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BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder with no effective cure. Targeting endoplasmic reticulum (ER) stress pathway may offer a novel approach to ameliorate cognitive deficits in AD. Bushen-Yizhi formula (BSYZ), a traditional Chinese medicine (TCM) prescription, has shown potential benefits for AD. To facilitate the development of new therapeutic agents for AD, it is important to identify the active components and the underlying mechanisms of BSYZ against AD. PURPOSE: The aim of this study was to systematically screen the active components of BSYZ that could improve learning and memory impairment in AD by modulating ER stress pathway. METHODS: A drug-target (D-T) network was constructed to analyze the herbal components of BSYZ. Network proximity method was used to identify the potential anti-AD components that targeted ER stress and evaluate their synergistic effects. The absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties and the literature evidence were considered to select promising candidates for further validation. The selected components were tested in vitro using an AD cell model (APPswe-SH-SY5Y). In vivo anti-AD effects of the components were assessed in APP/PS1 double-transgenic mice. RESULTS: 58 potential anti-AD components targeting ER stress were detected by network proximity analysis, and 13 out of them were selected based on ADMET properties and literature evidence. In vitro experiments confirmed that 5 components, namely gomisin B, ß-Carotene, imperatorin, chrysophanol, and osthole (OST), exhibited anti-AD effects on the APPswe-SH-SY5Y model. Moreover, network proximity analysis suggested that OST and Gomisin B might have synergistic effects on modulating ER stress. In vivo experiments demonstrated that OST, Gomisin B, OST+Gomisin B, and BSYZ all improved learning and memory function in APP/PS1 mice. Gomisin B and OST also restored cellular morphology and tissue structure in APP/PS1 mice. Thioflavine-S (Th-S) staining revealed that they reduced amyloid plaque deposition in the brain tissue of AD model mice. The qPCR results indicated that BSYZ, OST, and Gomisin B differentially regulated IRE1α, PERK, EIF2α, DDIT3, and Caspase 12 expression levels, while the OST and Gomisin B co-administration group showed better efficacy. This trend was further confirmed by immunofluorescence experiments. CONCLUSION: This study identified the active components of BSYZ that could ameliorate learning and memory impairment in AD by targeting ER stress pathway. OST and Gomisin B exhibited synergistic effects on modulating ER stress and reducing amyloid plaque deposition in vivo. Overall, our study elucidated the molecular mechanisms of BSYZ and its active components in attenuating AD symptoms which suggested the therapeutic potential of TCM for AD.
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Doença de Alzheimer , Neuroblastoma , Camundongos , Humanos , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Endorribonucleases , Placa Amiloide , Proteínas Serina-Treonina Quinases , Camundongos Transgênicos , Estresse do Retículo Endoplasmático , Modelos Animais de Doenças , Peptídeos beta-Amiloides , Precursor de Proteína beta-AmiloideRESUMO
BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease, characterized by progressive cognitive dysfunction and memory loss. However, the disease-modifying treatments for AD are still lacking. Traditional Chinese herbs, have shown their potentials as novel treatments for complex diseases, such as AD. PURPOSE: This study was aimed at investigating the mechanism of action (MOA) of Acanthopanax senticosusin (AS) for treatment of AD. METHODS: In this study, we firstly identified the chemical constituents in Acanthopanax senticosusin (AS) utilizing ultra-high performance liquid chromatography coupled with Q-TOF-mass spectrometry (UPLC-Q-TOF-MS), and next built the drug-target network of these compounds. We also performed the systems pharmacology-based analysis to preliminary explore the MOA of AS against AD. Moreover, we applied the network proximity approach to identify the potential anti-AD components in AS. Finally, experimental validations, including animal behavior test, ELISA and TUNEL staining, were conducted to verify our systems pharmacology-based analysis. RESULTS: 60 chemical constituents in AS were identified via the UPLC-Q-TOF-MS approach. The systems pharmacology-based analysis indicated that AS might exert its therapeutic effects on AD via acetylcholinesterase and apoptosis signaling pathway. To explore the material basis of AS against AD, we further identified 15 potential anti-AD components in AS. Consistently, in vivo experiments demonstrated that AS could protect cholinergic nervous system damage and decrease neuronal apoptosis caused by scopolamine. CONCLUSION: Overall, this study applied systems pharmacology approach, UPLC-Q-TOF-MS, network analysis, and experimental validation to decipher the potential molecular mechanism of AS against AD.
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Doença de Alzheimer , Medicamentos de Ervas Chinesas , Eleutherococcus , Doenças Neurodegenerativas , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Farmacologia em Rede , Espectrometria de Massas em Tandem/métodos , Acetilcolinesterase , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Cromatografia Líquida de Alta Pressão/métodosRESUMO
BACKGROUND: As a major risk factor for neurodegenerative diseases, aging has become a heavy health care burden worldwide. Age-related decline in mitochondrial function and oxidative stress is strongly associated with neurodegeneration. The previous study demonstrated that Bushen-Yizhi formula (BSYZ), a traditional Chinese medicine formula, is effective in reducing neurodegeneration. METHODS: This study is the first to investigate the effect of BSYZ on D-gal-induced learning memory in rats. Secondly, the potential metabolic mechanism of BSYZ was explored by 1H-NMR metabolomics analysis. Then based on the comparison of differential metabolites implied that BSYZ ameliorated mitochondrial dysfunction through choline metabolic pathway in D-gal-treated rats. Finally, pharmacological validation was conducted to explore the effects of BSYZ on D-gal-induced oxidative stress, neuroinflammation, and neuronal apoptosis. RESULTS: Our data showed that BSYZ increased aspartate and betaine levels, while decreasing choline levels. Furthermore, BSYZ also increased the proteins level of CHDH and BHMT to regulate choline metabolic pathway. Meanwhile, BSYZ alleviated mitochondrial damage and oxidative stress, including enhanced ATP production and the ratio of NAD+/NADH, reduced the level of MDA, enhanced GSH and SOD activity, upregulated the expressions of p-AMPK, SIRT1 proteins. In addition, BSYZ downregulated the levels of inflammatory cytokines, such as TNF-α, IL-1ß and IL-6, as well as suppressed Bcl-2 proteins family dependent apoptosis. CONCLUSION: BSYZ treatment effectively rescues neurobehavioral impairment by improving mitochondrial dysfunction, oxidative stress, neuroinflammation and neuroapoptosis via AMPK/SIRT1 pathway in D-gal-induced aging.
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Osthole, a natural coumarin found in various medicinal plants, has been previously reported to have neuroprotective effects. However, the specific mechanism by which Osthole alleviates dysmnesia associated with Alzheimer's disease (AD) remains unclear. This study aimed to investigate the neuroprotective properties of Osthole against cognitive impairment in rats induced by D-galactose and elucidate its pharmacological mechanism. The rat model was established by subcutaneously injecting D-galactose at a dose of 150 mg/kg/day for 56 days. The effect of Osthole on cognitive impairment was evaluated by behavior and biochemical analysis. Subsequently, a combination of in silico prediction and experimental validation was performed to verify the network-based predictions, using western blot, Nissl staining, and immunofluorescence. The results demonstrate that Osthole could improve memory dysfunction induced by D-galactose in Sprague Dawley male rats. A network proximity-based approach and integrated pathways analysis highlight two key AD-related pathological processes that may be regulated by Osthole, including neuronal apoptosis, i.e., neuroinflammation. Among them, the pro-apoptotic markers (Bax), anti-apoptotic protein (Bcl-2), the microgliosis (Iba-1), Astro-cytosis (GFAP), and inflammatory cytokines (TNF-R1) were evaluated in both hippocampus and cortex. The results indicated that Osthole significantly ameliorated neuronal apoptosis and neuroinflammation in D-galactose-induced cognitive impairment rats. In conclusion, this study sheds light on the pharmacological mechanism of Osthole in mitigating D-galactose-induced memory impairment and identifies Osthole as a potential drug candidate for AD treatment, targeting multiple signaling pathways through network proximity and integrated pathways analysis.
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Doença de Alzheimer , Disfunção Cognitiva , Ratos , Animais , Galactose/efeitos adversos , Doenças Neuroinflamatórias , Ratos Sprague-Dawley , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Cumarínicos/farmacologia , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológicoRESUMO
An-Gong-Niu-Huang-Wan (AGNHW) is a well-known formula for treating cerebrovascular diseases, with roles including clearing away heat, detoxification, and wake-up consciousness. In recent years, AGNHW has been commonly used for the treatment of ischemic stroke, but the mechanism by which AGNHW relieves stroke has not been clearly elucidated. In the current study, we developed a multiple systems pharmacology-based framework to identify the potential antistroke ingredients in AGNHW and explore the underlying mechanisms of action (MOA) of AGNHW against stroke from a holistic perspective. Specifically, we performed a network-based method to identify the potential antistroke ingredients in AGNHW by integrating the drug-target network and stroke-associated genes. Furthermore, the oxygen-glucose deprivation/reoxygenation (OGD/R) model was used to validate the anti-inflammatory effects of the key ingredients by determining the levels of inflammatory cytokines, including interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α. The antiapoptotic effects of the key ingredients were also confirmed in vitro. Integrated pathway analysis of AGNHW revealed that it might regulate three biological signaling pathways, including IL-17, TNF, and PI3K-AKT, to play a protective role in stroke. Moreover, 30 key antistroke ingredients in AGNHW were identified via network-based in silico prediction and were confirmed to have known neuroprotective effects. After drug-like property evaluation and pharmacological validation in vitro, scutellarein (SCU) and caprylic acid (CA) were selected for further antistroke investigation. Finally, systems pharmacology-based analysis of CA and SCU indicated that they might exert antistroke effects via the apoptotic signaling pathway and inflammatory response, which was further validated in an in vitro stroke model. Overall, the current study proposes an integrative systems pharmacology approach to identify antistroke ingredients and demonstrate the underlying pharmacological MOA of AGNHW in stroke, which provides an alternative strategy to investigate novel traditional Chinese medicine formulas for complex diseases.
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Medicamentos de Ervas Chinesas , Fármacos Neuroprotetores , Acidente Vascular Cerebral , Biologia Computacional , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Interleucina-6 , Medicina Tradicional Chinesa/métodos , Fármacos Neuroprotetores/farmacologia , Fosfatidilinositol 3-Quinases , Acidente Vascular Cerebral/tratamento farmacológicoRESUMO
BACKGROUND: Medicarpin is a natural pterocarpan-type phytoalexin widely distributed in many traditional Chinese medicines, such as Astragali Radix. A previous study showed that Astragali Radix demonstrated promising protective effects in neurons. However, there is no reported study on the neuroprotective function and the underlying mechanism of Medicarpin. PURPOSE: This study aimed to demonstrate the neuroprotective effect of Medicarpin on Alzheimer's disease (AD) and explore the therapeutic mechanisms. METHOD: First, we carried out animal behavioral tests and biochemical analysis to assess the anti-AD potential of Medicarpin for ameliorating spatial learning and memory and modulating cholinergic metabolism in scopolamine-induced amnesic mice. Subsequently, network proximity prediction was used to measure the network distance between the Medicarpin target network and AD-related endophenotype module. We identified Medicarpin-regulated AD pathological processes and highlighted the key disease targets via network analysis. Finally, experimental approaches including Nissl staining and Western blotting were conducted to validate our network-based findings. RESULT: In this study, we first observed that Medicarpin can ameliorate cognitive and memory dysfunction and significantly modulate cholinergic metabolism in scopolamine-induced amnesic mice. We then proposed an endophenotype network-based framework to comprehensively explore the AD therapeutic mechanisms of Medicarpin by integrating 25 AD-related endophenotype modules, gold-standard AD seed genes, an experimentally validated drug-target network of Medicarpin, and a global human protein-protein interactome. In silico prediction revealed that the effect of Medicarpin is highly relevant to neuronal apoptosis and synaptic plasticity, which was validated by experimental assays. Network analysis and Western blotting further identified two key targets, GSK-3ß and MAPK14 (p38), in the AD-related protein regulatory network, which play key roles in the regulation of neuronal apoptosis and synaptic plasticity by Medicarpin. CONCLUSIONS: This study presented a powerful endophenotype network-based strategy to explore the mechanisms of action (MOAs) of new AD therapeutics, and first identified Medicarpin as a potential anti-AD candidate by targeting multiple pathways.
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Doença de Alzheimer , Fármacos Neuroprotetores/farmacologia , Pterocarpanos , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Animais , Glicogênio Sintase Quinase 3 beta , Camundongos , Proteína Quinase 14 Ativada por Mitógeno , Pterocarpanos/farmacologia , EscopolaminaRESUMO
BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in the elderly, characterized by a progressive and irreversible loss of memory and cognitive abilities. Currently, the prevention and treatment of AD still remains a huge challenge. As a traditional Chinese medicine (TCM) prescription, Danggui-Shaoyao-san decoction (DSS) has been demonstrated to be effective for alleviating AD symptoms in animal experiments and clinical applications. However, due to the complex components and biological actions, its underlying molecular mechanism and effective substances are not yet fully elucidated. METHODS: In this study, we firstly systematically reviewed and summarized the molecular effects of DSS against AD based on current literatures of in vivo studies. Furthermore, an integrated systems pharmacology framework was proposed to explore the novel anti-AD mechanisms of DSS and identify the main active components. We further developed a network-based predictive model for identifying the active anti-AD components of DSS by mapping the high-quality AD disease genes into the global drug-target network. RESULTS: We constructed a global drug-target network of DSS consisting 937 unique compounds and 490 targets by incorporating experimental and computationally predicted drug-target interactions (DTIs). Multi-level systems pharmacology analyses revealed that DSS may regulate multiple biological pathways related to AD pathogenesis, such as the oxidative stress and inflammatory reaction processes. We further conducted a network-based statistical model, drug-likeness analysis, human intestinal absorption (HIA) and blood-brain barrier (BBB) penetration prediction to uncover the key ani-AD ingredients in DSS. Finally, we highlighted 9 key ingredients and validated their synergistic role against AD through a subnetwork. CONCLUSION: Overall, this study proposed an integrative systems pharmacology approach to disclose the therapeutic mechanisms of DSS against AD, which also provides novel in silico paradigm for investigating the effective substances of complex TCM prescription.
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Doença de Alzheimer/tratamento farmacológico , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Modelos Moleculares , Mapas de Interação de Proteínas , Animais , Estrutura MolecularRESUMO
Alzheimer's disease (AD) is a complex neurodegenerative disease characterized by cognitive dysfunction. Kai-Xin-San (KXS) is a traditional Chinese medicine (TCM) formula that has been used to treat AD patients for over a thousand years in China. However, the therapeutic mechanisms of KXS for treating AD have not been fully explored. Herein, we used a comprehensive network pharmacology approach to investigate the mechanism of action of KXS in the treatment of AD. This approach consists of construction of multiple networks and Gene Ontology enrichment and pathway analyses. Furthermore, animal experiments were performed to validate the predicted molecular mechanisms obtained from the systems pharmacology-based analysis. As a result, 50 chemicals in KXS and 39 AD-associated proteins were identified as major active compounds and targets, respectively. The therapeutic mechanisms of KXS in treating AD were primarily related to the regulation of four pathology modules, including amyloid beta metabolism, tau protein hyperphosphorylation process, cholinergic dysfunction, and inflammation. In scopolamine-induced cognitive dysfunction mice, we validated the anti-inflammatory effects of KXS on AD by determining the levels of inflammation cytokines including interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α. We also found cholinergic system dysfunction amelioration of KXS is correlated with upregulation of the cholinergic receptor CHRNB2. In conclusion, our work proposes a comprehensive systems pharmacology approach to explore the underlying therapeutic mechanism of KXS for the treatment of AD.
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Recent work has highlighted the potential of puerarin (PU) as a valuable compound to treat Parkinson's disease (PD), but its undesirable water solubility and bioavailability have constrained its utility. In this study, we sought to develop nanoparticles (NPs) that could be used to encapsulate PU, thereby extending its in vivo half-life and improving its bioavailability and accumulation in the brain to treat the symptoms of PD. We prepared spherical NPs (88.36 ± 1.67 nm) from six-armed star-shaped poly(lactide-co-glycolide) (6-s-PLGA) NPs that were used to encapsulate PU (PU-NPs) with 89.52 ± 1.74% encapsulation efficiency, 42.97 ± 1.58% drug loading, and a 48 h sustained drug release. NP formation and drug loading were largely mediated by hydrophobic interactions, while changes in the external environment led these NPs to become increasingly hydrophilic, thereby leading to drug release. Relative to PU alone, PU-NPs exhibited significantly improved cellular internalization, permeation, and neuroprotective effects. Upon the basis of Förster resonance energy transfer (FRET) of NPs-administered zebrafish, we were able to determine that these NPs were rapidly absorbed into circulation whereupon they were able to access the brain. We further conducted oral PU-NPs administration to rats, revealing significant improvements in PU accumulation within the plasma and brain relative to rats administered free PU. In MPTP-mediated neurotoxicity in mice, we found that PU-NPs treatment improved disease-associated behavioral deficits and depletion of dopamine and its metabolites. These findings indicated that PU-NPs represent a potentially viable approach to enhancing PU oral absorption, thus improving its delivery to the brain wherein it can aid in the treatment of PD.
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Encéfalo/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Medicamentos de Ervas Chinesas/administração & dosagem , Isoflavonas/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Administração Oral , Animais , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/instrumentação , Avaliação Pré-Clínica de Medicamentos , Liberação Controlada de Fármacos , Medicamentos de Ervas Chinesas/efeitos adversos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacocinética , Feminino , Humanos , Isoflavonas/efeitos adversos , Isoflavonas/química , Isoflavonas/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Ratos , Ratos Sprague-Dawley , Peixe-ZebraRESUMO
Kai Xin San (KXS, containing ginseng, hoelen, polygala, and acorus), a traditional Chinese herbal compound, has been found to regulate cognitive dysfunction; however, its mechanism of action is still unclear. In this study, 72 specific-pathogen-free male Kunming mice aged 8 weeks were randomly divided into a vehicle control group, scopolamine group, low-dose KXS group, moderate-dose KXS group, high-dose KXS group, and positive control group. Except for the vehicle control group and scopolamine groups (which received physiological saline), the doses of KXS (0.7, 1.4 and 2.8 g/kg per day) and donepezil (3 mg/kg per day) were gastrointestinally administered once daily for 2 weeks. On day 8 after intragastric treatment, the behavioral tests were carried out. Scopolamine group and intervention groups received scopolamine 3 mg/kg per day through intraperitoneal injection. The effects of KXS on spatial learning and memory, pathological changes of brain tissue, expression of apoptosis factors, oxidative stress injury factors, synapse-associated protein, and cholinergic neurotransmitter were measured. The results confirmed the following. (1) KXS shortened the escape latency and increased residence time in the target quadrant and the number of platform crossings in the Morris water maze. (2) KXS increased the percentage of alternations between the labyrinth arms in the mice of KXS groups in the Y-maze. (3) Nissl and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining revealed that KXS promoted the production of Nissl bodies and inhibited the formation of apoptotic bodies. (4) Western blot assay showed that KXS up-regulated the expression of anti-apoptotic protein Bcl-2 and inhibited the expression of pro-apoptotic protein Bax. KXS up-regulated the expression of postsynaptic density 95, synaptophysin, and brain-derived neurotrophic factor in the cerebral cortex and hippocampus. (5) KXS increased the level and activity of choline acetyltransferase, acetylcholine, superoxide dismutase, and glutathione peroxidase, and reduced the level and activity of acetyl cholinesterase, reactive oxygen species, and malondialdehyde through acting on the cholinergic system and reducing oxidative stress damage. These results indicate that KXS plays a neuroprotective role and improves cognitive function through reducing apoptosis and oxidative stress, and regulating synapse-associated protein and cholinergic neurotransmitters.
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Liver injury remains a significant global health problem and has a variety of causes, including oxidative stress (OS), inflammation, and apoptosis of liver cells. There is currently no curative therapy for this disorder. Sanwei Ganjiang Prescription (SWGJP), derived from traditional Chinese medicine (TCM), has shown its effectiveness in long-term liver damage therapy, although the underlying molecular mechanisms are still not fully understood. To explore the underlining mechanisms of action for SWGJP in liver injury from a holistic view, in the present study, a systems pharmacology approach was developed, which involved drug target identification and multilevel data integration analysis. Using a comprehensive systems approach, we identified 43 candidate compounds in SWGJP and 408 corresponding potential targets. We further deciphered the mechanisms of SWGJP in treating liver injury, including compound-target network analysis, target-function network analysis, and integrated pathways analysis. We deduced that SWGJP may protect hepatocytes through several functional modules involved in liver injury integrated-pathway, such as Nrf2-dependent anti-oxidative stress module. Notably, systems pharmacology provides an alternative way to investigate the complex action mode of TCM.
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Medicamentos de Ervas Chinesas/química , Hepatopatias/tratamento farmacológico , Fígado/efeitos dos fármacos , Medicamentos de Ervas Chinesas/administração & dosagem , Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Fígado/lesões , Fígado/metabolismo , Hepatopatias/genética , Hepatopatias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , FarmacologiaRESUMO
Parkinson's disease (PD), the second most common neurodegenerative disease, is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. Although the molecular mechanisms underlying dopaminergic neuronal degeneration in PD remain unclear, neuroinflammation is considered as the vital mediator in the pathogenesis and progression of PD. Bushen-Yizhi Formula (BSYZ), a traditional Chinese medicine, has been demonstrated to exert antineuroinflammation in our previous studies. However, it remains unclear whether BSYZ is effective for PD. Here, we sought to assess the neuroprotective effects and explore the underlying mechanisms of BSYZ in a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine- (MPTP-) induced mouse model of PD. Our results indicate that BSYZ significantly alleviates the motor impairments and dopaminergic neuron degeneration of MPTP-treated mice. Furthermore, BSYZ remarkably attenuates microglia activation, inhibits NLPR3 activation, and decreases the levels of inflammatory cytokines in MPTP-induced mouse brain. Also, BSYZ inhibits NLRP3 activation and interleukin-1ß production of the 1-methyl-4-phenyl-pyridinium (MPP+) stimulated BV-2 microglia cells. Taken together, our results indicate that BSYZ alleviates MPTP-induced neuroinflammation probably via inhibiting NLRP3 inflammasome activation in microglia. Collectively, BSYZ may be a potential therapeutic agent for PD and the related neurodegeneration diseases.
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The present study aimed to investigate the possible effects and underlying molecular mechanism of BushenYizhi formula (BSYZ), a traditional Chinese medicine, on agerelated degeneration of brain physiology in senescenceaccelerated mouse prone 8 (SAMP8) mice. SAMP8 mice (age, 6 months) were administered BSYZ (1.46, 2.92 and 5.84 g/kg/day) for 30 days. Morris water maze and stepdown tests demonstrated that BSYZ significantly improved memory impairments in SAMP8 mice. In addition, BSYZ significantly enhanced the expression levels of peroxisome proliferatoractivated receptorγ and Bcell lymphoma extralarge, and downregulated the expression levels of inflammatory mediators, glial fibrillary acidic protein, cyclooxygenase2, nuclear factorκB and interleukin1ß in the brain compared with untreated SAMP8 mice. Furthermore, BSYZ reversed disordered superoxide dismutase activity, malondialdehyde content and glutathione peroxidase activity, and ameliorated apoptosis and histological alterations. The present study indicated that BSYZ may attenuate cognitive impairment in SAMP8 mice, and modulate inflammation, oxidative stress and neuronal apoptosis. These results suggested that BSYZ may have the potential to be further developed into a therapeutic agent for protection against agerelated neurodegenerative diseases.
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Senilidade Prematura/complicações , Senilidade Prematura/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Inflamação/tratamento farmacológico , Memória/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Química Encefálica/efeitos dos fármacos , Ciclo-Oxigenase 2/análise , Proteína Glial Fibrilar Ácida/análise , Inflamação/etiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , PPAR gama/análiseRESUMO
Bushen-Yizhi prescription (BSYZ) has been an effective traditional Chinese medicine (TCM) prescription in treating Alzheimer's disease (AD) for hundreds of years. However, the underlying mechanisms have not been fully elucidated yet. In this work, a systems pharmacology approach was developed to reveal the underlying molecular mechanisms of BSYZ in treating AD. First, we obtained 329 candidate compounds of BSYZ by in silico ADME/T filter analysis and 138 AD-related targets were predicted by our in-house WEGA algorithm via mapping predicted targets into AD-related proteins. In addition, we elucidated the mechanisms of BSYZ action on AD through multiple network analysis, including compound-target network analysis and target-function network analysis. Furthermore, several modules regulated by BSYZ were incorporated into AD-related pathways to uncover the therapeutic mechanisms of this prescription in AD treatment. Finally, further verification experiments also demonstrated the therapeutic effects of BSYZ on cognitive dysfunction in APP/PS1 mice, which was possibly via regulating amyloid-ß metabolism and suppressing neuronal apoptosis. In conclusion, we provide an integrative systems pharmacology approach to illustrate the underlying therapeutic mechanisms of BSYZ formula action on AD.
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Doença de Alzheimer/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Alpinia , Doença de Alzheimer/metabolismo , Animais , Encéfalo/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Simulação por Computador , Modelos Animais de Doenças , Masculino , Medicina Tradicional Chinesa/métodos , Camundongos , Extratos VegetaisRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD), as the most common type of dementia, has brought a heavy economic burden to healthcare system around the world. However, currently there is still lack of effective treatment for AD patients. Herbal medicines, featured as multiple herbs, ingredients and targets, have accumulated a great deal of valuable experience in treating AD although the exact molecular mechanisms are still unclear. MATERIALS AND METHODS: In this investigation, we proposed a network pharmacology-based method, which combined large-scale text-mining, drug-likeness filtering, target prediction and network analysis to decipher the mechanisms of action for the most widely studied medicinal herbs in AD treatment. RESULTS: The text mining of PubMed resulted in 10 herbs exhibiting significant correlations with AD. Subsequently, after drug-likeness filtering, 1016 compounds were remaining for 10 herbs, followed by structure clustering to sum up chemical scaffolds of herb ingredients. Based on target prediction results performed by our in-house protocol named AlzhCPI, compound-target (C-T) and target-pathway (T-P) networks were constructed to decipher the mechanism of action for anti-AD herbs. CONCLUSIONS: Overall, this approach provided a novel strategy to explore the mechanisms of herbal medicine from a holistic perspective.
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Doença de Alzheimer/tratamento farmacológico , Fitoterapia , Preparações de Plantas/farmacologia , Doença de Alzheimer/metabolismo , Animais , Humanos , Preparações de Plantas/uso terapêutico , Plantas MedicinaisRESUMO
Epigenetic changes are involved in learning and memory, and histone deacetylase (HDAC) inhibitors are considered potential therapeutic agents for Alzheimer's disease (AD). We previously reported that (-)-epigallocatechin-3-gallate (EGCG) acts as an HDAC inhibitor. Here, we demonstrate that EGCG reduced ß-amyloid (Aß) accumulation in vitro and rescued cognitive deterioration in senescence-accelerated mice P8 (SAMP8) via intragastric administration of low- and high-dose EGCG (5 and 15 mg/kg, respectively) for 60 days. The AD brain has decreased levels of the rate-limiting degradation enzyme of Aß, neprilysin (NEP). We found an association between EGCG-induced reduction in Aß accumulation and elevated NEP expression. Further, NEP silencing prevented the EGCG-induced Aß downregulation. Our findings suggest that EGCG might be effective for treating AD.
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Doença de Alzheimer/tratamento farmacológico , Catequina/análogos & derivados , Transtornos Cognitivos/tratamento farmacológico , Neprilisina/metabolismo , Regulação para Cima/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Animais , Células CHO , Catequina/química , Catequina/farmacologia , Proliferação de Células , Células Cultivadas , Transtornos Cognitivos/metabolismo , Cricetulus , Modelos Animais de Doenças , Camundongos , EstereoisomerismoRESUMO
BushenYizhi formula (BSYZ), a traditional Chinese medicine formula consisting of six herbs has been reported to possess a neuroprotective effect. The present study aimed to investigate the effects of BSYZ on learning and memory abilities, as well as oxidative stress and neuronal apoptosis in the hippocampus of scopolamine (SCOP)induced senescence in mice, in order to reveal whether BSYZ is a potential therapeutic agent for Alzheimer's disease (AD). A highperformance liquid chromatography (HPLC) fingerprint was applied to provide a chemical profile of BSYZ. Extracts of BSYZ were orally administered to mice with SCOPinduced memory impairment for two weeks. The learning and memory abilities were determined by the Morris water maze test. The oxidant stressrelated indices, such as activity of superoxide dismutase (SOD) and levels of glutathione (GSH) and malondialdehyde (MDA) were examined in hippocampus of SCOPtreated mice. The cell death ratio was assessed by TUNEL staining, while apoptoticrelated proteins including Bcl2 and Bax were determined by immuno-fluorescent staining and western blot analysis. Caspase3 was determined by western blot analysis. Consequently, a chromatographic condition, which was conducted at 35ËC with a flow rate of 0.8 ml/min on the Gemini C18 column with mobile phase of acetonitrile and waterphosphoric acid (100:0.1, v/v), was established to yield common fingerprint chromatography under 203 nm with a similarity index of 0.986 within 10 batches of BSYZ samples. BSYZ at a dose of 2.92 g/kg significantly improved the cognitive ability, restored the abnormal activity of SOD and increased the levels of MDA and GSH induced by SCOP. Moreover, the neural apoptosis in the hippocampus of SCOPtreated mice was reversed by BSYZ by regulating the expression of Bcl2, Bax and caspase3. The results demonstrated that BSYZ had neuroprotective effects in SCOPinduced senescence in mice by ameliorating oxidative stress and neuronal apoptosis in the brain, supporting its potential in AD treatment.
Assuntos
Transtornos Cognitivos/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Envelhecimento/efeitos dos fármacos , Envelhecimento/patologia , Animais , Apoptose/efeitos dos fármacos , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/patologia , Humanos , Camundongos , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Escopolamina/toxicidadeRESUMO
Alzheimer's disease (AD) is a neurodegenerative disease that is characterized by the accumulation of senile plaque and neurofibrilary tangle formation in the brain, including the cerebral cortex and hippocampus. Nowadays, the first-line treatment for AD is the application of acetylcholinesterase inhibitors. However, acetylcholinesterase inhibitors are basically anti-symptomatic for a limited aspect of AD pathology and are associated with serious side-effects. With the advantage of multiple targets, pathways and systems, Chinese herbal compounds hold promising potential for the development of drugs for the treatment of AD. Over the past few years, with the development of Chinese herbal compounds and in vitro pharmacological studies, cell-based disease models are one of the main methods used to screen Chinese herbal compounds for potential efficacy. Testing the efficacy of possible anti-Alzheimer's disease drugs and the development of new drugs are hindered by the lack of objective high-throughput screening methods. Currently, the assessment of the effects of drugs is usually made by MTT assays, involving laborious, subjective, low-throughput methods. Herein, we suggest a novel application for a real-time cell monitoring device (xCELLigence) that can simply and objectively assess the effective composition of Chinese herbal compounds by assessing amyloid-ß peptide Aß1-42-induced apoptosis in PC12 cells. We detected the proliferation and motility of the cells using a fully automated high-throughput and real-time system. We quantitatively assessed cell motility and determined the real-time IC50 values of various anti-AD drugs that intervene in several developmental stages of Aß1-42-induced apoptosis in PC12 cells, Then, we identified the optimal time phase by curative efficacy. Our data indicate that this technique may aid in the discovery and development of novel anti-Alzheimer's disease drugs. It is possible to utilize a similar technique to measure changes in electrical impedance as cells attach and spread in a culture dish covered with a gold microelectrode array that covers approximately 80% of the area on the bottom of a well. As cells attach and spread on the electrode surface, it leads to an increase in electrical impedance of 9-12. The impedance is displayed as a dimensionless para-meter termed the cell index, which is directly proportional to the total area of tissue culture well that is covered by the cells. Hence, the cell index can be used to monitor cell adhesion, spreading, morphological variation and cell density.