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1.
Nanoscale ; 13(35): 15085-15099, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34533154

RESUMO

The discovery of effective anticancer drug delivery systems and elucidation of the mechanism are enormous challenges. Using two drug administration-approved biomaterials, we constructed a natural medicine (NM)-loaded ternary supramolecular nanocomplex (TSN) suitable for large-scale production. The TSN has a better effect against cancer cells/stem cells than NM with differentially upregulated (27 versus 59) and downregulated (165 versus 66) proteins, respectively. Treatment with the TSN induced apoptosis and G2/M arrest, inhibited cell proliferation, metastasis and invasion, reduced colony/sphere formation, and decreased the frequency of side population cells and CD133+CD44+ABCG2+ cells. These results were revealed by multiple analyses (proteomic analysis, transwell migration and colony/sphere formation assays, biomarker profiling, etc.). We first reported the proteomic analysis of small lung cancer cells responding to a drug or its nanovesicles. We first conducted a proteomic evaluation of tumor cells responding to a drug supramolecular nanosystem. The supramolecular conformation of the TSN and the interactions of the TSN with albumin were verified by molecular docking experiments. The dominant binding forces in the TSN complexation process were electrostatic interactions, van der Waalsinteractions and bond stretching. The TSN binds to albumin more readily than NM does. The TSN has good in situ absorptive and in vitro/vivo kinetic properties. The relative bioavailability of the TSN to EA was 458.39%. The NM-loaded TSN is a supramolecular vesicle that can be produced at an industrial scale for efficient cancer therapy.


Assuntos
Apoptose , Preparações Farmacêuticas , Linhagem Celular Tumoral , Pontos de Checagem da Fase G2 do Ciclo Celular , Simulação de Acoplamento Molecular , Proteômica
2.
Molecules ; 26(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34500640

RESUMO

Recently, the direct thrombin (thr) inhibitor dabigatran has proven to be beneficial in animal models of Alzheimer's disease (AD). Aiming at discovering novel multimodal agents addressing thr and AD-related targets, a selection of previously and newly synthesized potent thr and factor Xa (fXa) inhibitors were virtually screened by the Multi-fingerprint Similarity Searching aLgorithm (MuSSeL) web server. The N-phenyl-1-(pyridin-4-yl)piperidine-4-carboxamide derivative 1, which has already been experimentally shown to inhibit thr with a Ki value of 6 nM, has been flagged by a new, upcoming release of MuSSeL as a binder of cholinesterase (ChE) isoforms (acetyl- and butyrylcholinesterase, AChE and BChE), as well as thr, fXa, and other enzymes and receptors. Interestingly, the inhibition potency of 1 was predicted by the MuSSeL platform to fall within the low-to-submicromolar range and this was confirmed by experimental Ki values, which were found equal to 0.058 and 6.95 µM for eeAChE and eqBChE, respectively. Thirty analogs of 1 were then assayed as inhibitors of thr, fXa, AChE, and BChE to increase our knowledge of their structure-activity relationships, while the molecular determinants responsible for the multiple activities towards the target enzymes were rationally investigated by molecular cross-docking screening.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Trombina/metabolismo , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Butirilcolinesterase/metabolismo , Bovinos , Fator Xa/metabolismo , Inibidores do Fator Xa/farmacologia , Humanos , Simulação de Acoplamento Molecular , Piperidinas/farmacologia , Relação Estrutura-Atividade
3.
Molecules ; 26(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34500647

RESUMO

Diabetes mellitus is a major health problem globally. The management of carbohydrate digestion provides an alternative treatment. Flavonoids constitute the largest group of polyphenolic compounds, produced by plants widely consumed as food and/or used for therapeutic purposes. As such, isoxazoles have attracted the attention of medicinal chemists by dint of their considerable bioactivity. Thus, the main goal of this work was to discover new hybrid molecules with properties of both flavonoids and isoxazoles in order to control carbohydrate digestion. Moreover, the trifluoromethyl group is a key entity in drug development, due to its strong lipophilicity and metabolic stability. Therefore, the present work describes the condensation of a previously synthesized trifluoromethylated flavonol with different aryl nitrile oxides, affording 13 hybrid molecules indicated as trifluoromethylated flavonoid-based isoxazoles. The structures of the obtained compounds were deduced from by 1H NMR, 13C NMR, and HRMS analysis. The 15 newly synthesized compounds inhibited the activity of α-amylase with an efficacy ranging from 64.5 ± 0.7% to 94.7 ± 1.2% at a concentration of 50 µM, and with IC50 values of 12.6 ± 0.2 µM-27.6 ± 1.1 µM. The most effective compounds in terms of efficacy and potency were 3b, 3h, 3j, and 3m. Among the new trifluoromethylated flavonoid-based isoxazoles, the compound 3b was the most effective inhibitor of α-amylase activity (PI = 94.7 ± 1.2% at 50 µM), with a potency (IC50 = 12.6 ± 0.2 µM) similar to that of the positive control acarbose (IC50 = 12.4 ± 0.1 µM). The study of the structure-activity relationship based on the molecular docking analysis showed a low binding energy, a correct mode of interaction in the active pocket of the target enzyme, and an ability to interact with the key residues of glycosidic cleavage (GLU-230 and ASP-206), explaining the inhibitory effects of α-amylase established by several derivatives.


Assuntos
Fármacos Antiobesidade/farmacologia , Diabetes Mellitus/tratamento farmacológico , Flavonoides/farmacologia , Hipoglicemiantes/farmacologia , Isoxazóis/farmacologia , alfa-Amilases/antagonistas & inibidores , Fármacos Antiobesidade/química , Diabetes Mellitus/metabolismo , Flavonoides/química , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Hipoglicemiantes/química , Isoxazóis/química , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , alfa-Glucosidases/metabolismo
4.
Braz J Biol ; 83: e247604, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34495156

RESUMO

In the current report, we studied the possible inhibitors of COVID-19 from bioactive constituents of Centaurea jacea using a threefold approach consisting of quantum chemical, molecular docking and molecular dynamic techniques. Centaurea jacea is a perennial herb often used in folk medicines of dermatological complaints and fever. Moreover, anticancer, antioxidant, antibacterial and antiviral properties of its bioactive compounds are also reported. The Mpro (Main proteases) was docked with different compounds of Centaurea jacea through molecular docking. All the studied compounds including apigenin, axillarin, Centaureidin, Cirsiliol, Eupatorin and Isokaempferide, show suitable binding affinities to the binding site of SARS-CoV-2 main protease with their binding energies -6.7 kcal/mol, -7.4 kcal/mol, -7.0 kcal/mol, -5.8 kcal/mol, -6.2 kcal/mol and -6.8 kcal/mol, respectively. Among all studied compounds, axillarin was found to have maximum inhibitor efficiency followed by Centaureidin, Isokaempferide, Apigenin, Eupatorin and Cirsiliol. Our results suggested that axillarin binds with the most crucial catalytic residues CYS145 and HIS41 of the Mpro, moreover axillarin shows 5 hydrogen bond interactions and 5 hydrophobic interactions with various residues of Mpro. Furthermore, the molecular dynamic calculations over 60 ns (6×106 femtosecond) time scale also shown significant insights into the binding effects of axillarin with Mpro of SARS-CoV-2 by imitating protein like aqueous environment. From molecular dynamic calculations, the RMSD and RMSF computations indicate the stability and dynamics of the best docked complex in aqueous environment. The ADME properties and toxicity prediction analysis of axillarin also recommended it as safe drug candidate. Further, in vivo and in vitro investigations are essential to ensure the anti SARS-CoV-2 activity of all bioactive compounds particularly axillarin to encourage preventive use of Centaurea jacea against COVID-19 infections.


Assuntos
COVID-19 , Centaurea , Preparações Farmacêuticas , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases , SARS-CoV-2
5.
An Acad Bras Cienc ; 93(4): e20200443, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34495202

RESUMO

Phytochemical studies of Cespedesia spathulata (Ochnaceae) leaves using 1H, 13C NMR, and GC-MS have led to the isolation of some metabolites identified for the first time in these species such as cathechin, epicatechin, vitexin, orientin, 6''-O-acetyl-vitexin, sitosterol, stigmasterol, phytol, 4,5-dihydrovomifoliol and a mixture of aliphatic methyl esters, together with ochnaflavone, which was previously isolated from this plant. The modulating activity of some fractions and compounds from Cespedesia spathulata towards tyrosinase enzyme was assayed by spectroscopic and theoretical means/experiments. The dichloromethane fraction (133 µg mL-1) and ochnaflavone (333 µM) inhibited tyrosinase activity by 20 % and 2.0 %, respectively, whereas the ethyl acetate fraction (666 µg mL-1) and ±catechins (catechin and epicatechin - 800 µM) activated it by 104 % and 384 %, respectively. Quantum chemical calculations suggested that catechin and epicatechin are better activators than L-DOPA by interacting with Cu (II) ions. Molecular docking results suggested that hydrogen bonding and hydrophobic interactions are the main binding forces between each tyrosinase activator and the amino acid residues inside the active protein binding pocket.


Assuntos
Ochnaceae , Simulação de Acoplamento Molecular , Monofenol Mono-Oxigenase , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Folhas de Planta
7.
Int J Mol Sci ; 22(17)2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34502335

RESUMO

A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been identified as the pathogen responsible for the outbreak of a severe, rapidly developing pneumonia (Coronavirus disease 2019, COVID-19). The virus enzyme, called 3CLpro or main protease (Mpro), is essential for viral replication, making it a most promising target for antiviral drug development. Recently, we adopted the drug repurposing as appropriate strategy to give fast response to global COVID-19 epidemic, by demonstrating that the zonulin octapeptide inhibitor AT1001 (Larazotide acetate) binds Mpro catalytic domain. Thus, in the present study we tried to investigate the antiviral activity of AT1001, along with five derivatives, by cell-based assays. Our results provide with the identification of AT1001 peptide molecular framework for lead optimization step to develop new generations of antiviral agents of SARS-CoV-2 with an improved biological activity, expanding the chance for success in clinical trials.


Assuntos
Antivirais/farmacologia , Simulação de Acoplamento Molecular , Oligopeptídeos/química , Peptídeos/metabolismo , SARS-CoV-2/efeitos dos fármacos , Antivirais/química , Antivirais/metabolismo , Antivirais/uso terapêutico , Sítios de Ligação , COVID-19/tratamento farmacológico , COVID-19/virologia , Domínio Catalítico , Linhagem Celular , Citomegalovirus/efeitos dos fármacos , Reposicionamento de Medicamentos , Herpesvirus Humano 3/efeitos dos fármacos , Humanos , Simulação de Dinâmica Molecular , Peptídeos/síntese química , Peptídeos/farmacologia , Peptídeos/uso terapêutico , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/metabolismo , Proteínas da Matriz Viral/química , Proteínas da Matriz Viral/metabolismo
8.
Int J Mol Sci ; 22(17)2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34502340

RESUMO

The SARS-CoV-2 main protease (Mpro) is one of the molecular targets for drug design. Effective vaccines have been identified as a long-term solution but the rate at which they are being administered is slow in several countries, and mutations of SARS-CoV-2 could render them less effective. Moreover, remdesivir seems to work only with some types of COVID-19 patients. Hence, the continuous investigation of new treatments for this disease is pivotal. This study investigated the inhibitory role of natural products against SARS-CoV-2 Mpro as repurposable agents in the treatment of coronavirus disease 2019 (COVID-19). Through in silico approach, selected flavonoids were docked into the active site of Mpro. The free energies of the ligands complexed with Mpro were computationally estimated using the molecular mechanics-generalized Born surface area (MM/GBSA) method. In addition, the inhibition process of SARS-CoV-2 Mpro with these ligands was simulated at 100 ns in order to uncover the dynamic behavior and complex stability. The docking results showed that the selected flavonoids exhibited good poses in the binding domain of Mpro. The amino acid residues involved in the binding of the selected ligands correlated well with the residues involved with the mechanism-based inhibitor (N3) and the docking score of Quercetin-3-O-Neohesperidoside (-16.8 Kcal/mol) ranked efficiently with this inhibitor (-16.5 Kcal/mol). In addition, single-structure MM/GBSA rescoring method showed that Quercetin-3-O-Neohesperidoside (-87.60 Kcal/mol) is more energetically favored than N3 (-80.88 Kcal/mol) and other ligands (Myricetin 3-Rutinoside (-87.50 Kcal/mol), Quercetin 3-Rhamnoside (-80.17 Kcal/mol), Rutin (-58.98 Kcal/mol), and Myricitrin (-49.22 Kcal/mol). The molecular dynamics simulation (MDs) pinpointed the stability of these complexes over the course of 100 ns with reduced RMSD and RMSF. Based on the docking results and energy calculation, together with the RMSD of 1.98 ± 0.19 Å and RMSF of 1.00 ± 0.51 Å, Quercetin-3-O-Neohesperidoside is a better inhibitor of Mpro compared to N3 and other selected ligands and can be repurposed as a drug candidate for the treatment of COVID-19. In addition, this study demonstrated that in silico docking, free energy calculations, and MDs, respectively, are applicable to estimating the interaction, energetics, and dynamic behavior of molecular targets by natural products and can be used to direct the development of novel target function modulators.


Assuntos
Produtos Biológicos/metabolismo , SARS-CoV-2/enzimologia , Proteínas da Matriz Viral/metabolismo , Sítios de Ligação , Produtos Biológicos/química , Produtos Biológicos/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/patologia , COVID-19/virologia , Domínio Catalítico , Desenho de Fármacos , Humanos , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Inibidores de Proteases/uso terapêutico , Quercetina/análogos & derivados , Quercetina/química , Quercetina/metabolismo , Quercetina/uso terapêutico , SARS-CoV-2/isolamento & purificação , Proteínas da Matriz Viral/química
9.
ACS Infect Dis ; 7(9): 2637-2649, 2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34467755

RESUMO

As the existing therapeutic modalities for the treatment of cryptococcal meningitis (CM) have suboptimal efficacy, repurposing existing drugs for the treatment of CM is of great interest. The FDA-approved anthelmintic benzimidazoles, albendazole, mebendazole, and flubendazole, have demonstrated potent but variable in vitro activity against Cryptococcus neoformans, the predominant fungal species responsible for CM. We performed molecular docking studies to ascertain the interaction of albendazole, mebendazole, and flubendazole with a C. neoformans ß-tubulin structure, which revealed differential binding interactions and explained the different in vitro efficacies reported previously and observed in this investigation. Despite their promising in vitro efficacy, the repurposing of anthelmintic benzimidazoles for oral CM therapy is significantly hampered due to their high crystallinity, poor pharmaceutical processability, low and pH-dependent solubility, and drug precipitation upon entering the intestine, all of which result in low and variable oral bioavailability. Here, we demonstrate that the anthelmintic benzimidazoles can be transformed into partially amorphous low-melting ionic liquids (ILs) with a simple metathesis reaction using amphiphilic sodium docusate as a counterion. In vitro efficacy studies on a laboratory reference and a clinical isolate of C. neoformans showed 2- to 4-fold lower IC90 values for docusate-based ILs compared to the pure anthelmintic benzimidazoles. Furthermore, using a C. neoformans strain with green fluorescent protein (GFP)-tagged ß-tubulin and albendazole and its docusate IL as model candidates, we showed that the benzimidazoles and their ILs reduce the viability of C. neoformans by interfering with its microtubule assembly. Unlike pure anthelmintic benzimidazoles, the docusate-based ILs showed excellent solubility in organic solvents and >30-fold higher solubility in bioavailability-enhancing lipid vehicles. Finally, the docusate ILs were successfully incorporated into SoluPlus, a self-assembling biodegradable polymer, which upon dilution with water formed polymeric micelles with a size of <100 nm. Thus, the development of docusate-based ILs represents an effective approach to improve the physicochemical properties and potency of anthelmintic benzimidazoles to facilitate their repurposing and preclinical development for CM therapy.


Assuntos
Anti-Helmínticos , Cryptococcus neoformans , Líquidos Iônicos , Preparações Farmacêuticas , Anti-Helmínticos/farmacologia , Benzimidazóis/farmacologia , Ácido Dioctil Sulfossuccínico , Simulação de Acoplamento Molecular , Solubilidade
10.
J Hazard Mater ; 416: 125911, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34492845

RESUMO

Plant growth can be influenced by the application of triazole pesticides as these regulate physiological processes such as plant hormonal levels and enzyme activity. Homology modeling and molecular docking studies suggested that inhibition of ADP-glucose pyrophosphorylase activity in two trans-stereoisomers treatments hinders starch accumulation during the grain filling stage. A field experiment investigated the effects of metconazole racemate, cis-1R,5S-stereostereoisomer, and cis-1S,5R-stereoisomer application at the flowering stage on wheat grain ripening and yield. The concentrations of racemate and both cis-stereoisomers were detected in wheat plant and grain samples. Compared with the racemate, both cis-stereoisomers were more persistent in the matrices. Treatment with cis-1R,5S-stereoisomer decreased grain weight and yield of wheat by delaying chlorophyll degradation, increasing the ethylene content, and decreasing the level of abscisic acid. The germination of harvested seeds was adversely affected by racemate treatment as a result of gibberellin and abscisic acid metabolism regulation and the transcription of signaling-related genes. Therefore, cis-1S,5R-stereoisomer was recommended to be used as metconazole pesticide at the flowering stage.


Assuntos
Praguicidas , Triticum , Germinação , Simulação de Acoplamento Molecular , Sementes , Triazóis
11.
J Hazard Mater ; 416: 126116, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34492911

RESUMO

Galaxolide (HHCB), one of the most widely used synthetic musks in personal care products (PCPs), has been recognized as an emerging contaminant with potential human health concerns. To overcome such adverse effects, a systematic molecular design, screening and performance evaluation approach was developed to generate functionally improved and environmentally friendly HHCB derivatives. Among the 90 designed HHCB derivatives, 15 were screened with improved functional properties (i.e., odor stability and intensity) and less environmental impacts (i.e., lower bio-toxicity, bio-accumulation ability, and mobility) using 3D-QSAR models and density functional theory methods. Their human health risks were then assessed by toxicokinetic analysis, which narrowed the candidates to four. Derivative 7, the designed molecule with the least dermal adsorption potential, was evaluated for its interaction with other PCPs additives (i.e., anti-photosensitivity materials and moisturizer) and such impacts on human health risks using molecular docking and molecular dynamic simulation. The environmental fate of Derivative 7 after transformation (i.e., photodegradation, biotransformation, and chlorination) was also discussed. Biotransformation and chlorination were recognized as optimum options for Derivative 7 mitigation. This study provided the theoretical basis for the design of functionally improved and environmentally friendly HHCB alternatives and advanced the understanding of their environmental behaviors and health risks.


Assuntos
Cosméticos , Relação Quantitativa Estrutura-Atividade , Benzopiranos , Biotransformação , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular
12.
Zhongguo Zhong Yao Za Zhi ; 46(15): 3960-3969, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34472273

RESUMO

This study aimed to explore the mechanism of Tanreqing Injection in the treatment of acute lung injury(ALI) based on network pharmacology and molecular docking. The active components and action targets of Tanreqing Injection were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), PubChem, and SwissTargetPrediction databases, as well as available literature reports. The ALI-related targets were obtained from the GeneCards database and then mapped with Tanreqing Injection targets. Following the construction of "drug-component-potential target" network with Cytoscape 3.6.1, the potential targets were input into STRING to yield the protein-protein interaction(PPI) network, which was plotted using Cytoscape 3.6.1. Then the screened key targets were subjected to gene ontology(GO) and Kyoto encyclopedia of genes and genomes(KEGG) enrichment analysis based on DAVID database. The top three key targets RAC-alpha serine/threonine-protein kinase(AKT1), albumin(ALB) and interleukin-6(IL6) were docked to the top three key compounds by PyMOL and AutoDock vina. A total of 58 active components of Tanreqing Injection, 597 corresponding targets and 503 common targets shared by Tanreqing Injection and ALI were fi-gured out, with the key targets AKT1, ALB and IL6 involved. GO and KEGG enrichment analysis yielded 1 445 biological processes and 148 signaling pathways, respectively. Molecular docking verified a good binding ability of the top three key targets to the top three key compounds. The analysis based on network pharmacology and molecular docking uncovered that Tanreqing Injection directly or indirectly regulated the pulmonary capillary endothelial cells and alveolar epithelial cells via anti-inflammation, thus alleviating ALI.


Assuntos
Lesão Pulmonar Aguda , Medicamentos de Ervas Chinesas , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/genética , Células Endoteliais , Humanos , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular
13.
Zhongguo Zhong Yao Za Zhi ; 46(12): 3007-3015, 2021 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34467690

RESUMO

Cerebral ischemia is one of the most common diseases in China, and the drug pair of Chuanxiong Rhizoma and Paeoniae Radix Rubra can intervene in cerebral ischemia to reduce the inflammatory response of cerebral ischemia and apoptosis. To reveal the intervention mechanism of Chuanxiong Rhizoma-Paeoniae Radix Rubra drug pair on cerebral ischemia systematically, computer network pharmacology technology was used in this paper to predict the target and signaling pathway of the drug pair on the intervention of cerebral ischemia, and then the molecular docking technology was used to further analyze the mechanism of the intervention. The target results were then verified by the rat cerebral ischemia model. The target network results showed that the active compounds of Chuanxiong Rhizoma-Paeoniae Radix Rubra for cerebral ischemic disease contained 30 compounds, 38 targets and 9 pathways. The main compounds included phenolic acids in Chuanxiong Rhizoma and monoterpene glycosides in Paeoniae Radix Rubra. The key targets involved mitogen-activated protein kinase 1(MAPK1), steroid receptor coactivator(SRC), epidermal growth factor receptor(EGFR), mitogen-activated protein kinase 14(MAPK14), caspase-3(CASP3), caspase-7(CASP7), estrogen receptor 1(ESR1), and mitogen-activated protein kinase 8(MAPK8), etc. The target gene functions were biased towards protein kinase activity, protein autophosphorylation, peptidyl-serine phosphorylation and protein serine/threonine kinase activity, etc. The important KEGG pathways involved Ras signaling pathway, ErbB signaling pathway and VEGF signaling pathway. Molecular docking results showed that catechin, oxypaeoniflorin, albiflorin, paeoniflorin and benzoylpaeoniflorin had strong binding ability with MAPK1, SRC, EGFR, MAPK14 and CASP7. MCAO rat experimental results showed that Chuanxiong Rhizoma-Paeoniae Radix Rubra significantly improved the cerebral ischemia injury and interstitial edema, and significantly reduced the activation of caspase-7 and the phosphorylation of ERK1/2. The Chuanxiong Rhizoma-Paeoniae Radix Rubra drug pair alleviated cerebral ischemia injury through a network model of multi-phenotype intervention by promoting cell proliferation and differentiation, reducing inflammatory factor expression, protecting nerve cells from death and figh-ting against neuronal cell apoptosis, with its action signaling pathway most related to Ras signaling pathway, ErbB signaling pathway and VEGF signaling pathway. This study provides the basis for clinical intervention of Chuanxiong Rhizoma-Paeoniae Radix Rubra drug pair on cerebral ischemia, and also provides ideas for the modernization of drug pairs.


Assuntos
Isquemia Encefálica , Medicamentos de Ervas Chinesas , Paeonia , Animais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/genética , Infarto Cerebral , Simulação de Acoplamento Molecular , Ratos , Rizoma
14.
Zhongguo Zhong Yao Za Zhi ; 46(12): 3024-3033, 2021 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34467692

RESUMO

To explore the potential effective components and mechanism of Zhishe Tongluo Capsules in the treatment of ischemic stroke via network pharmacology, molecular docking and cellular experiment. The chemical constituents of Zhishe Tongluo Capsules were found by TCMSP, BATMAN-TCM and literatures. The constituents-target network was predicted by BATMAN-TCM database. Key words such as cerebral stroke, ischemic stroke and cerebral ischemic stroke were used to search ischemic stroke related targets, and then Venny Map was constructed based on the targets of traditional Chinese medicine and the targets of ischemic stroke. The overlapping targets were imported into STRING database to establish the interaction network. Furthermore, the core targets were screened out by Cytoscape software. Go and KEGG enrichment analysis were performed through DVIAD database. The results showed a total of 193 potential chemical constituents, 985 drug targets and 6 035 disease targets. There were 631 potential targets, 44 core targets and 55 potential active components for treating ischemic stroke through Venny mapping. GO enrichment analysis mainly involved response to hypoxia and positive regulation of ERK1/ERK2. KEGG pathway enrichment analysis mainly involved cholinergic synapse, cAMP signaling pathway, and calcium signaling pathway. Molecular docking data revealed that TP53, EGFR, IL6, INS, TNF and SRC had a good capability to bind with their corresponding active components. To ensure the protective effect Zhishe Tongluo Capsules on the inflammation reaction, an in vitro model of lipopolysaccharide(LPS)-induced RAW264.7 cells was built. The contents of IL-1α, IL-1ß, IL-6 and TNF-α in the supernatant were significantly decreased by enzyme linked immunosorbent assay(ELISA). The findings suggested that Zhishe Tongluo Capsules could prevent the injury of ischemic stroke by inhibiting the inflammation.


Assuntos
Isquemia Encefálica , Medicamentos de Ervas Chinesas , AVC Isquêmico , Acidente Vascular Cerebral , Isquemia Encefálica/tratamento farmacológico , Cápsulas , Humanos , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular , Acidente Vascular Cerebral/tratamento farmacológico
15.
Zhongguo Zhong Yao Za Zhi ; 46(12): 3052-3057, 2021 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34467695

RESUMO

To study the material basis and mechanism of volatile oil from Alpinia oxyphylla in treating Alzheimer's disease(AD) based on GC-MS and network pharmacology. Ingredients of volatile oil from A.oxyphylla were analyzed by GC-MS. Targets of those ingredients were obtained through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP). Relevant targets of AD were obtained through such databases as DrugBank, STITCH, OMIM. Intersection targets of ingredients and diseases were obtained by Online Venny map, and PPI network was established by STRING to screen out core targets. Gene ontology(GO) functional enrichment analysis and KEGG pathway enrichment analysis were performed by DAVID. The "ingredients-target-pathway" network was constructed by software Cytoscape 3.8.1 to screen out potential active ingredients of volatile oil from A.oxyphylla in the treatment of AD. The results showed that a total of 6 active ingredients were screened from the volatile oil of A.oxyphylla by GC-MS, 17 targets corresponding to 6 active ingredients were found in TCMSP database, and 3 448 AD targets were found in DrugBank database. "Ingredients-target-pathway" network and PPI network showed there were 4 potential active ingredients in the treatment of AD and 4 core targets. GO analysis and KEGG analysis showed 34(P<0.05) and 5(P<0.05) pathways, respectively, including nerve ligand receptor interaction, calcium signaling pathway, cholinergic synapse and 5-hydroxytryptaminergic synapse. This suggested that volatile oil from A.oxyphylla could synergistically treat AD by regulating calcium balance, cholinergic balance and phosphorylation. This study provided reference and guidance for further study of volatile oil from A.oxyphylla in the treatment of AD.


Assuntos
Alpinia , Doença de Alzheimer , Medicamentos de Ervas Chinesas , Óleos Voláteis , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Simulação de Acoplamento Molecular
16.
Zhongguo Zhong Yao Za Zhi ; 46(12): 3058-3065, 2021 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34467696

RESUMO

In this study, the compound search was completed through SciFinder and CNKI databases, and the drug-like properties were screened in FAFdrugs4 and SEA Search Server databases. In addition, based on the target sets related to acute myocardial ischemia(AMI) searched in disease target databases such as OMIM database, GeneCards database and DrugBank, a network diagram of chemical component-target-pathway-disease was established via Cytoscape to predict the potential active components of Corydalis Herba, a traditional Tibetan herbal medicine which derived from the aerial parts of Corydalis hendersonii and C. mucronifera against AMI. A protein-protein interaction(PPI) network was constructed through the STRING database and the core targets in the network were predicted. And the enrichment analyses of core targets were completed by DAVID database and R software. Furthermore, a molecular docking method was used to verify the binding of the components with core targets using softwares such as Autodock Vina. The present results showed that there were 60 compounds related to AMI in Corydalis Herba, involving 73 potential targets. The GO functional enrichment analysis obtained 282 biological processes(BP), 49 cell components(CC) and 78 molecular functions(MF). KEGG was enriched into 85 pathways, including alcoholism pathway, endocrine resistance pathway, calcium signaling pathway, cAMP signaling pathway, vascular endothelial growth factor signaling pathway and adrenergic signaling transduction pathway of myocardial cells. The results of network topology analysis showed that the key components of anti-AMI of Corydalis Herba might be tetrahydropalmatine, etrahydrocolumbamine, N-trans-feruloyloctopamine, N-cis-p-coumaroyloctopamine, N-trans-p-coumaroylnoradrenline and N-trans-p-coumaroyloctopamine, and their core targets might be CDH23, SCN4 B and NFASC. The results of molecular docking showed that the key components of Corydalis Herba had stable binding activity with the core targets. This study provides reference for further elucidation of the pharmacological effects of Corydalis Herba against AMI, subsequent clinical application, and development.


Assuntos
Corydalis , Medicamentos de Ervas Chinesas , Isquemia Miocárdica , Medicamentos de Ervas Chinesas/farmacologia , Medicina Tradicional Tibetana , Simulação de Acoplamento Molecular , Isquemia Miocárdica/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular
17.
Zhongguo Zhong Yao Za Zhi ; 46(12): 2889-2899, 2021 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34467710

RESUMO

Sophorae Flavescentis Radix,derived from the root of Sophora flavescens in the Leguminosae family,has been widely used in the medicine,agriculture,animal husbandry,and daily chemical industry. A pharmacophore model-based method for rapid discovery of tyrosinase inhibitors( TIs) from S. flavescens was established by molecular docking under Lipinski rules,and verified by enzyme assays. Briefly,the chemical constituent database of S. flavescens( CDSF) was established based on the previous papers. Theoptimal pharmacophore model( OPM) was constructed by DS 2019 on the basis of known active TIs. Eighty-three hits predominated by flavonoids having higher fitting scores with OPM than the positive control were screened out,and subjected to molecular docking based on the three-dimensional structure of tyrosinase crystal protein. The potential TIs such as kurarinone and nor-kurarinone were rapidly discovered from the compounds with higher docking scores than the positive control under the Lipinski rules. The results were verified by the in vitro enzyme assays. The inhibition activities of tyrosinase from non-medicinal parts of S. flavescens were also tested to explore the relationship between the inhibition activity and chemical compositions. This study is expected to provide data support for the comprehensive application and development of S. flavescens and also a new method for the rapid discovery of active substances or functional constituents in the complex systems.


Assuntos
Sophora , Animais , Flavonoides , Simulação de Acoplamento Molecular , Monofenol Mono-Oxigenase , Extratos Vegetais/farmacologia , Raízes de Plantas
18.
Zhongguo Zhong Yao Za Zhi ; 46(16): 4061-4068, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34467715

RESUMO

Reverse prediction and molecular docking techniques were employed to evaluate the feasibility of reniformin A(RA) as an anti-tumor leading compound. Based on the reverse prediction, network pharmacology was used to construct a "disease-compound-target-pathway" network. Thirty-nine tumor-related targets of RA were predicted, which participated in the regulation of multiple cellular activities such as apoptosis, cell cycle, and tumor metastasis, and regulated estrogen signal transduction and inflammatory response. Discovery Studio 2020 was adopted for molecular docking and toxicity prediction(TOPKAT). As revealed by the results, the binding affinity of RA with the tumor-related targets ABL1, ESR1, SRC and BCL-XL was stronger than that of oridonin(OD), while its mutagenicity, rodent carcinogenesis, and oral LD_(50) in rats were all inferior to that of OD. Furthermore, in vitro experiments were performed to confirm the anti-tumor activity of RA, and the mechanism was preliminarily discussed. The results demonstrated that RA was superior to OD in cytotoxicity, inhibition of cell colony formation, and induction of apoptosis. RA, possessing potent anti-tumor activity, is expected to be a new anti-tumor leading compound.


Assuntos
Medicamentos de Ervas Chinesas , Neoplasias , Animais , Medicamentos de Ervas Chinesas/farmacologia , Chumbo , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Ratos , Transdução de Sinais
19.
Zhongguo Zhong Yao Za Zhi ; 46(16): 4230-4237, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34467737

RESUMO

This study aimed to explore the mechanism of Xiaoyao San(XYS) in the treatment of three diseases of liver depression and spleen deficiency, ie, depression, breast hyperplasia, and functional dyspepsia, and to provide a theoretical basis for the interpretation of the scientific connotation of "treating different diseases with the same method" of traditional Chinese medicines. Traditional Chinese medicine systems pharmacology database and analysis platform(TCMSP) was used to screen the active components of XYS which underwent principal component analysis(PCA) with the available drugs for these three diseases to determine the corresponding biological activities. The targets of XYS on depression, breast hyperplasia, and functional dyspepsia were obtained from GeneCards, TTD, CTD, and DrugBank databases. Cytoscape was used to plot the "individual herbal medicine-active components-potential targets" network. The resulting key targets were subjected to Kyoto encyclopedia of genes and genomes(KEGG) pathway analysis and gene ontology(GO) enrichment analysis. A total of 121 active components of XYS and 38 common targets in the treatment of depression, breast hyperplasia, and functional dyspepsia were collected. The key biological pathways were identified, including advanced glycation and products(AGEs)-receptor for advanced glycation and products(RAGE) signaling pathway in diabetic complications, HIF-1 signaling pathway, and cancer-related pathways. The key targets of XYS in the treatment of depression, breast hyperplasia, and functional dyspepsia included IL6, IL4, and TNF, and the key components were kaempferol, quercetin, aloe-emodin, etc. As revealed by the molecular docking, a strong affinity was observed between the key components and the key targets, which confirmed the results. The therapeutic efficacy of XYS in the treatment of diseases of liver depression and spleen deficiency was presumedly achieved by reducing the inflammatory reactions. The current findings are expected to provide novel research ideas and approaches to classify the scientific connotation of "treating different diseases with the same method" of Chinese medicines, as well as a theoretical basis for understanding the mechanism of XYS and exploring its clinical applications.


Assuntos
Medicamentos de Ervas Chinesas , Dispepsia , Depressão/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Dispepsia/tratamento farmacológico , Humanos , Hiperplasia/tratamento farmacológico , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular
20.
Zhongguo Zhong Yao Za Zhi ; 46(16): 4238-4243, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34467738

RESUMO

Wuwei Ganlu, a formula for medicated bath, consists of medicinal materials of Ephedra sinica, Platycladus orientalis, Myricaria squamosa, Artemisia carvifolia, and Rhododendron anthopogonoides, which is effective in inducing perspiration, resisting inflammation, relieving pain, regulating yellow water disease, and activating blood circulation. On this basis, a variety of formulas for Tibetan medicated bath have been derived for the treatment of diseases in internal organs, joints, nerves, etc. Modern studies have confirmed that Wuwei Ganlu has a good therapeutic efficacy on knee osteoarthritis(KOA). The present study explored the mechanism of Wuwei Ganlu in treating KOA based on network pharmacology and molecular docking. Firstly, the chemical components of Wuwei Ganlu were obtained through literature mining and database retrieval, and corresponding potential targets were predicted according to the BATMAN-TCM database. The protein-protein interaction(PPI) network was obtained after the potential targets were input into the STRING database. The network function modules were analyzed by the Molecular Complex Detection(MCODE) algorithm, and the functions of the modules were annotated to analyze the action mode of Wuwei Ganlu. Secondly, the related targets of KOA were collected through the DisGeNET database, and the overlapping targets were confirmed to analyze the mechanism of Wuwei Ganlu in treating KOA. Finally, the key targets were selected for molecular docking with the main components of Wuwei Ganlu to verify the component-target interaction. A total of 550 chemical components and 1 365 potential targets of Wuwei Ganlu were obtained. PPI analysis indicated that this formula could exert the effects of oxidation-reduction, inflammation resistance, bone absorption, bone mineralization, etc. Nineteen common targets were obtained from the intersection of potential targets of Wuwei Ganlu and KOA disease targets. It was found that the Wuwei Ganlu mainly acts on nuclear factor-κB(NF-κB), interleukin-1 beta(IL1ß), tumor necrosis factor(TNF), IL6, IL1 receptor antagonist(IL1 RN), and prostaglandin-endoperoxide synthase-2(PTGS2) to treat KOA. Among the 550 chemical components of Wuwei Ganlu, 252 potential active components were docked with TNF and 163 with PTGS2, indicating good binding of the components with potential key targets. The study preliminarily explored the mechanism of Wuwei Ganlu in treating KOA to provide a reference for the further development and utilization of Tibetan medicated bath that has been included in the UN Intangible Cultural Heritage.


Assuntos
Medicamentos de Ervas Chinesas , Osteoartrite do Joelho , Bases de Dados Factuais , Humanos , Inflamação , Simulação de Acoplamento Molecular
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