RESUMO
Excessive stress plays a critical role in the pathogenesis of mood disorders such as depression. Fermented natural products have recently attracted attention because of their health benefits. We evaluated the antidepressant-like efficacy of fermented Perilla frutescens (FPF), and its underlying mechanisms, in sleep deprivation (SD)-induced stress mice. SD-stressed mice revealed a remarkable increase in the immobility time in both forced swimming test and tail suspension test; this increase was ameliorated by treatment with FPF at doses of 100 and 150 mg/kg. FPF treatment also reduced the level of stress hormones such as corticosterone and adrenocorticotropic hormone. Additionally, FPF increased the levels of serotonin and dopamine which were significantly decreased in the brain tissues of SD-stressed mice. The increased expression of proinflammatory cytokines, such as TNF-α and IL1ß, and the decreased expression of brain-derived neurotrophic factor (BDNF) in the stressed mice were significantly reversed by FPF treatment. Furthermore, FPF also increased phosphorylation of tropomyosin receptor kinase B (TrkB), extracellular regulated protein kinase (ERK), and cAMP response element binding protein (CREB). Among the six components isolated from FPF, protocatechuic acid and luteolin-7-O-glucuronide exhibited significant antidepressant-like effects, suggesting that they are major active components. These findings suggest that FPF has therapeutic potential for SD-induced stress, by correcting dysfunction of hypothalamic-pituitary-adrenal axis and modulating the BDNF/TrkB/ERK/CREB signaling pathway.
Assuntos
Depressão , Perilla frutescens , Camundongos , Animais , Depressão/tratamento farmacológico , Depressão/etiologia , Depressão/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Perilla frutescens/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Privação do Sono/complicações , Privação do Sono/tratamento farmacológico , Privação do Sono/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Estresse Psicológico/complicações , Estresse Psicológico/tratamento farmacológico , Modelos Animais de Doenças , Hipocampo/metabolismoRESUMO
Adhesion of leukocytes to endothelial cells plays an important role in neuroinflammation. Therefore, suppression of the expression of adhesion molecules in brain endothelial cells may inhibit neuroinflammation. Chrysin (5,7-dihydroxyflavone) is a flavonoid component of propolis, blue passion flowers, and fruits. In the present study, we examined the effects of chrysin on lipopolysaccharide (LPS)-induced expression of vascular cell adhesion molecule-1 (VCAM-1) in mouse cerebral vascular endothelial (bEnd.3) cells. In bEnd.3 cells, LPS increased mRNA expression of VCAM-1 in a time-dependent manner, and chrysin significantly decreased LPS-induced mRNA expression of VCAM-1. Chrysin also reduced VCAM-1 protein expression in a concentration-dependent manner. Furthermore, chrysin blocked adhesion of monocytes to bEnd.3 cells exposed to LPS. Nuclear factor-κB (NF-κB), p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase, which are all activated by LPS, were significantly inhibited by chrysin. These results indicate that chrysin inhibits the expression of VCAM-1 in brain endothelial cells by inhibiting NF-κB translocation and MAPK signaling, resulting in the attenuation of leukocyte adhesion to endothelial cells. The anti-inflammatory effects of chrysin suggest a possible therapeutic application of this agent to neurodegenerative diseases, such as multiple sclerosis, septic encephalopathy, and allergic encephalomyelitis.
Assuntos
Encéfalo/citologia , Células Endoteliais/citologia , Flavonoides/farmacologia , Lipopolissacarídeos/farmacologia , Monócitos/citologia , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/metabolismo , Animais , Adesão Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos , Fosforilação/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células U937 , Molécula 1 de Adesão de Célula Vascular/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
The ubiquitin-proteasome system (UPS) plays an important role in protein quality control, cellular signalings, and cell differentiation through the regulated turnover of key transcription factors in cardiac tissue. However, the molecular mechanism underlying Fbxo25-mediated ubiquitination of cardiac transcription factors remains elusive. We report that an Fbxo25-mediated SCF ubiquitination pathway regulates the protein levels and activities of Tbx5 and Nkx2-5 based on our studies using MG132, proteasome inhibitor, and the temperature sensitive ubiquitin system in ts20 cells. Our data indicate that Fbxo25 directly interacts with Tbx5 and Nkx2-5 in vitro and in vivo. In support of our findings, a dominant-negative mutant of Fbxo25, Fbxo251-236, prevents Tbx5 degradation and increases Tbx5 transcriptional activity in a Tbx5 responsive luciferase assay. Therefore, Fbxo25 facilitates Tbx5 degradation in an SCF-dependent manner. In addition, the silencing of endogenous Fbxo25 increases Tbx5 and Nkx2-5 mRNA levels and suppresses mESC-derived cardiomyocyte differentiation. Likewise, the exogenous expression of FBXO25 downregulates NKX2-5 level in human ESC-derived cardiomyocytes. In myocardial infarction model, Fbxo25 mRNA decreases, whereas the mRNA and protein levels of Tbx5 and Nkx2-5 increase. The protein levels of Tbx5 and Nkx2-5 are regulated negatively by Fbxo25-mediated SCF ubiquitination pathway. Thus, our findings reveal a novel mechanism for regulation of SCFFbox25-dependent Nkx2-5 and Tbx5 ubiquitination in cardiac development and provide a new insight into the regulatory mechanism of Nkx2-5 and Tbx5 transcriptional activity.
Assuntos
Diferenciação Celular/genética , Proteínas F-Box/genética , Proteínas de Homeodomínio/genética , Miócitos Cardíacos/metabolismo , Proteínas com Domínio T/genética , Fatores de Transcrição/genética , Animais , Células-Tronco Embrionárias , Proteínas F-Box/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Proteína Homeobox Nkx-2.5 , Proteínas de Homeodomínio/biossíntese , Humanos , Leupeptinas/administração & dosagem , Camundongos , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/genética , Proteólise , Proteínas Ligases SKP Culina F-Box , Proteínas com Domínio T/biossíntese , Fatores de Transcrição/biossíntese , Ativação Transcricional/efeitos dos fármacosRESUMO
The Forkhead box O 3a (FoxO3a), a transcription factor, is known to be involve in change of endothelial permeability. During hypoxia, blood-brain barrier (BBB) permeability is increased through degradation of vascular endothelium cadherin (VE-cadherin) and clsudin-5. The hypoxia also increased mRNA levels of matrix metalloproteinase (MMP)-3/9 and promoted translocation of FoxO3a into nucleus in endothelial cells. However, little is known about the role of FoxO3a in hypoxia-induced BBB hyperpermeability. Here, we examined whether FoxO3a regulates hypoxia-induced BBB permeability through induction of MMPs. The transfection of siFoxO3a suppressed hypoxia-induced BBB hyperpermeability. The transfection of siFoxO3a also inhibited hypoxia-induced degradation of VE-cadherin and claudin-5. In addition, the transfection of siFoxO3a reduced hypoxia-induced increase of MMP-3 mRNA levels. However, transfection of siFoxO3a did not inhibits transcription of MMP-9 induced by hypoxia. Taken together, our findings suggest that FoxO3a is involved in hypoxia-induced degradation of VE-cadherin and claudin-5 through induction of MMPs indirectly.
Assuntos
Barreira Hematoencefálica/fisiologia , Hipóxia Celular , Fatores de Transcrição Forkhead/fisiologia , Proteína Forkhead Box O3 , Humanos , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Chemokines are important mediators of cell migration, and thymus and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22) are well-known typical inflammatory chemokines involved in atopic dermatitis (AD). (+)-Nootkatone is the major component of Cyperus rotundus. (+)-Nootkatone has antiallergic, anti-inflammatory, and antiplatelet activities. The purpose of this study was to investigate the effect of (+)-nootkatone on tumor necrosis factor α (TNF-α)/interferon γ (IFN-γ)-induced expression of Th2 chemokines in HaCaT cells. We found that (+)-nootkatone inhibited the TNF-α/IFN-γ-induced expression of TARC/CCL17 and MDC/CCL22 mRNA in HaCaT cells. It also significantly inhibited TNF-α/IFN-γ-induced activation of nuclear factor kappa B (NF-κB), p38 mitogen-activated protein kinase (MAPK), and protein kinase Cζ (PKCζ). Furthermore, we showed that PKCζ and p38 MAPK contributed to the inhibition of TNF-α/IFN-γ-induced TARC/CCL17 and MDC/CCL22 expression by blocking IκBα degradation in HaCaT cells. Taken together, these results suggest that (+)-nootkatone may suppress TNF-α/IFN-γ-induced TARC/CCL17 and MDC/CCL22 expression in HaCaT cells by inhibiting of PKCζ and p38 MAPK signaling pathways that lead to activation of NF-κB. We propose that (+)-nootkatone may be a useful therapeutic candidate for inflammatory skin diseases such as AD.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Quimiocina CCL17/antagonistas & inibidores , Quimiocina CCL22/antagonistas & inibidores , Sesquiterpenos/farmacologia , Células Th2/efeitos dos fármacos , Linhagem Celular , Quimiocina CCL17/biossíntese , Quimiocina CCL17/genética , Quimiocina CCL22/biossíntese , Quimiocina CCL22/genética , Dermatite Atópica/imunologia , Humanos , Interferon gama/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Sesquiterpenos Policíclicos , Proteína Quinase C/antagonistas & inibidores , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Células Th2/imunologia , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Sleep is one of the most essential physiological phenomena for maintaining health. Sleep disturbances, such as insomnia, are often accompanied by psychiatric or physical conditions such as impaired attention, anxiety, and stress. Medication used to treat insomnia have concerns about potential side effects with long-term use, so interest in the use of alternative medicine is increasing. In this study, we investigated the hypnotic effects of ß-lapachone (ß-Lap), a natural naphthoquinone compound, using pentobarbital-induced sleep test, immunohistochemistry, real-time PCR, and western blot in mice. Our results indicated that ß-Lap exerts a significant hypnotic effect by showing a decrease in sleep onset latency and an increase in total sleep time in pentobarbital-induced sleep model. The results of c-Fos immunostaining showed that ß-Lap decreased neuronal activity in the basal forebrain and lateral hypothalamus, which are wakefulness-promoting brain regions, while increasing in the ventrolateral preoptic nucleus, a sleep-promoting region; all these effects were significantly abolished by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an adenosine A1 receptor (A1R) antagonist. Western blot analysis showed that ß-Lap increased extracellular signalregulated kinase phosphorylation and nuclear factor-kappa B translocation from the cytoplasm to the nucleus; these effects were inhibited by DPCPX. Additionally, ß-Lap increased the mRNA levels of A1R. Taken together, these results suggest that ß-Lap exerts hypnotic effects, potentially through A1R.
RESUMO
Insomnia is one of the most common sleep disorders, affecting 10-15% of the global population. Because classical remedies used to treat insomnia have various side effects, new therapeutics for insomnia are attracting attention. In the present study, we found that N2-Ethyl-N4-(furan-2-ylmethyl) quinazoline-2,4-diamine (AR-001) has adenosine A1 receptor agonistic activity and exhibits hypnotic efficacy by decreasing sleep onset latency and increasing total sleep time in a pentobarbital-induced sleep model. This hypnotic effect of AR-001 was significantly inhibited by the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). As a result of immunohistochemistry, AR-001 was shown to increase neural activity in the sleep-promoting region, ventrolateral preoptic nucleus (VLPO), and decrease neural activity in the wake-promoting region, basal forebrain (BF), and lateral hypothalamus (LH), and that these effects of AR-001 were significantly inhibited by DPCPX treatment. In addition, AR-001 increased adenosine A1 receptor mRNA levels in the hypothalamus. In conclusion, this study suggests that AR-001 has a hypnotic effect, at least partially, through adenosine A1 receptor and may have therapeutic potential for insomnia.
RESUMO
The antihypertensive effects of both extracts and glycosaminoglycan derived from Isaria sinclairii (IS) were investigated in a spontaneously hypertensive rat (SHR) model. Groups of rats were treated orally with 30 mg/kg each of: (1) saline control or extracts of (2) water-IS (3) methanol-IS, (4) butanol-IS, (5) ethyl acetate-IS, or (6) captopril as positive control. The 30-mg/kg dose was administered with a standard diet every day for a period of 2 wk. The antihypertensive effects of the individual extracts were in the following order: methanol > water > ethyl acetate > butanol. Glycosaminoglycan (GAG) obtained from IS as a water-soluble alcohol precipitation fraction produced an antihypertensive effect. One month following administration of GAG derived from IS to SHR animals there was a marked decrease in systolic blood pressure from 183 to 105 mm Hg and reduced diastolic blood pressure from 148 to 80 mm Hg compared to untreated control SHR rats. It was found that GAG produced an antihypertensive effect, which was more effective than the positive control captopril. In the SHR animal model a fall of 19% in body weight was observed in the group that received GAG. Data thus indicate that GAG derived from I. sinclairii may be a potent, naturally occurring antihypertensive agent.
Assuntos
Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Glicosaminoglicanos/farmacologia , Hipertensão/tratamento farmacológico , Hypocreales/química , Animais , Coagulação Sanguínea/efeitos dos fármacos , Glicosaminoglicanos/química , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/enzimologia , Humanos , Hipertensão/genética , Hipertensão/fisiopatologia , Masculino , Óxido Nítrico Sintase Tipo III/análise , Extratos Vegetais/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Aumento de Peso/efeitos dos fármacos , Tempo de Coagulação do Sangue TotalRESUMO
The seeds of Zizyphus jujuba (SZJ), a famous oriental traditional medicine, have been reported to exhibit diverse activities in biological systems including the cardiovascular system. However, little information is available on its antiplatelet activity. This study was undertaken to investigate the antiplatelet effects of the ethanolic extract of SZJ (ESZJ) and of its principal components jujuboside A and B. In the in vitro platelet aggregation study, ESZJ exhibited significant and concentration-dependent inhibitory effects on collagen-, thrombin-, and AA-induced platelet aggregation. In addition, ESZJ-treated mice showed significantly the prolongation of bleeding times and the protection against thromboembolic attack. A comparison of the effects of jujuboside A and B on platelet aggregation revealed that only jujuboside B had potent inhibitory effects on collagen-, thrombin-, AA-, and ADP-induced aggregation. Jujuboside B also exhibited superior protection on thromboembolic model. Furthermore, jujuboside B had a significant inhibitory effect on collagen-induced thromboxane A2 production in rat platelets. This study describes the antiplatelet effects of ESZJ and of its active component jujuboside B, and its findings suggest that these agents be considered as components of preventive and therapeutic herbal drugs targeting cardiovascular diseases associated with platelet hyperaggregation.
Assuntos
Extratos Vegetais/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Saponinas/farmacologia , Ziziphus/química , Animais , Plaquetas/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Embolia Pulmonar/tratamento farmacológico , Ratos , Ratos Sprague-DawleyRESUMO
Prostate cancer is the fifth leading cause of cancer-related mortality in men, primarily because of treatment resistance, recurrence, and metastasis. In the present study, we investigated the role of paracrine interleukin-8 (IL-8) in the antagonistic expression of IL-8 and androgen receptor (AR), and the contribution of IL-8 to prostate cancer aggressiveness. In hormone-responsive LNCaP cells that do not express IL-8, recombinant IL-8 treatment significantly increased expressions of IL-8, CXC chemokine receptor 2 (CXCR2), matrix metalloproteinase (MMP)-2/9, Snail, and vimentin. IL-8 treatment significantly decreased AR and E-cadherin expression. IL-8-induced gene expression changes were suppressed by navarixin, a CXCR1/2 inhibitor, and gallein, a Gßγ inhibitor. In PC-3 androgen-refractory prostate cancer cells, IL-8 knockdown reduced expressions of CXCR2, MMP-2/9, Snail, and vimentin, and increased AR and E-cadherin expressions at the mRNA and protein levels. Co-culture with MEG-01 human megakaryocytic cells secreting high levels of IL-8 induced gene expression changes in both LNCaP and PC-3 cells, similar to those induced by IL-8 treatment. The altered gene expressions were accompanied by significant activation of transcription factor Snail in LNCaP and PC-3 cells. Treatment with the CXCR blocker navarixin inhibited the invasion of PC-3 cells but not LNCaP cells. However, invasion induced by MEG-01 was inhibited by navarixin in both LNCaP and PC-3 cells. The collective findings demonstrate that IL-8 enhances CXCR2 expression, which antagonistically regulates AR expression. More importantly, through changes in IL-8/CXCR2-regulated gene expression, IL-8 induces antiandrogen therapy resistance and epithelial-mesenchymal transition in prostate cancer.
RESUMO
Dementia is a clinical syndrome characterized by progressive impairment of cognitive and functional abilities. As currently applied treatments for dementia can only delay the progression of dementia and cannot fundamentally cure it, much attention is being paid to reducing its incidence by preventing the associated risk factors. Cardiovascular and metabolic diseases are well-known risk factors for dementia, and many studies have attempted to prevent dementia by treating these risk factors. Growing evidence suggests that sex-based factors may play an important role in the pathogenesis of dementia. Therefore, a deeper understanding of the differences in the effects of drugs based on sex may help improve their effectiveness. In this study, we reviewed sex differences in the impact of therapeutics targeting risk factors for dementia, such as cardiovascular and metabolic diseases, to prevent the incidence and/or progression of dementia.
RESUMO
In the brain, Na+/H+ exchanger-1 (NHE-1) activation has a significant impact on ischemic injury, and, in recent studies, NHE-1 inhibition has been found to protect neurons from ischemic injury. This protective effect has been ascribed to the prevention of apoptosis, but neuronal cell death following ischemia is a consequence of both necrotic and apoptotic cell death. Here, we evaluated the ability of the potent NHE-1 inhibitor cariporide to prevent necrotic cell death in an in vitro model of excitotoxic neuronal death. Cariporide (100 nM) was found to reduce both glutamate-induced necrotic and apoptotic neuronal cell death. Ca2+ concentrations were observed to peak twice in cytosol and mitochondria in cultured neuronal cells after glutamate exposure, and cariporide was found to reduce the second Ca2+ concentration increase, but not the first. Furthermore, glutamate-mediated mitochondrial death pathways involving loss of mitochondrial membrane potential and reactive oxygen species (ROS) accumulation were found to be attenuated by cariporide. In addition, cariporide effectively prevented necrosis following exposure to glutamate and ameliorated the mitochondrial Ca2+ and ROS production increases implicated in necrotic cell death. These results suggest that NHE-1 participates in the necrotic cell death process and that its inhibition offers a means of preventing both necrosis and apoptosis.
Assuntos
Cálcio/metabolismo , Guanidinas/farmacologia , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Sulfonas/farmacologia , Animais , Anexina A5/metabolismo , Caspase 3/metabolismo , Morte Celular/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/citologia , Citosol/efeitos dos fármacos , Citosol/metabolismo , Relação Dose-Resposta a Droga , Interações Medicamentosas , Embrião de Mamíferos , Ácido Glutâmico/toxicidade , Marcação In Situ das Extremidades Cortadas , L-Lactato Desidrogenase/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/metabolismo , Propídio , Espécies Reativas de Oxigênio/metabolismo , Trocadores de Sódio-Hidrogênio/antagonistas & inibidoresRESUMO
Two novel glucosinolates along with one known glucosinolate were isolated from Broccoli (Brassica oleracea L. var. italica) florets. Their structures were established mainly by 1D ((1)H and (13)C NMR), 2D NMR ((1)H-(1)H COSY, DEPT 135°, HSQC and HMBC), and Tandem MS-MS spectrometric data as 2-mercaptomethyl sulfinyl glucosinolate [(Z)-4-(methylsulfinyl)-N-(sulfooxy)-2-((2'S,3'R,4'S,5'S,6'R)-3',4',5'-trihydroxy-6'(hydroxylmethyl)-2'-mercapto tetrahydro-2H-pyran-2-yl) butane amide] 1, (Z)-1-((2S,5S)-5-hydroxytetra-hydro-2H-pyran-2-ylthio)-2-(1H-indol-3-yl) ethylidene amino sulfate 2 and a known cinnamoyl [6'-O-trans-(4â³-hydroxy cinnamoyl)4-(methylsulphinyl)butyl glucosinolate] 3. Compound 1 exhibited scavenging activity against DPPH with an inhibitory concentration IC(50) of 20 mM, whereas compound 3 was a weak antioxidant when compared to the standard quercetin (5 mM) as a positive control. Both the compounds showed a significant and similar antimicrobial activity against Staphylococcus aureus with an IC(50) of <625 µg/mL when compared to antibiotic duricef. Against Salmonella typhimurium the IC(50) of 1 and 3 was determined as <625 µg/mL and <1250 µg/mL, respectively, when compared to ampicillin (IC(50) ≤ 39 µg/mL) as a positive control.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Brassica/química , Glucosinolatos/química , Glucosinolatos/farmacologia , Antibacterianos/isolamento & purificação , Antioxidantes/isolamento & purificação , Glucosinolatos/isolamento & purificação , Humanos , Concentração Inibidora 50 , Infecções por Salmonella/tratamento farmacológico , Salmonella typhimurium/efeitos dos fármacos , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacosRESUMO
Rhubarb is a widely used traditional medicine and has been reported to elicit a number of biological effects including anti-inflammatory and antiplatelet effects. In the present study, we investigated the effects of anthraquinone derivatives isolated from rhubarb on platelet activity. Of four anthraquinone derivatives isolated from rhubarb examined, chrysophanol-8-O-glucoside (CP-8-O-glc) was found to have the most potent inhibitory effect on collagen- and thrombin-induced platelet aggregation. CP-8-O-glc-treated mice showed significantly prolonged bleeding times. Furthermore, CP-8-O-glc was found to have a significant inhibitory effect on rat platelet aggregation ex vivo and on thromboxane A(2) formation in vitro. In coagulation tests, CP-8-O-glc did not alter prothrombin time, and it prolonged the activated partial thromboplastin time. However, CP-8-O-glc only inhibited platelet phosphatidylserine exposure, but not exert direct inhibition on intrinsic factors. This study demonstrates the antiplatelet and anticoagulant effects of CP-8-O-glc and suggests that this compound might be of therapeutic benefit for the prevention of platelet-related cardiovascular diseases.
Assuntos
Antraquinonas/farmacologia , Anticoagulantes/farmacologia , Glucosídeos/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Rheum/química , Animais , Antraquinonas/isolamento & purificação , Anticoagulantes/isolamento & purificação , Coagulação Sanguínea/efeitos dos fármacos , Colágeno/farmacologia , Glucosídeos/isolamento & purificação , Masculino , Camundongos , Camundongos Endogâmicos ICR , Tempo de Tromboplastina Parcial , Inibidores da Agregação Plaquetária/isolamento & purificação , Tempo de Protrombina , Ratos , Ratos Sprague-Dawley , Trombina/farmacologia , Tromboxano A2/metabolismoRESUMO
Cardiovascular (CVD) and cerebrovascular diseases, with 17 [...].
RESUMO
The blood-brain barrier (BBB), which consists mainly of brain microvascular endothelial cells and astrocytes connected by tight junctions (TJs) and adhesion molecules (AMs), maintains the homeostatic balance between brain parenchyma and extracellular fluid. Accumulating evidence shows that BBB dysfunction is a common feature of neurodegenerative diseases, including stroke, traumatic brain injury, and Alzheimer's disease. Among the various pathological pathways of BBB dysfunction, reactive oxygen species (ROS) are known to play a key role in inducing BBB disruption mediated via TJ modification, AM induction, cytoskeletal reorganization, and matrix metalloproteinase activation. Thus, antioxidants have been suggested to exert beneficial effects on BBB dysfunction-associated brain diseases. In this review, we summarized the sources of ROS production in multiple cells that constitute or surround the BBB, such as BBB endothelial cells, astrocytes, microglia, and neutrophils. We also reviewed various pathological mechanisms by which BBB disruption is caused by ROS in these cells. Finally, we summarized the effects of various natural polyphenols on BBB dysfunction to suggest a therapeutic strategy for BBB disruption-related brain diseases.
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Insomnia, the most common sleep disorder, is characterized by a longer sleep latency, greater sleep fragmentation, and consequent excessive daytime fatigue. Due to the various side effects of prescribed hypnotics, demand for new drugs is still high. Recent studies have suggested the adenosine receptor (AR) as a potential therapeutic target for insomnia, however, clinically useful hypnotics targeting AR are not yet available. In the present study, we evaluated the hypnotic effect of rosmarinic acid, a phenolic compound widely found in medicinal plants, through pentobarbital-induced sleep test, electroencephalography/electromyography (EEG/EMG), and immunohistochemistry in mice. The underlying mechanisms were assessed by pharmacological approach using 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and SCH5826, antagonists for A1R and A2AR, respectively. Receptor-binding assay and functional agonism were also performed. Our study provides a new evidence that rosmarinic acid has a direct binding activity (Ki = 14.21 ± 0.3 µM) and agonistic activity for A1R. We also found that rosmarinic acid significantly decreased sleep fragmentation and onset latency to NREM sleep, and these effects were abolished by DPCPX. The results from c-Fos immunostaining showed that rosmarinic acid decreased the neuronal activity in wake-promoting brain regions, such as the basal forebrain and the lateral hypothalamus, while increasing the neuronal activity in the ventrolateral preoptic nucleus, a sleep-promoting region; all these effects were significantly inhibited by DPCPX. Taken together, this study suggests that rosmarinic acid possesses novel activity as an A1R agonist and thereby exerts a hypnotic effect, and thus it may serve as a potential therapeutic agent for insomnia through targeting A1R.
Assuntos
Agonistas do Receptor A1 de Adenosina/farmacologia , Cinamatos/farmacologia , Depsídeos/farmacologia , Hipnóticos e Sedativos/farmacologia , Receptor A1 de Adenosina/metabolismo , Sono/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Eletroencefalografia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Pentobarbital , Receptor A2A de Adenosina/metabolismo , Ácido RosmarínicoRESUMO
Stress exposure is a major risk factor for mental disorders such as depression. Because of the limitations of classical antidepressants such as side effects, low efficacy, and difficulty in long-term use, new natural medicines and bioactive molecules from plants with greater safety and efficacy have recently attracted attention. Luteolin-7-O-glucuronide (L7Gn), a bioactive molecule present in Perilla frutescens, is known to alleviate severe inflammatory responses and oxidative stress in macrophages. However, its antistress and antidepressant effects have not been elucidated. The present study aims to explore the antidepressant the effect of L7Gn on stress-induced behaviors and the underlying mechanism in a mouse sleep deprivation (SD) model. L7Gn treatment improved depression-like and stress coping behaviors induced by SD stress, as confirmed by the tail suspension test and forced swimming test. Furthermore, L7Gn treatment reduced the blood corticosterone and hippocampal proinflammatory cytokine levels which were increased by SD stress, and L7Gn also increased the mRNA and protein levels of hippocampal brain-derived neurotrophic factor (BDNF) which were reduced by SD stress. Additionally, treatment with L7Gn resulted in increases in the phosphorylation of tropomyosin-related kinase B (TrkB), extracellular signal-regulated kinase (ERK), and cAMP response element-binding protein (CREB), which are downstream molecules of BDNF signaling. These findings suggest that L7Gn have therapeutic potential for SD-induced stress, via activating the BDNF signaling.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Depressão , Adaptação Psicológica , Animais , Antidepressivos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Humanos , Luteolina , Camundongos , Privação do Sono/complicações , Privação do Sono/tratamento farmacológico , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismoRESUMO
Neuronal precursor cells (NPCs) are temporally regulated and have the ability to proliferate and differentiate into mature neurons, oligodendrocytes, and astrocytes in the presence of growth factors (GFs). In the present study, the role of the Jak pathway in brain development was investigated in NPCs derived from neurosphere cultures using Jak2 and Jak3 small interfering RNAs and specific inhibitors. Jak2 inhibition profoundly decreased NPC proliferation, preventing further differentiation into neurons and glial cells. However, Jak3 inhibition induced neuronal differentiation accompanied by neurite growth. This phenomenon was due to the Jak3 inhibition-mediated induction of neurogenin (Ngn)2 and NeuroD in NPCs. Jak3 inhibition induced NPCs to differentiate into scattered neurons and increased the expression of Tuj1, microtubule associated protein 2 (MAP2), Olig2, and neuroglial protein (NG)2, but decreased glial fibrillary acidic protein (GFAP) expression, with predominant neurogenesis/polydendrogenesis compared with astrogliogenesis. Therefore, Jak2 may be important for NPC proliferation and maintenance, whereas knocking-down of Jak3 signaling is essential for NPC differentiation into neurons and oligodendrocytes but does not lead to astrocyte differentiation. These results suggest that NPC proliferation and differentiation are differentially regulated by the Jak pathway.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Janus Quinase 3/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Animais , Western Blotting , Encéfalo/embriologia , Encéfalo/metabolismo , Diferenciação Celular/genética , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Imuno-Histoquímica , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 3/genética , Camundongos , Neurogênese/efeitos dos fármacos , Neurogênese/genética , Neurônios/efeitos dos fármacos , Quinazolinas/farmacologia , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células-Tronco/efeitos dos fármacos , Tirfostinas/farmacologiaRESUMO
Eight compounds were isolated from the methanol fraction of Lindera erythrocarpa and assessed for their ability to protect H9c2 cardiomyocytes against oxidative stress-induced cell death. Three of the compounds significantly reduced the release of lactate dehydrogenase from H9c2 cardiomyocytes treated with buthionine-[S,R]-sulfoximine and reduced the uptake of propidium iodide by these cells. These effects were concentration-dependent. The three inhibitory compounds were identified as (-)-epicatechin, avicularin and quercitrin by spectroscopic techniques including one- and two-dimensional NMR and mass spectroscopy.