RESUMO
Mitochondrial remodeling is dysregulated in metabolic diseases but the underlying mechanism is not fully understood. We report here that BDNF (brain derived neurotrophic factor) provokes mitochondrial fission and clearance in skeletal muscle via the PRKAA/AMPK-PINK1-PRKN/Parkin and PRKAA-DNM1L/DRP1-MFF pathways. Depleting Bdnf expression in myotubes reduced fatty acid-induced mitofission and mitophagy, which was associated with mitochondrial elongation and impaired lipid handling. Muscle-specific bdnf knockout (MBKO) mice displayed defective mitofission and mitophagy, and accumulation of dysfunctional mitochondria in the muscle when they were fed with a high-fat diet (HFD). These animals also have exacerbated body weight gain, increased intramyocellular lipid deposition, reduced energy expenditure, poor metabolic flexibility, and more insulin resistance. In contrast, consuming a BDNF mimetic (7,8-dihydroxyflavone) increased mitochondrial content, and enhanced mitofission and mitophagy in the skeletal muscles. Hence, BDNF is an essential myokine to maintain mitochondrial quality and function, and its repression in obesity might contribute to impaired metabolism.Abbreviation: 7,8-DHF: 7,8-dihydroxyflavone; ACACA/ACC: acetyl Coenzyme A carboxylase alpha; ACAD: acyl-Coenzyme A dehydrogenase family; ACADVL: acyl-Coenzyme A dehydrogenase, very long chain; ACOT: acyl-CoA thioesterase; CAMKK2: calcium/calmodulin-dependent protein kinase kinase 2, beta; BDNF: brain derived neurotrophic factor; BNIP3: BCL2/adenovirus E1B interacting protein 3; BNIP3L/NIX: BCL2/adenovirus E1B interacting protein 3-like; CCL2/MCP-1: chemokine (C-C motif) ligand 2; CCL5: chemokine (C-C motif) ligand 5; CNS: central nervous system; CPT1B: carnitine palmitoyltransferase 1b, muscle; Cpt2: carnitine palmitoyltransferase 2; CREB: cAMP responsive element binding protein; DNM1L/DRP1: dynamin 1-like; E2: estrogen; EHHADH: enoyl-CoenzymeA hydratase/3-hydroxyacyl CoenzymeA dehydrogenase; ESR1/ER-alpha: estrogen receptor 1 (alpha); FA: fatty acid; FAO: fatty acid oxidation; FCCP: carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone; FFA: free fatty acids; FGF21: fibroblast growth factor 21; FUNDC1: FUN14 domain containing 1; HADHA: hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha; HFD: high-fat diet; iWAT: inguinal white adipose tissues; MAP1LC3A/LC3A: microtubule-associated protein 1 light chain 3 alpha; MBKO; muscle-specific bdnf knockout; IL6/IL-6: interleukin 6; MCEE: methylmalonyl CoA epimerase; MFF: mitochondrial fission factor; NTRK2/TRKB: neurotrophic tyrosine kinase, receptor, type 2; OPTN: optineurin; PA: palmitic acid; PARL: presenilin associated, rhomboid-like; PDH: pyruvate dehydrogenase; PINK1: PTEN induced putative kinase 1; PPARGC1A/PGC-1α: peroxisome proliferative activated receptor, gamma, coactivator 1 alpha; PRKAA/AMPK: protein kinase, AMP-activated, alpha 2 catalytic subunit; ROS: reactive oxygen species; TBK1: TANK-binding kinase 1; TG: triacylglycerides; TNF/TNFα: tumor necrosis factor; TOMM20: translocase of outer mitochondrial membrane 20; ULK1: unc-51 like kinase 1.
Assuntos
Proteínas Quinases Ativadas por AMP , Fator Neurotrófico Derivado do Encéfalo , Mitocôndrias Musculares , Músculo Esquelético , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Autofagia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ácidos Graxos/metabolismo , Feminino , Camundongos , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/fisiologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Zao-Jiao-Ci (ZJC), as the spine of Chinese Honey locust (Gleditsia sinensis Lam.), is traditionally used as Chinese medicine to reduce inflammation. AIM OF THE STUDY: The present study aimed to investigate an anti-inflammatory effect of ZJC aqueous extract both in vitro and in vivo, as well as its underlying mechanisms. MATERIALS AND METHODS: Anti-inflammatory effect of ZJC aqueous extract was evaluated by using carrageenan-induced paw edema in rats. In addition, the inhibitory effects of ZJC on nitric oxide production, intracellular reactive oxygen species production, pro-inflammatory mediator expression and prostaglandin E2 (PGE2) production were determined by using LPS-activated RAW 264.7 cells. The anti-oxidant activity of ZJC was assessed using 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid assay. RESULTS: ZJC aqueous extract showed significant suppressive effect on paw edema in rats at 100mg/kg. Moreover, ZJC aqueous extract decreased the expression of cyclooxygenase (COX)-2 and significantly decreased the PGE2, tumor necrosis factor-α, interleukin (IL)-1ß and IL-6 production in LPS-activated macrophages in dose-dependent manners. ZJC aqueous extract inhibited the mRNA expression of these inflammatory cytokines as well. Furthermore, ZJC aqueous extract was found as an anti-oxidant and could inhibit ROS production in the LPS-induced cells. CONCLUSIONS: These findings show the potential of ZJC aqueous extract as a naturally occurring COX-2 inhibitor to reduce inflammation.
Assuntos
Benzopiranos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Edema/prevenção & controle , Gleditsia/química , Macrófagos/efeitos dos fármacos , Caules de Planta/química , Animais , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Benzopiranos/isolamento & purificação , Carragenina , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/isolamento & purificação , Citocinas/genética , Citocinas/metabolismo , Dinoprostona/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/isolamento & purificação , Edema/induzido quimicamente , Edema/genética , Edema/metabolismo , Regulação da Expressão Gênica , Mediadores da Inflamação/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Fitoterapia , Plantas Medicinais , Células RAW 264.7 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Solventes/química , Água/químicaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Herba Cistanches (HC, Cistanche deserticola or Cistanche tubulosa) is a Chinese herb traditionally used for muscle problems. Previous studies demonstrated that HC extract could reduce muscle damage and improve ATP storage in post-exercised rats. However, its effect on statin-induced muscle toxicity has never been investigated. AIM: The objective of this study was to determine if the aqueous extract of HC (HCE) could prevent simvastatin-induced toxicity in L6 rat skeletal muscle cells; and whether verbascoside is the major bioactive constituent which contributes to the effects. MATERIALS AND METHODS: MTT was performed to determine the effects of HCE (0-2000µg/ml) or verbascoside (0-160µM) on simvastatin (10µM)-treated L6 cells. Annexin V-FITC/PI apoptosis assay and Caspase 3 assay were performed to determine the protective role of HCE on simvastatin-induced cell death, and to evaluate if HCE exerted its protective effect through the caspase pathway. ATP production was measured to investigate if HCE could prevent simvastatin-induced reduction in ATP production in vitro. RESULTS: Simvastatin significantly increased apoptotic cell death in L6 cells. HCE significantly exerted a dose-dependent reduction on simvastatin-induced apoptotic cells, possibly via caspase-3 pathway. Simvastatin reduced the ATP production in L6 cells, which was dose-dependently prevented by HCE. There was only a trend but not significant effect (except at high dose) of verbascoside on the protection of simvastatin-induced muscle toxicity. CONCLUSIONS: In conclusion, we demonstrated for the first time that HCE could exert dose-dependent protective effect on simvastatin-induced toxicity in vitro, which was unlikely due to the presence of verbascoside. Our study suggested the potential use of HC under the situation of simvastatin-induced muscle toxicity.
Assuntos
Apoptose/efeitos dos fármacos , Cistanche/química , Glucosídeos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/toxicidade , Fibras Musculares Esqueléticas/efeitos dos fármacos , Doenças Musculares/prevenção & controle , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Sinvastatina/toxicidade , Trifosfato de Adenosina/metabolismo , Animais , Caspase 3/metabolismo , Linhagem Celular , Cromatografia Líquida , Citoproteção , Relação Dose-Resposta a Droga , Glucosídeos/isolamento & purificação , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Doenças Musculares/induzido quimicamente , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Fenóis/isolamento & purificação , Fitoterapia , Extratos Vegetais/isolamento & purificação , Plantas Medicinais , Substâncias Protetoras/isolamento & purificação , RatosRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Traumatic brain injury (TBI) has an incident rate of 200-300 people per 100,000 annually in the developed countries. TBI has relatively high incidence at an early age and may cause long-term physical disability. Patients suffered from severe TBI would have motor and neuropsychological malfunctions, affecting their daily activities. Traditionally, Gastrodia elata Blume is a Chinese Medicines which was used for the head diseases, while their efficiency on reducing brain damage was still largely unknown. In the present study, we aimed to examine the effect of water extract of G. elata Blume (GE) against TBI and elucidate its underlying mechanism. MATERIALS AND METHODS: Sprague-Dawley rats were treated with GE for 7 days, immediately after controlled cortical impact-induced TBI. Impaired neurobehavioral functioning was measured on day 3 and 6 after TBI. Histology of TBI was examined to assess the extent of inflammation, and the expressions of pro-inflammatory cytokines were examined by immunofluorescence study on day 7. RESULTS: GE treatment significantly improved the impaired locomotor functions induced by TBI. GE treatment reduced inflammation and gliosis in the penumbral area. The increase in brain levels of pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha observed in non-GE treated TBI rats were also reversed. CONCLUSIONS: GE treatment attenuated the locomotor deficit caused by TBI. The anti-inflammatory activity might be mediated by inhibition of pro-inflammatory cytokines responses in the TBI-brain.
Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Gastrodia/química , Inflamação/tratamento farmacológico , Locomoção/efeitos dos fármacos , Extratos Vegetais/farmacologia , Rizoma/química , Animais , Feminino , Extratos Vegetais/química , Ratos , Ratos Sprague-DawleyRESUMO
This study aims to investigate the neuroprotective effect of the rhizome of Gastrodia elata (GE) aqueous extract on beta-amyloid(A ß )-induced toxicity in vivo and in vitro. Transgenic Drosophila mutants with A ß -induced neurodegeneration in pan-neuron and ommatidia were used to determine the efficacy of GE. The antiapoptotic and antioxidative mechanisms of GE were also studied in A ß -treated pheochromocytoma (PC12) cells. In vivo studies demonstrated that GE (5 mg/g Drosophila media)-treated Drosophila possessed a longer lifespan, better locomotor function, and less-degenerated ommatidia when compared with the A ß -expressing control (all P < 0.05). In vitro studies illustrated that GE increased the cell viability of A ß -treated PC12 cells in dose-dependent manner, probably through attenuation of A ß -induced oxidative and apoptotic stress. GE also significantly upregulated the enzymatic activities of catalase, superoxide dismutase, and glutathione peroxidase, leading to the decrease of reactive oxidation species production and apoptotic marker caspase-3 activity. In conclusion, our current data presented the first evidence that the aqueous extract of GE was capable of reducing the A ß -induced neurodegeneration in Drosophila, possibly through inhibition of apoptosis and reduction of oxidative stress. GE aqueous extract could be developed as a promising herbal agent for neuroprotection and novel adjuvant therapies for Alzheimer's disease.