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1.
Phys Chem Chem Phys ; 22(3): 1333-1348, 2020 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-31854415

RESUMEN

Using molecular dynamics simulations, herein, we illustrate that a bending structure shows different behaviors for fast water transport through aquaporin-mimicking membranes in multilayer graphene and tubular structures. This suggests that the bending structure enhances water transport through multilayer membranes, indicating the optimum state at θ = 45°. Disruption of the single-file water arrangement inside the membrane can contribute to promoting water transport in this system. However, a bending structure reduces the rate of water transport in tubular systems. Our results exhibit that a straight tubular membrane transfers water molecules faster than its non-straight counterpart. A stabilized form of the single-file water structure was observed in the membrane. Interestingly, we found that the tubular hourglass-shaped membranes possessed a lower free energy than the multilayer membranes with an hourglass shape. This can be attributed to the accommodation of the single-file water configuration in a confined space with hydrophobic characteristics. Accordingly, integrating an hourglass shape pore in a tubular structure in an impermeable membrane provides high water permeability compared with its multilayer counterpart. We also found that the wide variation in the dipole orientation of water molecules and the energy barrier have dominant effects in determining fast water transport through multilayer and tubular membranes, respectively. The contribution of interlayer spacing on fast water transport through multilayer membranes was also studied.


Asunto(s)
Acuaporinas/química , Membranas Artificiales , Agua/química , Grafito/química , Simulación de Dinámica Molecular , Imitación Molecular , Agua/metabolismo
2.
Clin Exp Pharmacol Physiol ; 46(9): 791-797, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31332816

RESUMEN

The aim of this study was to investigate whether the glutathione peroxidase-1 gene (GPx-1) affects cocaine-induced conditioned place preference (CPP) using a mouse model. Cocaine-induced CPP was accompanied by an increase in the level of σ-1 receptor in the nucleus accumbens (NAc). This phenomenon was more pronounced in the GPx-1 gene knockout (GPx-1 KO) than in wild type (WT) mice. In contrast, the CPP and expression of σ-1 receptor were much less pronounced in GPx-1-overexpressing transgenic (GPx-1 TG) mice than non-transgenic (non-TG) mice. Treatment of the mice with BD1047, a σ-1 receptor antagonist, significantly attenuated both cocaine-induced CPP and c-Fos-immunoreactivity (c-Fos-IR) in WT and GPx-1 KO mice, although the effects were more evident in the latter group. Despite the protective effects of BD1047 on cocaine-induced CPP and c-Fos in non-TG mice, there were no additional protective effects in cocaine-treated GPx-1 TG mice, indicating that the σ-1 receptor is a critical target for GPx-1-mediated psychoprotective activity. Overall, our results suggest that GPx-1 attenuates cocaine-induced CPP via inhibition of σ-1 receptor expression.


Asunto(s)
Conducta Animal/efectos de los fármacos , Cocaína/farmacología , Condicionamiento Psicológico/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Glutatión Peroxidasa/genética , Receptores sigma/genética , Animales , Técnicas de Inactivación de Genes , Glutatión Peroxidasa/deficiencia , Ratones , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Glutatión Peroxidasa GPX1 , Receptor Sigma-1
3.
J Neuroinflammation ; 15(1): 52, 2018 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-29467000

RESUMEN

BACKGROUND: We previously reported that ginsenoside Re (GRe) attenuated against methamphetamine (MA)-induced neurotoxicity via anti-inflammatory and antioxidant potentials. We also demonstrated that dynorphin possesses anti-inflammatory and antioxidant potentials against dopaminergic loss, and that balance between dynorphin and substance P is important for dopaminergic neuroprotection. Thus, we examined whether GRe positively affects interactive modulation between dynorphin and substance P against MA neurotoxicity in mice. METHODS: We examined changes in dynorphin peptide level, prodynorphin mRNA, and substance P mRNA, substance P-immunoreactivity, homeostasis in enzymatic antioxidant system, oxidative parameter, microglial activation, and pro-apoptotic parameter after a neurotoxic dose of MA to clarify the effects of GRe, prodynorphin knockout, pharmacological inhibition of κ-opioid receptor (i.e., nor-binaltorphimine), or neurokinin 1 (NK1) receptor (i.e., L-733,060) against MA insult in mice. RESULTS: GRe attenuated MA-induced decreases in dynorphin level, prodynorphin mRNA expression in the striatum of wild-type (WT) mice. Prodynorphin knockout potentiated MA-induced dopaminergic toxicity in mice. The imbalance of enzymatic antioxidant system, oxidative burdens, microgliosis, and pro-apoptotic changes led to the dopaminergic neurotoxicity. Neuroprotective effects of GRe were more pronounced in prodynorphin knockout than in WT mice. Nor-binaltorphimine, a κ-opioid receptor antagonist, counteracted against protective effects of GRe. In addition, we found that GRe significantly attenuated MA-induced increases in substance P-immunoreactivity and substance P mRNA expression in the substantia nigra. These increases were more evident in prodynorphin knockout than in WT mice. Although, we observed that substance P-immunoreactivity was co-localized in NeuN-immunreactive neurons, GFAP-immunoreactive astrocytes, and Iba-1-immunoreactive microglia. NK1 receptor antagonist L-733,060 or GRe selectively inhibited microgliosis induced by MA. Furthermore, L-733,060 did not show any additive effects against GRe-mediated protective activity (i.e., antioxidant, antimicroglial, and antiapoptotic effects), indicating that NK1 receptor is one of the molecular targets of GRe. CONCLUSIONS: Our results suggest that GRe protects MA-induced dopaminergic neurotoxicity via upregulatgion of dynorphin-mediated κ-opioid receptor and downregulation of substance P-mediated NK1 R.


Asunto(s)
Neuronas Dopaminérgicas/metabolismo , Dinorfinas/metabolismo , Ginsenósidos/farmacología , Metanfetamina/toxicidad , Receptores de Neuroquinina-1/metabolismo , Receptores Opioides kappa/metabolismo , Sustancia P/metabolismo , Animales , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Antagonistas del Receptor de Neuroquinina-1/farmacología , Piperidinas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiología
4.
J Appl Toxicol ; 38(12): 1502-1520, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30027653

RESUMEN

Since the cocaine-induced oxidative stress has been established to lead to hepatotoxicity, we examined the role of the glutathione peroxidase (GPx)-1 gene in cocaine-induced hepatotoxicity. Cocaine treatment significantly increased superoxide dismutase activity in as little as 1 hour, with a maximum level at 6 hours in wild-type mice, while significantly decreasing GPx activity and subsequently inducing oxidative damage (i.e., reactive oxygen species, lipid peroxidation and protein carbonylation). These changes were more prominent in the mitochondrial fraction than in the cytosolic fraction. In contrast, genetic overexpression of GPx-1 significantly attenuated cocaine-induced oxidative damage in mice. Cocaine treatment significantly increased alanine aminotransferase and aspartate aminotransferase levels in the serum. Consistently, cocaine significantly enhanced cleaved caspase-3 expression and intramitochondrial Ca2+ , while significantly reducing mitochondrial transmembrane potential. Cocaine treatment potentiated cleavage of protein kinase C δ (PKCδ), mitochondrial translocation of PKCδ, cytosolic release of cytochrome c and activation of caspase-3, followed by hepatopathologic changes. These results were more prominent in GPx-1 knockout than in wild-type mice, and they were less pronounced in overexpressing transgenic than in non-transgenic mice. Combined, our results suggest that the GPx-1 gene possesses protective potential against mitochondrial oxidative burden, mitochondrial dysfunction and hepatic degeneration induced by cocaine and that the protective mechanisms are associated with anti-apoptotic activity via inactivation of PKCδ.


Asunto(s)
Antioxidantes/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/enzimología , Cocaína/toxicidad , Glutatión Peroxidasa/genética , Estrés Oxidativo/genética , Animales , Calcio/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Citosol/efectos de los fármacos , Citosol/metabolismo , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Potencial de la Membrana Mitocondrial/genética , Ratones Noqueados , Mitocondrias Hepáticas/efectos de los fármacos , Mitocondrias Hepáticas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Carbonilación Proteica/efectos de los fármacos , Carbonilación Proteica/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transgenes , Glutatión Peroxidasa GPX1
5.
Phys Chem Chem Phys ; 19(31): 20749-20759, 2017 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-28740979

RESUMEN

In this study, molecular dynamics (MD) simulations are used to examine the water transport properties through asymmetric hourglass-shaped pores in multilayer nanoporous graphene with a constant interlayer separation of 6 Å. The properties of the tested asymmetric hourglass-shaped pores [with the models having long cone (l1, -P) and short cone (l2, +P) entrances] are compared to a symmetric pore model. The study findings indicate that the water occupancy increases across the asymmetric pore (l1, -P) compared to (l2, +P), because of the length effect. The asymmetric pore, (l1, -P), yields higher flux compared to (l2, +P) and even the symmetric model, which can be attributed to the increase in the hydrogen bonds. In addition, the single-file water molecules across the narrowest pore diameter inside the (l2, +P) pore exhibit higher viscosity compared to those in the (l1, -P) pore because of the increase in the water layering effect. Moreover, it is found that the permeability inside the multilayer hourglass-shaped pore depends on the length of the flow path of the water molecules before approaching the layer with the smallest pore diameter. The probability of dipole orientation exhibits wider distribution inside the (l1, -P) system compared to (l2, +P), implying an enhanced formation of hydrogen bonding of water molecules. This results in the fast flow of water molecules. The MD trajectory shows that the dipole orientation across the single-layer graphene has frequently flipped compared to the dipole orientation across the pores in multilayer graphene, which is maintained during the whole simulation time (although the dipole orientation has flipped for a few picoseconds at the beginning of the simulation). This can be attributed to the energy barrier induced by the individual layer. The diffusion coefficient of water molecules inside the (l2, +P) system increases with pressure difference, however, it decreases inside the (l1, -P) system because of the increase in the number of collisions. It was found that the velocity in the axial direction (z-direction) has a significant impact on the permeation ability of water molecules across the asymmetric nanopores examined in this study. Finally, the study results suggest that the appropriate design of an asymmetric hourglass-shaped nanopore in multilayer graphene can significantly improve the water permeation rate even compared to a symmetric structure.

6.
Exp Cell Res ; 336(2): 211-22, 2015 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-26172215

RESUMEN

The human CD99 protein is a 32-kDa type I transmembrane glycoprotein, while CD98 is a disulfide-linked 125-kDa heterodimeric type II transmembrane glycoprotein. It has been previously shown that CD99 and CD98 oppositely regulate ß1 integrin signaling, though the mechanisms by which this regulation occurs are not known. Our results revealed that antibody-mediated crosslinking of CD98 induced FAK phosphorylation at Y397 and facilitated the formation of the protein kinase Cα (PKCα)-syntenin-focal adhesion kinase (FAK), focal adhesions (FAs), and IPP-Akt1-syntenin complex, which mediates ß1 integrin signaling. In contrast, crosslinking of CD99 disrupted the formation of the PKCα-syntenin-FAK complex as well as FA via FAK dephosphorylation. The CD99-induced dephosphorylation of FAK was apparently mediated by the recruitment of Src homology region 2 domain-containing phosphatase-2 (SHP2) to the plasma membrane and subsequent activation of its phosphatase activity. Further consequences of the activation of SHP2 included the disruption of FAK-talin and talin-ß1 integrin interactions and attenuation in the formation of the IPP-Akt1-syntenin complex at the plasma membrane, which resulted in reduced cell-ECM adhesion. This report uncovers the molecular mechanisms underlying the inverse regulation of ß1 integrin signaling by CD99 and CD98 and may provide a novel therapeutic approach to treat inflammation and cancer.


Asunto(s)
Antígenos CD/metabolismo , Moléculas de Adhesión Celular/metabolismo , Quinasa 1 de Adhesión Focal/metabolismo , Proteína-1 Reguladora de Fusión/metabolismo , Integrina beta1/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Antígeno 12E7 , Adhesión Celular , Línea Celular Tumoral , Adhesiones Focales/metabolismo , Humanos , Fosforilación , Proteína Quinasa C-alfa/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Interferencia de ARN , ARN Interferente Pequeño , Transducción de Señal , Sinteninas/metabolismo
7.
Clin Exp Pharmacol Physiol ; 43(4): 428-37, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26850368

RESUMEN

The present study investigates the role of the glutathione peroxidase (GPx)-1 gene in cocaine-induced renal damage in mice. Multiple doses of cocaine increased lipid peroxidation, protein oxidation, and glutathione oxidation in the kidney of the non-transgenic mice (non-TG mice). The enzymatic activities of GPx and glutathione reductase were significantly decreased in non-TG mice, whereas superoxide dismutase was increased in the early phase of cocaine exposure. Treatment with cocaine resulted in significant decreases in expression of Bcl-2 and Bcl-xl in the kidney of non-TG mice, which resulted in significant increases in Bax and cleaved-caspase 3. Consistently, cocaine-induced tubular epithelial vacuolization and focal tubular necrosis were mainly observed in the proximal tubules in the kidneys of non-TG mice. These renal pathologic changes were much less pronounced in GPx-1 TG than in non-TG mice. These results suggest that the GPx-1 gene is a protective factor against nephrotoxicity induced by cocaine via interactive modulations between antioxidant and cell survival signaling processes.


Asunto(s)
Apoptosis/efectos de los fármacos , Cocaína/toxicidad , Glutatión Peroxidasa/genética , Riñón/citología , Riñón/efectos de los fármacos , Animales , Antioxidantes/metabolismo , Nitrógeno de la Urea Sanguínea , Creatinina/sangre , Relación Dosis-Respuesta a Droga , Expresión Génica , Disulfuro de Glutatión/metabolismo , Homeostasis/efectos de los fármacos , Riñón/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones , Ratones Transgénicos , Estrés Oxidativo/efectos de los fármacos , Glutatión Peroxidasa GPX1
8.
Arch Toxicol ; 90(4): 937-53, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25895139

RESUMEN

We investigated whether protein kinase C (PKC) is involved in trimethyltin (TMT)-induced neurotoxicity. TMT treatment (2.8 mg/kg, i.p.) significantly increased PKCδ expression out of PKC isozymes (i.e., α, ßI, ßII, δ, and ς) in the hippocampus of wild-type (WT) mice. Consistently, treatment with TMT resulted in significant increases in cleaved PKCδ expression. Genetic or pharmacological inhibition (PKCδ knockout or rottlerin) was less susceptible to TMT-induced seizures than WT mice. TMT treatment increased glutathione oxidation, lipid peroxidation, protein oxidation, and levels of reactive oxygen species. These effects were more pronounced in the WT mice than in PKCδ knockout mice. In addition, the ability of TMT to induce nuclear translocation of Nrf2, Nrf2 DNA-binding activity, and upregulation of γ-glutamylcysteine ligase was significantly increased in the PKCδ knockout mice and rottlerin (10 or 20 mg/kg, p.o. × 6)-treated WT mice. Furthermore, neuronal degeneration (as shown by nuclear chromatin clumping and TUNEL staining) in WT mice was most pronounced 2 days after TMT. At the same time, TMT-induced inhibition of phosphoinositol 3-kinase (PI3K)/Akt signaling was evident, thereby decreasing phospho-Bad, expression of Bcl-xL and Bcl-2, and the interaction between phospho-Bad and 14-3-3 protein, and increasing Bax expression and caspase-3 cleavage were observed. Rottlerin or PKCδ knockout significantly protected these changes in anti- and pro-apoptotic factors. Importantly, treatment of the PI3K inhibitor LY294002 (0.8 or 1.6 µg, i.c.v.) 4 h before TMT counteracted protective effects (i.e., Nrf-2-dependent glutathione induction and pro-survival phenomenon) of rottlerin. Therefore, our results suggest that down-regulation of PKCδ and up-regulations of Nrf2-dependent glutathione defense mechanism and PI3K/Akt signaling are critical for attenuating TMT neurotoxicity.


Asunto(s)
Glutatión/metabolismo , Hipocampo/efectos de los fármacos , Síndromes de Neurotoxicidad/etiología , Proteína Quinasa C-delta/metabolismo , Compuestos de Trimetilestaño/toxicidad , Acetofenonas/farmacología , Animales , Benzopiranos/farmacología , Relación Dosis-Respuesta a Droga , Hipocampo/metabolismo , Hipocampo/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Síndromes de Neurotoxicidad/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteína Quinasa C-delta/antagonistas & inhibidores , Proteína Quinasa C-delta/genética , Inhibidores de Proteínas Quinasas/farmacología , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico
9.
Biol Pharm Bull ; 38(8): 1208-13, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26235584

RESUMEN

We demonstrated the inhibitory effect of fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), on voltage-dependent K(+) (Kv) channels in freshly isolated rabbit coronary arterial smooth muscle cells using a whole-cell patch clamp technique. Fluvoxamine reduced the amplitude of Kv currents in a concentration-dependent manner with an IC50 value of 3.71±1.09 µM and a Hill coefficient of 0.62±0.14. Although fluvoxamine did not significantly affect the steady-state activation curve, it shifted the steady-state inactivation curve toward a more negative potential. Pretreatment with another SSRI, paroxetine, did not affect the basal Kv current and did not alter the inhibitory effect of fluvoxamine on Kv channels. We concluded that fluvoxamine inhibits the Kv current in a concentration-dependent manner and in a closed (inactivated) state of the Kv channels independent of serotonin reuptake inhibition.


Asunto(s)
Vasos Coronarios/efectos de los fármacos , Fluvoxamina/farmacología , Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Canales de Potasio con Entrada de Voltaje/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Animales , Vasos Coronarios/metabolismo , Relación Dosis-Respuesta a Droga , Fluvoxamina/efectos adversos , Masculino , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Técnicas de Placa-Clamp , Conejos , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos
10.
J Pharmacol Sci ; 125(3): 312-9, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24989838

RESUMEN

We demonstrated the inhibitory effect of NNC 55-0396, a T-type Ca(2+) channel inhibitor, on voltage-dependent K(+) (K(V)) channels in freshly isolated rabbit coronary arterial smooth muscle cells. NNC 55-0396 decreased the amplitude of K(V) currents in a concentration-dependent manner, with an IC(50) of 0.080 µM and a Hill coefficient of 0.76.NNC 55-0396 did not affect steady-state activation and inactivation curves, indicating that the compound does not affect the voltage sensitivity of K(V) channel gating. Both the K(V) currents and the inhibitory effect of NNC 55-0396 on K(V) channels were not altered by depletion of extracellular Ca(2+) or intracellular ATP, suggesting that the inhibitory effect of NNC 55-0396 is independent of Ca(2+)-channel activity and phosphorylation-dependent signaling cascades. From these results, we concluded that NNC 55-0396 dosedependently inhibits K(V) currents, independently of Ca(2+)-channel activity and intracellular signaling cascades.


Asunto(s)
Bencimidazoles/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/efectos de los fármacos , Vasos Coronarios/citología , Ciclopropanos/farmacología , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , Naftalenos/farmacología , Canales de Potasio con Entrada de Voltaje/antagonistas & inhibidores , Animales , Canales de Calcio Tipo T/fisiología , Señalización del Calcio , Células Cultivadas , Relación Dosis-Respuesta a Droga , Fosforilación , Canales de Potasio con Entrada de Voltaje/fisiología , Conejos
11.
Phys Chem Chem Phys ; 16(29): 15263-71, 2014 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-24939373

RESUMEN

Recent studies of graphene have demonstrated its great potential for highly sensitive resonators. In order to capture the intrinsic vibrational characteristics of graphene, we propose an atomistic modeling method called the elastic network model (ENM), in which a graphene sheet is modeled as a mass-spring network of adjacent atoms connected by various linear springs with specific bond ratios. Normal mode analysis (NMA) reveals the various vibrational features of bi-layer graphene sheets (BLGSs) clamped at two edges. We also propose a coarse-graining (CG) method to extend our graphene study into the meso- and macroscales, at which experimental measurements and synthesis of graphene become practical. The simulation results show good agreement with experimental observations. Therefore, the proposed ENM approach will not only shed light on the theoretical study of graphene mechanics, but also play an important role in the design of highly-sensitive graphene-based resonators.

12.
J Ginseng Res ; 47(4): 561-571, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37397414

RESUMEN

Background: Escalating evidence shows that ginseng possesses an antiaging potential with cognitive enhancing activity. As mountain cultivated ginseng (MCG) is cultivated without agricultural chemicals, MCG has emerged as a popular herb medicine. However, little is known about the MCG-mediated pharmacological mechanism on brain aging. Methods: As we demonstrated that glutathione peroxidase (GPx) is important for enhancing memory function in the animal model of aging, we investigated the role of MCG as a GPx inducer using GPx-1 (a major type of GPx) knockout (KO) mice. We assessed whether MCG modulates redox and cholinergic parameters, and memory function in aged GPx-1 knockout KOmice. Results: Redox burden of aged GPx-1 KO mice was more evident than that of aged wild-type (WT) mice. Alteration of Nrf2 DNA binding activity appeared to be more evident than that of NFκB DNA binding activity in aged GPx-1 KO mice. Alteration in choline acetyltransferase (ChAT) activity was more evident than that in acetylcholine esterase activity. MCG significantly attenuated reductions in Nrf2 system and ChAT level. MCG significantly enhanced the co-localization of Nrf2-immunoreactivity and ChAT-immunoreactivity in the same cell population. Nrf2 inhibitor brusatol significantly counteracted MCG-mediated up-regulation in ChAT level and ChAT inhibition (by k252a) significantly reduced ERK phosphorylation by MCG, suggesting that MCG might require signal cascade of Nrf2/ChAT/ERK to enhance cognition. Conclusion: GPx-1 depletion might be a prerequisite for cognitive impairment in aged animals. MCG-mediated cognition enhancement might be associated with the activations of Nrf2, ChAT, and ERK signaling cascade.

13.
Food Chem Toxicol ; 173: 113627, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36682417

RESUMEN

Ginsenoside Re (GRe) upregulates anti-aging klotho by mainly upregulating glutathione peroxidase-1 (GPx-1). However, the anti-aging mechanism of GPx-1 remains elusive. Here we investigated whether the GRe-mediated upregulation of GPx-1 modulates oxidative and proinflammatory insults. GPx-1 gene depletion altered redox homeostasis and platelet-activating factor receptor (PAFR) and nuclear factor kappa B (NFκB) expression, whereas the genetic overexpression of GPx-1 or GRe mitigated this phenomenon in aged mice. Importantly, the NFκB inhibitor pyrrolidine dithiocarbamate (PDTC) did not affect PAFR expression, while PAFR inhibition (i.e., PAFR knockout or ginkgolide B) significantly attenuated NFκB nuclear translocation, suggesting that PAFR could be an upstream molecule for NFκB activation. Iba-1-labeled microgliosis was more underlined in aged GPx-1 KO than in aged WT mice. Triple-labeling immunocytochemistry showed that PAFR and NFκB immunoreactivities were co-localized in Iba-1-positive populations in aged mice, indicating that microglia released these proteins. GRe inhibited triple-labeled immunoreactivity. The microglial inhibitor minocycline attenuated aging-related reduction in phospho-ERK. The effect of minocycline was comparable with that of GRe. GRe, ginkgolide B, PDTC, or minocycline also attenuated aging-evoked memory impairments. Therefore, GRe ameliorated aging-associated memory impairments in the absence of GPx-1 by inactivating oxidative insult, PAFR, NFkB, and microgliosis.


Asunto(s)
Glutatión Peroxidasa GPX1 , FN-kappa B , Ratones , Animales , FN-kappa B/metabolismo , Glutatión Peroxidasa/genética , Glutatión Peroxidasa/metabolismo , Minociclina/metabolismo , Minociclina/farmacología , Ratones Noqueados , Hipocampo
14.
Biochem Biophys Res Commun ; 423(1): 110-5, 2012 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-22634012

RESUMEN

We investigated the effect of a specific protein kinase C (PKC) inhibitor, bisindolylmaleimide I [BIM (I)], on L-type Ca(2+) channels in rat ventricular myocytes. BIM (I) alone inhibited the L-type Ca(2+) current in a concentration-dependent manner, with a K(d) value of 3.31 ± 0.25 µM, and a Hill coefficient of 2.34 ± 0.23. Inhibition was immediate after applying BIM (I) in the bath solution and then it partially washed out. The steady-state activation curve was not altered by applying 3µ M BIM (I), but the steady-state inactivation curve shifted to a more negative potential with a change in the slope factor. Other PKC inhibitors, PKC-IP and chelerythrine, showed no significant effects either on the L-type Ca(2+) current or on the inhibitory effect of BIM (I) on the L-type Ca(2+) current. The results suggest that the inhibitory effect of BIM (I) on the L-type Ca(2+) current is independent of the PKC pathway. Thus, our results should be considered in studies using BIM (I) to inhibit PKC activity and ion channel modulation.


Asunto(s)
Canales de Calcio Tipo L/metabolismo , Ventrículos Cardíacos/citología , Indoles/farmacología , Maleimidas/farmacología , Miocitos Cardíacos/efectos de los fármacos , Proteína Quinasa C/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Animales , Células Cultivadas , Ventrículos Cardíacos/metabolismo , Masculino , Miocitos Cardíacos/metabolismo , Ratas , Ratas Sprague-Dawley
15.
J Pharmacol Sci ; 120(3): 196-205, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23117866

RESUMEN

We examined the effects of mibefradil, a T-type Ca²âº channel inhibitor, on voltage-dependent K⁺ (Kv) channels in rabbit coronary arterial smooth muscle cells using the whole-cell patch clamp technique. Mibefradil reduced the Kv current amplitude in a dose-dependent manner, with an apparent K(d) value of 1.08 µM. Kv current inhibition by mibefradil was highly voltage-dependent over the full activation voltage range (-30 to +10 mV). The decay rate of Kv channel inactivation was accelerated by mibefradil without altering the kinetics of current activation. The rate constants of association and dissociation were 2.23 ± 0.07 µM⁻¹·s⁻¹ and 2.40 ± 0.42 s⁻¹, respectively. Mibefradil had no significant effect on the steady-state activation or inactivation curves. In the presence of mibefradil, the recovery time constant from inactivation was decreased, and the application of train pulses (1 or 2 Hz) increased mibefradil-induced Kv channel inhibition, suggesting that the inhibitory effects of mibefradil were use-dependent. The inhibitory effect of mibefradil on Kv channels was unaffected by extracellular Ca²âº-free conditions. Moreover, the absence of ATP inside the pipette did not alter the blocking effect of mibefradil. Therefore, we suggest that mibefradil directly inhibited the Kv current, independently of Ca²âº channel inhibition.


Asunto(s)
Arterias/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Vasos Coronarios/efectos de los fármacos , Mibefradil/farmacología , Músculo Liso Vascular/efectos de los fármacos , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio con Entrada de Voltaje/antagonistas & inhibidores , Animales , Antihipertensivos/farmacología , Arterias/citología , Arterias/metabolismo , Canales de Calcio Tipo T/química , Canales de Calcio Tipo T/metabolismo , Células Cultivadas , Vasos Coronarios/citología , Vasos Coronarios/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Cinética , Masculino , Potenciales de la Membrana/efectos de los fármacos , Músculo Liso Vascular/citología , Músculo Liso Vascular/metabolismo , Concentración Osmolar , Técnicas de Placa-Clamp , Canales de Potasio con Entrada de Voltaje/metabolismo , Conejos
16.
Micromachines (Basel) ; 13(10)2022 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-36296139

RESUMEN

In the present work, the effects on water transport due to the orientation of the layer in the multilayered porous graphene and the different patterns formed when the layer is oriented to some degrees are studied for both circular and non-circular pore configurations. Interestingly, the five-layered graphene membrane with a layer separation of 3.5 Å used in this study shows that the water transport through multilayered porous graphene can be augmented by introducing an angle to certain layers of the multilayered membrane system.

17.
Membranes (Basel) ; 12(11)2022 Nov 07.
Artículo en Inglés | MEDLINE | ID: mdl-36363664

RESUMEN

The water transport through nanoporous multilayered graphene at 300k is investigated using molecular dynamics (MD) simulation with different water models in this study. We used functionalized and non-functionalized membranes along with five different 3-point rigid water models: SPC (simple point charge), SPC/E (extended simple point charge), TIP3P-FB (transferable intermolecular potential with 3 points-Force Balance), TIP3P-EW (transferable intermolecular potential with 3 points with Ewald summation) and OPC3 (3-point optimal point charge) water models. Based on our simulations with two water reservoirs and a porous multilayered graphene membrane in-between them, it is evident that the water transport varies significantly depending on the water model used, which is in good agreement with previous works. This study contributes to the selection of a water model for molecular dynamics simulations of water transport through multilayered porous graphene.

18.
Membranes (Basel) ; 12(4)2022 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-35448365

RESUMEN

Reverse electrodialysis (RED) generates power directly by transforming salinity gradient into electrical energy. The ion transport properties of the ion-exchange membranes need to be investigated deeply to improve the limiting efficiencies of the RED. The interaction between "counterions" and "ionic species" in the membrane requires a fundamental understanding of the phase separation process. Here, we report on sulfonated poly(vinylidene fluoride-co-hexafluoropropylene)/graphitic carbon nitride nanocomposites for RED application. We demonstrate that the rearrangement of the hydrophilic and hydrophobic domains in the semicrystalline polymer at a nanoscale level improves ion conduction. The rearrangement of the ionic species in polymer and "the functionalized nanosheet with ionic species" enhances the proton conduction in the hybrid membrane without a change in the structural integrity of the membrane. A detailed discussion has been provided on the membrane nanostructure, chemical configuration, structural robustness, surface morphology, and ion transport properties of the prepared hybrid membrane. Furthermore, the RED device was fabricated by combining synthesized cation exchange membrane with commercially available anion exchange membrane, NEOSEPTA, and a maximum power density of 0.2 W m-2 was successfully achieved under varying flow rates at the ambient condition.

19.
Free Radic Biol Med ; 189: 2-19, 2022 08 20.
Artículo en Inglés | MEDLINE | ID: mdl-35840016

RESUMEN

Ginseng is known to possess anti-aging potential. Klotho mutant mice exhibit phenotypes that resemble the phenotype of the human aging process. Similar to Klotho deficient mice, patients with chronic kidney disease (CKD) suffer vascular damage and cognitive impairment, which might upregulate the angiotensin II AT1 receptor. Since AT1 receptor expression was more pronounced than endothelin ET-1 expression in the hippocampus of aged Klotho deficient (±) mice, we focused on the AT1 receptor in this study. Ginsenoside Re (GRe), but not ginsenoside Rb1 (GRb1), significantly attenuated the increase in AT1 receptor expression in aged Klotho deficient mice. Both GRe and the AT1 receptor antagonist losartan failed to attenuate the decrease in phosphorylation of JAK2/STAT3 in aged Klotho deficient (±) mice but significantly activated nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated signaling. Both GRe and losartan attenuated the increased NADPH oxidase (NOX) activity and reactive oxygen species (ROS) in aged Klotho deficient mice. Furthermore, of all the antioxidant enzymes, GRe significantly increased glutathione peroxidase (GPx) activity. GRe significantly attenuated the reduced phosphorylation of ERK and CREB in GPx-1 knockout mice; however, genetic overexpression of GPx-1 did not significantly affect them in aged mice. Klotho-, Nrf2-, and GPx-1-immunoreactivities were co-localized in the same cells of the hippocampus in aged Klotho wild-type mice. Both the GPx inhibitor mercaptosuccinate and Nrf2 inhibitor brusatol counteracted the effects of GRe on all neurobehavioral impairments in aged Klotho deficient (±) mice. Our results suggest that GRe attenuates all alterations, such as AT1 receptor expression, NOX-, ROS-, and GPx-levels, and cognitive dysfunction in aged Klotho deficient (±) mice via upregulation of Nrf2/GPx-1/ERK/CREB signaling.


Asunto(s)
Factor 2 Relacionado con NF-E2 , Receptor de Angiotensina Tipo 1 , Animales , Ratones , Angiotensina II , Antioxidantes/farmacología , Ginsenósidos , Glutatión Peroxidasa , Glutatión Peroxidasa GPX1 , Proteínas Klotho , Losartán/farmacología , Trastornos de la Memoria , Ratones Noqueados , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Especies Reactivas de Oxígeno
20.
Biochem Biophys Res Commun ; 411(2): 259-64, 2011 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-21723260

RESUMEN

Galectin-9 exhibited potent and selective eosinophil chemoattractant activity and attracted eosinophils in vitro and in vivo. Nasal polyposis is a chronic inflammatory disease of the upper airway characterized by the marked presence of inflammatory cells, particularly eosinophils. Thus, galectin-9 may be implicated in the pathogenesis of nasal polyposis. The study was designed to investigate whether interferon-gamma (IFN-γ) can induce the augmentation of galectin-9 expression and induce the expression of galectin-9 in nasal polyps. We examined the correlation between galectin-9 expression and eosinophil infiltration in nasal polyps. In addition, we identified the signaling pathways involved in the elevation of galectin-9 expression in response to IFN-γ. Our data demonstrate that the involvement of mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3 phosphate kinase (PI3K), and Janus kinase/signal transducer and activator of transcription (JAK/STAT) may play important roles in the selective recruitment of eosinophils in nasal polyp tissues through the production of galectin-9. These findings suggest that galectin-9 expression is associated with eosinophil infiltration in polyps of patients with nasal polyposis.


Asunto(s)
Eosinófilos/inmunología , Galectinas/biosíntesis , Interferón gamma/inmunología , Quinasas Janus/metabolismo , Pólipos Nasales/inmunología , Células Cultivadas , Eosinófilos/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Fibroblastos/inmunología , Humanos , Interferón gamma/farmacología , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Factores de Transcripción STAT/metabolismo
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