RESUMEN
Chronic cerebral hypoperfusion is considered as a pivotal factor of cognitive impairment that occurs in cerebrovascular diseases. This study investigated the ameliorating effect of scutellarin (SCT) on spatial cognitive impairment and ß-amyloid (Aß) formation in rats with chronic cerebral hypoperfusion induced by permanent bilateral common carotid artery occlusion (pBCAO). SCT is a flavonoid in medicinal herb of Erigeron breviscapus (vant.) Hand. Mazz. known to have neuroprotective, antioxidative and anti-inflammatory effects. However, the beneficial effect and pivotal mechanism of SCT on cognitive impairment are still unclear. SCT was treated orally with two doses (10 or 30 mg/kg) for 4 weeks. Results of Morris water maze test performed on the ninth week after pBCAO revealed that SCT (30 mg/kg)-treated rats had significantly shortened escape latencies in acquisition training trials, significantly prolonged swimming time at the platform and its surrounding zone, significant increase in memory score, significant reduction in the number of target heading, and significant reduction in the time required for the first target heading during the retention trial compared to rats in the sham-control group. SCT significantly inhibited the production of Aß(1-40) and Aß(142) in brain tissues. However, SCT significantly upregulated the expression levels of amyloid precursor protein and ß-site APP-converting enzyme-1 in the hippocampus. In addition, SCT significantly inhibited the activation of Iba1-expressing microglia in brain tissues. The results suggest that SCT can exert ameliorating effect on spatial cognitive impairment caused by chronic cerebral hypoperfusion through suppressing Aß formation and microglial activation in brain tissues. Therefore, SCT can be used as a beneficial drug for vascular dementia and Alzheimer's disease.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Apigenina/administración & dosificación , Glucuronatos/administración & dosificación , Hipoxia-Isquemia Encefálica/complicaciones , Hipoxia-Isquemia Encefálica/tratamiento farmacológico , Discapacidades para el Aprendizaje/tratamiento farmacológico , Discapacidades para el Aprendizaje/etiología , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/etiología , Microglía/metabolismo , Fragmentos de Péptidos/metabolismo , Fitoterapia , Administración Oral , Animales , Encéfalo/citología , Encéfalo/metabolismo , Proteínas de Unión al Calcio/metabolismo , Enfermedad Crónica , Erigeron/química , Masculino , Proteínas de Microfilamentos/metabolismo , Ratas Sprague-DawleyRESUMEN
How to maintain and enhance cognitive functions for both aged and young populations is a highly interesting subject. But candidate memory-enhancing reagents are tested almost exclusively on lesioned or aged animals. Also, there is insufficient information on the type of memory these reagents can improve. Working memory, located in the prefrontal cortex, manages short-term sensory information, but, by gaining significant relevance, this information is converted to long-term memory by hippocampal formation and/or amygdala, followed by tagging with space-time or emotional cues, respectively. Nobiletin is a product of citrus peel known for cognitive-enhancing effects in various pharmacological and neurodegenerative disease models, yet, it is not well studied in non-lesioned animals and the type of memory that nobiletin can improve remains unclear. In this study, 8-week-old male mice were tested using behavioral measurements for working, spatial referential, emotional and visual recognition memory after daily administration of nobiletin. While nobiletin did not induce any change of spontaneous activity in the open field test, freezing by fear conditioning and novel object recognition increased. However, the effectiveness of spatial navigation in the Y-maze and Morris water maze was not improved. These results mean that nobiletin can specifically improve memories of emotionally salient information associated with fear and novelty, but not of spatial information without emotional saliency. Accordingly, the use of nobiletin on normal subjects as a memory enhancer would be more effective on emotional types but may have limited value for the improvement of episodic memories.
Asunto(s)
Flavonas/uso terapéutico , Trastornos de la Memoria/tratamiento farmacológico , Memoria a Corto Plazo/efectos de los fármacos , Animales , Emociones , Flavonas/administración & dosificación , Masculino , RatonesRESUMEN
Astragaloside IV (AS-IV) has been reported to have a prominent antioxidant effect and was proposed as a promising agent for the prevention of neurodegenerative disorders accompanied by cognitive impairment. The present study investigated the ameliorating effect of AS-IV on learning and memory deficits induced by chronic cerebral hypoperfusion in rats. Rats were treated with two doses of AS-IV (10 and 20 mg/kg, i.p.) daily for 28 days starting from the 5th week after permanent bilateral common carotid artery occlusion. AS-IV treatment (at dose of 20 mg/kg) significantly improved the spatial learning and memory deficits assessed using the Morris water maze test in rats with chronic cerebral hypoperfusion. AS-IV significantly attenuated neuronal apoptosis as well as the levels of superoxide dismutase and lipid peroxidation markers, including malondialdehyde and 4-hydroxy-2-nonenal, in the hippocampus. AS-IV also significantly reduced 8-hydroxy-2'-deoxyguanosine expression, a maker of oxidative DNA damage, while significantly inhibited the astrocyte and microglia activation in the hippocampus. The results indicate that AS-IV has therapeutic potential for the prevention of dementia caused by cerebral hypoperfusion and suggest that the ameliorating effect of AS-IV on learning and memory deficits might be the result of suppressing neuronal apoptosis and oxidative damage in the hippocampus.
Asunto(s)
Antioxidantes/uso terapéutico , Enfermedades de las Arterias Carótidas/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Saponinas/uso terapéutico , Triterpenos/uso terapéutico , Animales , Antioxidantes/farmacología , Apoptosis , Proteínas de Unión al Calcio/metabolismo , Enfermedades de las Arterias Carótidas/complicaciones , Circulación Cerebrovascular , Enfermedad Crónica , Evaluación Preclínica de Medicamentos , Proteína Ácida Fibrilar de la Glía/metabolismo , Hipocampo/irrigación sanguínea , Hipocampo/efectos de los fármacos , Hipocampo/patología , Masculino , Aprendizaje por Laberinto , Proteínas de Microfilamentos/metabolismo , Neuroglía/fisiología , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo , Ratas Sprague-Dawley , Saponinas/farmacología , Triterpenos/farmacologíaRESUMEN
Secondary mechanisms, including inflammation and microglia activation, serve as targets for the development and application of pharmacological strategies in the management of spinal cord injury (SCI). Tetramethylpyrazine (TMP), an active ingredient of Ligusticum wallichii (chuanxiong), has shown anti-inflammatory and neuroprotective effects against SCI. However, it remains uncertain whether the inflammation-suppressive effects of TMP play a modulatory role over microglia activation in SCI. The present study investigated the effects of TMP on microglia activation and pro-inflammatory cytokines in spinal cord compression injury in mice. For a real-time PCR measurement of pro-inflammatory cytokines, SCI was induced in mice by the clip compression method (30 g force, 1 min) and TMP (15 or 30 mg/kg, i.p.) was administered once, 30 minutes before the SCI induction. For immunohistochemistry, TMP (30 mg/kg, i.p.) treatment was given three times during the first 48 hours after the SCI. 30 mg/kg of TMP treatment reduced the up-regulation of TNF-α, IL-1ß and COX-2 mRNA in the spinal tissue at four hours after the SCI induction. TMP also significantly attenuated microglia activation and neutrophil infiltration at 48 hours after the SCI induction. In addition, iNOS expression in the spinal tissue was attenuated with TMP treatment. These results suggest that TMP plays a modulatory role in microglia activation and may protect the spinal cord from or potentially delay secondary spinal cord injury.
Asunto(s)
Medicamentos Herbarios Chinos , Microglía/efectos de los fármacos , Microglía/patología , Fármacos Neuroprotectores , Fitoterapia , Pirazinas/administración & dosificación , Pirazinas/farmacología , Compresión de la Médula Espinal/complicaciones , Compresión de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/etiología , Animales , Ciclooxigenasa 2/metabolismo , Mediadores de Inflamación/metabolismo , Interleucina-1beta/metabolismo , Ligusticum , Masculino , Ratones , Ratones Endogámicos C57BL , Infiltración Neutrófila/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II/metabolismo , Médula Espinal/metabolismo , Médula Espinal/patología , Compresión de la Médula Espinal/metabolismo , Compresión de la Médula Espinal/patología , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/patología , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Ginsenoside Rb1 (GRb1) is a major ingredient of ginseng and has a wide range of neuroprotection effects. Neuroinflammation is a feature of neurodegenerative conditions and is characterized by microglia activation and the expression of major inflammatory mediators. The present study investigated the modulatory effect of GRb1 on microglia activation, the expression of pro-inflammatory cytokines and cyclooxygenase (COX)-2 in the brain induced by systemic lipopolysaccharide (LPS) treatment in C57BL/6 mice. Systemic LPS treatment induces immediate microglia activation in the brain. Based on this information, GRb1 was administered orally, at doses of 10 and 20 mg/kg, 1 h prior to the LPS (3 mg/kg, intraperitoneally) injection. At a dose of 20 mg/kg GRb1 attenuated Iba1 protein expression and morphological activation of microglia by LPS. GRb1 significantly reduced the upregulation of tumor necrosis factor-α, interleukin (IL)-1ß and IL-6 mRNA in the brain tissue at 4 h after LPS injection. In addition, the expression of COX-2 mRNA and protein in the brain tissue were also attenuated at the 20 mg/kg dose of GRb1. These results indicate that GRb1 plays a modulatory role in microglia activation and neuroinflammation. This study shows that GRb1 attenuates microglia activation in the brain using an in vivo animal model.
Asunto(s)
Encéfalo/efectos de los fármacos , Ginsenósidos/farmacología , Inflamación/tratamiento farmacológico , Microglía/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Animales , Encéfalo/metabolismo , Ciclooxigenasa 2/metabolismo , Inflamación/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolisacáridos , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Panax/química , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Neuroinflammation, characterized by activation of microglia and expression of major inflammatory mediators, contributes to neuronal damage in addition to acute and chronic central nervous system (CNS) disease progression. The present study investigated the immune modulatory effects of ginsenoside Rg3, a principle active ingredient in Panax ginseng, on pro-inflammatory cytokines and microglia activation in brain tissue induced by systemic lipopolysaccharide (LPS) treatment in C57BL/6 mice. Systemic LPS treatment induces immediate microglia activation in the brain. Based on this information, ginsenoside Rg3 was treated orally with 10, 20, and 30 mg/kg 1 h prior to the LPS (3 mg/kg, intraperitoneally (i.p.)) injection. Ginsenoside Rg3 at 20 and 30 mg/kg oral doses significantly attenuated up-regulation of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß) and IL-6 mRNA in brain tissue at 4 h after LPS injection. Morphological activation of microglia and Iba1 protein expression by systemic LPS injection were reduced with ginsenoside Rg3 (30 mg/kg) treatment. In addition, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in brain tissue were also attenuated with oral treatment of ginsenoside Rg3 at 30 mg/kg. These results indicate that ginsenoside Rg3 plays a modulatory role in neuroinflammation. This study shows that ginsenoside Rg3 attenuates microglia activation using an in vivo animal model.
Asunto(s)
Encéfalo/efectos de los fármacos , Ginsenósidos/uso terapéutico , Mediadores de Inflamación/metabolismo , Inflamación/prevención & control , Microglía/efectos de los fármacos , Panax/química , Fitoterapia , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Encéfalo/metabolismo , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Citocinas/metabolismo , Ginsenósidos/farmacología , Factores Inmunológicos/farmacología , Factores Inmunológicos/uso terapéutico , Inflamación/metabolismo , Lipopolisacáridos , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , ARN Mensajero/metabolismoRESUMEN
Disruption of the blood-brain barrier (BBB) contributes to the inflammatory response and edema formation in the brain, exacerbating brain damage. The present study evaluated the effects of Scutellaria baicalensis (SR) water extracts on BBB disruption after intracerebral hemorrhage (ICH) in rats. ICH was induced by stereotaxic intrastriatal injection of bacterial type VII collagenase, and SR was administrated orally three times (50 mg/ml/kg) during the 48 h after ICH onset. SR treatment significantly reduced the degree of (1) hemorrhage volume and edema percentage of the ipsilateral hemisphere, (2) brain water content, (3) MPO-positive neutrophil infiltration in the peri-hematoma, and (4) BBB permeability measured by Evans blue leakage. In addition, expression of matrix metalloproteinase (MMP)-9, MMP-12, and tissue inhibitor of MMPs (TIMP)-1 were investigated with immunohistochemistry. SR treatment reduced MMP-9 and MMP-12 expression in the peri-hematoma after ICH. These results indicate that SR attenuates the BBB disruption through anti-inflammatory effects and suppression of MMP expression. These findings provide a pharmacological basis for the use of SR in the treatment of the BBB disruption following stroke and trauma.
Asunto(s)
Barrera Hematoencefálica/efectos de los fármacos , Edema Encefálico/prevención & control , Hemorragia Cerebral/tratamiento farmacológico , Inflamación/prevención & control , Fitoterapia , Extractos Vegetales/uso terapéutico , Scutellaria baicalensis , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Barrera Hematoencefálica/inmunología , Barrera Hematoencefálica/metabolismo , Agua Corporal/metabolismo , Lesiones Encefálicas/prevención & control , Hemorragia Cerebral/inmunología , Hemorragia Cerebral/metabolismo , Colagenasas , Hematoma/tratamiento farmacológico , Hematoma/metabolismo , Masculino , Metaloproteinasa 12 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Infiltración Neutrófila/efectos de los fármacos , Permeabilidad , Extractos Vegetales/farmacología , Ratas , Ratas Sprague-Dawley , Inhibidor Tisular de Metaloproteinasa-1/metabolismoRESUMEN
CONTEXT: Cinnamon bark is a very popular herb used in traditional medicine to treat various disorders such as chronic gastric symptoms, arthritis, and the common cold. OBJECTIVE: The immunomodulatory effect of water extract of cinnamon bark (CWE) on cytokine secretion and involvement of intracellular signaling molecules in activated T cells have been examined. MATERIALS AND METHODS: Mice were orally administered CWE for 7 days. Serum was obtained 90 min after intravenous injection of anti-CD3 antibody (Ab). Splenocytes were cultured with anti-CD3 Ab and CWE for cytokine expression, cell cycle, apoptotic/necrotic changes, and viability. IκBα, p38, JNK, ERK1/2, STAT4, and STAT6 were analyzed using western blotting. RESULTS: Administration of CWE decreased systemic levels of IFN-γ, but not the levels of IL-4 or IL-2. In vitro, CWE inhibited anti-CD3 Ab-stimulated IFN-γ and IL-4 at the mRNA and secreted protein levels. Despite its inhibition of IL-2 transcript, CWE enhanced IL-2 secretion. CWE treatment caused a reduction in the sub-G1 phase, accompanied by an increased ratio of apoptotic cells to necrotic cells. The increased IL-2 secretion by CWE was not mediated by its direct effect on CD4 T cells. CWE inhibited the activation of p38, JNK, ERK1/2, and STAT4, but not IκBα degradation or STAT6. DISCUSSION AND CONCLUSIONS: These observations provided evidence that CWE was able to down-regulate IFN-γ expression in activated T cells without altering IL-2 production, involving inhibition of p38, JNK, ERK1/2, and STAT4. Our results contribute to a better understanding of the immunomodulatory action of cinnamon bark for the application of inflammatory disorders.
Asunto(s)
Anticuerpos Monoclonales de Origen Murino/farmacología , Complejo CD3 , Cinnamomum zeylanicum/química , Factores Inmunológicos/inmunología , MAP Quinasa Quinasa 4/inmunología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteína Quinasa 3 Activada por Mitógenos/inmunología , Extractos Vegetales/farmacología , Factor de Transcripción STAT4/inmunología , Proteínas Quinasas p38 Activadas por Mitógenos/inmunología , Animales , Anticuerpos Monoclonales de Origen Murino/inmunología , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Células Cultivadas , Citocinas/biosíntesis , Citocinas/inmunología , Activación Enzimática/efectos de los fármacos , Activación Enzimática/inmunología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Factores Inmunológicos/química , Inmunomodulación/efectos de los fármacos , Inmunomodulación/inmunología , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/metabolismo , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , MAP Quinasa Quinasa 4/metabolismo , Sistema de Señalización de MAP Quinasas/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Extractos Vegetales/química , Factor de Transcripción STAT4/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
OBJECTIVES: The anti-inflammatory effects of an aqueous extract of Schizonepeta tenuifolia on lipopolysaccharide (LPS)-induced tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in vivo and in vitro have been investigated. METHODS: C57BL/6 mice were orally administered phosphate-buffered saline (control) or S. tenuifolia water extract (50, 200, 500 or 1000 mg/kg) for 10 days before intraperitoneal administration of LPS (1.3 mg/kg). Blood samples were obtained 1 h after LPS challenge, followed by determination of TNF-alpha and IL-6 levels. Peritoneal macrophages from thioglycollate-injected mice were obtained and stimulated with LPS and S. tenuifolia water extract for viability assay, cytokine analysis, real-time RT PCR and Western blotting. KEY FINDINGS: Oral administration of S. tenuifolia water extract to mice significantly reduced LPS-induced serum levels of TNF-alpha, but not IL-6. When peritoneal macrophages were treated in vitro with S. tenuifolia water extract, the inhibition of LPS-induced TNF-alpha was more pronounced than that of IL-6 at the level of secreted protein and mRNA. S. tenuifolia water extract reduced the degradation of IkappaBalpha and the nuclear relocation of p65 NF-kappaB, but the phosphorylation of IkappaBalpha was not affected. Inhibition of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) by S. tenuifolia water extract led secondarily to the inhibition of phospho-c-Jun and phospho-ATF-2. CONCLUSIONS: These results indicated that the downregulation of TNF-alpha by S. tenuifolia water extract may have involved the inhibition of both IkappaBalpha degradation and activation of c-Jun and ATF-2 involving suppression of JNK/SAPK.
Asunto(s)
Antiinflamatorios/farmacología , Proteínas I-kappa B/metabolismo , Inflamación/prevención & control , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Lamiaceae , Macrófagos Peritoneales/efectos de los fármacos , Extractos Vegetales/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Transcripción Activador 2/metabolismo , Transporte Activo de Núcleo Celular , Administración Oral , Animales , Antiinflamatorios/administración & dosificación , Western Blotting , Células Cultivadas , Cromatografía Líquida de Alta Presión , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Activación Enzimática , Inflamación/inducido químicamente , Inflamación/enzimología , Inflamación/inmunología , Interleucina-6/metabolismo , Lipopolisacáridos , Macrófagos Peritoneales/enzimología , Macrófagos Peritoneales/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Inhibidor NF-kappaB alfa , Fosforilación , Extractos Vegetales/administración & dosificación , Procesamiento Proteico-Postraduccional , Proteínas Proto-Oncogénicas c-jun/metabolismo , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Factor de Transcripción ReIA/metabolismo , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Contact with antigen on T-cells is made via the T-cell receptor/CD3 complex plus CD28, resulting in the production of cytokines including interleukin (IL)-2, IL-4 and interferon (IFN)-gamma. In particular, dysregulation of IFN-gamma and IL-4 accounts in part for organ-specific autoimmune diseases, allergic inflammation and other chronic inflammatory disorders. The dried above-ground parts of Schizonepeta tenuifolia Briq are used for the treatment of common cold and skin rashes observed in allergic dermatitis, psoriasis and other dermatological disorders in oriental medicine. In the present study, we investigated whether S. tenuifolia water extract (STE) may modulate systemic levels of IFN-gamma, IL-4 and IL-2 in anti-CD3-stimulated mice and the production of those cytokines in anti-CD3-stimulated peripheral blood mononuclear cells (PBMCs). In addition, the effects of STE on anti-CD3-induced activation of several transcription factors were examined. Oral administration of STE significantly reduced the serum levels of IFN-gamma and IL-4 from anti-CD3-treated mice but enhanced those of IL-2. Similar patterns were demonstrated in anti-CD3-stimulated splenocytes and PBMCs in vitro. Further analysis showed that STE enhanced the nuclear translocation of nuclear factor of activated T cells (NFAT)c2 but reduced that of the nuclear factor (NF)-kappaB. The downregulation of IFN-gamma and IL-4 was not mediated by its effects on signal transducer and activator of transcription (STAT)4 and STAT6 activation. These results suggest that the differential regulation of STE on IFN-gamma, IL-4 and IL-2 may be due to its suppression of NF-kappaB, concomitant with its enhancement of NFATc2. Further mechanistic work is required to investigate the role of STE on its modulation of anti-CD3-induced cytokines.
Asunto(s)
Interferón gamma/metabolismo , Interleucina-2/metabolismo , Interleucina-4/metabolismo , Lamiaceae , FN-kappa B/metabolismo , Animales , Secuencia de Bases , Complejo CD3/metabolismo , Cartilla de ADN/genética , Femenino , Técnicas In Vitro , Interferón gamma/sangre , Interferón gamma/genética , Interleucina-2/sangre , Interleucina-2/genética , Interleucina-4/sangre , Interleucina-4/genética , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Ratones , Ratones Endogámicos BALB C , Factores de Transcripción NFATC/metabolismo , Extractos Vegetales/administración & dosificación , Extractos Vegetales/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factor de Transcripción STAT4/metabolismo , Factor de Transcripción STAT6/metabolismoRESUMEN
Cinnamomum cassia Blume (CC) is one of the world's oldest natural spices, and is commonly used in traditional oriental medicine. We investigated the protective effect of ethanol extract from Cinnamomum cassia Blume (CCE) on the activation of hepatic stellate cells (HSCs). In addition, we examined the effects of CC powder in Sprague-Dawley rats with acute liver injury induced by dimethylnitrosamine (DMN). In vitro, HSC-T6 cells exhibit an activated phenotype, as reflected in their fibroblast-like morphology. CCE significantly reduced the expression of alpha-smooth muscle actin (alpha-SMA), connective tissue growth factor (CTGF), transforming growth factor beta (TGF-beta1), and tissue inhibitor of metalloproteinase-1 (TIMP-1). In vivo, the results were significantly protected by CC powder in the serum total protein, albumin, total-bilirubin, direct-bilirubin, glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), and alkaline phosphatase (ALP). We suggest that CC inhibits fibrogenesis, followed by HSC-T6 cell activation and increased restoration of liver function, ultimately resulting in acute liver injury.
Asunto(s)
Cinnamomum aromaticum/química , Citoprotección , Dimetilnitrosamina/toxicidad , Células Estrelladas Hepáticas/efectos de los fármacos , Cirrosis Hepática/prevención & control , Extractos Vegetales/farmacología , Actinas/antagonistas & inhibidores , Animales , Factor de Crecimiento del Tejido Conjuntivo/antagonistas & inhibidores , Hígado/efectos de los fármacos , Cirrosis Hepática/inducido químicamente , Pruebas de Función Hepática , Masculino , Ratas , Ratas Sprague-Dawley , Inhibidor Tisular de Metaloproteinasa-1/antagonistas & inhibidores , Factor de Crecimiento Transformador beta1/antagonistas & inhibidoresRESUMEN
It was reported that Dipsaci radix (DR) has a reinforcement effect on the bone-muscle dysfunction in the oriental medical classics and the experimental animal studies. The muscle atrophy was induced by unilateral transection of the sciatic nerve of the rats. Water-extract of DR was used as treatment once a day for 12 days. The muscle weights of the hind limb, atrophic changes, glycogen contents, compositions and cross-section areas of muscle fiber types in soleus and medial gastrocnemius were investigated. Muscle fiber type was classified to type-I and type-II with MHCf immunohistochemistry. Furthermore, Bax and Bcl-2 expressions were observed with immunohistochemiatry. DR treatment significantly increased muscle weights of soleus, medial gastrocnemius, lateral gastrocnemius, and posterior tibialis of the damaged hind limb. DR treatment reduced apoptotic muscle nuclei and hyaline-degenerated muscle fibers in soleus and medial gastrocnemius of the damaged hind limb. DR treatment also significantly increased glycogen contents in medial gastrocnemius of the damaged hind limb. DR treatment significantly attenuated the slow-to-fast shift in soleus of the damaged hind limb but not in medial gastrocnemius. DR treatment significantly increased cross-section areas of type-I and type-II fibers in soleus and medial gastrocnemius of the damaged hind limb. In soleus and medial gastrocnemius, DR treatment significantly reduced Bax positive muscle nuclei in the damaged hind limb. These results suggest that DR treatment has an anti-atrophic effect and an anti-apoptotic effect against myonuclear apoptosis induced by the peripheral nerve damage.
Asunto(s)
Dipsacaceae , Glucógeno/metabolismo , Fibras Musculares Esqueléticas/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Atrofia Muscular/prevención & control , Extractos Vegetales/uso terapéutico , Sustancias Protectoras/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Núcleo Celular/efectos de los fármacos , Miembro Posterior/efectos de los fármacos , Hialina , Masculino , Fibras Musculares Esqueléticas/patología , Músculo Esquelético/patología , Atrofia Muscular/patología , Tamaño de los Órganos/efectos de los fármacos , Extractos Vegetales/farmacología , Raíces de Plantas , Sustancias Protectoras/farmacología , Ratas , Ratas Sprague-Dawley , Nervio Ciático/cirugía , Proteína X Asociada a bcl-2/metabolismoRESUMEN
This study examined the effect of Natrii sulfas, a treatment for stroke patients suffering constipation in Oriental medicine, on the physiological indices and brain edema of rats. Brain edema was induced by a middle cerebral artery occlusion (MCAO), Natrii sulfas was administered after the MCAO. At 3, 6, 15, 24, and 48 hours after reperfusion, the physiological indices such as the fecal weight, urine volume and water content in the stools were assessed. The edema index was measured 48 hours after reperfusion. At 48 hours, the expressions of iNOS, MMP9, VEGF, GFAP, Bax, Bcl-2, c-Fos, and HSP72 positive astrocytes were observed on the brain tissues by immunohistochemistry. Natrii sulfas significantly improved the decrease in fecal weight, urine volume and water content in the stool caused by the ischemic insult (p < 0.05) and attenuated the brain edema caused by the ischemia insult (p < 0.05). Natrii sulfas significantly down-regulated iNOS and MMP9 expressions and attenuated the astrocyte swelling due to brain edema in the penumbra of the cerebral cortex of MCAO rats. Natrii sulfas reduced the excess Bax and HSP72 expressions in ischemic brain, which was statistically significant in the penumbra of the cerebral cortex but not in the caudate putamen. These results suggest Natrii sulfas has a protective effect on ischemia-induced brain edema and improves the physiological symptoms.
Asunto(s)
Isquemia Encefálica/prevención & control , Materia Medica/uso terapéutico , Animales , Isquemia Encefálica/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteínas del Choque Térmico HSP72/metabolismo , Inmunohistoquímica , Masculino , Óxido Nítrico Sintasa de Tipo II/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Sprague-Dawley , Sulfatos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: So-Shi-Ho-Tang (SSHT) or known as Sho-Saiko-To in Japanese and Xiao-Chai-Hu-Tang in Chinese has been used to treat chronic liver disease and other infections, and its hepatoprotective effects have been widely studied. AIM OF THE STUDY: We tried to investigate the immunomodulatory effect of SSHT on interferon (IFN)-gamma and interleukin (IL)-4 and their Th1/Th2 transcription factors in vivo and in vitro since these two cytokines are important in determining the type of cell-mediated inflammatory and humoral responses. MATERIALS AND METHODS: SSHT was orally given to BALB/c mice for 7 days and then injected with anti-CD3 mAb intravenously. IFN-gamma, IL-4, IL-2 and Th1/Th2-specific transcription factors as well as splenocyte subsets were measured. Splenocytes and CD4 T cells were cultured with anti-CD3 or anti-CD3/anti-CD28 in the presence of SSHT, its constituent herbs and baicalin, and the levels of cytokines and transcription factors were measured by ELISA and western blotting. RESULTS: Oral administration of SSHT to mice in response to i.v. anti-CD3 injection enhanced the expression of IFN-gamma, IL-4 and IL-2 in the serum and spleen at the secreted protein and mRNA level. This was accompanied by the upregulation of CD69 and CD4 T cell populations by flow cytometry. The upregulation of IFN-gamma and IL-4 by SSHT did not occur in anti-CD3/anti-CD28 stimulated CD4 T cells in vitro. However, SSHT was capable of producing the cytokines in anti-CD3 stimulated splenocytes even in the absence of CD28, suggesting a role for some soluble factors produced by antigen presenting cells (APC). In support of this, we found that SSHT increased IL-12 and IL-6 in the same cells. STAT4, but not T-bet, was involved in the upregulation of IFN-gamma by SSHT while the increased IL-4 expression was accompanied by a parallel increase in c-Maf but independent of STAT6 and GATA-3. CONCLUSION: These data indicate that the upregulation of IFN-gamma and IL-4 by SSHT must occur through some interactions between APC and CD4 T cells. Taken together, the present data provide additional information on some of the immunological mechanisms of SSHT for treatment of liver diseases and infections.
Asunto(s)
Células Presentadoras de Antígenos/efectos de los fármacos , Linfocitos T CD4-Positivos/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Interferón gamma/metabolismo , Interleucina-4/metabolismo , Células TH1/efectos de los fármacos , Células Th2/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Animales , Células Presentadoras de Antígenos/metabolismo , Western Blotting , Linfocitos T CD4-Positivos/metabolismo , Cromatografía Líquida de Alta Presión , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Ratones , Ratones Endogámicos BALB C , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células TH1/metabolismo , Células Th2/metabolismoRESUMEN
Lithospermi radix (LR, Borraginaceae, the root of Lithospermum erythrorhizon Siebold. et Zuccarinii) is used in herbal medicine to treat such conditions as eczema, skin burns and frostbite. This study investigates the effects of LR on the anti-allergy mechanism. LR inhibited the release of histamine from rat peritoneal mast cells by compound 48/80 in a dose-dependent manner. LR orally administered at 6.59 mg/100 g also inhibited the anti-DNP IgE-induced passive cutaneous anaphylaxis reaction. LR inhibited the PMA plus A23187-induced increase in IL-6, IL-8, and TNF-alpha expression in HMC-1 cells. In addition, LR also inhibited nuclear factor-kappa B (NF-kappaB) activation and I kappaB-alpha degradation. These results show that LR had an inhibitory effect on the atopic allergic reaction. Furthermore, the in vivo and in vitro anti-allergic effect of LR suggests possible therapeutic applications of this agent for inflammatory allergic diseases.
Asunto(s)
Antialérgicos/farmacología , Citocinas/biosíntesis , Liberación de Histamina/efectos de los fármacos , Lithospermum/química , Mastocitos/efectos de los fármacos , Anafilaxia/prevención & control , Animales , Células Cultivadas , Histamina/biosíntesis , Proteínas I-kappa B/metabolismo , Inmunoglobulina E/inmunología , Mastocitos/metabolismo , Inhibidor NF-kappaB alfa , FN-kappa B/metabolismo , Extractos Vegetales/farmacología , Ratas , Ratas Sprague-Dawley , p-Metoxi-N-metilfenetilamina/farmacologíaRESUMEN
We investigated the protective effect of Cuscutae semen (CS) on acute liver injury induced by dimethylnitrosamine (DMN) in Sprague-Dawley rats. CS is an important traditional herbal medicine widely used as a tonic and aphrodisiac to nourish the liver and kidney and to treat impotence and seminal emission. Rats were given a single intraperitoneal injection of DMN (40 mg/kg), and were then treated with CS daily by oral gavage for 4 d. Immunohistochemical studies for alpha-smooth muscle actin (alpha-SMA) and proliferating cell nuclear antigen (PCNA) were performed, along with hydroxyproline and biological assay. Liver injury caused by DMN-injection was significantly inhibited in the CS-treated group compared to the silymarin-treated group. The results of blood biological assay were significantly protected by CS in serum total protein (T-protein), T-bilirubin (T-bili), D-bilirubin (D-bili), GOT, GPT, and ALP. The hydroxyproline content and amount of active alpha-SMA and PCNA were significantly decreased in the CS-treated group than in the silymarin-treated group. CS exhibited an in vivo hepatoprotective effect and anti-fibrogenic effects against DMN-induced acute liver injury and inhibited the formation of hydroxyproline, which suggests that CS may be useful in preventing fibrogenesis after liver injury.
Asunto(s)
Alquilantes/antagonistas & inhibidores , Alquilantes/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Dimetilnitrosamina/antagonistas & inhibidores , Dimetilnitrosamina/toxicidad , Plantas Medicinales/química , Actinas/metabolismo , Animales , Western Blotting , Peso Corporal/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Cromatografía Líquida de Alta Presión , Hidroxiprolina/metabolismo , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica , Indicadores y Reactivos , Hígado/patología , Masculino , Tamaño de los Órganos/efectos de los fármacos , Antígeno Nuclear de Célula en Proliferación/metabolismo , Ratas , Ratas Sprague-Dawley , Estándares de ReferenciaRESUMEN
Tetrandrine (TET), a plant alkaloid, is known primarily as a non-selective Ca(2+) channel blocker. On the contrary to the cytoprotective effect on ischemia/reperfusion injury, TET has also been reported to cause cytotoxicity. In this study, we wished to understand the apparently disparate effects of this potential drug and thus investigated molecular mechanisms on proliferation and apoptosis and its effect on oxidative stress-induced apoptosis in Neuro 2a mouse neuroblastoma cells. We showed that TET, at high concentrations, induced cell cycle arrest and apoptosis through oxidative stress with following observations. Firstly, 10 microM TET elevated the reactive oxygen species (ROS) level and accordingly depleted glutathione (GSH) content. Secondly, pretreatment with antioxidants (NAC or GSH) protected cells from TET-induced apoptosis. We also demonstrated that treatment with 10 microM TET caused not only induction of p53, p21(waf1), and Bax, but also nuclear translocation of p53 and hypo-phosphorylation of pRb concurrently. Our important finding is that the concentration-dependent dual effect of TET, either inhibiting or promoting cell death induced by H(2)O(2) was observed, probably through regulating redox balance, which was well reflected on the GSH content in each condition. Besides, inhibition of Ca(2+) influx protected cells from H(2)O(2)-induced apoptosis even in the presence of 10 microM TET. Taken together, our data suggest that TET regulation of cellular redox states may play a major role in its dual action of cytotoxicity and cytoprotection.