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Alzheimer's disease (AD) is a major cause of progressive dementia characterized by memory loss and progressive neurocognitive dysfunction. However, the molecular mechanisms are not fully understood. To elucidate the molecular mechanism contributing to AD, an integrated analytical workflow was deployed to identify pivotal regulatory target within the RNA-sequencing (RNA-seq) data of the temporal cortex from AD patients. Soluble transforming growth factor beta receptor 3 (sTGFBR3) was identified as a critical target in AD, which was abnormally elevated in AD patients and AD mouse models. We then demonstrated that sTGFBR3 deficiency restored spatial learning and memory deficits in amyloid precursor protein (APP)/PS1 and streptozotocin (STZ)-induced neuronal impairment mice after its expression was disrupted by a lentiviral (LV) vector expressing shRNA. Mechanistically, sTGFBR3 deficiency augments TGF-ß signaling and suppressing the NF-κB pathway, thereby reduced the number of disease-associated microglia (DAMs), inhibited proinflammatory activity and increased the phagocytic activity of DAMs. Moreover, sTGFBR3 deficiency significantly mitigated acute neuroinflammation provoked by lipopolysaccharide (LPS) and alleviated neuronal dysfunction induced by STZ. Collectively, these results position sTGFBR3 as a promising candidate for therapeutic intervention in AD.
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ZLDI-8 is an A disintegrin and metalloproteinase domain 17 (ADAM17) inhibitor that suppresses the shedding of Notch1 to the Notch1 intracellular domain (NICD). In previous studies, we found that ZLDI-8 was able to sensitize HCC to sorafenib, but the mechanism of action remains unclear. The sensitizing effects of ZLDI-8 were tested both in vitro and in vivo. EMT-related factors, sorafenib sensitivity-related proteins and ECM-related gene expression were assessed using immunohistochemistry, RTPCR and Western blotting. Knockdown assays were conducted to determine the relationship between the Notch and Integrin pathways. CoIP assays, nuclear and cytoplasmic fractionation and immunofluorescence colocalization were applied to explore the interaction between the Notch and Integrin pathways. Appropriate statistical analysis methods were used to assess the significance of the experimental results and to ensure the scientific validity and reliability of the experimental design. We found that ECM- and EMT-related proteins were downregulated after ZLDI-8 treatment (P<0.05). ZLDI-8 significantly downregulated Integrinß1 and Integrinß3 in HCC in vitro and in vivo (P<0.05), possibly through Foxc2-dependent regulation. Mechanistically, interfering with the expression of both Integrin-linked kinase (ILK) and the NICD may downregulate the expression of proteins targeted by sorafenib, thereby sensitizing cells to sorafenib. The retroregulation of Integrinß by ILK may occur through the interaction between the NICD and ILK and may be the result of the translocation of the complexus. Our study indicates that blocking the Notch pathway may affect Integrinß through crosstalk between the Notch1 and Integrinß/ILK signaling pathways, thus providing a potential therapeutic strategy for HCC.
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Proteína ADAM17 , Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Receptor Notch1 , Sorafenibe , Sorafenibe/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Humanos , Animais , Receptor Notch1/metabolismo , Receptor Notch1/genética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proteína ADAM17/metabolismo , Proteína ADAM17/antagonistas & inibidores , Camundongos Nus , Masculino , Cadeias beta de Integrinas/metabolismo , Cadeias beta de Integrinas/genética , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , CamundongosRESUMO
BACKGROUND: The incidence rate of malignant tumors after solid organ transplantation is higher than the normal population. The aim of our study is to identify the risk of renal cell carcinoma (RCC) after liver, kidney, heart and lung transplantation, respectively, and suggest that transplant patients can be screened early for tumors to avoid risk. METHODS: PubMed, Embase and the Cochrane Library from their inception until August 16,2023. Retrospective and cohort studies which focus on the statistical data of standardized incidence ratios (SIRs) of RCC after solid organ transplantation (SOT) more than one year have been included and extracted. The study was registered with PROSPERO, CRD4202022343633. RESULTS: Sixteen original studies have been included for meta-analysis. Liver transplantation could increase the risk of RCC (SIR = 0.73, 95%CI: 0.53 to 0.93) with no heterogeneity(P = 0.594, I2 = 0.0%). And kidney transplantation could increase the risk of RCC(8.54, 6.68 to 10.40; 0.000,90.0%). Besides, heart and lung transplantation also could increase the risk of RCC(SIR = 0.73, 95%CI: 0.53 to 0.93; SIR = 1.61, 95%CI:0.50 to 2.71). Moreover, significance could also be found in most subgroups, especially the European group and retrospective study group. What's more, after removing studies which have a greater impact on the overall outcome in RCC rate after kidney transplantation, heterogeneity did not solve and significant different was also observed in the European group (7.15, 5.49 to 8.81; 0.000, 78.6%). CONCLUSION: Liver, kidney, heart and lung transplantation patients have an increased risk of processing RCC compared to the general population and most subgroups, especially in geographic location of European subgroup, which suggested that patients should be screened frequently after transplantation.
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Carcinoma de Células Renais , Neoplasias Renais , Transplante de Rim , Humanos , Carcinoma de Células Renais/epidemiologia , Carcinoma de Células Renais/etiologia , Incidência , Estudos Retrospectivos , Transplante de Rim/efeitos adversos , Neoplasias Renais/epidemiologia , Neoplasias Renais/etiologiaRESUMO
Multitarget-directed ligands (MTDLs) have recently attracted significant interest due to their superior effectiveness in multifactorial Alzheimer's disease (AD). Combined inhibition of two important AD targets, glycogen synthase kinase-3ß (GSK-3ß) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), may be a breakthrough in the treatment of AD. Based on our previous work, we have designed and synthesized a series of novel harmine derivatives, investigated their inhibition of GSK-3ß and DYRK1A, and evaluated a variety of biological activities. The results of the experiments showed that most of these compounds exhibited good activity against GSK-3ß and DYRK1A in vitro. ZLQH-5 was selected as the best compound due to the most potent inhibitory effect against GSK-3ß and DYRK1A. Molecular docking studies demonstrated that ZLQH-5 could form stable interactions with the ATP binding pocket of GSK-3ß and DYRK1A. In addition, ZLQH-5 showed low cytotoxicity against SH-SY5Y and HL-7702, good blood-brain barrier permeability, and favorable pharmacokinetic properties. More importantly, ZLQH-5 also attenuated the tau hyperphosphorylation in the okadaic acid SH-SY5Y cell model. These results indicated that ZLQH-5 could be a promising dual-target drug candidate for the treatment of AD.
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Doença de Alzheimer , Neuroblastoma , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Glicogênio Sintase Quinase 3 beta , Harmina/farmacologia , Harmina/uso terapêutico , Proteínas tau/metabolismo , Proteínas tau/uso terapêutico , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , FosforilaçãoRESUMO
Purpose: To analyze whether adding PI3K/AKT/mTOR inhibitors to fulvestrant could restore endocrine therapy sensitivity for the treatment of postmenopausal patients with HR+, HER2- breast cancer. Methods: This meta-analysis was performed using RevMan 5.4 analysis software. Results: Nine studies that included a total of 3199 patients were analyzed. Compared with fulvestrant alone, the addition of PI3K/AKT/mTOR inhibitors significantly prolonged progression-free survival, overall survival and objective response rate of patients in both the total and PI3K-pathway-activated population. The number of grade 3-5 adverse events was also significantly higher. Conclusion: The addition of PI3K/AKT/mTOR to fulvestrant resulted in potential benefits; however, there may be a higher risk, which needs to be carefully managed.
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Neoplasias da Mama , Humanos , Feminino , Fulvestranto/uso terapêutico , Inibidores de MTOR , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Receptor ErbB-2 , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
We have previously shown that Liang-Yan-Yi-Zhen-San (LYYZS), an ancient Chinese herbal formula, can promote the browning of white adipose tissue. In this study, we sought to determine which active ingredients of LYYZS mediated its effects on the browning of white adipose tissue. Employing ultra-high performance liquid chromatography-Q-Exactive HF mass spectrometry, a total of 52 LYYZS ingredients were identified. On this basis, 1,560 ingredient-related targets of LYYZS were screened using the HERB databases. Meanwhile, RNA sequencing analysis of the inguinal white adipose tissue of mice produced a total of 3148 genes that were significantly differentially expressed following LYYZS treatment and differentially expressed genes regarded as browning-related targets. Through the network pharmacological analysis, a total of 136 intersection targets were obtained and an ingredient-target-pathway network was established. According to network pharmacology analysis, 10 ingredients containing trans-cinnamaldehyde, genistein, daidzein, calycosin, arginine, coumarin, oleic acid, isoleucine, palmitic acid and tyrosine were regarded as active ingredients of browning of white adipose tissue. Integrated evaluation using chemical analysis, transcriptomics and network pharmacology provides an efficient strategy for discovering the active ingredients involved in how LYYZS promotes the browning of white adipose tissue.
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Medicamentos de Ervas Chinesas , Farmacologia em Rede , Animais , Camundongos , Cromatografia Líquida de Alta Pressão , Transcriptoma , Tecido Adiposo Marrom , Cromatografia Gasosa-Espectrometria de Massas , Tecido Adiposo Branco , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/químicaRESUMO
Most land plants can establish symbiosis with arbuscular mycorrhizal (AM) fungi to increase fitness to environmental challenges. The development of AM symbiosis is controlled by intricate procedures involving all phytohormones. However, the mechanisms underlying the auxin-mediated regulation of AM symbiosis remains largely unknown. Here, we report that AM colonisation promotes auxin response and indole-3-acetic acid (IAA) accumulation, but downregulates IAA biosynthesis genes in tomato (Solanum lycopersicum). External IAA application modulates the AM symbiosis by promoting arbuscule formation at low concentrations but repressing it at high concentrations. An AM-induced GH3 gene, SlGH3.4, encoding a putative IAA-amido synthetase, negatively regulates mycorrhization via maintaining cellular auxin homoeostasis. Loss of SlGH3.4 function increased free IAA content and arbuscule incidence, while constitutively overexpressing SlGH3.4 in either tomato or rice resulted in decreased IAA content, total colonisation level and arbuscule abundance in mycorrhizal roots. Several auxin-inducible expansin genes involved in AM formation or resistance to pathogen infection were upregulated in slgh3.4 mycorrhizal roots but downregulated in the SlGH3.4-overexpressing plants. Taken together, our results highlight a positive correlation between the endogenous IAA content and mycorrhization level, particularly arbuscule incidence, and suggest that the SlGH3.4-mediated auxin homoeostasis and regulation of expansin genes is involved in finely tuning the AM development.
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Micorrizas , Solanum lycopersicum , Regulação da Expressão Gênica de Plantas , Ácidos Indolacéticos/farmacologia , Solanum lycopersicum/metabolismo , Micorrizas/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Raízes de Plantas/metabolismo , SimbioseRESUMO
Melatonin can improve mitochondrial dysfunction associated with the aging process by removing active oxygen, as well as inhibiting lipid peroxidation to maintain biofilm fluidity and resist free radical attack. However, there is poor understanding of the effect of melatonin on age-dependent mitochondrial function and lipid profile changes in brain. In this study, we investigated the energy metabolism of the whole body and brain of mice at 9 months, 13 months, and 25 months of continuous gastric administration of 3 mg/kg/d melatonin once per day morning for two months. In addition, we performed transcriptomic, proteomic and lipidomic analysis in the hippocampus of mice at different ages. Proteomics showed that melatonin regulated mitochondrial electron transport and leucine degradation in mouse hippocampus. Lipomics suggested that the long-chain unsaturated glycerol phospholipids in mouse hippocampus increased in an age-dependent manner, while ceramide and glycerol phospholipids decreased significantly in hippocampus of mouse chronically exposed to melatonin. The combined analysis of proteome and liposome demonstrated that Mpst, Ccsap, Hdhd5, Rpl5 and Flna were the key proteins of the network which involved in the regulation of numerous lipids. Furthermore, ultrastructure observation results illustrated that melatonin could improve the damaged mitochondrial and morphologies of 25-month-old mice hippocampus. In conclusion, we describe a mechanism that age-dependent up-regulation of long-chain unsaturated lipids is a driving risk factor for mitochondrial damage and this effect could be reversed by chronic supplement of low-dose melatonin.
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Melatonina , Animais , Glicerol/metabolismo , Glicerol/farmacologia , Hipocampo , Peroxidação de Lipídeos , Melatonina/metabolismo , Melatonina/farmacologia , Camundongos , Mitocôndrias/metabolismo , Fosfolipídeos , ProteômicaRESUMO
OBJECTIVE: At present, there is no definite suggestion about effective tumour biomarkers for the diagnostic accuracy and prognostic significance of hepatocellular carcinoma (HCC) and liver cirrhosis (LC). The aim of our research was to determine the value of the tumour biomarker osteopontin (OPN), which is encoded by the Spp1 gene, in the diagnosis, prognosis and development of HCC and LC through meta-analysis. METHODS: A systematic literature search was performed in the PubMed, Embase, Cochrane Library and China National Knowledge Infrastructure electronic databases up to March 2021. Studies evaluating the diagnostic and/or prognostic value of OPN in HCC and/or LC were included. RESULTS: From the systematic search, 35 studies including 9150 participants were eligible, 25 of which provided data on the diagnostic value of OPN overexpression, while 15 studies provided data on the prognostic value. OPN had high diagnostic accuracy in both HCC and LC patients compared with healthy controls, and the diagnostic efficiency was increased by the biomarker combination OPN + AFP. CONCLUSIONS: OPN may be adopted as a promising predictive tumour biomarker for the diagnosis and prognosis of HCC and LC and may be a potential therapeutic target.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Biomarcadores Tumorais , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Humanos , Cirrose Hepática/diagnóstico , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Osteopontina/genética , PrognósticoRESUMO
Epigenetics regulate the gene expression and chromatin organization associated with the development and occurrence of cancer. Histone deacetylase inhibitors (HDACis) have been proved to be an effective epigenetic targeting drug for cancer treatment. The structures of most HDACis were divided into four parts, including cap group, connection unit, linker region and zinc binding group. We designed a series of compounds containing the structure of phenoxyacetate for the linker region and cyclohexene for connection unit as a novel type of inhibitors. Representative compound YZ1 exhibited obvious antiproliferative activity against four different cell lines and potent enzymatic inhibitory activities to class I HDACs, which IC50 of HDAC1-3 were 1.6 nM, 1.9 nM and 3.8 nM respectively. In addition, YZ1 concentration-dependently inhibited cell proliferation, induced apoptosis and cycle arrest at G2/M phase in HCT116 cells. With biological activity assessment and docking studies, these results indicate YZ1 has the potential to be a lead compound for further optimization as HDAC inhibitors.
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Antineoplásicos , Inibidores de Histona Desacetilases , Aminas/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/química , Humanos , Simulação de Acoplamento Molecular , Relação Estrutura-AtividadeRESUMO
A series of novel ß-carboline 1,3,4-oxadiazole based hybrids were designed, synthesized, and tested for cytotoxicity and HDAC inhibition. Among the target compounds, compound ZDLT-1 displayed high inhibitory activity for class I HDACs 1, 2, and 3, and potent anti-proliferative activity against HCT116 cells with an IC50 value of 0.173 ± 0.018 µM, it also exhibited better inhibitory activity with an IC50 value of 6 nM for HDAC6 than SAHA (IC50 = 15 nM). Furthermore, the pharmacological experiment of Hoechst staining, colony formation, cell apoptosis assay, and wound healing scratch assay indicated that compound ZDLT-1 was a potent cytotoxic agent against HCT116 cells with cell apoptosis induction. Further, in silico prediction of physicochemical properties, drug-likeness, and ADME parameters suggested that compound ZDLT-1 is a promising anticancer agent. Taken together, the high potency cytotoxicity and class I HDACs inhibitory activity of compound ZDLT-1, which with the ß-carboline 1,3,4-oxadiazole based hybrids as potent anticancer agents could be nominated for further modification and optimization.
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Antineoplásicos , Inibidores de Histona Desacetilases , Antineoplásicos/química , Carbolinas/química , Carbolinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/química , Humanos , Estrutura Molecular , Oxidiazóis , Relação Estrutura-AtividadeRESUMO
Neutrophil extracellular traps (NETs) may be associated with the development of thrombosis. Experimental studies have confirmed the presence of NETs in thrombi specimens and potential role of NETs in the mechanisms of thrombosis. Clinical studies also have demonstrated significant changes in the levels of serum or plasma NETs biomarkers, such as citrullinated histones, myeloperoxidase, neutrophil elastase, nucleosomes, DNA, and their complexes in patients with thrombosis. This paper aims to comprehensively review the currently available evidence regarding the change in the levels of NETs biomarkers in patients with thrombosis, summarize the role of NETs and its biomarkers in the development and prognostic assessment of venous thromboembolism, coronary artery diseases, ischemic stroke, cancer-associated thromboembolism, and coronavirus disease 2019-associated thromboembolism, explore the potential therapeutic implications of NETs, and further discuss the shortcomings of existing NETs biomarkers in serum and plasma and their detection methods.
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Cyclin-dependent kinase 4 (CDK4), which is involved in dynamic regulation of cell cycle, has gained particularly attention for its role in controlling tumor growth.Increasing evidence showed that ß-carboline derivatives have the potential to inhibit CDK4. Herein, on the basis of previous work, we designed and synthesized a series of novel ß-carbolines and evaluated their antitumor activity.Among them, compounds ZDLD13 and ZDLD20, with the most potent anti-proliferative activity and CDK4 enzymatic inhibition activity, were selected for further pharmacological research in vitro and in vivo. The results in vitro showed that ZDLD13 and ZDLD20 exhibited potent anti-HCT116 activityincluding inhibition of colony formation, inhibition of invasion and migration, inducing of apoptosis, and arresting of G1 phase in cell cycle.In vivo,ZDLD13showed significant tumor growth inhibition in HCT116 tumor xenograft model without causing significant weight loss and toxicityconsistent with the acute toxicity test. In addition, silico study showed ZDLD13 and ZDLD20 not only have good biological actions, but also acceptable predicted ADME and physicochemical properties.Taken together, compoundsZDLD13and ZDLD20 could be selected for further modification and preclinical evaluation.
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Antineoplásicos , Neoplasias , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carbolinas/farmacologia , Carbolinas/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Quinase 4 Dependente de Ciclina , Humanos , Estrutura Molecular , Neoplasias/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
Alzheimer's disease (AD) is characterized by progressive cognitive impairment and mental behavior. The combination inhibition of two essential AD targets, acetylcholinesterase (AChE) and glycogen synthase kinase-3ß (GSK-3ß), might be a breakthrough in the discovery of therapeutic success. Herein, 17 ß-carboline-1,2,3-triazole hybrids were designed, synthesized, and evaluated for their AChE and GSK-3ß inhibitory potential. The results indicated that compound 21 has the most potent inhibition against eeAChE (IC50 = 0.20 ± 0.02 µM), hAChE (IC50 = 0.34 ± 0.01 µM) and GSK-3ß (IC50 = 1.14 ± 0.05 µM) among these compounds. In addition, it inhibited hAChE in a mixed type manner and could occupy the binding pocket forming diverse interactions with the target of AChE and GSK-3ß. Moreover, compound 21 showed low cytotoxicity against SH-SY5Y and HepG2 cell lines and good BBB permeability. Compound 21 also attenuated the tau hyperphosphorylation in the Tau (P301L) 293T cell model. The ADME projection exhibited that compound 21 has acceptable physicochemical characteristics. This study provides new leads for the assessment of AChE and GSK-3ß dual inhibition as a promising strategy for AD treatment.
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Doença de Alzheimer , Neuroblastoma , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Triazóis/farmacologia , Triazóis/uso terapêutico , Acetilcolinesterase/metabolismo , Carbolinas/farmacologia , Carbolinas/uso terapêutico , Proteínas tau/metabolismo , FosforilaçãoRESUMO
Uncontrolled cell proliferation is a hallmark of cancer. The major regulator of the cell cycle, cyclin dependent kinase 2 (CDK2), has become a mature target for cancer treatment. Herein, we describe our efforts toward the discovery of a series of benzofuro[3,2-b]quinoline alkaloid derivatives as CDK2 inhibitors through a scaffold hopping strategy. Compound ZLHQ-5f has topoisomerase I (Topo I) inhibitory activity due to the unique structure of benzofurano[3,2-b]quinoline. Resultantly, ZLHQ-5f exhibited promising anti-proliferative and CDK2 inhibitory activities. It also arrests the cell cycle in S-phase, triggers apoptosis in HCT116 cells, and has a good safety profile in vivo. There has yet to be a report on dual CDK2/Topo I inhibitor, thus this will be a novel attempt.
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Antineoplásicos , Quinolinas , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células , Quinase 2 Dependente de Ciclina , Células HCT116 , Humanos , Estrutura Molecular , Quinolinas/química , Quinolinas/farmacologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/farmacologiaRESUMO
Tacrine was the first approved drug by the FDA for the treatment of Alzheimer's disease (AD) but was withdrawn from the market due to its dose-dependent hepatotoxicity. Herein, we describe our efforts toward the discovery of a novel series of tacrine derivatives for cancer therapeutics. Intensive structural modifications of tacrine led to the identification of N-(4-{9-[(3S)-3-aminopyrrolidin-1-yl]-5,6,7,8-tetrahydroacridin-2-yl}pyridin-2-yl)cyclopropanecarboxamide hydrochloride ((S)-45, ZLWT-37) as a potent antiproliferative agent (GI50 = 0.029 µM for HCT116). In addition, ZLWT-37 exhibited lower inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) compared to tacrine. The in vitro studies demonstrated that ZLWT-37 could significantly induce apoptosis and arrest the cell cycle in the G2/M phase in HCT116 cells. The in vivo studies revealed that compound ZLWT-37 showed excellent antitumor efficacy in HCT116 xenograft tumor model and favorable pharmacokinetics profiles (F% = 28.70%) as well as low toxicity in the acute toxicity test with a median lethal dose (LD50) of 380.3 mg/kg. Encouragingly, ZLWT-37 had no obvious hepatotoxicity, nephrotoxicity, and hematologic toxicity. Kinase assay suggested that ZLWT-37 possessed potent cyclin-dependent kinase 9 (CDK9) inhibitory activity (IC50 = 0.002 µM) and good selectivity over CDK2 (IC50 = 0.054 µM). Collectively, these findings indicate that compound ZLWT-37 is a promising anti-cancer agent that deserves further preclinical evaluation.
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Doença de Alzheimer , Antineoplásicos , Doença Hepática Induzida por Substâncias e Drogas , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Butirilcolinesterase/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Inibidores da Colinesterase/química , Quinases Ciclina-Dependentes/metabolismo , Humanos , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Tacrina/químicaRESUMO
1,3,5-Tri-O-caffeoyl quinic acid is a caffeoylquinic acid derivative isolated from the roots of Arctium lappa L. Our previous studies have revealed that the ethyl acetate extract of the roots of A. lappa L. and the caffeoylquinic acids contained in it possess antioxidant properties, especially 1,3,5-tri-O-caffeoyl quinic acid. The present study aimed to investigate the protective effects of 1,3,5-tri-O-caffeoyl quinic acid against hydrogen peroxide-induced oxidative stress and explore the underlying mechanism. We found that 1,3,5-tri-O-caffeoyl quinic acid prevented the decline of cell viability and excessive release of lactate dehydrogenase induced by hydrogen peroxide. In addition, Hoechst 33â342 staining and Annexin V-PI double staining showed that 1,3,5-tri-O-caffeoyl quinic acid inhibited hydrogen peroxide-induced neuronal cell apoptosis. 1,3,5-Tri-O-caffeoyl quinic acid reduced the excessive production of intracellular reactive oxygen species, decreased the malondialdehyde content, and improved the activity of superoxide dismutase. Furthermore, 1,3,5-tri-O-caffeoyl quinic acid restored the loss of mitochondrial membrane potential in SH-SY5Y cells induced by hydrogen peroxide. 1,3,5-Tri-O-caffeoyl quinic acid downregulated the overexpression of proapoptotic proteins, including Bax, cytochrome c, cleaved caspase-9, and cleaved caspase-3 as well as promoted the expression of the antiapoptotic protein Bcl-2. Moreover, the phosphorylation of mitogen-activated protein kinases induced by hydrogen peroxide was inhibited by 1,3,5-tri-O-caffeoyl quinic acid. Pretreatment with 1,3,5-tri-O-caffeoyl quinic acid also promoted the activation of phosphorylated Akt. Taken together, these findings suggest that 1,3,5-tri-O-caffeoyl quinic acid exerts protective effects against hydrogen peroxide-induced neuronal apoptosis. In addition, inhibition of the mitogen-activated protein kinase signaling pathway and the activation of Akt are implicated in the antioxidant activity of 1,3,5-tri-O-caffeoyl quinic acid, giving new insight in searching for a compound with antioxidant activity for the treatment of oxidative stress-associated neurological diseases.
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Peróxido de Hidrogênio , Neuroblastoma , Humanos , Ácido Quínico/farmacologia , Caspase 3/metabolismo , Caspase 9/metabolismo , Caspase 9/farmacologia , Fosforilação , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Citocromos c/metabolismo , Citocromos c/farmacologia , Anexina A5/metabolismo , Anexina A5/farmacologia , Proteína X Associada a bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Apoptose , Transdução de Sinais , Malondialdeído/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Superóxido Dismutase/metabolismo , Lactato Desidrogenases/metabolismoRESUMO
Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease, characterized by irreversible cognitive impairment, memory loss, and behavioral disturbances, ultimately resulting in death. The critical roles of glycogen synthase kinase-3ß (GSK-3ß) in tau pathology have also received considerable attention. Based on molecular docking studies, a series of novel α-carboline derivatives were designed, synthesized, and evaluated as GSK-3ß inhibitors for their various biological activities. Among them, compound ZCH-9 showed the most potent inhibitory activity against GSK-3ß, with an IC50 value of 1.71 ± 0.09 µM. The cytotoxicity assay showed that ZCH-9 had low cytotoxicity toward the cell lines SH-SY5Y, HepG2, and HL-7702. Moreover, Western blot analysis indicated that ZCH-9 effectively inhibited hyperphosphorylation of the tau protein in okadaic acid-treated SH-SY5Y cells. The binding mode between ZCH-9 and GSK-3ß was analyzed and further clarified throughout the molecular dynamics simulations. In general, these results suggested that the α-carboline-based small-molecule compounds could serve as potential candidates targeting GSK-3ß for the treatment of AD.
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Doença de Alzheimer , Neuroblastoma , Doenças Neurodegenerativas , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Carbolinas , Glicogênio Sintase Quinase 3 beta , Humanos , Simulação de Acoplamento Molecular , Ácido Okadáico/metabolismo , Fosforilação , Relação Estrutura-Atividade , Proteínas tau/metabolismoRESUMO
Breast cancer (BC) occurrence and development tremendously affect female health. Currently breast cancer targeted drugs are still scarce. Natural products have become the main source of targeted drug for breast cancer due to low toxicity and high efficiency. Cimigenoside, natural compound isolated and purified from Cimicifuga dahurica (Turcz.) Maxim has been suggested to utilize for breast cancer treatment, however the mechanism of action has not been elucidated yet. In this article, the antitumor potential of Cimigenoside against breast cancer in vitro and in vivo study. Moreover, we further predicted the possible binding mode of Cimigenoside with γ-secretase through molecular docking studies. The results show that Cimigenoside has a significant inhibitory effect towards the proliferation or metastasis of breast cancer cells via suppressing the Notch signaling pathway-mediated mitochondrial apoptosis and EMT (epithelial mesenchymal transition). In terms of mechanism, Cimigenoside could inhibit the activation of PSEN-1, the catalytic subunit of γ-secretase, and also by cleaving the Notch protein mediated by PSEN-1. Overall, our findings provide scientific support to utilize Cimigenoside as an effective targeted drug for clinical treatment of BC.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Receptores Notch/metabolismo , Triterpenos/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral/efeitos dos fármacos , Feminino , Humanos , Células MCF-7/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Transplante de Neoplasias , Triterpenos/uso terapêuticoRESUMO
OBJECTIVE: We aimed to evaluate the association between coffee and/or tea consumption and breast cancer (BC) risk among premenopausal and postmenopausal women and to conduct a network meta-analysis. DESIGN: Systematic review and network meta-analysis. SETTING: We conducted a systematic review of electronic publications in the last 30 years to identify case-control studies or prospective cohort studies that evaluated the effects of coffee and tea intake. RESULTS: Forty-five studies that included more than 3 323 288 participants were eligible for analysis. Network meta-analysis was performed to determine the effects of coffee and/or tea consumption on reducing BC risk in a dose-dependent manner and differences in coffee/tea type, menopause status, hormone receptor and the BMI in subgroup and meta-regression analyses. According to the first pairwise meta-analysis, low-dose coffee intake and high-dose tea intake may exhibit efficacy in preventing ER(estrogen receptor)- BC, particularly in postmenopausal women. Then, we performed another pairwise and network meta-analysis and determined that the recommended daily doses were 2-3 cups/d of coffee or ≥5 cups/d of tea, which contained a high concentration of caffeine, particularly in postmenopausal women. CONCLUSIONS: Coffee and tea consumption is not associated with a reduction in the overall BC risk in postmenopausal women and is associated with a potentially lower risk of ER- BC. And the highest recommended dose is 2-3 cups of coffee/d or ≥5 cups of tea/d. They are potentially useful dietary protectants for preventing BC.