RESUMEN
This study aims to investigate the mechanism of the anti-atherosclerosis effect of Huayu Qutan Recipe (HYQT) on the inhibition of foam cell formation. In vivo, the mice were randomly divided into three groups: CTRL group, MOD group and HYQT group. The HYQT group received HYQT oral administration twice a day (20.54 g/kg/d), and the plaque formation in ApoE-/- mice was observed using haematoxylin-eosin (HE) staining and oil red O (ORO) staining. The co-localization of aortic macrophages and lipid droplets (LDs) was examined using fluorescent labelling of CD11b and BODIPY fluorescence probe. In vitro, RAW 264.7 cells were exposed to 50 µg/mL ox-LDL for 48 h and then treated with HYQT for 24 h. The accumulation of LDs was evaluated using ORO and BODIPY. Cell viability was assessed using the CCK-8 assay. The co-localization of LC3b and BODIPY was detected via immunofluorescence and fluorescence probe. LysoTracker Red and BODIPY 493/503 were used as markers for lysosomes and LDs, respectively. Autophagosome formation were observed via transmission electron microscopy. The levels of LC3A/B II/LC3A/B I, p-mTOR/mTOR, p-4EBP1/4EBP1, p-P70S6K/P70S6K and TFEB protein level were examined via western blotting, while SQSTM1/p62, Beclin1, ABCA1, ABCG1 and SCARB1 were examined via qRT-PCR and western blotting. The nuclear translocation of TFEB was detected using immunofluorescence. The components of HYQT medicated serum were determined using Q-Orbitrap high-resolution MS analysis. Molecular docking was employed to identify the components of HYQT medicated serum responsible for the mTOR signalling pathway. The mechanism of taurine was illustrated. HYQT has a remarkable effect on atherosclerotic plaque formation and blood lipid level in ApoE-/- mice. HYQT decreased the co-localization of CD11b and BODIPY. HYQT (10% medicated serum) reduced the LDs accumulation in RAW 264.7 cells. HYQT and RAPA (rapamycin, a mTOR inhibitor) could promote cholesterol efflux, while chloroquine (CQ, an autophagy inhibitor) weakened the effect of HYQT. Moreover, MHY1485 (a mTOR agonist) also mitigated the effects of HYQT by reduced cholesterol efflux. qRT-PCR and WB results suggested that HYQT improved the expression of the proteins ABCA1, ABCG1 and SCARB1.HYQT regulates ABCA1 and SCARB1 protein depending on the mTORC1/TFEB signalling pathway. However, the activation of ABCG1 does not depend on this pathway. Q-Orbitrap high-resolution MS analysis results demonstrated that seven core compounds have good binding ability to the mTOR protein. Taurine may play an important role in the mechanism regulation. HYQT may reduce cardiovascular risk by promoting cholesterol efflux and degrading macrophage-derived foam cell formation. It has been observed that HYQT and ox-LDL regulate lipophagy through the mTOR/TFEB signalling pathway, rather than the mTOR/4EBP1/P70S6K pathway. Additionally, HYQT is found to regulate cholesterol efflux through the mTORC1/TFEB/ABCA1-SCARB1 signal axis, while taurine plays a significant role in lipophagy.
Asunto(s)
Aterosclerosis , Compuestos de Boro , Proteínas Quinasas S6 Ribosómicas 70-kDa , Animales , Ratones , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Colesterol/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Simulación del Acoplamiento Molecular , Células Espumosas/metabolismo , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Autofagia , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Taurina/metabolismoRESUMEN
Vascular dementia (VaD) represents a severe cognitive dysfunction syndrome closed linked to cardiovascular function. In the present study, we assessed the potential of Xinshubao tablet (XSB), a traditional Chinese prescription widely used for cardiovascular diseases, to mitigate neuropathological damage in a mouse model of VaD and elucidated the underlying mechanisms. Our findings revealed that oral administration of XSB rescued the cardiac dysfunction resulting from bilateral common carotid artery stenosis (BCAS), improved the cerebral blood flow (CBF) and cognitive function, reduced white matter injury, inhibited excessive microglial and astrocytic activation, stimulated hippocampal neurogenesis, and reduced neural apoptosis in the brains of BCAS mice. Mechanistically, RNA-seq analysis indicated that XSB treatment was significantly associated with neuroinflammation, vasculature development, and synaptic transmission, which were further confirmed by q-PCR assays. Western blot results revealed that XSB treatment hindered the nuclear translocation of nuclear factor-κB (NF-κB), thereby suppressing the NF-κB signaling pathway. These results collectively demonstrated that XSB could ameliorate cognitive dysfunction caused by BCAS through regulating CBF, reducing white matter lesions, suppressing glial activation, promoting neurogenesis, and mitigating neuroinflammation. Notably, the NF-κB signaling pathway emerged as a pivotal player in this mechanism.
Asunto(s)
Estenosis Carotídea , Disfunción Cognitiva , Demencia Vascular , Animales , Ratones , Demencia Vascular/tratamiento farmacológico , Enfermedades Neuroinflamatorias , FN-kappa B , Disfunción Cognitiva/tratamiento farmacológico , Neurogénesis , Modelos Animales de EnfermedadRESUMEN
Traditional Chinese medicine offer unique advantages in mitigating and preventing early or intermediate stage for treating heart failure (HF). The purpose of this study was to assess the in vivo therapeutic efficacy of Xin-shu-bao (XSB) at different stages of HF following induction of a myocardial infarction (MI) in mice and use mass spectrometry-based proteomics to identify potential therapeutic targets for different stages of HF based on the molecular changes following XSB treatment. XSB had high cardioprotective efficacy in the pre-HF with reduced ejection fraction (HFrEF) stages, but had a weak or no effect in the post-HFrEF stages. This was supported by echocardiographic measurements showing that XSB decreased ejection fraction and fractional shortening in HF. XSB administration improved cardiac function in the pre- and post-HFrEF mouse model, ameliorated deleterious changes to the morphology and subcellular structure of cardiomyocytes, and reduced cardiac fibrosis. Proteomics analysis showed that XSB intervention exclusively targeted thrombomodulin (THBD) and stromal interaction molecule 1 (STIM1) proteins when administered to the mice for both 8 and 6 weeks. Furthermore, XSB intervention for 8, 6, and 4 weeks after MI induction increased the expression of fibroblast growth factor 1 (FGF1) and decreased arrestin ß1 (ARRB1), which are classic biomarkers of cardiac fibroblast transformation and collagen synthesis, respectively. Overall, the study suggests that early intervention with XSB could be an effective strategy for preventing HFrEF and highlights potential therapeutic targets for further investigation into HFrEF remediation strategies.
Asunto(s)
Insuficiencia Cardíaca , Infarto del Miocardio , Animales , Ratones , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Volumen Sistólico , Factor 1 de Crecimiento de Fibroblastos/metabolismo , Arrestina/metabolismo , Molécula de Interacción Estromal 1 , Trombomodulina , Infarto del Miocardio/tratamiento farmacológicoRESUMEN
Impaired immunomodulatory capacity and oxidative stress are the key factors limiting the effectiveness of mesenchymal stem cell transplantation therapy. The present study was aimed to investigate the effects of jujuboside A (JuA) on the protective effect and immunomodulatory capacity of human umbilical cord mesenchymal stem cells (hUC-MSCs). Hydrogen peroxide was used to establish an oxidative damage model of hUC-MSCs, while PBMCs isolated from rats were used to evaluate the effect of JuA pre-treatment on the immunomodulatory capacity of hUC-MSCs. Furthermore, Hoechst 33258 staining, lactate dehydrogenase test, measurement of malondialdehyde, Western blot, high-performance liquid chromatography; and flow cytometry were performed. Our results indicated that JuA (25 µmol·L-1) promoted the proliferation of hUC-MSCs, but did not affect the differentiating capability of these cells. JuA pre-treatment inhibited apoptosis, prevented oxidative damage, and up-regulated the protein expression of nuclear factor-erythroid factor 2-related factor 2 and heme oxygenase 1 in hUC-MSCs in which oxidative stress was induced with H2O2. In addition, JuA pre-treatment enhanced the inhibitory effect of hUC-MSCs against abnormally activated PBMCs, which was related to stimulation of the expression and activity of indoleamine 2,3-dioxygenase. In conclusion, our results demonstrate that JuA pre-treatment can enhance the survival and immunomodulatory ability through pathways related to oxidative stress, providing a new option for the improvement of hUC-MSCs in the clinical setting.
Asunto(s)
Células Madre Mesenquimatosas , Cordón Umbilical , Animales , Diferenciación Celular , Humanos , Peróxido de Hidrógeno/metabolismo , Estrés Oxidativo , Ratas , Saponinas , Cordón Umbilical/metabolismoRESUMEN
An herbal prescription is usually composed of several herbal medicines. The complex and diverse components bring great challenges to its bioactivity study. To comprehensively analyze the bioactivity of an herbal prescription, a new strategy based on peak-by-peak cutting and knock-out chromatography was proposed. In this strategy, active compounds were screened out via peak-by-peak cutting from an herbal extract, and the influence of a compound on the overall activity of the herbal extract was evaluated by knock-out chromatography. Qiliqiangxin capsule is an herbal prescription composed of 11 herbal medicines for the treatment of chronic heart failure. A total of 71 peaks were collected through peak-by-peak cutting, and each peak was identified by a high-resolution mass spectrum. The bioassay against 1,1-diphenyl-2-picrylhydrazyl showed that two types of compounds namely salvianolic acids and caffeoylquinic acids were potent scavengers. Knock-out chromatography suggested that the removal of one single compound had no obvious influence on the overall activity of the Qiliqiangxin capsule. After all the main peaks in the Qiliqiangxin capsule were knocked out, the remaining part still exhibited a potent activity, indicating high activity stability of the Qiliqiangxin capsule. The proposed strategy is helpful for the comprehensive analysis of the bioactivity of other herbal prescriptions.
Asunto(s)
Medicamentos Herbarios Chinos , Plantas Medicinales , Cromatografía Líquida de Alta Presión/métodos , Medicamentos Herbarios Chinos/análisis , Plantas Medicinales/química , PrescripcionesRESUMEN
Praeruptorin A (PA) is a natural coumarin compound from the roots of Radix Peucedani and is commonly used in the treatment of certain respiratory diseases and hypertension. Although previous studies identified relaxant effects of PA on tracheal and arterial preparations, little is known about its vasodilative effects and underlying mechanisms. Here, an organ bath system and tension recording methods were used to prepare and analyze isolated rat thoracic aorta artery rings. Aorta artery rings were pre-contracted with phenylephrine and then incubated with PA, and the possible mechanism of relaxation was investigated by adding inhibitors of nitric oxide synthase (NG-nitro-L-arginine methyl ester, L-NAME), endothelial nitric oxide synthase (L-NG-nitroarginine, L-NNA), cyclooxygenase (indomethacin), guanylyl cyclase (1 H-[1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one, ODQ), and KCa channels (tetraethylammonium, TEA). Our study showed that PA-induced vasodilation was blocked by L-NAME, L-NNA, and ODQ, while CaCl2-induced vasoconstriction was countered by PA. Thus, PA may exert a vasodilatory effect by influencing the amounts of endothelium-derived relaxing factors through endothelial-dependent NO-cGMP and prostacyclin pathways (such as NO and prostacyclin 2). In the rat thoracic aorta, PA reduces vasoconstriction by inhibiting Ca2+ inflow.
Asunto(s)
Aorta Torácica , Vasodilatadores , Animales , Aorta Torácica/metabolismo , Cumarinas , Endotelio Vascular/metabolismo , Epoprostenol/metabolismo , Epoprostenol/farmacología , NG-Nitroarginina Metil Éster/metabolismo , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/metabolismo , Ratas , Ratas Wistar , Vasodilatadores/metabolismo , Vasodilatadores/farmacologíaRESUMEN
Restoring the compromised neurogenesis has been served as a potential strategy to rescue cognitive dysfunction of Alzheimer's disease (AD). In this study, we explored whether icarisid II (ICS II), a natural product possessing powerful neuroprotection, could recover the neurogenesis dysfunction of APP/PS1 mice, and investigated its underlying mechanisms. Our results showed that oral administration of ICS II could alleviate cognitive injuries of APP/PS1 mice, promote hippocampal neurogenesis, as well as stimulate Wnt/ß-catenin signal pathway confirmed by upregulated Wnt-3a, phosphorylated glycogen synthase kinase-3ß (p-GSK-3ß), and ß-catenin. ICS II also depressed mitochondrial fission evidenced by upregulated Mitofusin 1 (Mfn 1) and Mitofusin 2 (Mfn 2), and downregulated mitochondrial fission 1 protein (Fis 1), mitochondrial fission factor (Mff), and phosphorylated dynamin-related protein 1 (p-Drp 1). However, these effects of ICS II were blunted by XAV-939, an inhibitor of Wnt/ß-catenin signaling pathway. In summary, our findings revealed that ICS II could improve neurogenesis and inhibit mitochondrial fission via activation of the Wnt/ß-catenin signaling pathway, which contributed to cognitive function restoration of APP/PS1 mice. This study discovered a novel mechanism involving neurogenesis regulation underlying the therapeutic effects of ICS II against AD.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Disfunción Cognitiva/tratamiento farmacológico , Flavonoides , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Hipocampo , Ratones , Ratones Transgénicos , Neurogénesis , Oligopéptidos/metabolismo , Vía de Señalización Wnt , beta Catenina/metabolismoRESUMEN
Mobilization of hippocampal neurogenesis has been considered as a potential strategy for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD). In present study, we evaluated both the neuroprotective effects and the effects on the proliferation and differentiation of APP-overexpressing neural stem cells (APP-NSCs) by Jujuboside A (JuA) in vitro. Our results demonstrated that JuA (50 µM) decreased apoptosis and suppressed oxidative stress damage of APP-NSCs. JuA (50 µM) upregulated the secretion of brain-derived neurotrophic factor and promoted the proliferation and neuronal differentiation of APP-NSCs. Moreover, JuA (50 µM) upregulated Wnt-3a and ß-catenin protein expression, and enhanced the expression of downstream genes Ccnd1, Neurod1 and Prox1. However, XAV-939, an inhibitor of the Wnt/ß-catenin signaling pathway, inhibited these positive effects of JuA. Taken together, these findings suggest that JuA promote proliferation and neuronal differentiation of APP-NSCs partly by activating the Wnt/ß-catenin signaling pathway. We hope that this study will provide a viable strategy for the treatment of AD.
Asunto(s)
Proliferación Celular , Células-Madre Neurales/efectos de los fármacos , Neurogénesis , Saponinas/farmacología , Vía de Señalización Wnt , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Línea Celular Tumoral , Células Cultivadas , Femenino , Compuestos Heterocíclicos con 3 Anillos/farmacología , Hipocampo/citología , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Células-Madre Neurales/fisiología , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , beta Catenina/metabolismoRESUMEN
BACKGROUND: Alzheimer's disease (AD) is the most common dementia worldwide, and there is still no satisfactory drug or therapeutic strategy. Polygala tenuifolia is a traditional Chinese medicine with multiple neuroprotective effects. In present study, we investigated the effects of three active constituents [3,6'-disinapoyl sucrose (DISS), onjisaponin B (OB) and tenuifolin (TEN)] of Polygala tenuifolia (PT) on the proliferation and differentiation of neural stem cells (NSCs) to identify the potential active constituent of PT promoting hippocampal neurogenesis. METHODS: NSCs were isolated from hippocampi of newborn C57BL/6 mice, and transfected with mutant amyloid precursor protein (APP) gene to establish an AD cell model (APP-NSCs). 3-(4,5- Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays were performed, and the proliferation and differentiation of NSCs were assessed by neurosphere formation assay, 5-bromo-2'-deoxyuridine (BrdU) incorporation assay and immunofluorescence (IF) staining analysis. APP/PS1 transgenic mice were administrated with the potential active constituent DISS for 4 weeks. Morris water maze (MWM), Nissl staining assay and IF staining assays were carried out to evaluate the cognitive function, neural damages and hippocampal neurogenesis, respectively. RESULTS: DISS exerted the optimal ability to strengthen APP-NSCs proliferation and neuronal differentiation, followed by OB and TEN. Furthermore, DISS treatment for 4 weeks strikingly rescued the cognitive deficits, neuronal injures, and neurogenesis disorder in adult APP/PS1 transgenic mice. CONCLUSIONS: Our findings demonstrated that DISS is the constituent of PT that triggers the most potent increase of hippocampal neurogenesis in our mouse model of AD.
Asunto(s)
Enfermedad de Alzheimer , Hipocampo , Medicina Tradicional China , Células-Madre Neurales , Neurogénesis , Animales , Ratones , Enfermedad de Alzheimer/tratamiento farmacológico , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Medicina Tradicional China/métodos , Ratones Endogámicos C57BL , Ratones Transgénicos , Estructura Molecular , Prueba del Laberinto Acuático de Morris , Células-Madre Neurales/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Polygala/químicaRESUMEN
Lead compound is an important concept for modern drug discovery. In this study, a new concept of lead chemome and an efficient strategy to discover lead chemome were proposed. Compared with the concept of lead compound, lead chemome can provide not only the starting point for drug development, but also the direction for structure optimization. Two traditional Chinese medicines of Mahonia bealei and Mahonia fortunei were used as examples to illustrate the strategy. Based on natural chromatogram-effect correlation (NCEC), berberine, palmatine and jatrorrhizine were discovered as acetylcholinesterase (AchE) inhibitors. Taking the three compounds as template molecules, a lead chemome consisting of 10 structurally related natural compounds were generated through natural structure-effect correlation (NSEC). In the lead chemome, the IC50 values of jatrorrhizine, berberine, coptisine, palmatine and epiberberine are at nanomolar level, which are comparable to a widely used drug of galantamine. Pharmacophore modeling shows that the positive ionizable group and aromatic rings are important substructures for AchE inhibition. Molecular docking further shows that pi-cation interaction and pi-pi stacking are critical for compounds to maintain nanomolar IC50 values. The structure-activity information is helpful for drug design and structure optimization. This work also expanded the traditional understanding of "stem is the medicinal part of Mahonia bealei and Mahonia fortunei". Actually, all parts except the leaf of Mahonia bealei exhibited potent AchE-inhibitory activity. This study provides not only a strategy to discover lead chemome for modern drug development, but also a reference for the application of different parts of medicinal plants.
Asunto(s)
Medicamentos Herbarios Chinos/química , Plomo , Mahonia/química , Plomo/análisis , Plomo/química , Simulación del Acoplamiento Molecular , Fitoquímicos/análisis , Fitoquímicos/química , Hojas de la Planta/químicaRESUMEN
Acute lung injury (ALI), which is induced by renal ischemia-reperfusion (IR), is one of the leading causes of acute renal IR-related death. Obesity raises the frequency and severity of acute kidney injury (AKI) and ALI. Tanshinone IIA (TIIA) combined with cyclosporine A (CsA) was employed to lessen the lung apoptosis led by renal IR and to evaluate whether TIIA combined with CsA could alleviate lung apoptosis by regulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats. Hematoxylin-eosin (HE) staining was used to assess the histology of the lung injury. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) was used to assess apoptosis of the lung. Electron microscopy was used to assess mitochondrial morphology in lung cells. Arterial blood gas and pulmonary function were used to assess the external respiratory function. Mitochondrial function was used to assess the internal respiratory function and mitochondrial dynamics and biogenesis. Western blot (WB) was used to examine the PI3K/Akt/Bad pathway-related proteins. TIIA combined with CsA can alleviate lung apoptosis by regulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats.
RESUMEN
OBJECTIVE: To investigate the expression and clinical value of the E-selectin gene (SELE) in colorectal cancer (CRC). METHODS: Using gene expression profiles and clinicopathological data for patients with CRC from The Cancer Genome Atlas, and tumor and adjacent normal tissues from 31 patients with CRC from Xianyang Central Hospital, we studied the correlation between SELE gene expression and clinical parameters using Kaplan-Meier and Cox proportional hazards regression analyses. RESULTS: Higher expression of SELE was significantly associated with a poorer prognosis and shorter survival in patients with CRC. The median expression level of SELE was significantly higher in CRC tissues compared with healthy adjacent tissue. Cox regression analysis showed that the prognosis of CRC was significantly correlated with the expression of SELE. Immunohistochemical analysis also showed that positive expression of E-selectin increased significantly in line with increasing TNM stage.Conclusion: This study confirmed that SELE gene expression is an independent prognostic factor in patients with CRC.
Asunto(s)
Neoplasias del Colon , Neoplasias Colorrectales , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Pronóstico , Modelos de Riesgos ProporcionalesRESUMEN
Adult neurogenesis plays a vital role in maintaining cognitive functions in mammals and human beings. Mobilization of hippocampal neurogenesis has been regarded as a promising therapeutic approach to restore injured neurons in neurodegenerative diseases including Alzheimer's disease (AD). Icarisid II (ICS II), an active ingredient derived from Epimedii Folium, has been reported to exhibit multiple neuroprotective effects. In the present study, we investigated the effects of ICS II on the proliferation and differentiation of neural stem cells (NSCs) and amyloid precusor protein (APP)-overexpressing NSCs (APP-NSCs) in vitro. Our results demonstrated that ICS II dose-dependently suppressed apoptosis and elevated viability of APP-NSCs. ICS II (1 µM) potently promoted proliferation and neuronal differentiation of NSCs and APP-NSCs. ICS II (1 µM) significantly upregulated Wnt-3a expression, increased the phosphorylation of glycogen synthase kinase-3ß and enhanced the nuclear transfer of ß-catenin. Moreover, ICS II also promoted astrocytes to secrete Wnt-3a, which positively modulates Wnt/ß-catenin signaling pathway. These findings demonstrate that ICS II promotes NSCs proliferation and neuronal differentiation partly by activating the Wnt/ß-catenin signaling pathway.
RESUMEN
Alzheimer's disease (AD) is a neurodegenerative disorder with notable factors of dysfunction in multiple neurological changes, encompassing neuronal loss in the frontal cortex and hippocampal regions. Dysfunction of proliferation and self-renewal of neural stem cells (NSCs) was observed in AD patients and animals. Thereby, mobilizing endogenous neurogenesis by pharmacological agents would provide a promising route for neurodegeneration. Osthole (Ost), a natural coumarin derivative, has been reported to exert extensive neuroprotective effects in AD. However, whether ost can facilitate endogenous neurogenesis against AD in vivo is still unknown. In this study, by using Morris water maze (MWM) test, hematoxylin-eosin (HE) staining, Nissl staining, immunofluorescence analysis and western blot, we demonstrated that oral administration of ost could improve the learning and memory function, inhibit neuronal apoptosis, elevate the expression of glial cell line derived neurotrophic factor (GDNF), synaptophysin (SYP) and postsynaptic density protein 95 (PSD95). Moreover, ost could remarkably enhance proliferation of NSCs and increase the amount of mature neurons in APP/PS1 transgenic mice. Together, our findings demonstrated that ost possessed the ability of promoting endogenous neurogenesis and ost could be served as a plausible agent to reverse or slow down the progress of AD.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad de Alzheimer/tratamiento farmacológico , Precursor de Proteína beta-Amiloide/genética , Animales , Disfunción Cognitiva/tratamiento farmacológico , Cumarinas/farmacología , Modelos Animales de Enfermedad , Humanos , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , NeuronasRESUMEN
Osthole (Ost) is a coumarin compound and a potential drug for Alzheimer's disease (AD). However, the effectiveness of Ost is limited by solubility, bioavailability, and low permeability of the blood-brain barrier. In this study, we constructed Ost liposomes with modified CXCR4 on the surface (CXCR4-Ost-Lips), and investigated the intracellular distribution of liposomes in APP-SH-SY5Y cells. In addition, the neuroprotective effect of CXCR4-Ost-Lips was examined in vitro and in vivo. The results showed that CXCR4-Ost-Lips increased intracellular uptake by APP-SH-SY5Y cells and exerted a cytoprotective effect in vitro. The results of Ost brain distribution showed that CXCR4-Ost-Lips prolonged the cycle time of mice and increased the accumulation of Ost in the brain. In addition, CXCR4-Ost-Lips enhanced the effect of Ost in relieving AD-related pathologies. These results indicate that CXCR4-modified liposomes are a potential Ost carrier to treat AD.
Asunto(s)
Enfermedad de Alzheimer , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Encéfalo , Cumarinas , Liposomas , RatonesRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: According to the theory of traditional Chinese medicine (TCM), Alzheimer's disease (AD) is identified as "forgetfulness" or "dementia", and is mainly caused by "kidney essence deficiency" which ultimately induces "encephala reduction". Therefore, herbal formulas possessing the efficacy of nourishing kidney essence or replenishing brain marrow are commonly served as effective strategies for AD treatment. Shenzao jiannao oral liquid (SZJN), a traditional Chinese preparation approved by the China Food and Drug Administration (CFDA), is used for the treatment of insomnia and mind fatigue at present for its efficacy of nourishing kidneys. In present study, we found that SZJN could improve cognitive function of AD-like mice. AIMS OF STUDY: This study aims to investigate the effects of SJZN on ameliorating cognitive deficits of AD-like mouse model, and to illuminate the underlying mechanisms from the perspective of neuroprotection and neurogenesis. MATERIALS AND METHODS: Kunming mice (28 ± 2 g) were randomly allocated into seven groups: control, sham, model, donepezil and SZJN groups (low, middle and high). The AD mouse model was established by Aß42 combined with scopolamine. SZJN were intragastrically administrated at doses of 0.3, 1.5 and 7.5 g/kg for 28 days. Morris water maze (MWM) test was applied to determine the cognitive function. Hematoxylin eosin (HE) and Nissl staining were carried out to evaluate pathological damages in the cortex and hippocampal tissues. To explore the protective effects of SZJN on multiple pathogenic factors of AD, protein levels of Aß42, glial fibrillary acidic protein (GFAP), Bax, Bcl-2, Caspase-3, synaptophysin (SYP), brain-derived neurotrophic factor (BDNF), and neurogenesis related proteins were assessed using Immunofluorescence (IF) and western blot analysis. In vitro, the AD cell model was established by transduction of APP695swe genes into Neural stem cells (NSCs) isolated from the hippocampal tissues of neonatal C57BL/6 mice. Cell viability assay and neurosphere formation assay were carried out to verify the efficacy of SZJN on proliferation of NSCs. RESULTS: Our results demonstrated that SZJN (1.5 g/kg and 7.5 g/kg) treatment significantly ameliorated cognitive deficits of AD-like mice. SZJN (7.5 g/kg) treatment significantly retarded the pathological damages including neuronal degeneration, neuronal apoptosis, Aß peptides aggregation and reaction of astrocytes in AD-like mice. In addition, SZJN (7.5 g/kg) increased the expression of BDNF and SYP, and restored the abnormal level of MDA and SOD in the brain of AD-like mice. Furthermore, SZJN treatment for 28 days remarkably increased the proliferation of NSCs evidenced by more Nestin+ and BrdU+ cells in the hippocampal DG regions, and increased the amount of mature neurons marked by NeuN both in the cortex and hippocampal DG regions. In vitro, SZJN treatement (16, 32, 64 mg/ml) promoted the proliferation of NSCs evidenced by the increased amount and enlarged size of the neurospheres (p < 0.05). CONCLUSIONS: Our findings indicated that SZJN could ameliorate cognitive deficits by protecting neurons from death and triggering endogenous neurogenesis. Therefore, SZJN may be considered as a promising agent to restore neuronal loss and deter the deterioration in AD patients.
Asunto(s)
Enfermedad de Alzheimer/prevención & control , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Cognición/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Neurogénesis/efectos de los fármacos , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Nootrópicos/farmacología , Administración Oral , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides , Animales , Encéfalo/metabolismo , Encéfalo/patología , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/administración & dosificación , Reacción de Fuga/efectos de los fármacos , Femenino , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Neuronas/metabolismo , Neuronas/patología , Fármacos Neuroprotectores/administración & dosificación , Nootrópicos/administración & dosificación , Fragmentos de Péptidos , Escopolamina , Transducción de SeñalRESUMEN
INTRODUCTION: Osthole (Ost) is a coumarin compound that strengthens hippocampal neurons and neural stem cells against Aß oligomer-induced neurotoxicity in mice, and is a potential drug for the treatment of Alzheimer's disease (AD). However, the effectiveness of the drug is limited by its solubility and bioavailability, as well as by the low permeability of the blood-brain barrier (BBB). In this study, a kind of transferrin-modified Ost liposomes (Tf-Ost-Lip) was constructed, which could improve the bioavailability and enhance brain targeting. METHODS: Tf-Ost-Lip was prepared by thin-film hydration method. The ability of liposomal formulations to translocate across BBB was investigated using in vitro BBB model. And the protective effect of Tf-Ost-Lip was evaluated in APP-SH-SY5Y cells. In addition, we performed pharmacokinetics study and brain tissue distribution analysis of liposomal formulations in vivo. We also observed the neuroprotective effect of the varying formulations in APP/PS-1 mice. RESULTS: In vitro studies reveal that Tf-Ost-Lip could increase the intracellular uptake of hCMEC/D3 cells and APP-SH-SY5Y cells, and increase the drug concentration across the BBB. Additionally, Tf-Ost-Lip was found to exert a protective effect on APP-SH-SY5Y cells. In vivo studies of pharmacokinetics and the Ost distribution in brain tissue indicate that Tf-Ost-Lip prolonged the cycle time in mice and increased the accumulation of Ost in the brain. Furthermore, Tf-Ost-Lip was also found to enhance the effect of Ost on the alleviation of Alzheimer's disease-related pathology. CONCLUSION: Transferrin-modified liposomes for delivery of Ost has great potential for AD treatment.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Barrera Hematoencefálica/efectos de los fármacos , Cumarinas/farmacología , Liposomas/farmacología , Fármacos Neuroprotectores/farmacología , Enfermedad de Alzheimer/patología , Animales , Barrera Hematoencefálica/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/patología , Línea Celular , Cumarinas/química , Cumarinas/farmacocinética , Humanos , Liposomas/química , Liposomas/farmacocinética , Ratones Transgénicos , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacocinética , Polietilenglicoles/química , Presenilina-1/genética , Ratas Sprague-Dawley , Distribución Tisular , Transferrina/químicaRESUMEN
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of Editor-in-Chief. The journal was initially contacted by the corresponding author to request the retraction of the article because the "same pictures were confused" in Figure 3B. The further investigation of the editor found that Dr. Elisabeth Bik has pointed out some problems of this article, including similarities between features and sections of panels within Figures 3A and 3B, as well as between Western Blots within Figures 6A,B, 8C and 10A,B, and therefore the Editor has decided to retract the article.