Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 26.787
Filtrar
1.
Food Chem Toxicol ; 170: 113502, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36404522

RESUMO

In vitro cell systems can support hazard characterization and identify mechanisms involved in toxicity; however, using in vitro data for risk assessment still is challenging. As part of an effort to develop approaches for a complex operating site used for biocide packaging and distribution, we evaluated in vitro assays that could be used in a site management format. Across 66 studies, 108 pesticides were assessed on ten human-derived cell types at four endpoints. In vitro IC50s were compared to in vivo guidelines, NOEL/NOAELs, and ADIs using Spearman correlation and linear regression models. While human neuroblastoma cells (SH-SY5Y) were the most sensitive, HepG2 was the most used cell line in evaluating the toxicity of pesticides. Amongst the ten human cell lines, the IC50s derived from SH-SY5Y cells, using MTT-24 & 48 h (the most used assay) correlated (rho = 0.56-0.79; p < 0.05) with ADIs and NOEL/NOAELs. Although in vitro cell systems have some limitations, the correlation between in vitro data derived from SH-SY5Y cells and in vivo safety guidelines can provide site investigators with a tool to survey and prioritize areas and media of concern at complex operating sites impacted by pesticide mixtures.


Assuntos
Neuroblastoma , Praguicidas , Humanos , Praguicidas/toxicidade , Concentração Inibidora 50 , Bioensaio , Linhagem Celular
2.
Bosn J Basic Med Sci ; 22(4): 580-592, 2022 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-35694767

RESUMO

Preclinical models of tumors have the potential to become valuable tools for commercial drug research and development, and 3D culture systems are gaining traction in this area, particularly in prostate cancer (PCa) research. However, nearly all 3D drug design and screening assessments are based on 2D experiments, suggesting limitations of 3D drug testing. To simulate the natural response of human cells to the drug, we detected the half-maximal inhibitory concentration (IC50) changes of 2D/3D LNCaP cells in the drug docetaxel, as well as the sensitivity of different morphologies of 2D/3D LNCaP to docetaxel treatment. In contrast to 2D LNCaP cells, the evaluation of LNCaP spheroids' susceptibility to treatment was more complicated; the fitness of IC50 curves of 2D and 3D tumor cell preclinical models differs significantly. IC50 curves were unsuitable for large-sized LNCaP spheroids. More evaluation indexes (such as max inhibition) and experiments (such as spheroids formation) should be explored and performed to evaluate the susceptibility systematically.


Assuntos
Antineoplásicos , Neoplasias da Próstata , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Humanos , Concentração Inibidora 50 , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia
3.
Bioinformatics ; 38(10): 2810-2817, 2022 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-35561188

RESUMO

MOTIVATION: Predicting drug response is critical for precision medicine. Diverse methods have predicted drug responsiveness, as measured by the half-maximal drug inhibitory concentration (IC50), in cultured cells. Although IC50s are continuous, traditional prediction models have dealt mainly with binary classification of responsiveness. However, since there are few regression-based IC50 predictions, comprehensive evaluations of regression-based IC50 prediction models, including machine learning (ML) and deep learning (DL), for diverse data types and dataset sizes, have not been addressed. RESULTS: Here, we constructed 11 input data settings, including multi-omics settings, with varying dataset sizes, then evaluated the performance of regression-based ML and DL models to predict IC50s. DL models considered two convolutional neural network architectures: CDRScan and residual neural network (ResNet). ResNet was introduced in regression-based DL models for predicting drug response for the first time. As a result, DL models performed better than ML models in all the settings. Also, ResNet performed better than or comparable to CDRScan and ML models in all settings. AVAILABILITY AND IMPLEMENTATION: The data underlying this article are available in GitHub at https://github.com/labnams/IC50evaluation. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Aprendizado de Máquina , Redes Neurais de Computação , Sobrevivência Celular , Concentração Inibidora 50 , Medicina de Precisão
4.
J Tissue Eng Regen Med ; 16(8): 732-743, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35621199

RESUMO

Utilizing recent advances in human induced pluripotent stem cell (hiPSC) technology, nonlinear analysis and machine learning we can create novel tools to evaluate drug-induced cardiotoxicity on human cardiomyocytes. With cardiovascular disease remaining the leading cause of death globally it has become imperative to create effective and modern tools to test the efficacy and toxicity of drugs to combat heart disease. The calcium transient signals recorded from hiPSC-derived cardiomyocytes (hiPSC-CMs) are highly complex and dynamic with great degrees of response characteristics to various drug treatments. However, traditional linear methods often fail to capture the subtle variation in these signals generated by hiPSC-CMs. In this work, we integrated nonlinear analysis, dimensionality reduction techniques and machine learning algorithms for better classifying the contractile signals from hiPSC-CMs in response to different drug exposure. By utilizing extracted parameters from a commercially available high-throughput testing platform, we were able to distinguish the groups with drug treatment from baseline controls, determine the drug exposure relative to IC50 values, and classify the drugs by its unique cardiac responses. By incorporating nonlinear parameters computed by phase space reconstruction, we were able to improve our machine learning algorithm's ability to predict cardiotoxic levels and drug classifications. We also visualized the effects of drug treatment and dosages with dimensionality reduction techniques, t-distributed stochastic neighbor embedding (t-SNE). We have shown that integration of nonlinear analysis and artificial intelligence has proven to be a powerful tool for analyzing cardiotoxicity and classifying toxic compounds through their mechanistic action.


Assuntos
Inteligência Artificial , Cardiotoxicidade/diagnóstico , Cardiotoxicidade/etiologia , Células-Tronco Pluripotentes Induzidas , Aprendizado de Máquina , Algoritmos , Cardiotoxicidade/metabolismo , Humanos , Concentração Inibidora 50 , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Dinâmica não Linear , Preparações Farmacêuticas
5.
Sci Rep ; 12(1): 6610, 2022 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-35459284

RESUMO

To facilitate rapid determination of cellular viability caused by the inhibitory effect of drugs, numerical deep learning algorithms was used for unlabeled cell culture images captured by a light microscope as input. In this study, A549, HEK293, and NCI-H1975 cells were cultured, each of which have different molecular shapes and levels of drug responsiveness to doxorubicin (DOX). The microscopic images of these cells following exposure to various concentrations of DOX were trained with the measured value of cell viability using a colorimetric cell proliferation assay. Convolutional neural network (CNN) models for the study cells were constructed using augmented image data; the predicted cell viability using CNN models was compared to the cell viability measured by colorimetric assay. The linear relationship coefficient (r2) between measured and predicted cell viability was determined as 0.94-0.95 for the three cell types. In addition, the measured and predicted IC50 values were not statistically different. When drug responsiveness was estimated using allogenic models that were trained with a different cell type, the correlation coefficient decreased to 0.004085-0.8643. Our models could be applied to label-free cells to conduct rapid and large-scale tests while minimizing cost and labor, such as high-throughput screening for drug responsiveness.


Assuntos
Algoritmos , Redes Neurais de Computação , Doxorrubicina/farmacologia , Células HEK293 , Humanos , Processamento de Imagem Assistida por Computador/métodos , Concentração Inibidora 50 , Coloração e Rotulagem
6.
Antimicrob Agents Chemother ; 66(4): e0143721, 2022 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-35266828

RESUMO

We measured susceptibilities of Ugandan Plasmodium falciparum isolates assayed on the day of collection or after storage at 4°C. Samples were incubated with serial dilutions of 8 antimalarials, and susceptibilities were determined from 72-h growth inhibition assays. Storage was associated with decreased growth and lower 50% inhibitory concentration values, but differences between assays beginning on day 0 or after 1 or 2 days of storage were modest, indicating that short-term storage before drug susceptibility determination is feasible.


Assuntos
Antimaláricos , Malária Falciparum , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Resistência a Medicamentos , Humanos , Concentração Inibidora 50 , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum , Uganda
7.
Viruses ; 14(2)2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-35215911

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to have a significant impact on global public health. Multiple mechanisms for SARS-CoV-2 cell entry have been described; however, the role of transferrin receptor 1 (TfR1) in SARS-CoV-2 infection has received little attention. We used ferristatin II to induce the degradation of TfR1 on the surface of Vero cells and to study the consequences of such treatment on the viability of the cells and the replication of SARS-CoV-2. We demonstrated that ferristatin II is non-toxic for Vero cells in concentrations up to 400 µM. According to confocal microscopy data, the distribution of the labeled transferrin and receptor-binding domain (RBD) of Spike protein is significantly affected by the 18h pretreatment with 100 µM ferristatin II in culture medium. The uptake of RBD protein is nearly fully inhibited by ferristatin II treatment, although this protein remains bound on the cell surface. The findings were well confirmed by the significant inhibition of the SARS-CoV-2 infection of Vero cells by ferristatin II with IC50 values of 27 µM (for Wuhan D614G virus) and 40 µM (for Delta virus). A significant reduction in the infectious titer of the Omicron SARS-CoV-2 variant was noted at a ferristatin II concentration as low as 6.25 µM. We hypothesize that ferristatin II blocks the TfR1-mediated SARS-CoV-2 host cell entry; however, further studies are needed to elucidate the full mechanisms of this virus inhibition, including the effect of ferristatin II on other SARS-CoV-2 receptors, such as ACE2, Neuropilin-1 and CD147. The inhibition of viral entry by targeting the receptor on the host cells, rather than the viral mutation-prone protein, is a promising COVID-19 therapeutic strategy.


Assuntos
Compostos de Bifenilo/farmacologia , SARS-CoV-2/efeitos dos fármacos , Sulfonas/farmacologia , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , Chlorocebus aethiops , Concentração Inibidora 50 , Ligação Proteica , Domínios Proteicos , Receptores da Transferrina/antagonistas & inibidores , Células Vero
8.
Food Funct ; 13(5): 2456-2464, 2022 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-35147627

RESUMO

Codonopsis pilosula (Franch.) Nannf. (CPN), mainly planted in the northwest region, is a traditional Chinese medicine/good health food for nourishing qi and promoting blood circulation. This study firstly evaluated the inhibitory effects of the CPN extraction (CPNE) on α-glucosidase in vitro and in vivo, and tentatively confirmed its chemical ingredients by employing UHPLC-Triple-TOF-MS/MS. The CPNE had strong inhibitory activities against mammalian α-glucosidase (sucrase and maltase) and yeast α-glycosidase with semi-inhibitory concentrations (IC50) of 0.241 mg mL-1, 0.326 mg mL-1 and 1.167 mg mL-1, respectively. In addition, the CPNE could significantly decrease the postprandial blood glucose (PBG) levels in the sucrose/maltose/starch tolerance assays of diabetic mice. Furthermore, a total of 29 compounds, including 3 alkaloids, 13 phenolic acids, 8 alcohol glycosides and 5 alkynosides, were assigned based on comparison with the standards and references, as well as the analysis of main fragments. These results demonstrated that CPN could be used as an adjuvant therapy or dietary supplements to effectively control the occurrence and development of diabetes.


Assuntos
Codonopsis , Diabetes Mellitus Experimental/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Hipoglicemiantes/farmacologia , Extratos Vegetais/farmacologia , Aloxano , Animais , Animais não Endogâmicos , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/química , Glucosidases/efeitos dos fármacos , Hipoglicemiantes/química , Concentração Inibidora 50 , Masculino , Camundongos , Fitoterapia , Extratos Vegetais/química , Raízes de Plantas
9.
Pharmacol Res Perspect ; 10(1): e00930, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35142090

RESUMO

We and others have shown that aberrant activation of the mammalian target of rapamycin (mTOR) signalling is essential for retinoblastoma progression and has potential therapeutic value. TAK-228 is a potent inhibitor of mTOR1 and 2 with preclinical activity in a variety of cancers. In this study, we report that TAK-228 is a dual inhibitor of retinoblastoma and angiogenesis. TAK-228 inhibits growth and induces apoptosis in a panel of retinoblastoma cell lines, with IC50 at ~0.2 µM. Under the same experimental conditions, TAK-228 was less effective in inhibiting growth and survival in normal retinal and fibroblast cells than retinoblastoma cells. In addition, TAK-228 inhibited retinal endothelial cell capillary network formation, migration, growth and survival. We further demonstrate that TAK-228 inhibits retinoblastoma and retinal angiogenesis through inhibiting mTOR signalling. Rescue studies confirm that mTOR is the target of TAK-228 in both retinoblastoma and retinal endothelial cells. Finally, we confirm the inhibitory effects of TAK-228 on tumor and angiogenesis in retinoblastoma xenograft mouse model. Our findings provide a preclinical rationale to explore TAK-228 as a strategy to treat retinoblastoma and highlight the therapeutic value of targeting mTOR in retinoblastoma.


Assuntos
Antineoplásicos/farmacologia , Benzoxazóis/farmacologia , Pirimidinas/farmacologia , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neovascularização Patológica/tratamento farmacológico , Neoplasias da Retina/patologia , Retinoblastoma/patologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Microbiol Spectr ; 10(1): e0189921, 2022 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-35138140

RESUMO

The free-living amoeba Naegleria fowleri, which typically dwells within warm, freshwater environments, can opportunistically cause primary amoebic meningoencephalitis (PAM), a disease with a mortality rate of >97%. The lack of positive treatment outcomes for PAM has prompted the discovery and development of more effective therapeutics, yet most studies utilize only one or two clinical isolates. The inability to assess possible heterogenic responses to drugs among isolates from various geographical regions hinders progress in the discovery of more effective drugs. Here, we conducted drug efficacy and growth rate determinations for 11 different clinical isolates by applying a previously developed CellTiter-Glo 2.0 screening technique and flow cytometry. We found significant differences in the susceptibilities of these isolates to 7 of 8 drugs tested, all of which make up the cocktail that is recommended to physicians by the U.S. Centers for Disease Control and Prevention. We also discovered significant variances in growth rates among isolates, which draws attention to the differences among the amoeba isolates collected from different patients. Our results demonstrate the need for additional clinical isolates of various genotypes in drug assays and highlight the necessity for more targeted therapeutics with universal efficacy across N. fowleri isolates. Our data establish a needed baseline for drug susceptibility among clinical isolates and provide a segue for future combination therapy studies as well as research related to phenotypic or genetic differences that could shed light on mechanisms of action or predispositions to specific drugs. IMPORTANCE Naegleria fowleri, also known as the brain-eating amoeba, is ubiquitous in warm freshwater and is an opportunistic pathogen that causes primary amoebic meningoencephalitis. Although few cases are described each year, the disease has a case fatality rate of >97%. In most laboratory studies of this organism, only one or two well-adapted lab strains are used; therefore, there is a lack of data to discern if there are major differences in potency of currently used drugs for multiple strains and genotypes of the amoeba. In this study, we found significant differences in the susceptibilities of 11 N. fowleri isolates to 7 of the 8 drugs currently used to treat the disease. The data from this study provide a baseline of drug susceptibility among clinical isolates and suggest that new drugs should be tested on a larger number of isolates in the future.


Assuntos
Antiprotozoários/farmacologia , Naegleria fowleri/efeitos dos fármacos , Naegleria fowleri/crescimento & desenvolvimento , Preparações Farmacêuticas , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Infecções Protozoárias do Sistema Nervoso Central/parasitologia , Descoberta de Drogas , Genótipo , Humanos , Concentração Inibidora 50 , Naegleria fowleri/genética , Naegleria fowleri/isolamento & purificação
11.
Int J Mol Sci ; 23(3)2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-35163062

RESUMO

Triple-negative breast cancer (TNBC) is unresponsive to typical hormonal treatments, causing it to be one of the deadliest forms of breast cancer. Investigating alternative therapies to increase survival rates for this disease is essential. The goal of this study was to assess cytotoxicity and apoptosis mechanisms of prenylated stilbenoids in TNBC cells. The prenylated stilbenoids arachidin-1 (A-1) and arachidin-3 (A-3) are analogs of resveratrol (RES) produced in peanut upon biotic stress. The anticancer activity of A-1 and A-3 isolated from peanut hairy root cultures was determined in TNBC cell lines MDA-MB-231 and MDA-MB-436. After 24 h of treatment, A-1 exhibited higher cytotoxicity than A-3 and RES with approximately 11-fold and six-fold lower IC50, respectively, in MDA-MB-231 cells, and nine-fold and eight-fold lower IC50, respectively, in MDA-MB-436 cells. A-1 did not show significant cytotoxicity in the non-cancerous cell line MCF-10A. While A-1 blocked cell division in G2-M phases in the TNBC cells, it did not affect cell division in MCF-10A cells. Furthermore, A-1 induced caspase-dependent apoptosis through the intrinsic pathway by activating caspase-9 and PARP cleavage, and inhibiting survivin. In conclusion, A-1 merits further research as a potential lead molecule for the treatment of TNBC.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Arachis/química , Caspase 9/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Estilbenos/farmacologia , Neoplasias de Mama Triplo Negativas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Raízes de Plantas/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
12.
Food Funct ; 13(5): 2857-2864, 2022 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-35179535

RESUMO

Two undescribed phenolic glycosides, trochinenols B and C (1 and2), together with four known analogues (3-6), were isolated from the functional tea Trollius chinensis Bunge and their α-glucosidase inhibitory kinetics and mechanisms were investigated. It was found that 1 inhibited α-glucosidase in a noncompetitive manner with an IC50 value of 25.96 µM, while 3 showed a notable inhibitory effect against α-glucosidase in an uncompetitive manner with an IC50 value of 3.14 µM. Analysis of synchronous fluorescence and circular dichroism spectroscopy indicated that the binding of 1 to α-glucosidase led to the rearrangement and conformational alteration of the α-glucosidase enzyme. Furthermore, molecular docking indicated that 1 had a high affinity close to the active site pocket of α-glucosidase and indirectly inhibited the catalytic activity of the enzyme. However, 3 was bound to the entrance part of the active center of α-glucosidase and could hinder the release of the substrate as well as the catalytic reaction product, eventually suppressing the catalytic activity of α-glucosidase.


Assuntos
Inibidores de Glicosídeo Hidrolases/farmacologia , Glicosídeos/farmacologia , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Ranunculaceae , alfa-Glucosidases/efeitos dos fármacos , Flores , Inibidores de Glicosídeo Hidrolases/química , Glicosídeos/química , Glicosídeos/farmacocinética , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Fenóis/química , Fenóis/farmacocinética , Extratos Vegetais/química , Extratos Vegetais/farmacocinética , alfa-Glucosidases/química
13.
Drug Deliv ; 29(1): 624-636, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35174748

RESUMO

Chemodynamic therapy (CDT) by triggering Fenton reaction or Fenton-like reaction to generate hazardous hydroxyl radical (•OH), is a promising strategy to selectively inhibit tumors with higher H2O2 levels and relatively acidic microenvironment. Current Fe-based Fenton nanocatalysts mostly depend on slowly releasing iron ions from Fe or Fe oxide-based nanoparticles, which leads to a limited rate of Fenton reaction. Herein, we employed black phosphorene nanosheets (BPNS), a biocompatible and biodegradable photothermal material, to develop iron-mineralized black phosphorene nanosheet (BPFe) by in situ deposition method for chemodynamic and photothermal combination cancer therapy. This study demonstrated that the BPFe could selectively increase cytotoxic ·OH in tumor cells whereas having no influence on normal cells. The IC50 of BPFe for tested tumor cells was about 3-6 µg/mL, which was at least one order of magnitude lower than previous Fe-based Fenton nanocatalysts. The low H2O2 level in normal mammalian cells guaranteed the rare cytotoxicity of BPFe. Moreover, the combination of photothermal therapy (PTT) with CDT based on BPFe was proved to kill tumors more potently with spatiotemporal accuracy, which exhibited excellent anti-tumor effects in xenografted MCF-7 tumor mice models.


Assuntos
Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Nanoestruturas/química , Neoplasias/patologia , Terapia Fototérmica/métodos , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Química Farmacêutica , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Humanos , Peróxido de Hidrogênio/metabolismo , Concentração Inibidora 50 , Ferro/química , Camundongos , Fósforo/química , Distribuição Aleatória , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Pharm Biol ; 60(1): 427-436, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35175176

RESUMO

CONTEXT: Cyanidin has been shown to have therapeutic potential in osteoarthritis. However, it is unclear whether cyanidin prevents the progression of intervertebral disc degeneration (IVDD). OBJECTIVE: This study evaluates the effects of cyanidin on IVDD in vitro and in vivo. MATERIALS AND METHODS: Nucleus pulposus cells (NPCs) isolated from lumbar IVD of 4-week-old male Sprague-Dawley (SD) rats were exposed to 20 ng/mL IL-1ß, and then treated with different doses (0-120 µM) of cyanidin for 24 h. SD rats were classified into three groups (n = 8) and treated as follows: control (normal saline), IVDD (vehicle), IVDD + cyanidin (50 mg/kg). Cyanidin was administered intraperitoneally for 8 weeks. RESULTS: The IC50 of cyanidin for NPCs was 94.78 µM, and cyanidin had no toxicity at concentrations up to 500 mg/kg in SD rats. Cyanidin inhibited the apoptosis of NPCs induced by IL-1ß (12.73 ± 0.61% vs. 18.54 ± 0.60%), promoted collagen II (0.82-fold) and aggrecan (0.81-fold) expression, while reducing MMP-13 (1.02-fold) and ADAMTS-5 (1.40-fold) expression. Cyanidin increased the formation of autophagosomes in IL-1ß-induced NPCs, and promoted LC3II/LC3I (0.83-fold) and beclin-1 (0.85-fold) expression, which could be reversed by chloroquine. Cyanidin inhibited the phosphorylation of JAK2 (0.47-fold) and STAT3 (0.53-fold) in IL-1ß-induced NPCs. The effects of cyanidin could be enhanced by AG490. Furthermore, cyanidin mitigated disc degeneration in IVDD rats in vivo. DISCUSSION AND CONCLUSIONS: Cyanidin improved the function of NPCs in IVDD by regulating the JAK2/STAT3 pathway, which may provide a novel alternative strategy for IVDD. The mechanism of cyanidin improving IVDD still needs further work for in-depth investigation.


Assuntos
Antocianinas/farmacologia , Apoptose/efeitos dos fármacos , Degeneração do Disco Intervertebral/prevenção & controle , Núcleo Pulposo/efeitos dos fármacos , Animais , Antocianinas/administração & dosagem , Relação Dose-Resposta a Droga , Concentração Inibidora 50 , Interleucina-1beta/administração & dosagem , Janus Quinase 2/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
Int J Mol Sci ; 23(3)2022 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-35163532

RESUMO

Since the beginning of the HIV epidemic, lasting more than 30 years, the main goal of scientists was to develop effective methods for the prevention and treatment of HIV infection. Modern medicines have reduced the death rate from AIDS by 80%. However, they still have side effects and are very expensive, dictating the need to search for new drugs. Earlier, it was shown that phospholipases A2 (PLA2s) from bee and snake venoms block HIV replication, the effect being independent on catalytic PLA2 activity. However, the antiviral activity of human PLA2s against Lentiviruses depended on catalytic function and was mediated through the destruction of the viral membrane. To clarify the role of phospholipolytic activity in antiviral effects, we analyzed the anti-HIV activity of several snake PLA2s and found that the mechanisms of their antiviral activity were similar to that of mammalian PLA2. Our results indicate that snake PLA2s are capable of inhibiting syncytium formation between chronically HIV-infected cells and healthy CD4-positive cells and block HIV binding to cells. However, only dimeric PLA2s had pronounced virucidal and anti-HIV activity, which depended on their catalytic activity. The ability of snake PLA2s to inactivate the virus may provide an additional barrier to HIV infection. Thus, snake PLA2s might be considered as candidates for lead molecules in anti-HIV drug development.


Assuntos
Fármacos Anti-HIV/farmacologia , Linfócitos T CD4-Positivos/citologia , Células Gigantes/citologia , HIV-1/fisiologia , Fosfolipases A2/farmacologia , Venenos de Serpentes/enzimologia , Serpentes/metabolismo , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , Linhagem Celular , Células Cultivadas , Células Gigantes/efeitos dos fármacos , Células Gigantes/virologia , HIV-1/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Proteínas de Répteis/farmacologia , Serpentes/classificação , Ativação Viral/efeitos dos fármacos , Ligação Viral/efeitos dos fármacos
16.
Fitoterapia ; 157: 105139, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35108573

RESUMO

A phytochemical investigation was conducted on Euphorbia helioscopia, resulting in the isolation of thirteen compounds, including nine undescribed diterpenoids, Euphzycopias A - I (1-9), of which the skeletons of compounds 1-4 were found in E. helioscopia L. Compounds 1-3 had 5/7/6 cyclic systems, while compound 4 had a 4/11 polycyclic system with a 4,7-cyclic ether between C-4 and C-7. The anti-inflammasome test using the isolated compounds (1-6, 8-13) showed that the diterpenes from E. helioscopia L. had a strong inhibitory effect on NLRP3 inflammasomes with IC50 values of 3.34-14.92 µM.


Assuntos
Diterpenos/farmacologia , Euphorbia/química , Inflamassomos/farmacologia , Diterpenos/química , Diterpenos/isolamento & purificação , Humanos , Inflamassomos/química , Inflamassomos/isolamento & purificação , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Rotação Ocular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Espectrofotometria Infravermelho
17.
Oxid Med Cell Longev ; 2022: 7969825, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35126821

RESUMO

The present study deals with extracellular synthesis and characterization of copper sulfide (CuS) nanoparticles using Aeromonas hydrophila, and the biological applications of the synthesized CuS like antibacterial, anti-inflammatory, and antioxidant activity were reported. Further, the toxicological effects of the CuS were evaluated using zebrafish as an animal model. The primary step of the synthesis was carried out by adding the precursor copper sulfates to the culture supernatant of Aeromonas hydrophila. The UV-visible spectrophotometer was used to characterize the synthesized nanoparticles, and the peak was obtained at 307 nm through the reduction process. Fourier transform infrared spectroscopy (FTIR) was involved to find out the functional groups (carboxylic acid, alcohols, alkanes, and nitro compounds) associated with copper sulfide nanoparticles (CuS-NPs). Atomic force microscopy (AFM) was used to characterize the CuS topographically, and a scanning electron microscope (SEM) revealed about 200 nm sized CuS nanoparticles with agglomerated structures. Overall, the characterized nanoparticles can be considered as a potential candidate with therapeutic proficiencies as antibacterial, antioxidant, and anti-inflammatory mediator/agents.


Assuntos
Aeromonas hydrophila/metabolismo , Antibacterianos/química , Antibacterianos/toxicidade , Anti-Inflamatórios/química , Anti-Inflamatórios/toxicidade , Antioxidantes/química , Antioxidantes/toxicidade , Cobre/química , Cobre/toxicidade , Nanopartículas Metálicas/química , Nanopartículas Metálicas/toxicidade , Sulfetos/química , Sulfetos/toxicidade , Peixe-Zebra/metabolismo , Animais , Técnicas de Cultura de Células/métodos , Sulfato de Cobre/metabolismo , Eritrócitos/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Microscopia de Força Atômica/métodos , Microscopia Eletrônica de Varredura/métodos , Modelos Animais , Tamanho da Partícula , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Peixe-Zebra/embriologia
18.
Food Funct ; 13(4): 2200-2215, 2022 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-35119449

RESUMO

Multidrug resistance (MDR) is a major cause of chemotherapy failure. Adriamycin (ADR) has been widely used to treat cancer, however, as a substrate of the adenosine triphosphate binding cassette (ABC) transporter, it is easy to develop drug resistance during the treatment. Here, we demonstrated that steroidal saponin S-20 isolated from the berries of black nightshade has comparable cytotoxicity in ADR-sensitive and resistant K562 cell lines. Autophagy is generally considered to be a protective mechanism to mediate MDR during treatment. However, we found that S-20-induced cell death in K562/ADR is associated with autophagy. We further explored the underlying mechanisms and found that S-20 induces caspase-dependent apoptosis in ADR-sensitive and resistant K562 cell lines. Most importantly, S-20-induced autophagy activates the ERK pathway and then inhibits the expression of drug resistance protein, which is the main reason to overcome K562/ADR resistance, rather than apoptosis. Taken together, our findings emphasize that S-20 exerts anti-multidrug resistance activity in K562/ADR cells through autophagic cell death and ERK activation, which may be considered as an effective strategy.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Saponinas/uso terapêutico , Solanum nigrum , Morte Celular/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Frutas , Humanos , Concentração Inibidora 50 , Células K562/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Saponinas/farmacologia
19.
Toxicology ; 468: 153116, 2022 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-35121066

RESUMO

Per- and polyfluoroalkyl substances (PFASs) are a group of synthetic compounds with a wide range of industrial applications. PFOA and PFOS have been the most extensively studied and have been associated with hepatotoxicity. Recently, the interaction with cytochrome P450 (CYP) has been proposed as a potential key molecular event leading to PFAS-induced hepatotoxicity. In the present study, we aimed to determine a structure-activity relationship between thirteen PFASs and their inhibitory potential on the activities of four CYPs (CYP2E1, CYP2D6, CYP3A4 and CYP2C19). The influence of PFASs (5-3200 µM) on CYP enzyme activities was measured using the Vivid® P450 metabolism assays. Using the same assays, Michaelis-Menten saturation curves were determined to explore the type of PFAS-induced CYP inhibition. Most PFASs were capable of inhibiting activity of the tested CYPs, as shown by their IC50 values. CYP2E1 is particularly inhibited by 3:1 FTOH, PFOA, and PFOS, whereas CYP2D6 is inhibited by PFHxS, PFHpA, PFOA, PFOS, PFNA, and PFDA. Additionally, CYP3A4 is most strongly inhibited by PFHxS, PFOA, PFOS, PFNA, and PFDA. Finally, CYP2C19 is inhibited by PFBS, PFHxS, PFHpA, PFOA, PFOS, PFNA, and PFDA. Interestingly, PFHxA and PFHxS induced an increase in CYP2E1 activity, whereas 4:2 FTOH strongly induced CYP2D6 activity. The mechanism of inhibition of CYPs by PFASs differed per CYP isoenzyme. CYP3A4 was competitively inhibited by PFBS, PFHxS, PFOS, PFNA and PFDA and non-competitively by PFOA. Additionally, CYP2C19 was competitively inhibited by PFHxA, PFOS and PFNA, whereas PFBS and PFHxS induced a mixed inhibition. Inhibition of CYP2C19 by PFHpA was atypical with an increased Vmax and a decreased Km. Finally, PFHxS competitively inhibited CYP2D6, whereas PFBS, PFOA, PFOS, PFDA and PFNA induced an atypical inhibition. Our results show that CYP inhibition by PFASs appears to be structure-dependent as well as CYP dependent. Inhibition of CYP2D6, CYP2C19 and CYP3A4 increased with increasing chain-lengths between six and nine carbons. The PFTOHs were only able to inhibit CYP2E1 and did not affect any of the other CYPS. Some PFASs remarkably induced the enzyme activity of CYPs. These results indicate that in addition to PFOA and PFOS, multiple novel PFASs may alter drug metabolism by the interference with CYPs.


Assuntos
Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Fluorcarbonetos/farmacologia , Citocromo P-450 CYP2C19/efeitos dos fármacos , Citocromo P-450 CYP2D6/efeitos dos fármacos , Citocromo P-450 CYP3A/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Concentração Inibidora 50
20.
Eur J Pharmacol ; 919: 174795, 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35122868

RESUMO

N-methyl-D-aspartate (NMDA) receptors are affected by many pharmaceuticals. In this work, we studied the action of the serine protease inhibitors nafamostat, gabexate and camostat, and an antiprotozoal compound, furamidine, on native NMDA receptors in rat hippocampal pyramidal neurons. Nafamostat, furamidine and gabexate inhibited these receptors with IC50 values of 0.20 ± 0.04, 0.64 ± 0.13 and 16 ± 3 µM, respectively, whereas camostat was ineffective. Nafamostat and furamidine showed voltage-dependent inhibition, while gabexate showed practically voltage-independent inhibition. Nafamostat and furamidine demonstrated tail currents, implying a 'foot-in-the-door' mechanism of action; gabexate did not demonstrate any signs of 'foot-in-the-door' or trapping channel block. Gabexate action was also not competitive, suggesting allosteric inhibition of NMDA receptors. Furamidine and nafamostat are structurally similar to the previously studied diminazene and all three demonstrated a 'foot-in-the-door' mechanism. They have a rather rigid, elongated structures and cannot fold into more compact forms. By contrast, the gabexate molecule can fold, but its folded structure differs drastically from that of typical NMDA receptor blockers, in agreement with its voltage-independent inhibition. These findings provide a better understanding of the structural determinants of NMDA receptor antagonism, while also supporting the potential clinical repurposing of these drugs as neuroprotectors for glaucoma and other neurodegenerative diseases.


Assuntos
Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Inibidores de Serino Proteinase/farmacologia , Animais , Benzamidinas/farmacologia , Benzamidinas/uso terapêutico , Reposicionamento de Medicamentos , Ésteres/farmacologia , Ésteres/uso terapêutico , Gabexato/farmacologia , Gabexato/uso terapêutico , Guanidinas/farmacologia , Guanidinas/uso terapêutico , Hipocampo/efeitos dos fármacos , Concentração Inibidora 50 , Masculino , Modelos Animais , Doenças Neurodegenerativas/tratamento farmacológico , Células Piramidais/efeitos dos fármacos , Ratos , Ratos Wistar , Inibidores de Serino Proteinase/uso terapêutico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...