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1.
Neurochem Res ; 49(3): 785-799, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38103103

RESUMEN

Abundant investigations have shown that hypobaric hypoxia (HH) causes cognitive impairment, mostly attributed to oxidative stress, inflammation, and apoptosis. HPN (4'-hydroxyl-2-subsitiuted phenylnitronyl nitroxide) is an excellent free radical scavenger with anti-inflammatory and anti-apoptotic activities. Our previous study has found that HPN exhibited neuroprotective effect on HH induced brain injury. In the present study, we examined the protective effect and potential mechanism of HPN on HH-induced cognitive impairment. Male mice were exposed to HH at 8000 m for 3 days with and without HPN treatment. Cognitive performance was assessed by the eight-arm radical maze. The histological changes were assayed by Nissle staining. The hippocampus cell apoptosis was detected by Tunnel staining. The levels of inflammatory cytokines and oxidative stress markers were detected. The expression of oxidative stress, inflammation-related and apoptosis-related proteins was determined by western blot. HPN administration significantly and mitigated HH induced histological damages and spatial memory loss with the evidence of decreased working memory error (WME), reference memory error (RME), total errors (TE) and total time (TT). In addition, HPN treatment significantly decreased the content of H2O2 and MDA, increased the levels of SOD, CAT, GSH-Px and GSH, and inhibited the synthesis of TNF-α, IL-1ß and IL-6. Moreover, HPN administration could down-regulate the expression of NF-κB, TNF-α, Bax, and cleaved caspase-3 and up-regulate the expression of Nrf2, HO-1 and Bcl-2. The number of apoptotic cells was also significantly decreased in the hippocampus of mice in the HPN group. There results indicate that HPN improve HH-induced cognitive impairment by alleviating oxidative stress damage, suppressing inflammatory response and apoptosis and may be a powerful candidate compound for alleviating memory loss induced by HH.


Asunto(s)
Disfunción Cognitiva , Óxidos de Nitrógeno , Factor de Necrosis Tumoral alfa , Ratones , Masculino , Animales , Factor de Necrosis Tumoral alfa/metabolismo , Peróxido de Hidrógeno/farmacología , Estrés Oxidativo , Hipoxia/metabolismo , Apoptosis , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/etiología , Proteínas Reguladoras de la Apoptosis/metabolismo , Inflamación/metabolismo , Disfunción Cognitiva/tratamiento farmacológico
2.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 53(1): 116-125, 2024 Feb 05.
Artículo en Inglés, Zh | MEDLINE | ID: mdl-38426693

RESUMEN

OBJECTIVES: To prepare 7-hydroxyethyl chrysin (7-HEC) loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles and to detect the in vitro release. METHODS: The 7-HEC/PLGA nanoparticles were prepared by emulsification solvent volatilization method. The particle size, polydispersity index (PDI), encapsulation rate, drug loading and zeta potential were measured. The prescription was optimized by single factor investigation combined with Box-Behnken response surface method. Mannitol was used as protectant to prepare lyophilized powder, and the optimal formulation was characterized and studied for the in vitro release. RESULTS: The optimal formulation of 7-HEC/PLGA nanoparticles was as follows: drug loading ratio of 2.12∶20, oil-water volume ratio of 1∶14.7, and 2.72% soybean phospholipid as emulsifier. With the optimal formulation, the average particle size of 7-HEC/PLGA nanoparticles was (240.28±0.96) nm, the PDI was 0.25±0.69, the encapsulation rate was (75.74±0.80)%, the drug loading capacity was (6.98±0.83)%, and the potentiostatic potential was (-18.17±0.17) mV. The cumulative in vitro release reached more than 50% within 48 h. CONCLUSIONS: The optimized formulation is stable and easy to operate. The prepared 7-HEC/PLGA nanoparticles have uniform particle size, high encapsulation rate and significantly higher dissolution rate than 7-HEC.


Asunto(s)
Flavonoides , Nanopartículas , Ácido Poliglicólico , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Ácido Láctico , Tamaño de la Partícula , Portadores de Fármacos
3.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 49(2): 236-246, 2024 Feb 28.
Artículo en Inglés, Zh | MEDLINE | ID: mdl-38755719

RESUMEN

OBJECTIVES: Hypoxia is a common pathological phenomenon, usually caused by insufficient oxygen supply or inability to use oxygen effectively. Hydroxylated and methoxylated flavonoids have significant anti-hypoxia activity. This study aims to explore the synthesis, antioxidant and anti-hypoxia activities of 6-hydroxygenistein (6-OHG) and its methoxylated derivatives. METHODS: The 6-OHG and its methoxylated derivatives, including 4',6,7-trimethoxy-5-hydroxyisoflavone (compound 3), 4',5,6,7-tetramethoxyisoflavone (compound 4), 4',6-imethoxy-5,7-dihydroxyisoflavone (compound 6), and 4'-methoxy-5,6,7-trihydroxyisoflavone (compound 7), were synthesized by methylation, bromination, methoxylation, and demethylation using biochanin A as raw material. The structure of these products were characterized by 1hydrogen-nuclear magnetic resonance spectroscopy (1H-NMR) and mass spectrometry (MS). The purity of these compounds was detected by high pressure chromatography (HPLC). The antioxidant activity in vitro was investigated by 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) free radical scavenging assay. PC12 cells were divided into a normal group, a hypoxia model group, rutin (1×10-9-1×10-5 mol/L) groups, and target compounds (1×10-9-1×10-5 mol/L) groups under normal and hypoxic conditions. Cell viability was detected by cell counting kit-8 (CCK-8) assay, the target compounds with excellent anti-hypoxia activity and the drug concentration at the maximum anti-hypoxia activity were screened. PC12 cells were treated with the optimal concentration of the target compound or rutin with excellent anti-hypoxia activity, and the cell morphology was observed under light microscope. The apoptotic rate was determined by flow cytometry, and the expressions of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) were detected by Western blotting. RESULTS: The structure of 6-OHG and its 4 methylated derivatives were correct, and the purity was all more than 97%. When the concentration was 4 mmol/L, the DPPH free radical removal rates of chemical compounds 7 and 6-OHG were 81.16% and 86.94%, respectively, which were higher than those of rutin, the positive control. The removal rates of chemical compounds 3, 4, and 6 were all lower than 20%. Compared with the normal group, the cell viability of the hypoxia model group was significantly decreased (P<0.01). Compared with the hypoxia model group, compounds 3, 4, and 6 had no significant effect on cell viability under hypoxic conditions. At all experimental concentrations, the cell viability of the 6-OHG group was significantly higher than that of the hypoxia model group (all P<0.05). The cell viability of compound 7 group at 1×10-7 and 1×10-6 mol/L was significantly higher than that of the hypoxia model group (both P<0.05). The anti-hypoxia activity of 6-OHG and compound 7 was excellent, and the optimal drug concentration was 1×10-6 and 1×10-7 mol/L. After PC12 cells was treated with 6-OHG (1×10-6 mol/L) and compound 7 (1×10-7 mol/L), the cell damage was reduced, the apoptotic rate was significantly decreased (P<0.01), and the protein expression levels of HIF-1α and VEGF were significantly decreased in comparison with the hypoxia model group (both P<0.01). CONCLUSIONS: The optimized synthesis route can increase the yield of 6-OHG and obtain 4 derivatives by methylation and selective demethylation. 6-OHG and compound 7 have excellent antioxidant and anti-hypoxia activities, which are related to the structure of the A-ring ortho-triphenol hydroxyl group in the molecule.


Asunto(s)
Antioxidantes , Genisteína , Isoflavonas , Genisteína/análogos & derivados , Isoflavonas/síntesis química , Isoflavonas/química , Isoflavonas/farmacología , Antioxidantes/síntesis química , Antioxidantes/química , Antioxidantes/farmacología , Radicales Libres/química
4.
J Cell Physiol ; 238(11): 2692-2709, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37796139

RESUMEN

Oxidative stress has been considered to be closely related to spaceflight-induced bone loss; however, mechanism is elusive and there are no effective countermeasures. Using cultured rat calvarial osteoblasts exposed to microgravity simulated by a random positioning machine, this study addressed the hypotheses that microgravity-induced shortening of primary cilia leads to oxidative stress and that primary cilium protection prevents oxidative stress and osteogenesis loss. Microgravity was found to induce oxidative stress (as represented by increased levels of reactive oxygen species (ROS) and malondialdehyde production, and decreased activities of antioxidant enzymes), which was perfectly replicated in osteoblasts growing in NG with abrogated primary cilia (created by transfection of an interfering RNA), suggesting the possibility that shortening of primary cilia leads to oxidative stress. Oxidative stress was accompanied by mitochondrial dysfunction (represented by increased mitochondrial ROS and decreased mitochondrial membrane potential) and intracellular Ca2+ overload, and the latter was found to be caused by increased activity of Ca2+ channel transient receptor potential vanilloid 4 (TRPV4), as also evidenced by TRPV4 agonist GSK1016790A-elicited Ca2+ influx. Supplementation of HC-067047, a specific antagonist of TRPV4, attenuated microgravity-induced mitochondrial dysfunction, oxidative stress, and osteogenesis loss. Although TRPV4 was found localized in primary cilia and expressed at low levels in NG, microgravity-induced shortening of primary cilia led to increased TRPV4 levels and Ca2+ influx. When primary cilia were protected by miR-129-3p overexpression or supplementation with a natural flavonoid moslosooflavone, microgravity-induced increased TRPV4 expression, mitochondrial dysfunction, oxidative stress, and osteogenesis loss were all prevented. Our data revealed a new mechanism that primary cilia function as a controller for TRPV4 expression. Microgravity-induced injury on primary cilia leads to increased expression and overactive channel of TRPV4, causing intracellular Ca2+ overload and oxidative stress, and primary cilium protection could be an effective countermeasure against microgravity-induced oxidative stress and loss of osteogenic potential of osteoblasts.


Asunto(s)
Cilios , Osteoblastos , Osteogénesis , Estrés Oxidativo , Canales Catiónicos TRPV , Ingravidez , Animales , Ratas , Cilios/metabolismo , Osteoblastos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Canales Catiónicos TRPV/agonistas , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/metabolismo , Células Cultivadas , Morfolinas/farmacología , Pirroles/farmacología , Gravitación
5.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 51(4): 415-421, 2022 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-37202092

RESUMEN

OBJECTIVE: To design and synthesize long-chain substituted 2-[(4'-hydroxyethoxy) phenyl]-4,4,5,5-tetramethyl-2-imidazoline-1-oxyl 3-oxide (HPN) derivatives with enhanced anti-hypoxic activity. METHODS: HPN derivatives 1, 3, 5 containing lipophilic long chains were synthesized via the alkylation of HPN with 6-bromohexan-1-ol, ethyl 6-bromohexanoate or 6-bromohexane, respectively using acetonitrile as the solvent and K 2CO 3 as the acid-binding agent at 60 ℃. Derivative 2 was synthesized via hydrolysis reactions of derivative 1 in the NaOH/CH 3OH/H 2O system. Using dichloromethane as the solvent and N, N'-diisopropylcarbodiimide as the dehydrating agent, HPN underwent esterification with hexanoic acid to obtain derivative 4. The structures of derivatives 1-5 were characterized by infrared spectroscopy, electron paramagnetic resonance and high resolution mass spectrometry. The purities of derivatives were detected by high performance liquid chromatography, and the lipid solubilities of derivatives were evaluated by calculating the oil-water partition coefficients (log P). Anti-hypoxia activities of HPN and its long-chain lipophilic derivatives 1-5 were evaluated using normobaric hypoxia test and acute decompression hypoxia test. RESULTS: The structures of the derivatives were confirmed by infrared spectroscopy, electron paramagnetic resonance and high resolution mass spectroscopy. The yields of target derivatives were all above 92%, and the purities were all above 96%. The log P values of derivatives 1-5 were 2.78, 2.00, 2.04, 2.88 and 3.10, which were higher than that of HPN (0.97). Derivatives 1-5 significantly prolonged the survival time of mice at the dose of 0.3 mmol/kg in normobaric hypoxic test and reduced the mortality rate of acute decompression hypoxic mice to 60%, 70%, 60%, 70% and 40%, respectively. CONCLUSIONS: The synthesis of derivatives 1-5 is convenient, and the yield is high. The synthesized derivatives especially derivative 5 show anti-hypoxic activity similar to or better than HPN at lower doses.


Asunto(s)
Hipoxia , Ratones , Animales , Solventes
6.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 50(5): 614-620, 2021 Oct 25.
Artículo en Inglés | MEDLINE | ID: mdl-34986528

RESUMEN

To construct a hypobaric hypoxia-induced cell injury model. Rat pheochromocytoma PC12 cells were randomly divided into control group, normobaric hypoxia group and hypobaric hypoxia group. The cells in control group were cultured at normal condition, while cells in other two groups were cultured in normobaric hypoxia and hypobaric hypoxia conditions, respectively. CCK-8 method was used to detect cell viability to determine the optimal modeling conditions like the oxygen concentration, atmospheric pressure and low-pressure hypoxia time. The contents of lactate dehydrogenase (LDH), superoxide dismutase (SOD) and malondialdehyde (MDA) were detected by microplate method. The apoptosis ratio and cell cycle were analyzed by flow cytometry. The hypobaric hypoxia-induced cell injury model can be established by culturing for 24 h at 1% oxygen concentration and 41 kPa atmospheric pressure. Compared with the control group and normobaric hypoxia group, the activity of LDH and the content of MDA in hypobaric hypoxia group were significantly increased, the activity of SOD was decreased, the percentage of apoptosis was increased (all <0.05), and the cell cycle was arrested in G0/G1 phase. A stable and reliable cell injury model induced by hypobaric hypoxia has been established with PC12 cells, which provides a suitable cell model for the experimental study on nerve injury induced by hypoxia at high altitude.


Asunto(s)
Hipoxia , Superóxido Dismutasa , Animales , Hipoxia de la Célula , Malondialdehído , Células PC12 , Ratas , Superóxido Dismutasa/metabolismo
7.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 50(5): 575-581, 2021 Oct 25.
Artículo en Inglés | MEDLINE | ID: mdl-34986529

RESUMEN

: To investigate the protective effect of 7-hydroxyethyl chrysin (7-HEC) on rats with exercise-induced fatigue in hypobaric hypoxic condition.Forty healthy male Wistar rats were randomly divided into four groups with 10 rats in each group: control group, model group, chrysin group and 7-HEC group. The rats in control group were raised at local altitude but other three groups were raised in a simulating altitude of for hypobaric hypoxia treatment. The chrysin group and 7-HEC group were given chrysin or 7-HEC by gavage for respectively; while the control group and model group were given the same amount of sterilized water. The weight-bearing swimming tests were performed 3 d later, and the weight-bearing swimming time was documented. After rats were sacrificed, the liver and skeletal muscle tissue samples were taken for pathological examination and determination of lactate, malondialdehyde (MDA), total superoxide dismutase (T-SOD) and glycogen levels. Blood urea nitrogen was also determined. Compared with the model group, weight-bearing swimming times were significantly prolonged in 7-HEC group [ vs. (4.04±1.30) min, <0.01]; pathological changes in liver and skeletal muscle tissue were attenuated; generation rate of blood urea nitrogen vs. 0.60) mmol·L·min, <0.05], lactate [liver: (0.14±0.05) vs. (0.10±0.03) mg·g·min, skeletal muscle: vs. (0.18±] and MDA [liver: (0.48) vs. (0.78±0.28) nmol·mg·min, skeletal muscle: (0.87±0.19) vs. (0.63±0.11) nmol·mg·min] were significantly reduced (all < 0.05); glycogen content [liver: (15.16±2.69) vs. skeletal muscle: (1.46±0.49) vs.0.48) mg/g] and T-SOD [liver: (1.87±0.01) vs. (2.68±0.12) U/mL, skeletal muscle: 0.42) vs. 0.96) U/mL] were significantly improved (all <0.05). 7-HEC has significant protective effect on the rats with exercise-induced fatigue in hypobaric hypoxia condition.


Asunto(s)
Altitud , Hipoxia , Animales , Fatiga/etiología , Fatiga/prevención & control , Flavonoides , Masculino , Ratas , Ratas Wistar
8.
Pak J Pharm Sci ; 34(2): 513-519, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-34275824

RESUMEN

Severe oxidative stress triggered by acute hypobaric hypoxia (AHH) is harmful for lots of organs in body, especial brain and heart. Flavonoids with antioxidant properties can protect organs from oxidative stress. Our previous study found that 5,6,7,8-trtrahydroxyflavone (5,6,7,8-THF), a flavones with four consecutive hydrogen group on ring A, showed excellent antioxidant properties in vitro. In the present study, the protective of 5,6,7,8-THF against oxidative stress caused by AHH was investigated. Mice were administered with 5,6,7,8-THF(500mg/kg) for 5 consecutive days before HH exposure. The heart rate (HR) and blood pressure (BP) was measured. The activity of SOD, CAT, GSH-Px, LDH, Na+-K+-ATPase and Ca2+-Mg2+-ATPase and the content of H2O2, MDA, LD and ATP in brain and heart tissue was evaluated using commercial kit. AHH led to a significant increase in HR and decrease in BP. Pretreatment of 5,6,7,8-THF could reversed these changes. In addition, administration of 5,6,7,8-THF could significantly increase the activity of SOD, CAT and GSH-Px and decrease the content of H2O2 and MDA in the brain and heart of mice under AHH. Furthermore, 5,6,7,8-THF inhibited the activity of LDH, decreased the level of LD and improved ATPase activity. These results indicate that 5,6,7,8-THF may protect the mice against AHH injury via scavenging free radical, inhibiting lipid peroxidation, enhancing antioxidant enzyme activity, preserving energy metabolism and can be further explored as an excellent anti-hypoxia agent for preventing acute mountain sickness.


Asunto(s)
Encéfalo/efectos de los fármacos , Corazón/efectos de los fármacos , Hipoxia/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Flavonas/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Peróxido de Hidrógeno/metabolismo , L-Lactato Deshidrogenasa/efectos de los fármacos , L-Lactato Deshidrogenasa/metabolismo , Ácido Láctico/metabolismo , Malondialdehído/metabolismo , Ratones , Miocardio/metabolismo , Presión Parcial , Tasa de Supervivencia
9.
Biochem Cell Biol ; 98(3): 345-353, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-31689131

RESUMEN

Hypoxia induces cellular oxidative stress that is associated with neurodegenerative diseases. HPN (4'-hydroxyl-2-substituted phenyl nitronyl nitroxide), a stable nitronyl nitroxide, has excellent free radical scavenging properties. The purpose of this study was to investigate the protective effects of HPN on hypoxia-induced damage in PC12 cells. It was shown that HPN significantly attenuated hypoxia-induced loss of cell viability, release of lactate dehydrogenase (LDH), and morphological changes in PC12 cells. Moreover, hypoxic PC12 cells had increased levels of reactive oxygen species (ROS), malondialdehyde (MDA), and expression of HIF-1α and VEGF, but had reduced levels of superoxide dismutase (SOD) and catalase (CAT), and HPN reversed these changes. HPN also inhibited hypoxia-induced cell apoptosis via suppressing the expression of Bax, cytochrome c, and caspase-3, and inducing the expression of Bcl-2. These results indicate that the protective effects of HPN on hypoxia-induced damage in PC12 cells is associated with the suppression of hypoxia-induced oxidative stress and cell apoptosis. HPN could be a promising candidate for the development of a novel neuroprotective agent.


Asunto(s)
Apoptosis , Hipoxia de la Célula/efectos de los fármacos , Óxidos de Nitrógeno/farmacología , Animales , Antioxidantes/metabolismo , Caspasa 3/metabolismo , Citocromos c/metabolismo , Depuradores de Radicales Libres/farmacología , L-Lactato Deshidrogenasa/metabolismo , Peroxidación de Lípido , Malondialdehído/metabolismo , Células PC12 , Ratas , Especies Reactivas de Oxígeno/metabolismo , Proteína X Asociada a bcl-2/metabolismo
10.
Neural Plast ; 2020: 8830670, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32952549

RESUMEN

Background: Previous researches indicate that Itpr2 -/- mice (inositol 1,4,5-trisphosphate receptor type 2 knockout mice) show depressive-like symptoms; however, little is known regarding the in vivo neurobiological effect of Itpr2 as well as the specific pattern of brain abnormalities in Itpr2 -/- mice. Methods/Materials. First, behavioral tests, structural magnetic resonance imaging (MRI), and resting-state functional MRI were performed on Itpr2 -/- mice and matched healthy controls. Voxel-based morphometry and seed-based voxel-wise functional connectivity (FC) were, respectively, calculated to assess the gray matter volume and the functional activities of the brain in vivo. Second, the sample of relevant changed brain regions was extracted to detect the expression of BDNF. Finally, to further validate the relationship between Itpr2 deficiency and the observed brain abnormalities, we performed Western blotting to detect the expression of pro-BDNF and mBDNF in Itpr2 -/- C8-D1A (a type of astrocyte). Results: Compared with controls, Itpr2 -/- mice showed depressive-like behaviors as well as significantly lower gray matter volume in striatums mainly, periaqueductal GM, and the right frontoparietal cortices as well as lower striatal-hippocampal and striatal-right parietal cortex (mainly for the primary and secondary somatosensory cortex) FC. Moreover, decreased expression of mBDNF was found in both sample tissues of the striatum in Itpr2 -/- mice and Itpr2 -/- C8-D1A. Conclusion: By combining biochemistry and MR analyses, this study provides evidences to support that the Itpr2-related neuropathological effect is possibly mediated by the striatal abnormality associated with dysfunctional astrocytes in Itpr2 -/- mice in vivo, thus may help us better understand underlying mechanisms of Itpr2 deficiency as well as its relation to depressive-like behavior.


Asunto(s)
Astrocitos/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cuerpo Estriado/patología , Cuerpo Estriado/fisiopatología , Depresión/patología , Depresión/fisiopatología , Receptores de Inositol 1,4,5-Trifosfato/genética , Receptores de Inositol 1,4,5-Trifosfato/fisiología , Animales , Línea Celular , Depresión/metabolismo , Sustancia Gris/patología , Ratones Noqueados
11.
Cancer Sci ; 110(5): 1724-1734, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30839155

RESUMEN

Inducing angiogenesis is a hallmark of cancers that sustains tumor growth and metastasis. Neovascularization is a surprisingly early event during the multistage progression of cancer. Cinobufagin, an important bufadienolide originating from Chan Su, has been clinically used to treat cancer in China since the Tang dynasty. Here, we show that cinobufagin suppresses colorectal cancer (CRC) growth in vivo by downregulating angiogenesis. The hierarchized neovasculature is significantly decreased and the vascular network formation is disrupted in HUVEC by cinobufagin in a dose-dependent way. Endothelial apoptosis is observed by inducing reactive oxygen species (ROS) accumulation and mitochondrial dysfunction which can be neutralized by N-acetyl-l-cysteine (NAC). Expression of hypoxia-inducible factor 1α (HIF-1α) is reduced and phosphorylation of mTOR at Ser2481 and Akt at Ser473 is downregulated in HUVEC. Endothelial apoptosis is triggered by cinobufagin by stimulation of Bax and cascade activation of caspase 9 and caspase 3. Increased endothelial apoptosis rate and alterations in the HIF-1α/mTOR pathway are recapitulated in tumor-bearing mice in vivo. Further, the anti-angiogenesis function of cinobufagin is consolidated based on its pro-apoptotic effects on an EOMA-derived hemangioendothelioma model. In conclusion, cinobufagin suppresses tumor neovascularization by disrupting the endothelial mTOR/HIF-1α pathway to trigger ROS-mediated vascular endothelial cell apoptosis. Cinobufagin is a promising natural anti-angiogenetic drug that has clinical translation potential and practical application value.


Asunto(s)
Inhibidores de la Angiogénesis/administración & dosificación , Bufanólidos/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Inhibidores de la Angiogénesis/farmacología , Animales , Bufanólidos/farmacología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias Colorrectales/irrigación sanguínea , Neoplasias Colorrectales/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Trasplante de Neoplasias , Fosforilación , Especies Reactivas de Oxígeno/metabolismo
12.
Psychol Med ; 49(15): 2608-2616, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-30520409

RESUMEN

BACKGROUND: We hypothesize that the tumor necrosis factor-α (TNF-α) may play a role in disturbing the effect of selective serotonin reuptake inhibitor (SSRI) on the striatal connectivity in patients with major depressive disorder (MDD). METHODS: We performed a longitudinal observation by combining resting-state functional magnetic resonance imaging (rs-fMRI) and biochemical analyses to identify the abnormal striatal connectivity in MDD patients, and to evaluate the effect of TNF-α level on these abnormal connectivities during SSRI treatment. Eighty-five rs-fMRI scans were collected from 25 MDD patients and 35 healthy controls, and the scans were repeated for all the patients before and after a 6-week SSRI treatment. Whole-brain voxel-wise functional connectivity (FC) was calculated by correlating the rs-fMRI time courses between each voxel and the striatal seeds (i.e. spherical regions placed at the striatums). The level of TNF-α in serum was evaluated by Milliplex assay. Factorial analysis was performed to assess the interaction effects of 'TNF-α × treatment' in the regions with between-group FC difference. RESULTS: Compared with controls, MDD patients showed significantly higher striatal FC in the medial prefrontal cortex (MPFC) and bilateral middle/superior temporal cortices before SSRI treatment (p < 0.001, uncorrected). Moreover, a significant interaction effect of 'TNF-α × treatment' was found in MPFC-striatum FC in MDD patients (p = 0.002), and the significance remained after adjusted for age, gender, head motion, and episode of disease. CONCLUSION: These findings provide evidence that treatment-related brain connectivity change is dependent on the TNF-α level in MDD patients, and the MPFC-striatum connectivities possibly serve as an important target in the brain.


Asunto(s)
Cuerpo Estriado/fisiopatología , Trastorno Depresivo Mayor/fisiopatología , Corteza Prefrontal/fisiopatología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Factor de Necrosis Tumoral alfa/sangre , Adulto , Mapeo Encefálico , Estudios de Casos y Controles , Trastorno Depresivo Mayor/sangre , Trastorno Depresivo Mayor/tratamiento farmacológico , Femenino , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Descanso , Adulto Joven
14.
J Transl Med ; 16(1): 201, 2018 07 20.
Artículo en Inglés | MEDLINE | ID: mdl-30029665

RESUMEN

BACKGROUND: Necroptotic susceptibility is probably an intrinsic weakness of cancer. Here, we report that resibufogenin, a member of bufadienolide family, suppresses the growth and metastasis of colorectal cancer (CRC) through induction of necroptosis in vivo. METHODS: SW480 cells with stably expressing enhanced green fluorescence protein were xenografted to BALB/c-nu mice to observe the growth of tumors. Liver metastasis was observed by injection of MC38 cells beneath the splenic capsule of mice. Protein expression was determined by immunohistochemistry, immunofluorescence and western blot. RESULTS: Consolidated in vitro results indicate that resibufogenin has anti-proliferative activity on CRC cells. PI staining and transmission electron microscope imaging suggest that the cell death induced by resibufogenin are mainly through necrosis, which is further confirmed by the ineffectiveness of z-VAD, a pan-caspase general inhibitor. In particular, resibufogenin induced necrosis is substantially abrogated in receptor-interacting protein kinase 3 (RIPK3) knockout mouse embryo fibroblasts. The RIP3-dependent necrosis has been classified as necroptosis. Resibufogenin triggeres necroptosis through upregulating RIP3 and phosphorylating mixed lineage kinase domain-like protein at Ser358. Resibufogenin also activates the expression of PYGL, GLUD1 and GLUL in a RIP3-dependent manner. Resibufogenin exerts cytotoxic effect by inducing reactive oxygen species accumulation which can be neutralized by N-acetylcysteine. Remarkably, resibufogenin significantly suppresses liver-metastasis from spleen implantation. The anti-neoplastic effect of this compound can be abrogated by RIP3 knockdown. CONCLUSION: Resibufogenin suppresses growth and metastasis of CRC through RIP3-mediated necroptosis.


Asunto(s)
Apoptosis/efectos de los fármacos , Bufanólidos/farmacología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/ultraestructura , Humanos , Ratones , Necrosis , Metástasis de la Neoplasia
15.
BMC Cancer ; 18(1): 578, 2018 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-29783958

RESUMEN

BACKGROUND: Previous studies showed sanguinarine induced apoptosis in CRC cells but did not define the underlying mechanisms. The purpose of this work was to determine the in vivo and in vitro effects of sanguinarine on CRC tumors and to elucidate the mechanism in regulating the intrinsic apoptosis. METHODS: Cell viability of CRC cell lines treated with sanguinarine was measured by MTT assay. Apoptotic cells stained with Annexin V and 7-AAD were detected by flow cytometry. Mitochondrial membrane potential and reactive oxygen species (ROS) were analyzed by JC-1 and DCFH-DA staining, respectively. The in vitro kinase activity of MELK was analyzed by using HTRF® KinEASE™-STK kit. The expression of proteins were determined using Western blotting and immunohistochemistry. Co-immunoprecipitation and immunofluorecence were used to study the interaction between STRAP and MELK. The anti-neoplastic effect of sanguinarine was observed in vivo in an orthotopic CRC model. RESULTS: Sanguinarine decreased the tumor size in a dose-dependent manner in orthotopical colorectal carcinomas through intrinsic apoptosis pathway in BALB/c-nu mice. It significantly increased cleavage of caspase 3 and PARP in implanted colorectal tissues. Sanguinarine increased mitochondrial ROS and triggered mitochondrial outer membrane permeabilization in multiple colorectal cancer (CRC) cell lines. NAC pretreatment lowered ROS level and downregulated apoptosis induced by sanguinarine. The intrinsic apoptosis induced by sanguinarine was Bax-dependent. The elevated expression and association between serine-threonine kinase receptor-associated protein (STRAP) and maternal embryonic leucine zipper kinase (MELK) were observed in Bax positive cells but not in Bax negative cells. Sanguinarine dephosphorylated STRAP and MELK and disrupted the association between them in HCT116 and SW480 cells. The expression and association between STRAP and MELK were also attenuated by sanguinarine in the tumor tissues. Importantly, we found that STRAP and MELK were overexpressed and highly phosphorylated in colorectal adenocarcinomas and their expression were significantly correlated with tumor stages. Furthermore, the expression of MELK, but not STRAP, was associated with lymph node metastasis. CONCLUSIONS: Sanguinarine dephosphorelates STRAP and MELK and disassociates the interaction between them to trigger intrinsic apoptosis. Overexpression of STRAP and MELK may be markers of CRC and their disassociation may be a determinant of therapeutic efficacy.


Asunto(s)
Apoptosis/efectos de los fármacos , Benzofenantridinas/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Isoquinolinas/farmacología , Proteínas de Neoplasias/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Benzofenantridinas/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/patología , Femenino , Células HCT116 , Humanos , Isoquinolinas/uso terapéutico , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Membranas Mitocondriales/efectos de los fármacos , Membranas Mitocondriales/metabolismo , Papaveraceae/química , Permeabilidad/efectos de los fármacos , Fosforilación/efectos de los fármacos , Unión Proteica/efectos de los fármacos , Proteínas de Unión al ARN , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Biol Pharm Bull ; 38(9): 1280-9, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26328483

RESUMEN

Nitric oxide (NO) may act as either a pro-oxidant or an antioxidant in biological systems. Previous work has found inhalation of NO improved survival in a high altitude rat model. NO donor isosorbide mononitrate derivants might have a protective effect against hypoxia. We synthesized a series of isosorbide mononitrate derivant compounds to test their anti-hypoxia activities. Normobaric hypoxia and hypobaric hypoxia models were used to study the protective role of NO donor in mice. The results showed isosorbide mononitrate derivants had protective effects in hypoxia mice. Among those compounds, acetyl ferulic isosorbide mononitrate (AFIM) was the most effective. It prolonged the survival time during the normobaric hypoxia test. It decreased malondialdehyde (MDA) and H2O2 in hypobaric hypoxia mice. The antioxidase activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) remained in normal ranges in the AFIM group. As a sign of mitochondrial dysfunction, the activities of ATPase were down regulated in mice under hypobaric hypoxia conditions. AFIM also protected ATPase activities. The protective effects of AFIM might come from a sustained NO supply and the release of acetyl ferulic acid with anti-oxidant activity.


Asunto(s)
Mal de Altura/tratamiento farmacológico , Hipoxia/tratamiento farmacológico , Dinitrato de Isosorbide/análogos & derivados , Donantes de Óxido Nítrico/uso terapéutico , Adenosina Trifosfato/metabolismo , Mal de Altura/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Catalasa/metabolismo , Cerebro/efectos de los fármacos , Cerebro/metabolismo , Glutatión Peroxidasa/metabolismo , Frecuencia Cardíaca/efectos de los fármacos , Peróxido de Hidrógeno/metabolismo , Hipoxia/metabolismo , Dinitrato de Isosorbide/farmacología , Dinitrato de Isosorbide/uso terapéutico , L-Lactato Deshidrogenasa/metabolismo , Ácido Láctico/sangre , Malondialdehído/metabolismo , Ratones Endogámicos BALB C , Miocardio/metabolismo , Donantes de Óxido Nítrico/farmacología , Ratas , Superóxido Dismutasa/metabolismo
17.
BMC Complement Altern Med ; 15: 287, 2015 Aug 18.
Artículo en Inglés | MEDLINE | ID: mdl-26283543

RESUMEN

BACKGROUND: Rhododendron anthopogonoides Maxim, a kind of traditional Tibetan medicine, has been used to remove body heat, body detoxification, cough, asthma, stomachic and swelling, eliminate abundant phlegm and inflammatory for a long time. In the present study, the total phenols and total flavonoid contents as well as antioxidative properties of the crude extract and solvent fractions of R. anthopogonoides were determined using seven antioxidant assays. Additionally, the protective effect of the extracts on hypoxia-induced injury in PC12 cells was also investigated. METHODS: The content of total flavonoid and total phenolic was determined by the aluminum colorimetric method and Folin-Ciocalteu assay, respectively. In vitro antioxidant study, the effect of the crude extract and solvent fractions on total antioxidant activity, reducing power, DPPH radical scavenging, ABTS radical scavenging, superoxide radical scavenging, hydroxyl radical scavenging and nitric oxide radical scavenging were examined. The correlation between the phenolic and flavonoid content of the extracts and their antioxidant properties also analyzed. Furthermore, the protective effect of extracts on hypoxia-induced damage on PC12 cells was investigated by cell viability, lactate dehydrogenase (LDH) release, malondialdehyde (MDA) production and the activities of antioxidant enzymes. RESULTS: Our results showed that ethyl acetate and n-butanol fractions had higher content of phenolics and flavonoid compounds than other fractions. Except ABTS radical assay, n-butanol fraction exhibited the strongest antioxidant activity. While the hexane fraction showed the lowest antioxidant activity. Ethyl acetate also presented excellent antioxidant activity, which was just lower than n-butanol fraction. Significant correlation between the phenolic, flavonoid content of the extract and fractions with antioxidant assay excluding ABTS, OH scavenging assay was observed. Moreover, ethyl acetate and n-butanol fractions showed protective effect in PC12 cell under hypoxia condition, while crude extract and water fraction had no protective effect. In contrast, hexane fraction exhibited strong cytoprotective effect. Further study indicated that pretreatment of PC12 cells with ethyl acetate and n-butanol fractions, prior to hypoxia exposure, significantly increased the survival of cells and the activities of SOD, CAT, GSH-Px and T-AOC, as well as reduced the level of LDH and MDA. The gathered data demonstrated that ethyl acetate and n-butanol fractions were able to protect PC12 cells against hypoxia induced injury through direct free radical scavenging and modulation of endogenous antioxidant enzymes. CONCLUSION: These findings suggested that ethyl acetate and n-butanol fractions of R. anthopogonoides had significant antioxidant activity and could prevent PC12 cells against hypoxia-induced injury. So it might be regarded as an excellent source of antioxidants and had great potential to explore as therapeutic agent for preventing hypoxia related sickness in future.


Asunto(s)
Antioxidantes/farmacología , Flavonoides/farmacología , Fenoles/farmacología , Extractos Vegetales/farmacología , Rhododendron/química , Animales , Antioxidantes/análisis , Flavonoides/análisis , Hipoxia , Oxidación-Reducción , Células PC12 , Fenoles/análisis , Extractos Vegetales/química , Ratas
18.
BMC Complement Altern Med ; 15: 126, 2015 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-25897964

RESUMEN

BACKGROUND: Shenling Baizhu San (SBS) is a well-known and classical Chinese medicine formula. It has been used for treatment of gastrointestinal disorders for about nine hundred years. Recent reports showed that it was effective in curing colitis and ameliorating the major manifestations of postoperational colorectal cancer (CRC). This study was to evaluate the effects of SBS on azoxymethane (AOM) and dextran sodium sulfate (DSS) induced colitis associated CRC (caCRC) and to analyze the underlying mechanism of SBS in preventing CRC. METHODS: The colon tissue of mice in different group was determined by immunohistochemistry and western blot. TGF-ß1 in serum was measured by ELISA. Myeloid-derived suppressor cells (MDSCs) were identified by flow cytometry and immunohistochemistry. RESULTS: The formed neoplasms phenotypically resembled human caCRC with upregulated ß-catenin, p53 and proliferating cell nuclear antigen (PCNA). SBS treatment reduced the death rate of mice and decreased the incidence and multiplicity of colonic neoplasms. SBS decreased the number of MDSCs and the level of transforming growth factor ß1 (TGF-ß1). SBS alleviated epithelial mesenchymal transition (EMT) through downregulating N-cadherin (N-cad), Vimentin, Fibronectin, Snail, and upregulating E-cadherin (E-cad). It reduced the activation of Wnt5a and EMT induced by TGF-ß1. CONCLUSIONS: SBS reduced the death rate through decreasing the incidence and multiplicity of colonic tumors. SBS lowered MDSCs infiltration and inhibited TGF-ß1 induced EMT to exert its anti-caCRC effects.


Asunto(s)
Colitis/complicaciones , Colon/efectos de los fármacos , Neoplasias Colorrectales/prevención & control , Medicamentos Herbarios Chinos/uso terapéutico , Transición Epitelial-Mesenquimal/efectos de los fármacos , Células Mieloides/metabolismo , Fitoterapia , Animales , Azoximetano , Cadherinas/metabolismo , Colon/metabolismo , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/metabolismo , Sulfato de Dextran , Regulación hacia Abajo , Medicamentos Herbarios Chinos/farmacología , Fibronectinas/metabolismo , Humanos , Masculino , Ratones Endogámicos C57BL , Antígeno Nuclear de Célula en Proliferación/metabolismo , Factor de Crecimiento Transformador beta1/sangre , Vimentina/metabolismo , beta Catenina/metabolismo
19.
Zhong Yao Cai ; 38(1): 89-92, 2015 Jan.
Artículo en Zh | MEDLINE | ID: mdl-26214875

RESUMEN

OBJECTIVE: To investigate the chemical constituents with anti-hypoxia activity from Saussurea involucrata. METHODS: The chemical constituents, isolated and purified by column chromatography from Saussurea involucrata, were identified by several spectroscopic methods. The anti-hypoxic activities of these compounds were examined using the normobaric hypoxic model of mice. RESULTS: Twelve compounds were isolated from petroleum ether extract of Saussurea involucrata and identified as n-octacosane (1), 1-undecanol (2), heptadecan-l-ol(3), heptacosan-1-ol(4), myristicin (5), apiol(6), ß-sitosterol(7), lupeol(8), moslosooflavone (9), mosloflavone (10), negletein(11), and 5, 6-dihydroxy-7, 8-dimethoxyflavone(12). CONCLUSION: All compounds except 7 and 8 are isolated from this plant for the first time. Compound 1, 5 and 8 - 12 can significantly prolong the survival time of hypoxic mice.


Asunto(s)
Hipoxia/tratamiento farmacológico , Fitoquímicos/farmacología , Extractos Vegetales/farmacología , Saussurea/química , Alcanos , Animales , Flavonoides , Ratones , Fitoquímicos/aislamiento & purificación , Extractos Vegetales/química , Sitoesteroles , Solventes
20.
Zhong Yao Cai ; 38(4): 790-3, 2015 Apr.
Artículo en Zh | MEDLINE | ID: mdl-26672349

RESUMEN

OBJECTIVE: To study the protective effect of Saussurea involucrata alcohol extract on liver mitochondria in mice under hypoxia condition. METHODS: The hypoxia mice model was established, the BALB/c mice were randomly divided into four groups:normal group ,hypoxia model group, positive control group and Saussurea involucrata alcohol extract group. Mice were put into low pressure oxygen chamber and decompressed, adapted to hypobaric hypoxia environment of simulated altitude of 8,000 m for 12 h, and then recovered to normal altitude. The mice were sacrificed and the liver mitochondria was isolated, the mitochondrial membrane potential and the activity of malate dehydrogenase, aconitase, α-ketoglutarate dehydrogenase, pyruvate dehydrogenase and mitochondrial complex I, II and V were measured. RESULTS: Compared with hypoxia model group, Saussurea involucrata alcohol extract protected mitochondrial membrane potential, sustained the activities of aconitase, α-ketoglutarate dehydrogenase, pyruvate dehydrogenase, and mitochondrial complex I, II and V under hypoxia condition. CONCLUSION: Saussurea involucrata alcohol extract can protect the liver mitochondrial function in mice under hypoxia condtion.


Asunto(s)
Hipoxia/tratamiento farmacológico , Mitocondrias Hepáticas/efectos de los fármacos , Extractos Vegetales/farmacología , Saussurea/química , Altitud , Animales , Descompresión , Modelos Animales de Enfermedad , Etanol , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C
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