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1.
Int J Mol Sci ; 24(11)2023 Jun 02.
Artículo en Inglés | MEDLINE | ID: mdl-37298615

RESUMEN

Tissue plasminogen activator, aiming to restore cerebral blood flow (CBF), has been used for acute ischemic strokes in clinics; however, its narrow therapeutic time window remains a serious concern. To develop novel prophylactic drugs to alleviate cerebral ischemia/reperfusion injuries, ferulic acid derivative 012 (FAD012) was synthesized and showed comparable antioxidant properties to ferulic acid (FA) and probably possesses the potent ability to cross the blood-brain barrier. A more potent cytoprotective effect of FAD012 against H2O2-induced cytotoxicity in PC12 cells was also observed. In vivo toxicity was not observed in rats given a long-term oral administration of FAD012, indicating its good tolerability. A one-week-course oral administration of FAD012 significantly alleviated middle cerebral artery occlusion (MCAO)-induced cerebral ischemia/reperfusion injuries in rats, accompanied by the restoration of CBF and endothelial nitrogen oxide synthetase (eNOS) expression. Treatment with FAD012 significantly restored the cell viability and eNOS expression damaged by H2O2, used to mimic MCAO-triggered oxidative stress, in rat brain microvascular endothelial cells. Our findings suggested that FAD012 protected the viability of vascular endothelium and maintained eNOS expression, ultimately contributing to the restoration of CBF, and may provide a rationale for the development of FAD012 into an effective prophylactic drug for patients at high risk of stroke.


Asunto(s)
Isquemia Encefálica , Fármacos Neuroprotectores , Daño por Reperfusión , Animales , Ratas , Isquemia Encefálica/tratamiento farmacológico , Circulación Cerebrovascular , Células Endoteliales/metabolismo , Peróxido de Hidrógeno/uso terapéutico , Infarto de la Arteria Cerebral Media/metabolismo , Fármacos Neuroprotectores/farmacología , Óxido Nítrico Sintasa , Ratas Sprague-Dawley , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/prevención & control , Daño por Reperfusión/metabolismo , Activador de Tejido Plasminógeno/uso terapéutico
2.
Molecules ; 27(19)2022 Oct 04.
Artículo en Inglés | MEDLINE | ID: mdl-36235115

RESUMEN

The cytotoxicity of a trivalent arsenic derivative (arsenite, AsIII) combined with arenobufagin or gamabufotalin was evaluated in human U-87 glioblastoma cells. Synergistic cytotoxicity with upregulated intracellular arsenic levels was observed, when treated with AsIII combined with arenobufagin instead of gamabufotalin. Apoptosis and the activation of caspase-9/-8/-3 were induced by AsIII and further strengthened by arenobufagin. The magnitude of increase in the activities of caspase-9/-3 was much greater than that of caspase-8, suggesting that the intrinsic pathway played a much more important role in the apoptosis. An increase in the number of necrotic cells, enhanced LDH leakage, and intensified G2/M phase arrest were observed. A remarkable increase in the expression level of γH2AX, a DNA damage marker, was induced by AsIII+arenobufagin. Concomitantly, the activation of autophagy was observed, suggesting that autophagic cell death associated with DNA damage was partially attributed to the cytotoxicity of AsIII+arenobufagin. Suppression of Notch signaling was confirmed in the combined regimen-treated cells, suggesting that inactivation of Jagged1/Notch signaling would probably contribute to the synergistic cytotoxic effect of AsIII+arenobufagin. Given that both AsIII and arenobufagin are capable of penetrating into the blood-brain barrier, our findings may provide fundamental insight into the clinical application of the combined regimen for glioblastoma.


Asunto(s)
Antineoplásicos , Arsénico , Arsenitos , Bufanólidos , Glioblastoma , Antineoplásicos/farmacología , Apoptosis , Arsénico/metabolismo , Arsenitos/farmacología , Bufanólidos/farmacología , Caspasa 8/metabolismo , Caspasa 9/metabolismo , Línea Celular , Línea Celular Tumoral , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Humanos
3.
Int J Mol Sci ; 18(3)2017 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-28273833

RESUMEN

Ferulic acid (FA), a phenolic phytochemical, has been reported to exert antioxidative and neuroprotective effects. In this study, we investigated the protective effects of FA against the dysfunction of the swallowing reflex induced by ligation of bilateral common carotid arteries (2VO) in rats. In 2VO rats, topical administration of water or citric acid to the pharyngolaryngeal region evoked a diminished number of swallowing events with prolonged latency compared to sham-operated control rats. 2VO rats had an increased level of superoxide anion radical, and decreased dopamine and tyrosine hydroxylase enzyme levels in the striatum, suggesting that 2VO augmented cerebral oxidative stress and impaired the striatal dopaminergic system. Furthermore, substance P (SP) expression in the laryngopharyngeal mucosa, which is believed to be positively regulated by dopaminergic signaling in the basal ganglia, was decreased in 2VO rats. Oral treatment with FA (30 mg/kg) for 3 weeks (from one week before 2VO to two weeks after) improved the swallowing reflex and maintained levels of striatal dopamine and laryngopharyngeal SP expression in 2VO rats. These results suggest that FA maintains the swallowing reflex by protecting the dopamine-SP system against ischemia-induced oxidative damage in 2VO rats.


Asunto(s)
Isquemia Encefálica/etiología , Isquemia Encefálica/patología , Corteza Cerebral/irrigación sanguínea , Corteza Cerebral/patología , Ácidos Cumáricos/farmacología , Fármacos Neuroprotectores/farmacología , Animales , Apoptosis/efectos de los fármacos , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/fisiopatología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/fisiopatología , Circulación Cerebrovascular/efectos de los fármacos , Cuerpo Estriado/irrigación sanguínea , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Dopamina/biosíntesis , Neuronas Dopaminérgicas/metabolismo , Expresión Génica , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Tirosina 3-Monooxigenasa/genética , Tirosina 3-Monooxigenasa/metabolismo
4.
BMC Complement Altern Med ; 13: 370, 2013 Dec 26.
Artículo en Inglés | MEDLINE | ID: mdl-24369991

RESUMEN

BACKGROUND: Ganoderma lucidum is a popular medicinal mushroom used for promoting health and longevity in Asian countries. Previously, we reported that a water-soluble extract from a culture medium of Ganoderma lucidum mycelia (MAK) exerts antioxidative and cerebroprotective effects against ischemia-reperfusion injury in vivo. Here, we evaluated the antidepressant and anxiolytic activities of MAK in rats. METHODS: MAK (0.3 or 1 g/kg, p.o.) was administered in the experimental animals 60 min before the forced swimming, open-field, elevated plus-maze, contextual fear-conditioning, and head twitch tests. Additionally, the mechanisms involved in the antidepressant-like action of MAK were investigated by the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP)- or 5-HT2A agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI)-induced head twitch responses. RESULTS: Treatment with MAK (1 g/kg) exhibited antidepressant-like effects in the forced swimming test, attenuated freezing behavior in the contextual fear-conditioning test, and decreased the number of head twitches induced by DOI, but not with 5-HTP. No significant response was observed in locomotion or anxiety-like behavior, when the animals were evaluated in the open-field or elevated plus-maze test, respectively. CONCLUSIONS: These data suggest that MAK has antidepressant-like potential, which is most likely due to the antagonism of 5-HT2A receptors, and possesses anxiolytic-like effects toward memory-dependent and/or stress-induced anxiety in rats.


Asunto(s)
Antidepresivos/farmacología , Conducta Animal/efectos de los fármacos , Extractos Vegetales/farmacología , Reishi/química , 5-Hidroxitriptófano/toxicidad , Análisis de Varianza , Animales , Antidepresivos/química , Antidepresivos/uso terapéutico , Medios de Cultivo Condicionados , Miedo/efectos de los fármacos , Masculino , Micelio/metabolismo , Extractos Vegetales/química , Ratas , Ratas Sprague-Dawley , Reishi/metabolismo , Estrés Fisiológico , Estrés Psicológico , Tics/inducido químicamente , Tics/tratamiento farmacológico , Tics/fisiopatología
5.
Mol Cell Biol ; 27(7): 2538-47, 2007 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-17242193

RESUMEN

Transcription-coupled repair (TCR) efficiently removes a variety of lesions from the transcribed strand of active genes. Mutations in Cockayne syndrome group A and B genes (CSA and CSB) result in defective TCR, but the molecular mechanism of TCR in mammalian cells is not clear. We have found that CSA protein is translocated to the nuclear matrix after UV irradiation and colocalized with the hyperphosphorylated form of RNA polymerase II and that the translocation is dependent on CSB. We developed a cell-free system for the UV-induced translocation of CSA. A cytoskeleton (CSK) buffer-soluble fraction containing CSA and a CSK buffer-insoluble fraction prepared from UV-irradiated CS-A cells were mixed. After incubation, the insoluble fraction was treated with DNase I. CSA protein was detected in the DNase I-insoluble fraction, indicating that it was translocated to the nuclear matrix. In this cell-free system, the translocation was dependent on UV irradiation, CSB function, and TCR-competent CSA. Moreover, the translocation was dependent on functional TFIIH, as well as chromatin structure and transcription elongation. These results suggest that alterations of chromatin at the RNA polymerase II stall site, which depend on CSB and TFIIH at least, are necessary for the UV-induced translocation of CSA to the nuclear matrix.


Asunto(s)
Enzimas Reparadoras del ADN/metabolismo , Matriz Nuclear/metabolismo , ARN Polimerasa II/metabolismo , Factor de Transcripción TFIIH/metabolismo , Factores de Transcripción/metabolismo , Rayos Ultravioleta , Línea Celular Transformada , Núcleo Celular/metabolismo , Sistema Libre de Células , Cromatina/fisiología , Cromatina/ultraestructura , Enzimas Reparadoras del ADN/genética , Fibroblastos/citología , Humanos , Transporte de Proteínas/efectos de la radiación , Factor de Transcripción TFIIH/genética , Factores de Transcripción/genética , Transcripción Genética
6.
Biomed Res Int ; 2015: 189292, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26665003

RESUMEN

Diabetes mellitus is known to exacerbate acute cerebral ischemic injury. Previous studies have demonstrated that infarction volumes caused by transient cerebral ischemia were greater in diabetic rats than in nondiabetic rats. Tumor necrosis factor-α (TNF-α) is a proinflammatory protein produced in the brain in response to cerebral ischemia that promotes apoptosis. Etanercept (ETN), a recombinant TNF receptor (p75)-Fc fusion protein, competitively inhibits TNF-α. Therefore, we evaluated the neuroprotective effects of chronic or acute treatment with ETN on cerebral injury caused by middle cerebral artery occlusion/reperfusion (MCAO/Re) in rats with streptozotocin-induced diabetes. Furthermore, we evaluated the effects of ETN against the apoptosis and myeloperoxidase activity. Single administration of ETN before MCAO significantly suppressed exacerbation of cerebral damage in nondiabetic rats, as assessed by infarct volume. In contrast, the diabetic state markedly aggravated MCAO/Re-induced cerebral damage despite ETN treatment within 24 h before MCAO. However, the damage was improved by repeated administration of ETN at 900 µg/kg/daily in rats in an induced diabetic state. These results suggested that repeated administration of ETN can prevent exacerbation of cerebral ischemic injury in the diabetic state and is mainly attributed to anti-inflammatory effects.


Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Etanercept/administración & dosificación , Inflamación/tratamiento farmacológico , Ataque Isquémico Transitorio/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/fisiopatología , Humanos , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/genética , Infarto de la Arteria Cerebral Media/fisiopatología , Inflamación/genética , Inflamación/patología , Ataque Isquémico Transitorio/complicaciones , Ataque Isquémico Transitorio/genética , Ataque Isquémico Transitorio/fisiopatología , Fármacos Neuroprotectores , Ratas , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismo
7.
Artículo en Inglés | MEDLINE | ID: mdl-25945116

RESUMEN

Type 2 diabetes mellitus has been known to increase systemic oxidative stress by chronic hyperglycemia and visceral obesity and aggravate cerebral ischemic injury. On the basis of our previous study regarding a water-soluble extract from the culture medium of Ganoderma lucidum mycelia (designed as MAK), which exerts antioxidative and neuroprotective effects, the present study was conducted to evaluate the preventive effects of MAK on apoptosis and necroptosis (a programmed necrosis) induced by hypoxia/ischemia (H/I) in type 2 diabetic KKAy mice. H/I was induced by a combination of unilateral common carotid artery ligation with hypoxia (8% O2 for 20 min) and subsequent reoxygenation. Pretreatment with MAK (1 g/kg, p.o.) for a week significantly reduced H/I-induced neurological deficits and brain infarction volume assessed at 24 h of reoxygenation. Histochemical analysis showed that MAK significantly suppressed superoxide production, neuronal cell death, and vacuolation in the ischemic penumbra, which was accompanied by a decrease in the numbers of TUNEL- or cleaved caspase-3-positive cells. Furthermore, MAK decreased the expression of receptor-interacting protein kinase 3 mRNA and protein, a key molecule for necroptosis. These results suggest that MAK confers resistance to apoptotic and necroptotic cell death and relieves H/I-induced cerebral ischemic injury in type 2 diabetic mice.

8.
Nutrients ; 6(4): 1554-77, 2014 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-24739976

RESUMEN

Diabetes mellitus is known to exacerbate cerebral ischemic injury. In the present study, we investigated antiapoptotic and anti-inflammatory effects of oral supplementation of ascorbic acid (AA) on cerebral injury caused by middle cerebral artery occlusion and reperfusion (MCAO/Re) in rats with streptozotocin-induced diabetes. We also evaluated the effects of AA on expression of sodium-dependent vitamin C transporter 2 (SVCT2) and glucose transporter 1 (GLUT1) after MCAO/Re in the brain. The diabetic state markedly aggravated MCAO/Re-induced cerebral damage, as assessed by infarct volume and edema. Pretreatment with AA (100 mg/kg, p.o.) for two weeks significantly suppressed the exacerbation of damage in the brain of diabetic rats. AA also suppressed the production of superoxide radical, activation of caspase-3, and expression of proinflammatory cytokines (tumor necrosis factor-α and interleukin-1ß) in the ischemic penumbra. Immunohistochemical staining revealed that expression of SVCT2 was upregulated primarily in neurons and capillary endothelial cells after MCAO/Re in the nondiabetic cortex, accompanied by an increase in total AA (AA + dehydroascorbic acid) in the tissue, and that these responses were suppressed in the diabetic rats. AA supplementation to the diabetic rats restored these responses to the levels of the nondiabetic rats. Furthermore, AA markedly upregulated the basal expression of GLUT1 in endothelial cells of nondiabetic and diabetic cortex, which did not affect total AA levels in the cortex. These results suggest that daily intake of AA attenuates the exacerbation of cerebral ischemic injury in a diabetic state, which may be attributed to anti-apoptotic and anti-inflammatory effects via the improvement of augmented oxidative stress in the brain. AA supplementation may protect endothelial function against the exacerbated ischemic oxidative injury in the diabetic state and improve AA transport through SVCT2 in the cortex.


Asunto(s)
Ácido Ascórbico/administración & dosificación , Diabetes Mellitus Experimental/tratamiento farmacológico , Transportador de Glucosa de Tipo 1/metabolismo , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Neuronas/efectos de los fármacos , Transportadores de Sodio Acoplados a la Vitamina C/metabolismo , Administración Oral , Animales , Apoptosis/efectos de los fármacos , Encéfalo/efectos de los fármacos , Caspasa 3 , Suplementos Dietéticos , Células Endoteliales/efectos de los fármacos , Transportador de Glucosa de Tipo 1/genética , Infarto de la Arteria Cerebral Media/patología , Interleucina-1beta/metabolismo , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Transportadores de Sodio Acoplados a la Vitamina C/genética , Estreptozocina , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia Arriba
9.
Proc Natl Acad Sci U S A ; 99(1): 201-6, 2002 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-11782547

RESUMEN

Transcription-coupled repair (TCR) efficiently removes a variety of lesions from the transcribed strand of active genes. By allowing rapid resumption of RNA synthesis, the process is of major importance for cellular resistance to transcription-blocking genotoxic damage. Mutations in the Cockayne syndrome group A or B (CSA or CSB) gene result in defective TCR. However, the exact mechanism of TCR in mammalian cells remains to be elucidated. We found that CSA protein is rapidly translocated to the nuclear matrix after UV irradiation. The translocation of CSA was independent of Xeroderma pigmentosum group C, which is specific to the global genome repair subpathway of nucleotide excision repair (NER) and of the core NER factor Xeroderma pigmentosum group A but required the CSB protein. In UV-irradiated cells, CSA protein colocalized with the hyperphosphorylated form of RNA polymerase II, engaged in transcription elongation. The translocation of CSA was also induced by treatment of the cells with cisplatin or hydrogen peroxide, both of which produce damage that is subjected to TCR but not induced by treatment with dimethyl sulfate, which produces damage that is not subjected to TCR. The hydrogen peroxide-induced translocation of CSA was also CSB dependent. These findings establish a link between TCR and the nuclear matrix mediated by CSA.


Asunto(s)
Transporte Activo de Núcleo Celular , Reparación del ADN , Proteínas/metabolismo , Transcripción Genética , Alquilantes/farmacología , Línea Celular , Núcleo Celular/metabolismo , Cisplatino/farmacología , Enzimas Reparadoras del ADN , Células HeLa , Humanos , Peróxido de Hidrógeno/farmacología , Microscopía Fluorescente , Mutágenos/farmacología , Oxidantes/farmacología , Fosforilación , Transporte de Proteínas , Proteínas/genética , Fármacos Sensibilizantes a Radiaciones/farmacología , Fracciones Subcelulares/metabolismo , Ésteres del Ácido Sulfúrico/farmacología , Factores de Tiempo , Factores de Transcripción , Transfección , Rayos Ultravioleta
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