendin-4 has previously shown disease modifying effects in two clinical trials in Parkinson patients.
Asunto(s)
Receptor del Péptido 1 Similar al Glucagón/agonistas , Intoxicación por MPTP/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Péptidos/uso terapéutico , Receptores de la Hormona Gastrointestinal/agonistas , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Animales , Glucemia/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Citocinas/metabolismo , Modelos Animales de Enfermedad , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Receptor del Péptido 1 Similar al Glucagón/química , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Hipoglucemiantes/uso terapéutico , Liraglutida/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Neurotoxinas/toxicidad , Receptores de la Hormona Gastrointestinal/química , Receptores de la Hormona Gastrointestinal/metabolismoRESUMEN
Type 2 diabetes mellitus (T2DM) is one of the risk factors for Parkinson's disease (PD). Insulin desensitisation has been observed in the brains of patients, which may promote neurodegeneration. Incretins are a family of growth factors that can re-sensitise insulin signalling. We have previously shown that mimetics of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine (MPTP) mouse model of PD. Recently, dual GLP-1/GIP receptor agonists have been developed. We therefore tested the novel dual agonist DA3-CH in comparison with the best GLP-1 analogue currently on the market, liraglutide (both drugs 25nmol/kg ip once-daily for 7 days) in the MPTP mouse model of PD (25mg/kg ip once-daily for 7 days). In the Rotarod and grip strength assessment, DA3-CH was superior to liraglutide in reversing the MPTP-induced motor impairment. Dopamine synthesis as indicated by levels of tyrosine hydroxylase was much reduced by MPTP in the substantia nigra and striatum, and DA3-CH reversed this while liragutide only partially reversed this. The chronic inflammation response as shown in increased levels of activated microglia and astrocytes was reduced by both drugs. Importantly, expression levels of the neuroprotective growth factor Glial Derived Neurotrophic Factor (GDNF) was much enhanced by both DA3-CH and liragutide. The results demonstrate that the combination of GLP-1 and GIP receptor activation is superior to single GLP-1 receptor activation alone. Therefore, new dual agonists may be a promising treatment for PD. The GLP-1 receptor agonist exendin-4 has already shown disease modifying effects in clinical trials in PD patients.
Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Receptor del Péptido 1 Similar al Glucagón/agonistas , Liraglutida/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Receptores de la Hormona Gastrointestinal/agonistas , Animales , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Proteínas de Unión al Calcio/metabolismo , Dopamina/biosíntesis , Fuerza de la Mano , Inflamación/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas de Microfilamentos/metabolismo , Actividad Motora/efectos de los fármacos , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/fisiopatología , Prueba de Desempeño de Rotación con Aceleración ConstanteRESUMEN
The growth factor glucagon-like peptide-1 (GLP-1) is neuroprotective in several animal models of neurodegeneration. Here, we analyzed the neuroprotective effects of a novel protease-resistant GLP-1 analogue, (Val(8))GLP-1-Glu-PAL, which has advantages over older analogues, such as improvement of hippocampal neurogenesis, glucose homeostasis, and insulin secretion. We established an in vitro model of Parkinson's disease using the mitochondrial stressor rotenone in primary cultured mouse neurons pretreated with (Val(8))GLP-1-Glu-PAL. (Val(8))GLP-1-Glu-PAL alone did not affect neuronal viability, but prevented the rotenone-induced reduction in cell viability in a dose-dependent manner. In addition, (Val(8))GLP-1-Glu-PAL pretreatment prevented rotenone-induced proapoptotic changes manifesting as downregulation of procaspase-3 and Bcl-2 and upregulation of cleaved caspase-3. These results demonstrate that the novel agent (Val(8))GLP-1-Glu-PAL shows promise as a drug treatment for Parkinson's disease.
RESUMEN
This study aimed to determine the effects of different concentrations of soluble beta-amyloid 25-35 (Aß25-35) on cell viability, calcium overload, and PI3K-p85 expression in cultured cortical rat neurons. Primary cultured cerebral cortical neurons of newborn rats were divided randomly into six groups. Five groups were treated with soluble Aß25-35 at concentrations of 10nmol/L, 100nmol/L, 1µmol/L, 10µmol/L, or 30µmol/L. Cell Counting Kit-8 staining was used to measure cell viability, laser-scanning confocal imaging was used to detect changes in intracellular free calcium concentration, and western blot assay was used to measure neuronal PI3K-p85 expression. Soluble Aß25-35 was found to reduce cell viability and induce calcium overload in primary cultured rat cerebral cortical neurons, in a concentration-dependent manner. At certain concentrations, soluble Aß25-35 also increased neuronal PI3K-p85 expression. These findings reveal that soluble Aß25-35 reduces the viability of cultured cerebral cortical rat neurons. The neurotoxicity mechanism may involve calcium overload and disruption of insulin signal transduction pathways.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Corteza Cerebral/metabolismo , Neuronas/metabolismo , Fragmentos de Péptidos/metabolismo , Péptidos beta-Amiloides/toxicidad , Animales , Animales Recién Nacidos , Calcio/metabolismo , Supervivencia Celular , Corteza Cerebral/citología , Corteza Cerebral/efectos de los fármacos , Fosfatidilinositol 3-Quinasa Clase Ia/metabolismo , Insulina/fisiología , Neuronas/citología , Neuronas/efectos de los fármacos , Fragmentos de Péptidos/toxicidad , Cultivo Primario de Células , Ratas Wistar , Transducción de Señal , SolubilidadRESUMEN
The incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are growth factors. GLP-1 mimetics are on the market as treatments for type 2 diabetes. Both GLP-1 and GIP mimetics have shown neuroprotective properties in previous studies. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in a clinical trial in Parkinson's disease (PD) patients. Novel GLP-1/GIP dual-agonist peptides have been developed to treat diabetes. Here, we report the neuroprotective effects of a novel dual agonist (DA-JC1) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected once daily (20 mg/kg intraperitoneally) for 7 days and the dual agonist was coinjected once daily (50 nmol/kg intraperitoneally). We found that the drug reduced most of the MPTP-induced motor impairments in the rotarod, open-field locomotion, and muscle strength test. The number of tyrosine hydroxylase-positive neurons in the substantia nigra and striatum was reduced by MPTP and increased by DA-JC1. Synapse numbers (synaptophysin expression) were reduced in the substantia nigra and the striatum by MPTP and DA-JC1 reversed this effect. The activation of a chronic inflammation response by MPTP was considerably reduced by the dual agonist (DA) (astroglia and microglia activation). Therefore, dual agonists show promise as a novel treatment of PD.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Encéfalo/metabolismo , Intoxicación por MPTP/patología , Intoxicación por MPTP/prevención & control , Péptidos/uso terapéutico , Análisis de Varianza , Animales , Encéfalo/efectos de los fármacos , Proteínas de Unión al Calcio , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismo , Receptor del Péptido 1 Similar al Glucagón/agonistas , Locomoción/efectos de los fármacos , Intoxicación por MPTP/inducido químicamente , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas de Microfilamentos , Receptores de la Hormona Gastrointestinal/agonistas , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Glucose-dependent insulinotropic polypeptide (GIP) is a member of the incretin hormones and growth factors. Neurons express the GIP receptor, and GIP and its agonists can pass through the blood brain barrier and show remarkable neuroprotective effects by protecting synapse function and numbers, promoting neuronal proliferation, reducing amyloid plaques in the cortex and reducing the chronic inflammation response of the nervous system. Long-acting analogues of GIP that are protease resistant had been developed as a treatment for type 2 diabetes. It has been found that such GIP analogues show good protective effects in animal models of Alzheimer's disease. Novel dual agonist peptides that activate the GIP receptor and another incretin receptor, glucagon-like peptide -1 (GLP-1), are under development that show superior effects in diabetic patients compared to single GLP-1 agonists. The dual agonists also show great promise in treating neurodegenerative disorders, and there are currently several clinical trials ongoing, testing GLP-1 mimetics in people with Alzheimer's or Parkinson's disease.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Polipéptido Inhibidor Gástrico/análogos & derivados , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Alzheimer/prevención & control , Animales , Polipéptido Inhibidor Gástrico/farmacología , Receptor del Péptido 1 Similar al Glucagón/agonistas , Humanos , Fármacos Neuroprotectores/farmacología , Receptores de la Hormona Gastrointestinal/agonistas , Transducción de Señal , Sinapsis/efectos de los fármacosRESUMEN
The incretins glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) are growth factors with neuroprotective properties. GLP-1 mimetics are on the market as treatments for type 2 diabetes and are well tolerated. Both GLP-1 and GIP mimetics have shown neuroprotective properties in animal models of Parkinson's and Alzheimer's disease. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in a clinical trial in Parkinson's disease (PD) patients. Novel GLP-1/GIP dual-agonist peptides have been developed and are tested in diabetic patients. Here we demonstrate the neuroprotective effects of a novel dual agonist (DA-JC1) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected once-daily (20 mg/kg i.p.) for 7 days, and the dual agonist was injected 30 min later i.p. (50 nmol/kg bw). The PI3k inhibitor LY294002 (0.6 mg/kg i.v.) was co-injected in one group. DA-JC1 reduced or reversed most of the MPTP induced motor impairments in the rotarod and in a muscle strength test. The number of tyrosine hydroxylase (TH) positive neurons in the substantia nigra (SN) was reduced by MPTP and increased by DA-JC1. The ratio of anti-inflammatory Bcl-2 to pro-inflammatory BAX as well as the activation of the growth factor kinase Akt was reduced by MPTP and reversed by DA-JC1. The PI3k inhibitor had only limited effect on the DA-JC1 drug effect. Importantly, levels of the neuroprotective brain derived neurotropic factor (BDNF) were reduced by MPTP and enhanced by DA-JC1. The results demonstrate that DA-JC1 shows promise as a novel treatment for PD.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Receptor del Péptido 1 Similar al Glucagón/agonistas , Fármacos Neuroprotectores/administración & dosificación , Trastornos Parkinsonianos/metabolismo , Receptores de la Hormona Gastrointestinal/agonistas , Animales , Apoptosis/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Fuerza Muscular/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Trastornos Parkinsonianos/prevención & control , Proteínas Proto-Oncogénicas c-akt/metabolismo , Prueba de Desempeño de Rotación con Aceleración Constante , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have been shown to be neuroprotective in previous studies in animal models of Alzheimer's or Parkinson's disease. Recently, novel dual-GLP-1/GIP receptor agonists that activate both receptors (DA) were developed to treat diabetes. We tested the protective effects of a novel potent DA against middle cerebral artery occlusion injury in rats and compared it with a potent GLP-1 analog, Val(8)-GLP-1(glu-PAL). Animals were evaluated for neurologic deficit score, infarct volume, and immunohistochemical analyses of the brain at several time points after ischemia. The Val(8)-GLP-1(glu-PAL)-treated and DA-treated groups showed significantly reduced scores of neurological dysfunction, cerebral infarction size, and percentage of TUNEL-positive apoptotic neurons. Furthermore, the expression of the apoptosis marker Bax, the inflammation marker iNOS, and the survival marker Bcl-2 was significantly increased. The DA-treated group was better protected against neurodegeneration than the Val(8)-GLP-1(glu-PAL) group, and the scores of neurological dysfunction, cerebral infarction size, and expression of Bcl-2 were higher, whereas the percentage of TUNEL-positive neurons and the levels of Bax and iNOS were lower in the DA group. DA treatment reduced the infarct volume and improved the functional deficit. It also suppressed the inflammatory response and cell apoptosis after reperfusion. In conclusion, the novel GIP and GLP-1 dual-receptor agonist is more neuroprotective than a GLP-1 receptor agonist in key biomarkers of neuronal degeneration.
Asunto(s)
Encéfalo/efectos de los fármacos , Péptido 1 Similar al Glucagón/análogos & derivados , Receptor del Péptido 1 Similar al Glucagón/agonistas , Ataque Isquémico Transitorio/tratamiento farmacológico , Lipopéptidos/farmacología , Receptores de la Hormona Gastrointestinal/agonistas , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Péptido 1 Similar al Glucagón/farmacología , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Infarto de la Arteria Cerebral Media , Ataque Isquémico Transitorio/complicaciones , Ataque Isquémico Transitorio/metabolismo , Ataque Isquémico Transitorio/patología , Masculino , Actividad Motora/efectos de los fármacos , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/etiología , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Fármacos Neuroprotectores/farmacología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Distribución Aleatoria , Ratas Sprague-Dawley , Receptores de la Hormona Gastrointestinal/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
OBJECTIVE: Ferrous iron is a major source inducing oxidative stress after intracerebral hemorrhage (ICH). Divalent metal transporter1 (DMT1) is the important and well-known plasma membrane transport protein which was proved to be involved in the transport of free ferrous iron in mammals. Ferroportin 1 (FPN1) is the unique exporter of ferrous iron from mammalian cells. The role of DMT1 and FPN1 in brain after ICH is still not elucidated. Therefore, we measure the expression of DMT1 and FPN1, to explore the correlations between ferrous iron and its specific transporters after ICH. METHODS: Ninety-six Sprague-Dawley rats received intra-striatal infusions of 0.5 U type IV collagenase to establish ICH model. Ferrous iron content in brain was determined using Turnbull's method. DMT1 and FPN1 expression were examined by immunohistochemical staining and Real-Time quantitative polymerase chain reaction (RT-PCR). With the use of confocal laser microscopy, we determined the colocalization of DMT1 and FPN1 at 1, 3, 7 and 14 days after ICH. RESULTS: Ferrous iron deposition was shown in the perihematomal zone as early as 1 day after ICH; it reached a peak after 7 days and was not elevated within 14 days following ICH. The expression of the DMT1 upregulated and reached to peak at day 7 after ICH. FPN1 reached a plateau at 3 days post-ICH. Expression levels of DMT1 and FPN1 were in parallel with ferrous iron deposition. There was a positive correlation between FPN1 and DMT1. DMT1 mainly localized in the cytoplasm of glias and neurons. FPN1 were mostly distributed on the membrane of endothelial cells and glias. Confocal microscope showed that DMT1 colocalized with FPN1. CONCLUSIONS: DMT1 and FPN1 are positively influenced by ferrous iron status in brain after ICH. DMT1 and FPN1 attenuate iron overload after ICH via increasing transmembrane iron export.
Asunto(s)
Encéfalo/metabolismo , Proteínas de Transporte de Catión/metabolismo , Hemorragia Cerebral/metabolismo , Hierro/metabolismo , Animales , Transporte Biológico , Encéfalo/patología , Proteínas de Transporte de Catión/genética , Hemorragia Cerebral/inducido químicamente , Hemorragia Cerebral/genética , Hemorragia Cerebral/patología , Colagenasas , Modelos Animales de Enfermedad , Masculino , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Geniposide, a monomer extracted from gardenia and widely used in Chinese medicine, is a novel agonist at the glucagon-like peptide-1 receptor. This receptor is involved in neuroprotection. In the present study, we sought to identify an anti-apoptotic mechanism for the treatment of neurodegenerative diseases. Primary cultured neurons were treated with different concentrations of rotenone for 48 hours. Morphological observation, cell counting kit-8 assay, lactate dehydrogenase detection and western blot assay demonstrated that 0.5 nM rotenone increased lactate dehydrogenase release, decreased the expression of procaspase-3 and Bcl-2, and increased cleaved caspase-3 expression in normal neurons. All these effects were prevented by geniposide. Our results indicate that geniposide diminished rotenone-induced injury in primary neurons by suppressing apoptosis. This may be one of the molecular mechanisms underlying the efficacy of geniposide in the treatment of neurodegenerative diseases.
RESUMEN
A Caulobacter crescentus swarmer cell is propelled by a helical flagellum, which is rotated by a motor at its base. The motor alternates between rotating in clockwise and counterclockwise directions and spends variable intervals of time in each state. We measure the distributions of these intervals for cells either free swimming or tethered to a glass slide. A peak time of around one second is observed in the distributions for both motor directions with counterclockwise intervals more sharply peaked and clockwise intervals displaying a larger tail at long times. We show that distributions of rotation intervals fit first passage time statistics for a biased random walker and the dynamic binding of CheY-P to FliM motor subunits accounts for this behavior. Our results also suggest that the presence of multiple CheY proteins in C. crescentus may be responsible for differences between its switching behavior and that of the extensively studied E. coli.
Asunto(s)
Caulobacter crescentus/fisiología , Flagelos/fisiología , Modelos Biológicos , Proteínas Bacterianas/fisiología , Proteínas de Escherichia coli , Proteínas de la Membrana/fisiología , Proteínas Quimiotácticas Aceptoras de Metilo , Modelos Estadísticos , Proteínas Motoras Moleculares/fisiologíaRESUMEN
A growing body of evidence has linked two of the most common aged-related diseases: type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD). It has led to the notion that drugs developed for the treatment of T2DM may be beneficial in modifying the pathophysiology of AD. As a receptor agonist of glucagon-like peptide-1 (GLP-1R), which is a newer drug class to treat T2DM, geniposide shows clear effects in inhibiting pathological processes underlying AD, such as promoting neurite outgrowth. In the present article, we review the possible molecular mechanisms of geniposide to protect the brain from pathologic damages underlying AD: reducing amyloid plaques, inhibiting τ phosphorylation, preventing memory impairment and loss of synapses, reducing oxidative stress and the chronic inflammatory response, and promoting neurite outgrowth via the GLP-1R signaling pathway. In summary, the Chinese herb geniposide shows great promise as a novel treatment for AD.
Asunto(s)
Enfermedad de Alzheimer/prevención & control , Iridoides/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/patología , Animales , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/patología , Humanos , Iridoides/farmacología , Fármacos Neuroprotectores/farmacologíaRESUMEN
BACKGROUND: Motility of flagellated bacteria depends crucially on their organelles such as flagella and pili, as well as physical properties of the external medium, such as viscosity and matrix elasticity. We studied the motility of wild-type and two mutant strains of Caulobacter crescentus swarmer cells in two different types of media: a viscous and hyperosmotic glycerol-growth medium mixture and a viscoelastic growth medium, containing polyethylene glycol or polyethylene oxide of different defined sizes. RESULTS: For all three strains in the medium containing glycerol, we found linear drops in percentage of motile cells and decreases in speed of those that remained motile to be inversely proportional to viscosity. The majority of immobilized cells lost viability, evidenced by their membrane leakage. In the viscoelastic media, we found less loss of motility and attenuated decrease of swimming speed at shear viscosity values comparable to the viscous medium. In both types of media, we found more severe loss in percentage of motile cells of wild-type than the mutants without pili, indicating that the interference of pili with flagellated motility is aggravated by increased viscosity. However, we found no difference in swimming speed among all three strains under all test conditions for the cells that remained motile. Finally, the viscoelastic medium caused no significant change in intervals between flagellar motor switches unless the motor stalled. CONCLUSION: Hyperosmotic effect causes loss of motility and cell death. Addition of polymers into the cell medium also causes loss of motility due to increased shear viscosity, but the majority of immobilized bacteria remain viable. Both viscous and viscoelastic media alter the motility of flagellated bacteria without affecting the internal regulation of their motor switching behavior.
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Caulobacter crescentus/fisiología , Medios de Cultivo/química , Elasticidad , Locomoción , Viscosidad , Viabilidad Microbiana , Presión OsmóticaRESUMEN
Microbes inhabiting Earth have adapted to diverse environments of water, air, soil, and often at the interfaces of multiple media. In this study, we focus on the behavior of Caulobacter crescentus, a singly flagellated bacterium, at the air/water interface. Forward swimming C. crescentus swarmer cells tend to get physically trapped at the surface when swimming in nutrient-rich growth medium but not in minimal salt motility medium. Trapped cells move in tight, clockwise circles when viewed from the air with slightly reduced speed. Trace amounts of Triton X100, a nonionic surfactant, release the trapped cells from these circular trajectories. We show, by tracing the motion of positively charged colloidal beads near the interface that organic molecules in the growth medium adsorb at the interface, creating a high viscosity film. Consequently, the air/water interface no longer acts as a free surface and forward swimming cells become hydrodynamically trapped. Added surfactants efficiently partition to the surface, replacing the viscous layer of molecules and reestablishing free surface behavior. These findings help explain recent similar studies on Escherichia coli, showing trajectories of variable handedness depending on media chemistry. The consistent behavior of these two distinct microbial species provides insights on how microbes have evolved to cope with challenging interfacial environments.
Asunto(s)
Aire , Caulobacter crescentus/citología , Movimiento , Agua , Adsorción , Microscopía , Propiedades de SuperficieRESUMEN
BACKGROUND: Adhesion to surfaces facilitates many crucial functions of microbes in their natural habitats. Thus understanding the mechanism of microbial adhesion is of broad interest to the microbiology research community. RESULTS: We report a study by fluorescence imaging and atomic force microscopy on the growth in size and thickness of the holdfast of synchronized Caulobacter crescentus cells as they attach to a glass surface. We found that the holdfast undergoes a two-stage process of spreading and thickening during its morphogenesis. The holdfast first forms a thin plate on the surface. The diameter of the holdfast plate reaches its final average value of 360 nm by the cell age of ~ 30 min, while its thickness further increases until the age of ~ 60 min. Our AFM analysis indicates that the holdfast is typically thicker in the middle, with gradual falloff in thickness towards the outer edge. CONCLUSIONS: We propose that the newly secreted holdfast substance is fluid-like. It has strong affinity to the surface and cures to form a plate-like holdfast capable of supporting strong and permanent adhesion.
Asunto(s)
Adhesión Bacteriana , Caulobacter crescentus/fisiología , Caulobacter crescentus/crecimiento & desarrollo , Procesamiento de Imagen Asistido por Computador , Microscopía de Fuerza Atómica , Microscopía FluorescenteRESUMEN
OBJECTIVE: To explore the influence of the storage conditions on the seed development of Corydalis yanhusuo. METHODS: The embryo formation process of the wild Corydalis yanhusuo was observed,and the germination rate of wild Corydalis yanhusuo seeds stored under different conditions was measured. RESULTS: The seed development of the wild Corydalis yanhusuo depended on the storage conditions. The seeds subjected to stratification had the highest germination percentage. Those stored in dry conditions would lose the vitality completely. The seeds in isothermal storage had very low germination rates. As revealed by slices, only the seeds after stratification treatment had the ability to form a complete embryo. CONCLUSION: The Corydalis yanhusuo seed is a kind of seed without fully developed embryo, and needs further after-ripening for its development. Its vitality has a great seasonal and annual dependence.
Asunto(s)
Corydalis/embriología , Corydalis/crecimiento & desarrollo , Germinación/fisiología , Semillas/crecimiento & desarrollo , Corydalis/fisiología , Plantas Medicinales/crecimiento & desarrollo , Plantas Medicinales/fisiología , Plantones/crecimiento & desarrollo , Semillas/fisiología , Temperatura , Factores de TiempoRESUMEN
Monodisperse 11 nm indium tin oxide (ITO) nanocrystals (NCs) were synthesized by thermal decomposition of indium acetylacetonate, In(acac)(3), and tin bis(acetylacetonate)dichloride, Sn(acac)(2)Cl(2), at 270 °C in 1-octadecene with oleylamine and oleic acid as surfactants. Dispersed in hexane, these ITO NCs were spin-cast on centimeter-wide glass substrates, forming uniform ITO NC assemblies with root-mean-square roughness of 2.9 nm. The assembly thickness was controlled by ITO NC concentrations in hexane and rotation speeds of the spin coater. Via controlled thermal annealing at 300 °C for 6 h under Ar and 5% H(2), the ITO NC assemblies became conductive and transparent with the 146 nm-thick assembly showing 5.2 × 10(-3) Ω·cm (R(s) = 356 Ω/sq) resistivity and 93% transparency in the visible spectral range--the best values ever reported for ITO NC assemblies prepared from solution phase processes. The stable hexane dispersion of ITO NCs was also readily spin-cast on polyimide (T(g) ~360 °C), and the resultant ITO assembly exhibited a comparable conductivity and transparency to the assembly on a glass substrate. The reported synthesis and assembly provide a promising solution to the fabrication of transparent and conducting ITO NCs on flexible substrates for optoelectronic applications.
RESUMEN
Most nanomaterials enter the natural environment as nanoenabled products, which are typically composites with primary nanoparticles bound on substrates or embedded in liquid or solid matrices. The environmental risks associated with these products are expected to differ from those associated with the as-produced particles. This article presents a case study on the end-of-life emission of a commercial prototype polymer/quantum-dot (QD) composite used in solid-state lighting for homes. We report the extent of cadmium release upon exposure to a series of environmental and biological simulant fluids, and track the loss of QD-characteristic fluorescence as a marker for chemical damage to the CdSe/ZnS nanoparticles. Measured cadmium releases after 30-day exposure range from 0.007 to 1.2 mg/g of polymer, and the higher values arise for low-pH simulants containing nitric or gastric acid. Centrifugal ultrafiltration and ICP was used to distinguish soluble cadmium from particulate forms. The leachate is found to contain soluble metals with no evidence of free QDs or QD-containing polymeric debris. The absence of free nanoparticles suggests that this product does not raise nanotechnology-specific environmental issues associated with degradation and leaching, but is more usefully regarded as a conventional chemical product that is a potential source of small amounts of soluble cadmium.
Asunto(s)
Compuestos de Cadmio/química , Cadmio/análisis , Iluminación , Nanocompuestos/química , Puntos Cuánticos , Compuestos de Selenio/química , Sulfuros/química , Compuestos de Zinc/química , Benzopiranos/química , Seguridad de Productos para el Consumidor , Ácido Gástrico/química , Sustancias Húmicas , Peróxido de Hidrógeno/química , Microscopía Fluorescente , Ácido Nítrico/química , Oxidantes/química , Cloruro de Sodio/química , Agua/químicaRESUMEN
The attachment of bacteria to surfaces provides advantages such as increasing nutrient access and resistance to environmental stress. Attachment begins with a reversible phase, often mediated by surface structures such as flagella and pili, followed by a transition to irreversible attachment, typically mediated by polysaccharides. Here we show that the interplay between pili and flagellum rotation stimulates the rapid transition between reversible and polysaccharide-mediated irreversible attachment. We found that reversible attachment of Caulobacter crescentus cells is mediated by motile cells bearing pili and that their contact with a surface results in the rapid pili-dependent arrest of flagellum rotation and concurrent stimulation of polar holdfast adhesive polysaccharide. Similar stimulation of polar adhesin production by surface contact occurs in Asticcacaulis biprosthecum and Agrobacterium tumefaciens. Therefore, single bacterial cells respond to their initial contact with surfaces by triggering just-in-time adhesin production. This mechanism restricts stable attachment to intimate surface interactions, thereby maximizing surface attachment, discouraging non-productive self-adherence, and preventing curing of the adhesive.