RESUMO
2,4-dichlorophenol (2,4-DCP), 2,5-DCP, 2,4,5-trichlorophenol (2,4,5-TCP), 2,4,6-TCP, and ortho-phenylphenol (OPP) are widely present in the environment. However, their associations with risk and prognosis of diabetes and prediabetes remains unclear. We investigated the associations of these five phenols with the risk of diabetes and prediabetes, and with all-cause and cardiovascular disease (CVD) mortality, in adults with diabetes or prediabetes (n=6419). Information on diabetes and prediabetes indicators, and mortality data was collected from the National Health and Nutrition Examination Survey. Logistic and Cox regression models were used to explore the associations of the five phenols with risk and prognosis of diabetes and prediabetes. Participants in the highest urinary 2,4-DCP and 2,5-DCP tertiles had higher odds of diabetes [adjusted odds ratio (aOR), 1.34, 95â¯% confidence interval (CI): 1.10, 1.62; aOR, 1.29, 95â¯% CI: 1.07, 1.56, respectively] than those in the lowest tertiles. Participants with urinary OPP concentrations above the limit of detection (LOD), but below median had an aOR of 1.25 (95â¯% CI: 1.08, 1.46) for prediabetes compared to those with concentrations below the LOD. In adults with diabetes, the highest 2,4-DCP and 2,5-DCP tertiles were associated with all-cause mortality [adjusted hazard ratio (aHR), 1.49; 95â¯% CI: 1.08, 2.06; aHR, 1.49; 95â¯% CI: 1.08, 2.05, respectively] and CVD mortality (aHR, 2.58; 95 % CI: 1.33, 4.97; aHR, 1.96; 95â¯% CI: 1.06, 3.60, respectively) compared with the lowest tertiles. Compared with 2,4,5-TCP concentrations below the LOD, those above median were associated with all-cause mortality (aHR: 1.75; 95â¯% CI: 1.24, 2.48) and CVD mortality (aHR: 2.34; 95â¯% CI: 1.19, 4.63) in adults with prediabetes. Furthermore, the associations between these phenols and mortality were strengthened in some subgroups. Environmental exposure to 2,4-DCP, 2,5-DCP, 2,4,5-TCP, and OPP increases the risk or adverse prognosis of diabetes or prediabetes in adults in the US. Further studies are required to confirm these findings.
Assuntos
Clorofenóis , Diabetes Mellitus , Poluentes Ambientais , Estado Pré-Diabético , Humanos , Clorofenóis/urina , Masculino , Estado Pré-Diabético/urina , Estado Pré-Diabético/epidemiologia , Estado Pré-Diabético/induzido quimicamente , Feminino , Pessoa de Meia-Idade , Diabetes Mellitus/epidemiologia , Adulto , Poluentes Ambientais/urina , Fenóis/urina , Prognóstico , Inquéritos Nutricionais , Idoso , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/epidemiologia , Exposição Ambiental/estatística & dados numéricos , Exposição Ambiental/efeitos adversosRESUMO
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.
Assuntos
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
Inflammatory bowel disease (IBD) is a chronic idiopathic disorder causing inflammation in the gastro-intestinal tract, which is lack of effective drug targets and medications. To identify novel therapeutic agents against consistent targets, we exploited a systems pharmacology-driven framework that incorporates drug-target networks of natural product and IBD disease genes. Our in silico approach found that Ligustilide (LIG), one of the major active components of Angelica acutiloba and Cnidium Officinale, potently attenuated IBD. The following in vivo and in vitro results demonstrated that LIG prevented experimental mice colitis induced by dextran sulfate sodium (DSS) via suppressing inflammatory cell infiltration, the activity of MPO and iNOS, and the expression and production of IL-1ß, IL-6, and TNF-α. Subsequently, the network analysis helped to validate that LIG alleviated colitis by inhibiting NF-κB and MAPK/AP-1 pathway through activating PPARγ, which were further confirmed in RAW 264.7 cells and bone marrow-derived macrophages in vitro. In summary, this study reveals that LIG activated PPARγ to inhibit the activation of NF-κB and AP-1 signaling thus eventually alleviated DSS-induced colitis, which has promising activities and may serve as a candidate for the treatment of IBD.Graphical abstract This study suggested novel computational and experimental pharmacology approaches to identify potential IBD therapeutic agents by exploiting polypharmacology of natural products. We demonstrated that LIG could attenuate inflammation in IBD by inhibiting NF-κB and AP-1 pathways via PPARγ activation to reduce the expression of pro-inflammatory cytokines in macrophages. These findings offer comprehensive pre-clinical evidence that LIG may serve as a promising candidate for IBD therapy in the future. Graphical headlights: 1. Systems pharmacology uncovered Ligustilide attenuates experimental colitis in mice. 2. Network-based analysis predicted the mechanism of Ligustilide against IBD, which was validated by inhibiting PPARγ-mediated inflammation pathways. 3. Ligustilide activated PPARγ to inhibit NF-κB and AP-1 activation thus eventually alleviated DSS-induced colitis.4. Ligustilide has promising activities and may serve as a candidate for the treatment of IBD.
Assuntos
4-Butirolactona/análogos & derivados , Colite/induzido quimicamente , Colite/tratamento farmacológico , Inflamação/patologia , Farmacologia em Rede , PPAR gama/metabolismo , Transdução de Sinais , 4-Butirolactona/química , 4-Butirolactona/farmacologia , 4-Butirolactona/uso terapêutico , Animais , Produtos Biológicos/farmacologia , Colite/complicações , Colo/patologia , Citocinas/metabolismo , Sulfato de Dextrana , Feminino , Inflamação/complicações , Mediadores da Inflamação/metabolismo , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/patologia , Camundongos Endogâmicos C57BL , Modelos Biológicos , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição AP-1/metabolismoRESUMO
Puerarin (PU) has emerged as a promising herb-derived anti-Parkinsonism compound. However, the undesirable water solubility as well as the unwanted bioavailability of PU limit its application. Therefore, this study aimed to develop and characterize PU nanocrystals (PU-NCs) with enhanced oral bioavailability and improved brain accumulation for the treatment of Parkinson's disease (PD). The fabricated PU-NCs were approximately spherical, with a mean size of 83.05 ± 1.96 nm, a PDI of 0.047 ± 0.009, a drug loading of 72.7%, and a rapid dissolution rate in vitro. Molecular dynamics simulation of PU and Pluronic F68 demonstrated the interaction energy and binding energy of -88.1 kJ/mol and -40.201 ± 0.685 kJ/mol, respectively, indicating a spontaneous binding with van der Waals interactions. In addition, the cellular uptake and permeability of PU-NCs were significantly enhanced as compared to PU alone ( p < 0.01). Moreover, PU-NCs exerted a significant neuroprotective effect against the cellular damage induced by the 1-methyl-4-phenylpyridinium ion (MPP+). Besides, PU-NCs demonstrated no obvious toxic effects on zebrafish, as evidenced by the unaltered morphology, hatching, survival rate, body length, and heart rate. Fluorescence resonance energy transfer (FRET) imaging revealed that intact nanocrystals were found in the intestine and brain of adult zebrafish gavaged with DiO/DiI/PU-NCs. Increased values of Cmax and AUC0- t were observed in the plasma of rats following oral administration of PU-NCs compared to PU suspension. Likewise, brain accumulation of PU-NCs was higher than that of PU suspension. Furthermore, PU-NCs attenuated dopamine depletion, ameliorated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral deficits, and enhanced the levels of dopamine and its metabolites. Taken altogether, this study provides evidence that PU-NCs could be exploited as a potential oral delivery system to treat PD, by improving the poor bioavailability of PU and enhancing their delivery into the brain.
Assuntos
Antiparkinsonianos/administração & dosagem , Encéfalo/efeitos dos fármacos , Isoflavonas/administração & dosagem , Nanopartículas/química , Fármacos Neuroprotetores/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Vasodilatadores/administração & dosagem , Administração Oral , Animais , Antiparkinsonianos/farmacologia , Disponibilidade Biológica , Encéfalo/metabolismo , Dopaminérgicos/toxicidade , Portadores de Fármacos/química , Isoflavonas/farmacologia , Intoxicação por MPTP/complicações , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Ratos , Ratos Sprague-Dawley , Vasodilatadores/farmacologia , Peixe-ZebraRESUMO
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint swelling, joint tenderness and destruction of synovial joints, leading to severe disability. Anti-inflammatory drugs and disease-modifying anti-rheumatic drugs (DMARDs) may improve RA process. However, in most patients the treatment effect is still not satisfactory. Cyclin-dependent kinase 7 (CDK7) plays a well-established role in the regulation of the eukaryotic cell division cycle, and recent studies indicated that it exerted anti-inflammatory effect. In our previous research, we found that inhibition of CDK7 by highly selective inhibitor BS-181 significantly impeded the development of collagen-induced arthritis (CIA) mice. However, the underlying mechanism of CDK7 in RA remains to be explored. We elucidated the molecular mechanism of CDK7 inhibition in RA inflammation by administration of CDK7 highly selective inhibitor BS-181 and siRNA-CDK7. We found that both IL-1ß, IL-6, IL-8 and RANKL transcript levels and IL-1ß/IL-6 secretion were effectively suppressed by BS-181 treatment as well as CDK7 knockdown. Furthermore, CDK7 inhibition prevented NF-κB signalling pathway activation and restrained p65 nuclear translocation. Moreover, CDK7 selective inhibitor BS-181 also blocked phosphorylation of p65 in MH7A cells. These results strongly indicate that CDK7 inhibition by BS-181 and siRNA-CDK7 significantly suppresses rheumatoid arthritis inflammation, which may be via blockage of NF-κB signalling pathway and IL-1ß/IL-6 secretion.
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Artrite Reumatoide/patologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Inflamação/patologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , NF-kappa B/metabolismo , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Técnicas de Silenciamento de Genes , Humanos , Interleucina-1beta/genética , Interleucina-6/genética , Lipopolissacarídeos , Fosforilação/efeitos dos fármacos , Pirazóis/farmacologia , Pirimidinas/farmacologia , Ligante RANK/genética , Ligante RANK/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/metabolismo , Fator de Transcrição RelA/metabolismo , Quinase Ativadora de Quinase Dependente de CiclinaRESUMO
Elevated ß-amyloid (Aß) is a hallmark of Alzheimer's disease (AD). Recent evidence has suggested that the receptor of advanced glycation end products (RAGE) is a key target for Aß-induced perturbation in AD, and blockade of RAGE significantly alleviates synaptic injury. Our previous study has suggested that ß-asarone could reduce neuronal apoptosis and improve memory deficits in ß-amyloid precursor protein and presenilin-1 (APP/PS1) double transgenic AD-model mice. In the present study, we evaluated the effects of ß-asarone on amyloidosis in APP/PS1 mice. We found that the survival of neurons of APP/PS1 mice was improved by ß-asarone, meanwhile, ß-asarone decreased Aß deposition and down-regulated Aß1-42 levels in cortex and hippocampus of APP/PS1 mice brain. Interestingly, the level of RAGE was also significantly down-regulated by ß-asarone. Our findings suggest that ß-asarone might be effective for the treatment of AD, and the decreasing effects of ß-asarone on Aß might associate with its down-regulation of RAGE.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Amiloidose/tratamento farmacológico , Anisóis/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Derivados de Alilbenzenos , Doença de Alzheimer/complicações , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Amiloidose/complicações , Amiloidose/patologia , Animais , Anisóis/administração & dosagem , Anisóis/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Córtex Cerebral/patologia , Modelos Animais de Doenças , Hipocampo/patologia , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Placa Amiloide/complicações , Placa Amiloide/tratamento farmacológico , Placa Amiloide/patologia , Presenilina-1/metabolismoRESUMO
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.
Assuntos
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
Pigment epithelium-derived factor (PEDF), a potent antiangiogenesis agent, has recently attracted attention for targeting tumor cells in several types of tumors. However, less is known about the apoptosis-inducing effect of PEDF on human lung cancer cells and the underlying molecular events. Here we report that PEDF has a growth-suppressive and proapoptotic effect on lung cancer xenografts. Accordingly, in vitro, PEDF apparently induced apoptosis in A549 and Calu-3 cells, predominantly via the Fas-L/Fas death signaling pathway. Interestingly, A549 and Calu-3 cells are insensitive to the Fas-L/Fas apoptosis pathway because of the low level of cell surface Fas. Our results revealed that, in addition to the enhancement of Fas-L expression, PEDF increased the sensitivity of A549 and Calu-3 cells to Fas-L-mediated apoptosis by triggering the translocation of Fas protein to the plasma membrane in a p53- and FAP-1-dependent manner. Similarly, the up-regulation of Fas-L by PEDF was also mediated by p53. Furthermore, peroxisome proliferator-activated receptor γ was determined to be the upstream regulator of p53. Together, these findings uncover a novel mechanism of tumor cell apoptosis induced by PEDF and provide a potential therapeutic strategy for tumors that are insensitive to Fas-L/Fas-dependent apoptosis because of a low level of cell surface Fas.
Assuntos
Antineoplásicos/farmacologia , Apoptose , Proteínas do Olho/farmacologia , Proteína Ligante Fas/genética , Fatores de Crescimento Neural/farmacologia , Serpinas/farmacologia , Proteína Supressora de Tumor p53/fisiologia , Receptor fas/metabolismo , Animais , Antineoplásicos/uso terapêutico , Caspase 8/metabolismo , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Proteínas do Olho/fisiologia , Proteínas do Olho/uso terapêutico , Proteína Ligante Fas/metabolismo , Humanos , Neoplasias Pulmonares , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica/prevenção & controle , Fatores de Crescimento Neural/fisiologia , Fatores de Crescimento Neural/uso terapêutico , PPAR gama/metabolismo , Transporte Proteico , Proteína Tirosina Fosfatase não Receptora Tipo 13/metabolismo , Serpinas/fisiologia , Serpinas/uso terapêutico , Regulação para Cima , Ensaios Antitumorais Modelo de XenoenxertoAssuntos
Apoptose/efeitos dos fármacos , Catequina/análogos & derivados , Proteína Semelhante a ELAV 1/metabolismo , Neoplasias/metabolismo , Proteína ADAM10/genética , Proteína ADAM10/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Apoptose/genética , Catequina/farmacologia , Proteína Semelhante a ELAV 1/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Neoplasias/genética , Neoplasias/patologia , Células PC12 , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Proteína X Associada a bcl-2/metabolismoRESUMO
Pigment epithelium-derived factor (PEDF) plays an important role in the tumor growth and metastasis inhibition. It has been reported that PEDF expression is significantly reduced in breast cancer, and associated with disease progression and poor patient outcome. However, the exact mechanism of PEDF on breast cancer metastasis including liver and lung metastasis remains unclear. The present study aims to reveal the impact of PEDF on breast cancer. The orthotopic tumor mice model inoculated by MDA-MB-231 cells stably expressing PEDF or control cells was used to assess liver and lung metastasis of breast cancer. In vitro, migration and invasion experiments were used to detect the metastatic abilities of MDA-MB-231 and SKBR3 breast cancer cells with or without overexpression of PEDF. The metastatic-related molecules including EMT makers, fibronectin, and p-AKT and p-ERK were detected by qRT-PCR, Western blot, and Fluorescent immunocytochemistry. PEDF significantly inhibited breast cancer growth and metastasis in vivo and in vitro. Mechanically, PEDF inhibited breast cancer cell migration and invasion by down-regulating fibronectin and subsequent MMP2/MMP9 reduction via p-ERK and p-AKT signaling pathways. However, PEDF had no effect on EMT conversion in the breast cancer cells which was usually involved in cancer metastasis. Furthermore, the study showed that laminin receptor mediated the down-regulation of fibronectin by PEDF. These results reported for the first time that PEDF inhibited breast cancer metastasis by down-regulating fibronectin via laminin receptor/AKT/ERK pathway. Our findings demonstrated PEDF as a dual effector in limiting breast cancer growth and metastasis and highlighted a new avenue to block breast cancer progression.
Assuntos
Neoplasias da Mama/patologia , Proteínas do Olho/metabolismo , Fibronectinas/biossíntese , Regulação Neoplásica da Expressão Gênica/fisiologia , Fatores de Crescimento Neural/metabolismo , Serpinas/metabolismo , Animais , Western Blotting , Movimento Celular , Regulação para Baixo , Feminino , Xenoenxertos , Humanos , Imuno-Histoquímica , Camundongos , Invasividade Neoplásica/patologia , Reação em Cadeia da Polimerase em Tempo Real , TransfecçãoRESUMO
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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Despite the massive investment in Alzheimer's disease (AD), there are still no disease-modifying treatments (DMTs) for AD. One major reason is attributed to the limitation of clinical "one-size-fits-all" approach, since the same AD treatment solely based on clinical diagnosis was unlikely to achieve good clinical efficacy. In recent years, computational approaches based on multiomics data have provided an unprecedented opportunity for drug discovery since they can substantially lower the costs and boost the efficiency. In this study, we intended to identify potential drug candidates for different pathological stages of AD by computationally repurposing Food and Drug Administration (FDA) approved drugs. First, we assembled gene expression data from three different AD pathological stages, which include mild cognitive impairment (MCI) and early and late stages of AD (EAD, LAD). We next quantified the network distances between drug target networks and AD modules by utilizing a network proximity approach, and identified 193 candidates that possessed significant associations with AD. After searching for previous literature evidence, 63 out of 193 (32.6%) predicted drugs were demonstrated to exert therapeutic effects on AD. We further explored the novel mechanism of action (MOA) for these drug candidates by determining the specific brain cells they might function on based on AD patient single cell transcriptomic data. Additionally, we selected several promising candidates that could cross the blood brain barrier together with confirmed neuroprotective effects, and subsequently determined the antioxidative activity of these compounds. Experimental results showed that azathioprine decreased the reactive oxygen species (ROS) and malondialdehyde (MDA) levels and improved the superoxide dismutase (SOD) activity in APP-SH-SY5Y cells. Finally, we deciphered the potential MOA of azathioprine against AD via network analysis and validated several apoptosis-related proteins (Caspase 3, Cleaved Caspase 3, Bax, Bcl2) through western blotting. In summary, this study presented an effective computational strategy utilizing omics data for AD drug repurposing, which provides a new perspective for drug discovery and development.
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[This corrects the article DOI: 10.3389/fphar.2020.00381.].
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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.
Assuntos
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
PURPOSE OF THE RESEARCH: To evaluate the association of the exposure of trichlorophenols (TCPs) on the morbidity and mortality of patients with Parkinson's disease (PD) and Alzheimer's disease (AD) using the data from the National Health and Nutrition Examination Survey (NHANES) 2003-2010. Multivariable logistic regression models and COX regression were used to evaluate the association between TCP exposure and the AD and PD risk. Least Absolute Shrinkage and Selection Operator (LASSO) methods were used to screen latent covariates. PRINCIPAL RESULTS: A total of 6333 participants over the age of 18 years were included in the analysis. After the adjustments for major confounders, participants with higher concentrations of urinary 2,4,6-TCP had higher risk of AD (odds ratios (ORs), 3.19; 95% CI: 1.07, 9.45) than the group below the limit of detection (LOD). Compared to group of below the LOD, higher urinary concentrations of 2,4,5-TCP was associated with higher risk of all-cause mortality in PD patients (log-rank P = 0.022) and all participants (log-rank P < 0.001) without adjustments for confounders. In addition, a higher risk of all-cause mortality in all participants with high urinary concentrations of 2,4,6-TCP (log-rank P = 0.001) was found without adjustments for confounders. With the adjustments for major confounders, participants with higher concentrations of urinary 2,4,5-TCP had a higher risk of death in patients with PD (hazard ratios (HRs), 53.19; 95% CI: 2.82, 1004.13) than in the group below the LOD. MAJOR CONCLUSIONS: Exposure to high concentration of 2,4,6-TCP may increase the risk of AD, and the level of 2,4,5-TCP may be associated with the risk of death in patients with PD. Our findings reveal the potential toxicity of TCPs, highlight the potential impact of TCPs on neurodegenerative diseases, and express concerns regarding the use of organochlorine pesticides.
Assuntos
Clorofenóis , Doenças Neurodegenerativas , Doença de Parkinson , Praguicidas , Adulto , Humanos , Pessoa de Meia-Idade , Clorofenóis/toxicidade , Estudos Transversais , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/epidemiologia , Inquéritos NutricionaisRESUMO
Alzheimer's disease (AD) is one of the most common progressive neurodegenerative diseases, accompanied by global alterations in metabolic profiles. In the past 10 years, over hundreds of metabolomics studies have been conducted to unravel metabolic changes in AD, which provides insight into the identification of potential biomarkers for diagnosis, treatment, and prognostic assessment. However, since different species may lead to systemic abnormalities in metabolomic profiles, it is urgently needed to perform a comparative metabolomics analysis between AD animal models and human patients. In this study, we integrated 78 metabolic profiles from public literatures, including 11 metabolomics studies in different AD mouse models and 67 metabolomics studies from AD patients. Metabolites and enrichment analysis were further conducted to reveal key metabolic pathways and metabolites in AD. We totally identified 14 key metabolites and 16 pathways that are both differentially significant in AD mouse models and patients. Moreover, we built a metabolite-target network to predict potential protein markers in AD. Finally, we validated HER2 and NDF2 as key protein markers in APP/PS1 mice. Overall, this study provides a comprehensive strategy for AD metabolomics research, contributing to understanding the pathological mechanism of AD.
RESUMO
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.
Assuntos
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
Alzheimer's disease (AD), the most common cause of dementia, is a complex and multifactorial disease involving genetic and environmental factors, with hypercholesterolemia considered as one of the risk factors. Numerous epidemiological studies have reported a positive association between AD and serum cholesterol levels, and experimental studies also provide evidence that elevated cholesterol levels accelerate AD pathology. However, the underlying mechanism of hypercholesterolemia accelerating AD pathogenesis is not clear. Here, we review the metabolism of cholesterol in the brain and focus on the role of oxysterols, aiming to reveal the link between hypercholesterolemia and AD. 27-hydroxycholesterol (27-OHC) is the major peripheral oxysterol that flows into the brain, and it affects ß-amyloid (Aß) production and elimination as well as influencing other pathogenic mechanisms of AD. Although the potential link between hypercholesterolemia and AD is well established, cholesterol-lowering drugs show mixed results in improving cognitive function. Nevertheless, drugs that target cholesterol exocytosis and conversion show benefits in improving AD pathology. Herbs and natural compounds with cholesterol-lowering properties also have a potential role in ameliorating cognition. Collectively, hypercholesterolemia is a causative risk factor for AD, and 27-OHC is likely a potential mechanism for hypercholesterolemia to promote AD pathology. Drugs that regulate cholesterol metabolism are probably beneficial for AD, but more research is needed to unravel the mechanisms involved in 27-OHC, which may lead to new therapeutic strategies for AD.