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1.
J Ethnopharmacol ; 264: 112915, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32360044

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The genus Stellera Linn. consists of species of perennial herbs and shrubs, and is mainly distributed in the temperate regions of east Asia to west Asia. There are 10∼12 species in the world, two species in China: Stellera chamaejasme Linn. and Stellera formosana Hayata ex Li. As recorded, the roots of Stellera species are used to dissipate phlegm and relieve pain. The roots and the barks can be used for papermaking. AIM OF THIS REVIEW: This review aims to summarize the ethnopharmacological uses, chemical constituents, pharmacological activities, clinical applications and toxicology of the genus Stellera to better understand their therapeutic potential in the future. MATERIALS AND METHODS: The relevant information of the genus Stellera was collected from scientific databases (Pubmed, ACS website, SciFinder Scholar, Elsevier, Google Scholar, Web of Science and CNKI). Information was also gathered from 'Flora Republicae Popularis Sinicae (〈〈〉〉)', folk records, conference papers on ethnopharmacology, Ph.D. and Masters' Dissertation. RESULTS: Stellera plants have been studied as traditional folk medicines all around the world. The chemical constituents of Stellera species mainly comprise terpenoids, flavonoids, coumarins, lignans, and so on. Extracts and compounds of Stellera species exhibit extensive pharmacological activities, such as anti-tumor, anti-viral, anti-convulsive, anti-epileptic, anti-bacterial and anti-insect activities, etc. Clinical applications have suggested that the genus Stellera has the effects in treating several skin diseases and cancers, however, the results should be further verification. The genus Stellera plants are toxic and should be used reasonable. CONCLUSION: This paper reviewed the ethnopharmacological uses, chemical constituents, pharmacology, clinical applications and toxicology of the genus Stellera. The genus Stellera has broad application prospects. However, further in-depth studies are needed to determine the medical uses of the genus and its chemical constituents, pharmacological activities, clinical applications and toxicology.

2.
Eur J Pharmacol ; 882: 173309, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32598952

RESUMO

Studies have shown that the ginsenoside Rg1 can improve depressive symptoms in vitro and in vivo. However, the efficacy of Rg1on the hippocampal astrocyte gap junctions in depression are unclear. We mainly aimed to explore the relationship between Rg1, hippocampal astrocyte gap junctions and depression. Using primary cultured astrocytes, corticosterone (CORT) was used to induce stress. CORT (100 µM) significantly reduced the survival rate in astrocytes, and this effect was prevented by additional Rg1 administration. Interestingly, the gap junction blocker carbenoxolone (CBX) was able to revert this Rg1 effect. In in vivo models, one group was exposed to chronic unpredictable stress (CUS) for 47 days, while another group was bilaterally injected with CBX (100 µM) into the hippocampal CA1 region. Rats treated with Rg1 (20 mg/kg) showed an improvement in the sucrose preference and the forced swimming test in both models, indicating an antidepressive activity of Rg1. The levels of astrocyte gap junction connexin 43 (Cx43) were detected by immunofluorescence (IF) and western blotting. The levels of glial fibrillary acidic protein (GFAP) were detected by IF. The gap junctions in the hippocampal CA1 area were evaluated using dye transfer and electron microscopy. The reduction in Cx43 expression, the decrease in the Cx43 to GFAP ratio, the shorter dye diffusion distance, and the abnormal ultrastructure of gap junctions in rats exposed to CUS were markedly alleviated by concomitant Rg1 treatment. Taken together, the ginsenoside Rg1 could improve depression-like behavior in rats induced by astrocyte gap junction dysfunction in the hippocampus.

3.
Neuropharmacology ; 170: 108041, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32213357

RESUMO

Our previous studies have shown that ginsenoside Rg1 (Rg1) exerts antidepressant-like effects in animal models of depression, accompanied by an improvement of astrocytic gap junction functions. However, whether connexin 43 (Cx43), the major connexin forming gap junctions between astrocytes, is the key regulator of Rg1-induced antidepressant-like effects is still unknown. In this study, we examine in vitro and in vivo the involvement of Cx43 in the antidepressant effects of Rg1. Corticosterone was used to establish an in vitro rat model of depression. Treatment with Rg1 1 h prior to corticosterone significantly improved the cell viability of astrocytes, which was significantly inhibited by carbenoxolone, a widely used gap junction inhibitor. Moreover, Rg1 treatment significantly ameliorated antidepressant-sensitive behaviours induced by infusion of carbenoxolone or Gap26, a selective inhibitor of Cx43, into the prefrontal cortex of the animals. Rg1 treatment increased the expression of Cx43 compared with Gap26 group. According to these results, the antidepressant-like effects of Rg1 were mainly mediated by Cx43-formed gap junctions.

4.
Neurochem Int ; 136: 104731, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32201280

RESUMO

Increasing evidences support that glial connexins are involved in the demyelination pathology of multiple sclerosis (MS), a chronic inflammatory demyelinating disorder. Here, we review the data from patients with MS and animal models of MS that implicate connexins in demyelination. Connexins expressed in oligodendrocytes and astrocytes show diverse changes at the different phases of MS. Loss of oligodendrocyte or astrocyte connexins contributes to demyelination and exaggerates the pathology of MS. Channel-dependent and -independent connexins are involved in the pathology of demyelination, which is related with myelin integrity, metabolic homeostasis, the brain-blood barrier, the immune cell infiltration, and the inflammatory response. A comprehensive understanding of connexin function in demyelination may provide new therapeutic targets for MS.

5.
Phytochemistry ; 171: 112232, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31911266

RESUMO

Corni Fructus, also known as the fruit of Cornus officinalis Sieb. et Zucc., has long been used as a traditional Chinese medicine and is widely consumed as a nutritional food in the form of function drink and wine. Recently, Corni Fructus has attracted considerable interest because of its anti-diabetic effects. A systematic phytochemical investigation of Corni Fructus was performed to find anti-diabetic components, which led to the isolation of 10 unreported iridoid glycosides, cornusdiglycosides A-J (1-8, 9a/9b and 10a/10b). Their chemical structures were determined through spectroscopic analysis (ultraviolet [UV], infrared [IR], high-resolution electrospray ionisation mass spectroscopy [HRESIMS], one-dimensional [1D] and two-dimensional [2D] nuclear magnetic resonance [NMR]). Such morroniside-type diglycosides were first reported from natural sources, and all isolates were evaluated for α-glucosidase inhibitory activity. The results showed that all compounds (1-10) exhibited α-glucosidase (from Saccharomyces cerevisiae) inhibitory activities with IC50 values ranging from 78.9 ± 4.09 to 162.2 ± 9.17 µM, whereas acarbose, the positive control, displayed α-glucosidase inhibitory activity with IC50 value of 118.9 ± 7.89 µM.


Assuntos
Cornus/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Glicosídeos/farmacologia , Glucosídeos Iridoides/farmacologia , Compostos Fitoquímicos/farmacologia , alfa-Glucosidases/metabolismo , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Glicosídeos/química , Glicosídeos/isolamento & purificação , Humanos , Glucosídeos Iridoides/química , Glucosídeos Iridoides/isolamento & purificação , Conformação Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação
6.
Front Pharmacol ; 10: 409, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31068813

RESUMO

Corni fructus, the fruit of Cornus officinalis Sieb. et Zucc., has been used as a tonic for the kidney in China for thousands of years. Loganin is one of the major constituents derived from Corni fructus. In this study, we revealed the sedative and hypnotic activity of loganin and investigated its mechanisms for the first time. Pentobarbital-induced sleep test and insomnia mice models [induced by caffeine and p-chlorophenylalanine (PCPA)] were used for the assessment of sedative and hypnotic effects of loganin. It was found that loganin (20-50 mg/kg) exerted sedative effect in normal mice. Loganin exhibited hypnotic effect by increasing sleep onset and sleep duration in pentobarbital-treated mice, recovering PCPA-induced insomnia and exerting synergistic hypnosis effect with 5-HTP. In addition, electroencephalograph (EEG) and electromyography (EMG) recordings of rats showed that loganin (35 mg/kg) prolonged the ratio of non-rapid eye movement (NREM) sleep and shortened wakefulness significantly, further immunohistochemistry showed that loganin (35 mg/kg) increased c-Fos expression in GABAergic neurons of rats in the ventrolateral preoptic nucleus (VLPO). The levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT) and its metabolite were measured in the hippocampus, prefrontal cortex and striatum of mice, 1 h after loganin (35 mg/kg) treatment. 5-HT, 5-HIAA/5-HT, DA, and DOPAC were decreased significantly in the prefrontal cortex. In conclusion, these results indicated that loganin produced beneficial sedative and hypnotic activity, which might be mainly mediated by modification of the serotonergic system and GABAergic neurons.

7.
J Asian Nat Prod Res ; 21(8): 782-797, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30608002

RESUMO

Inappropriate use of acetaminophen (APAP) can lead to morbidity and mortality secondary to hepatic necrosis. Ginsenoside Rg1 is a major active ingredient in processed Panax ginseng, which is proved to elicit biological effects. We hypothesized the beneficial effect of Rg1 on APAP-mediated hepatotoxicity was through Nrf2/ARE pathway. The study was conducted in cells and mice, comparing the actions of Rg1. Rg1 significantly improved cell survival rates and promoted the expression of antioxidant proteins. Meanwhile, Rg1 reduced the excessive ROS and the occurrence of cell apoptosis, which were related to Nrf2/ARE pathway. Expression of Nrf2 has a certain cell specificity.


Assuntos
Acetaminofen/toxicidade , Elementos de Resposta Antioxidante/fisiologia , Apoptose/efeitos dos fármacos , Ginsenosídeos/farmacologia , Fator 2 Relacionado a NF-E2/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Células HEK293 , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos
8.
Brain Res Bull ; 146: 12-21, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30496784

RESUMO

Fractalkine (CX3C chemokine ligand 1, CX3CL1) is an essential chemokine, for regulating adhesion and chemotaxis through binding to CX3CR1, which plays a critical role in the crosstalk between glial cells and neurons by direct or indirect ways in the central nervous system (CNS). Fractalkine/CX3CR1 axis regulates microglial activation and function, neuronal survival and synaptic function by controlling the release of inflammatory cytokines and synaptic plasticity in the course of the neurological disease. The multiple functions of fractalkine/CX3CR1 make it exert neuroprotective or neurotoxic effects, which determines the pathogenesis. However, the role of fractalkine/CX3CR1 in the CNS remains controversial. Whether it can be used as a therapeutic target for neurological diseases needs to be further investigated. In this review, we summarize the studies highlighting fractalkine/CX3CR1-mediated effects and discuss the potential neurotoxic and neuroprotective actions of fractalkine/CX3CR1 in brain injury for providing useful insights into the potential applications of fractalkine/CX3CR1 in neurological diseases.


Assuntos
Receptor 1 de Quimiocina CX3C/metabolismo , Quimiocina CX3CL1/metabolismo , Doenças do Sistema Nervoso/fisiopatologia , Animais , Receptor 1 de Quimiocina CX3C/fisiologia , Sistema Nervoso Central/metabolismo , Quimiocina CX3CL1/fisiologia , Humanos , Inflamação/metabolismo , Microglia/metabolismo , Doenças do Sistema Nervoso/metabolismo , Neuroglia/metabolismo , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Fármacos Neuroprotetores/metabolismo
9.
Psychopharmacology (Berl) ; 235(9): 2529-2540, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30069586

RESUMO

RATIONALE: The decrease of astrocyte number and hypothalamic-pituitary-adrenal (HPA) axis overactivity are observed in individuals with major depressive disorder. Elevated levels of glucocorticoids induced by hyperactivation of the HPA axis may result in glucocorticoid receptor (GR) activation. However, it is unclear whether there is a direct link between GR activation and the decrease of astrocyte number. METHODS: Animals were exposed to chronic unpredictable stress (CUS) for 28 days and treated with continuous subcutaneous injections of vehicle or corticosterone (CORT; 40 mg/kg/day) for 21 days. We then administered mifepristone on day 21 after CUS and on day 18 after the CORT treatment. We observed behavioral deficits in the sucrose preference test, open field test, and forced swim test. Protein expression was analyzed using immunofluorescence (IF) and western blot (WB). RESULTS: Animals exposed to CUS exhibited behavioral deficits in tests measuring anhedonia, anxiety, and despair state. They also had decreases in glial fibrillary acidic protein (GFAP) expression and numbers of GFAP-positive cells in the hippocampus. The behavioral and cellular alterations induced by CUS were reversed by subchronic treatment with the GR antagonist mifepristone. We also found that the subcutaneous injection of glucocorticoids may induce depression-like behavior and reduce GFAP protein expression in rats, which was similarly reversed by mifepristone. CONCLUSIONS: These findings provide experimental evidence that GR activation due to elevated CORT levels induces the decrease of hippocampal astrocyte number in rats.


Assuntos
Astrócitos/metabolismo , Astrócitos/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Receptores de Glucocorticoides/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Contagem de Células/tendências , Corticosterona/metabolismo , Depressão/metabolismo , Depressão/psicologia , Glucocorticoides/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Mifepristona/farmacologia , Mifepristona/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores de Glucocorticoides/antagonistas & inibidores , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia
10.
Eur Neuropsychopharmacol ; 28(4): 483-498, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29519610

RESUMO

Major depressive disorder (MDD) is a chronic and debilitating illness that affects over 350 million people worldwide; however, current treatments have failed to cure or prevent the progress of depression. Increasing evidence suggests a crucial role for connexins in MDD. In this review, we have summarised recent accomplishments regarding the role of connexins, gap junctions, and hemichannels in the aetiology of MDD, and discussed the limitations of current research. A blockage of gap junctions or hemichannels induces depressive behaviour. Possible underlying mechanisms include the regulation of neurosecretory functions and synaptic activity by gap junctions and hemichannels. Gap junctions are functionally inhibited under stress conditions. Conversely, hemichannel permeability is increased. Antidepressants inhibit hemichannel permeability; however, they have contrasting effects on the function of gap junctions under normal conditions and can protect them against stress. In conclusion, the blockage of hemichannels concurrent with improvements in gap junction functionality might be potential targets for depression treatment.


Assuntos
Conexinas/metabolismo , Transtorno Depressivo Maior/metabolismo , Animais , Depressão/tratamento farmacológico , Depressão/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , Humanos
11.
Psychopharmacology (Berl) ; 235(1): 1-12, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29178009

RESUMO

BACKGROUND: Major depressive disorder (MDD) remains a major public health problem worldwide. The association between MDD and the dysfunction of gap junction channels (GJCs) in glial cells, especially astrocytes, is still controversial. OBJECTIVE: This review provides an overview of the role of astrocyte GJCs in LMDD. RESULTS: Exposure to chronic unpredictable stress caused a reduction in connexin expression in the rat prefrontal cortex, a result that is consistent with clinical findings reported in postmortem studies of brains from MDD patients. Chronic antidepressant treatment in these rats increased the expression of connexins. However, pharmacological GJC blockade in normal rodents decreased connexin expression and caused depressive-like behaviors. Furthermore, GJC dysfunction affects electrical conductance, metabolic coupling and secondary messengers, and inflammatory responses, which are consistent with current hypotheses on MDD. All these results provide a comprehensive overview of the neurobiology of MDD. CONCLUSION: This review supports the hypothesis that the regulation of GJCs between astrocytes could be an underlying mechanism for the therapeutic effect of antidepressants.


Assuntos
Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Conexinas/efeitos dos fármacos , Transtorno Depressivo Maior/tratamento farmacológico , Junções Comunicantes/efeitos dos fármacos , Animais , Humanos
12.
Neuropharmacology ; 131: 20-30, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29223529

RESUMO

Increasing evidence has implicated astrocyte pathology in the etiopathology of major depressive disorder (MDD). In particular, dysfunction of gap junctions in astrocytes is a potential target for MDD treatment. However, the mechanism underlying stress-induced dysfunction of gap junctions is still unknown. We therefore studied the mechanism of stress-induced dysfunction of gap junctions in prefrontal cortical and hippocampal astrocytes. Corticosterone (CORT) was used to induce stress conditions; CORT damaged the function of gap junctions, which resulted from less distribution of connexin43 (Cx43) on membranes and the enhanced phosphorylation of Cx43 at S368. Moreover, CORT downregulated the biosynthesis of Cx43 but increased the degradation of Cx43. Interestingly, both autophagy and the proteasome system were involved in the degradation of Cx43 in prefrontal cortical astrocytes, but only the proteasome system was involved in the degradation of Cx43 in hippocampal astrocytes. CORT significantly induced the formation of annular gap junction vesicles in prefrontal cortical astrocytes; however, Cx43 mainly presented as small dots in the hippocampal astrocytes. Furthermore, CORT increased N-Cadherin expression and the interactions of Cx43 with ZO-1/drebrin in prefrontal cortical astrocytes, but these interactions were oppositely modulated in hippocampal astrocytes. In conclusion, this study clarified the alternations of the Cx43 life cycle in the prefrontal cortical and hippocampal astrocytes exposed to CORT, which may contribute to our understanding of the mechanisms underlying stress-induced dysfunction of gap junctions.


Assuntos
Astrócitos/efeitos dos fármacos , Corticosterona/farmacologia , Junções Comunicantes/efeitos dos fármacos , Hipocampo/citologia , Córtex Pré-Frontal/citologia , Animais , Animais Recém-Nascidos , Caderinas/metabolismo , Células Cultivadas , Conexina 43/genética , Conexina 43/metabolismo , Cicloeximida/farmacologia , Relação Dose-Resposta a Droga , Junções Comunicantes/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Imunoprecipitação , Inibidores da Síntese de Proteínas/farmacologia , Ratos , Sincalida/genética , Sincalida/metabolismo , Transfecção
13.
J Ethnopharmacol ; 208: 207-213, 2017 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-28642095

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ginsenoside Rg1 (Rg1), one of the major bioactive ingredients of Panax ginseng C. A. Mey, has neuroprotective effects in animal models of depression, but the mechanism underlying these effects is still largely unknown AIM OF THE STUDY: Gap junction intercellular communication (GJIC) dysfunction is a potentially novel pathogenic mechanism for depression. Thus, we investigated that whether antidepressant-like effects of Rg1 were related to GJIC. MATERIALS AND METHODS: Primary rat prefrontal cortical and hippocampal astrocytes cultures were treated with 50µM CORT for 24h to induce gap junction damage. Rg1 (0.1, 1, or 10µM) or fluoxetine (1µM) was added 1h prior to CORT treatment. A scrape loading and dye transfer assay was performed to identify the functional capacity of gap junctions. Western blot was used to detect the expression and phosphorylation of connexin43 (Cx43), the major component of gap junctions. RESULTS: Treatment of primary astrocytes with CORT for 24h inhibited GJIC, decreased total Cx43 expression, and increased the phosphorylation of Cx43 at serine368 in a dose-dependent manner. Pre-treatment with 1µM and 10µM Rg1 significantly improved GJIC in CORT-treated astrocytes from the prefrontal cortex and hippocampus, respectively, and this was accompanied by upregulation of Cx43 expression and downregulation of Cx43 phosphorylation. CONCLUSION: These findings provide the first evidence indicating that Rg1 can alleviate CORT-induced gap junction dysfunction, which may have clinical significance in the treatment of depression.


Assuntos
Astrócitos/efeitos dos fármacos , Junções Comunicantes/efeitos dos fármacos , Ginsenosídeos/farmacologia , Animais , Astrócitos/metabolismo , Comunicação Celular/efeitos dos fármacos , Células Cultivadas , Conexina 43/metabolismo , Corticosterona , Regulação para Baixo , Junções Comunicantes/fisiologia , Hipocampo/citologia , Fosforilação/efeitos dos fármacos , Córtex Pré-Frontal/citologia , Ratos
14.
Acta Pharmacol Sin ; 37(12): 1525-1533, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27616576

RESUMO

AIM: Accumulation of α-synuclein (α-syn) in the brain is a characteristic of Parkinson's disease (PD). In this study, we investigated whether treatment with tunicamycin, an endoplasmic reticulum (ER) stress inducer, led to the accumulation of α-syn in PC12 cells, and where α-syn protein was accumulated, and finally, whether bibenzyl compound 20c, a novel compound isolated from Gastrodia elata (Tian ma), could alleviate the accumulation of α-syn and ER stress activation in tunicamycin-treated PC12 cells. METHODS: PC12 cells were treated with tunicamycin for different time (6 h, 12 h, 24 h, 48 h). Cell viability was determined by a MTT assay. Subcellular fractions of ER and mitochondria were extracted with the Tissue Endoplasmic reticulum Isolation Kit. The levels of α-syn protein and ER-stress-associated downstream chaperones were detected using Western blots and immunofluorescence. RESULTS: Treatment of PC12 cells with tunicamycin (0.5-10 µg/mL) dose-dependently increased the accumulation of α-syn monomer (19 kDa) and oligomer (55 kDa), and decreased the cell viability. Accumulation of the two forms of α-syn was observed in both the ER and mitochondria with increasing treatment time. Co-treatment with 20c (10-5 mol/L) significantly increased the viability of tunicamycin-treated cells, reduced the level of α-syn protein and suppressed ER stress activation in the cells, evidenced by the reductions in phosphorylation of eIF2α and expression of spliced ATF6 and XBP1. CONCLUSION: Tunicamycin treatment caused accumulation of α-syn monomer and oligomer in PC12 cells. Bibenzyl compound 20c reduces the accumulation of α-syn and inhibits the activation of ER stress, which protected PC12 cells against the toxicity induced by tunicamycin.


Assuntos
Compostos Benzidrílicos/farmacologia , Bibenzilas/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Gastrodia/química , Fenóis/farmacologia , Substâncias Protetoras/farmacologia , Tunicamicina/toxicidade , Animais , Células PC12 , Ratos , alfa-Sinucleína/metabolismo
15.
Int Immunopharmacol ; 39: 140-148, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27474951

RESUMO

Microglial phenotype alternation is a potential novel pathogenic mechanism for cerebral ischemia. Cerebral ischemia induced autophagy aggravates inflammation and neural injury. However, the effect of autophagy in the modulation of microglial phenotype is still unknown. In this study, we investigated the role of autophagic flux in the alternation of microglial phenotype following oxygen glucose deprivation/reperfusion (OGD/R) in BV-2 cells. Inhibition of autophagic flux by NH4Cl exposure significantly increased the level of microtubule-associated protein 1 light chain 3 (LC3)-II and p62 in control and OGD/R (12h, 24h and 48h) groups, but did not change their expression in OGD/R 72h group, indicating that autophagic flux was inhibited at OGD/R 72h. Once autophagic flux was inhibited at OGD/R 72h or at OGD/R 24h (with NH4Cl), BV-2 cells mainly showed M1 phenotype with increased tumor necrosis factor alpha (TNF-α), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and decreased M2 markers including interleukin-10 (IL-10), Arginase 1 (Arg-1), and brain derived neurotrophic factor (BDNF). Further study indicated that inhibition of autophagic flux activated NF-κB pathway and decreased the activity of cAMP-response element binding protein (CREB), which contributed to the alternation of microglial phenotype. Therefore, inhibition of autophagic flux regulated the alternation of microglial phenotype by modulating the balance between NF-κB and CREB.


Assuntos
Isquemia Encefálica/imunologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Microglia/efeitos dos fármacos , NF-kappa B/metabolismo , Traumatismo por Reperfusão/imunologia , Cloreto de Amônio/farmacologia , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular , Camundongos , Microglia/fisiologia , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fenótipo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
16.
J Asian Nat Prod Res ; 18(8): 765-78, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27229011

RESUMO

Rg1 has shown multiple pharmacological activities and been considered to be evaluated for hepatic protective activity, as Rg1 could modulate different pathways in various diseases. Herein we assessed its effect and potential mechanism in a newly modified ethanol model. C57BL/6 mice were fed with Lieber-DeCarli liquid diet containing ethanol or isocaloric maltose dextrin as control diet with or without Rg1. Meanwhile, bicyclol was treated as positive drug to compare the efficacy of Rg1 against alcoholic hepatotoxicity. According to our data, Rg1 indeed improved the survival rate and lowered the abnormal high levels of serum parameters. H&E and Oil Red O staining indicated that the condition of liver damage was mitigated by Rg1 administration. Furthermore, AMPK and Nrf2 pathways were all modulated at both RNA and protein levels. In accordance with these findings, Rg1 effectively protected against alcoholic liver injury, possibly by modulating metabolism, suppressing oxidative stress, and enhancing oxidant defense systems of Nrf2 pathway. In vitro, Rg1 has no cell toxicity and promotes Nrf2 translocate into nuclear. In summary, we demonstrate that Rg1 is a potent activator of Nrf2 pathway, and could therefore be applied for prevention of hepatic damage.


Assuntos
Ginsenosídeos/farmacologia , Fígado/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Feminino , Ginsenosídeos/química , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
17.
Neurotoxicology ; 52: 72-83, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26408940

RESUMO

The present study investigated the neuroprotective effects of Forsythia suspense extract in a rotenone-induced neurotoxic model. FS8, one of the herbal extracts, markedly protected PC12 cells against rotenone toxicity and was selected for the in vivo study. Gavage administration of FS8 (50 and 200mg/kg, but not 10mg/kg) for 25 days significantly improved the behavior function, decreased the loss of dopaminergic neurons in substantia nigra (SN), and maintained the level of dopamine in striatum after unilateral infusion of rotenone in SN. Wherein, the protective effects of FS8 at the dose of 200mg/kg were better than selegiline. Further study indicated the excellent antioxidant activity of FS8 on the 5th and 21st days after intranigral injection of rotenone. Moreover, FS8 could inhibit microglia activity and accumulation in SN, and obviously decreased the expression of pro-inflammatory molecules (IL-6, TNF-α, iNOS and COX-2), which indicated the anti-inflammatory effects of FS8. In the PI3K/Akt/NF-κB and MAPK pathways, FS8 significantly down-regulated the protein expression of p-PI3K, p-Akt, p-IκB, p-P65, cleaved Caspase 8, p-p38 and p-JNK but not p-mTOR, cleaved Caspase 3 and p-ERK. Therefore, FS8 protected dopamine neurons against rotenone toxicity via antioxidant and anti-inflammatory effects, which suggested the promising application of FS8 in the prevention and treatment of Parkinson disease.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Forsythia/química , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Rotenona/toxicidade , Animais , Anti-Inflamatórios/química , Antioxidantes/química , Apomorfina/farmacologia , Corpo Estriado/metabolismo , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Frutas/química , Mediadores da Inflamação/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/química , Células PC12 , Extratos Vegetais/efeitos adversos , Extratos Vegetais/análise , Extratos Vegetais/química , Ratos , Teste de Desempenho do Rota-Rod , Rotenona/antagonistas & inibidores
18.
Int Immunopharmacol ; 25(2): 377-82, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25704852

RESUMO

Resident microglia are the major immune cells in the brain, acting as the first defense of the central nervous system. Following cerebral ischemia, microglia respond to this injury at first and transform from surveying microglia to active state. The activated microglia play a dual role in the ischemic injury, due to distinct microglia phenotypes, including deleterious M1 and neuroprotective M2. However, microglia show transient M2 phenotype followed by a shift to M1. The high ratio of M1 to M2 is significantly related to ischemic injury. Many signal pathways participate in the alternation of microglial phenotype, presenting potential therapeutic targets for selectively modulating M2 polarization of microglia. In this review, we discuss how the M2 phenotype mediates neuroprotective effects and summarize the alternation of signaling cascades that control microglial phenotype after ischemic stroke.


Assuntos
Microglia/imunologia , Neuroproteção/imunologia , Acidente Vascular Cerebral/imunologia , Animais , Fenótipo , Acidente Vascular Cerebral/tratamento farmacológico
19.
Acta Pharmacol Sin ; 36(3): 311-22, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25640478

RESUMO

AIM: Protopanaxtriol (Ppt) is extracted from Panax ginseng Mayer. In the present study, we investigated whether Ppt could protect against 3-nitropropionic acid (3-NP)-induced oxidative stress in a rat model of Huntington's disease (HD) and explored the mechanisms of action. METHODS: Male SD rats were treated with 3-NP (20 mg/kg on d 1, and 15 mg/kg on d 2-5, ip). The rats received Ppt (5, 10, and 20 mg/kg, po) daily prior to 3-NP administration. Nimodipine (12 mg/kg, po) or N-acetyl cysteine (NAC, 100 mg/kg, po) was used as positive control drugs. The body weight and behavior were monitored within 5 d. Then the animals were sacrificed, neuronal damage in striatum was estimated using Nissl staining. Hsp70 expression was detected with immunohistochemistry. Reactive oxygen species (ROS) generation was measured using dihydroethidium (DHE) staining. The levels of components in the Nrf2 pathway were measured with immunohistochemistry and Western blotting. RESULTS: 3-NP resulted in a marked reduction in the body weight and locomotion activity accompanied by progressive striatal dysfunction. In striatum, 3-NP caused ROS generation mainly in neurons rather than in astrocytes and induced Hsp70 expression. Administration of Ppt significantly alleviated 3-NP-induced changes of body weight and behavior, decreased ROS production and restored antioxidant enzymes activities in striatum. Moreover, Ppt directly scavenged free radicals, increased Nrf2 entering nucleus, and the expression of its downstream products heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidase 1 (NQO1) in striatum. Similar effects were obtained with the positive control drugs nimodipine or NAC. CONCLUSION: Ppt exerts a protective action against 3-NP-induced oxidative stress in the rat model of HD, which is associated with its anti-oxidant activity.


Assuntos
Antioxidantes/farmacologia , Gânglios da Base/efeitos dos fármacos , Doença de Huntington/prevenção & controle , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Nitrocompostos , Propionatos , Sapogeninas/farmacologia , Animais , Gânglios da Base/metabolismo , Gânglios da Base/patologia , Gânglios da Base/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Proteínas de Choque Térmico HSP70/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Humanos , Doença de Huntington/induzido quimicamente , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Doença de Huntington/fisiopatologia , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Atividade Motora/efeitos dos fármacos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Perda de Peso/efeitos dos fármacos
20.
Neuropharmacology ; 86: 103-15, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25018043

RESUMO

Mitochondria dysfunction is implicated in diverse conditions, including metabolic and neurodegenerative disorders. Mitochondrial dynamics has attracted increasing attention as to its relationship with mitochondria autophagy, also known as mitophagy, which is critical for degradation of dysfunctional mitochondria maintaining mitochondrial homeostasis. Mitochondrial fission and its role in clearance of injured mitochondria in acute ischemic injury, however, have not been elucidated yet. Here we showed that hypoxic/ischemic conditions led to fragmentation of mitochondria and induction of mitophagy in permanent middle cerebral artery occlusion (pMCAO) rats and oxygen-glucose deprivation (OGD) PC12 cells. Inhibition of Drp1 by pharmacologic inhibitor or siRNA resulted in accumulation of damaged mitochondria mainly through selectively blocking mitophagy without affecting mitochondrial biogenesis and non-selective autophagy. Drp1 inhibitors increased the infarct volume and aggravated the neurological deficits in a rat model of pMCAO. We demonstrated that the devastating role of disturbed mitochondrial fission by inhibiting Drp1 contributed to the damaged mitochondria-mediated injury such as ROS generation, cyt-c release and activation of caspase-3. Taken together, we proved that under hypoxic/ischemic stress a Drp1-dependent mitophagy was triggered which was involved in the removal of damaged mitochondria and cellular survival at the early stage of hypoxic/ischemic injury. Thus, Drp1 related pathway involved in selective removal of dysfunctional mitochondria is proposed as an efficient target for treatment of cerebral ischemia.


Assuntos
Autofagia/fisiologia , Isquemia Encefálica/fisiopatologia , Dinaminas/metabolismo , Mitocôndrias/fisiologia , Mitofagia/fisiologia , Animais , Autofagia/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/fisiopatologia , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/patologia , Caspase 3/metabolismo , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Modelos Animais de Doenças , Dinaminas/antagonistas & inibidores , Dinaminas/genética , Glucose/deficiência , Infarto da Artéria Cerebral Média , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Mitofagia/efeitos dos fármacos , Células PC12 , RNA Interferente Pequeno , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
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