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1.
Chem Res Toxicol ; 36(9): 1532-1548, 2023 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-37594911

RESUMO

Structure-activity relationship (SAR)-based read-across is an important and effective method to establish the safety of a data-poor target chemical (structure of interest (SOI)) using hazard data from structurally similar source chemicals (analogues). Many methods use quantitative similarity scores to evaluate the structural similarity for searching and selecting analogues as well as for evaluating analogue suitability. However, studies suggest that read-across based purely on structural similarity cannot accurately predict the toxicity of an SOI. As mechanistic data become available, we gain a greater understanding of the mode of action (MOA), the relationship between structures and metabolism/bioactivation pathways, and the existence of "activity cliffs" in chemical chain length, which can improve the analogue rating process. For this purpose, the current work identifies a series of classes of chemicals where a small change at a key position can result in a significant change in metabolism and bioactivation pathways and may eventually result in significant changes in chemical toxicity that have a big impact on the suitability of analogues for read-across. Additionally, a series of SAR-based read-across case studies are presented, which cover a variety of chemical classes that commonly link to different toxic endpoints. The case study results indicate that SAR-based read-across can be refined and strengthened by considering MOAs or proposed reactive metabolite formation pathways, which can improve the overall accuracy, consistency, transparency, and confidence in evaluating analogue suitability.


Assuntos
Relação Estrutura-Atividade , Testes de Toxicidade
2.
J Proteome Res ; 16(8): 2729-2742, 2017 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-28644030

RESUMO

Phospholipase C gamma 1 (PLC-γ1) occupies a critically important position in the T-cell signaling pathway. While its functions as a regulator of both Ca2+ signaling and PKC-family kinases are well characterized, PLC-γ1's role in the regulation of early T-cell receptor signaling events is incompletely understood. Activation of the T-cell receptor leads to the formation of a signalosome complex between SLP-76, LAT, PLC-γ1, Itk, and Vav1. Recent studies have revealed the existence of both positive and negative feedback pathways from SLP-76 to the apical kinase in the pathway, Lck. To determine if PLC-γ1 contributes to the regulation of these feedback networks, we performed a quantitative phosphoproteomic analysis of PLC-γ1-deficient T cells. These data revealed a previously unappreciated role for PLC-γ1 in the positive regulation of Zap-70 and T-cell receptor tyrosine phosphorylation. Conversely, PLC-γ1 negatively regulated the phosphorylation of SLP-76-associated proteins, including previously established Lck substrate phosphorylation sites within this complex. While the positive and negative regulatory phosphorylation sites on Lck were largely unchanged, Tyr192 phosphorylation was elevated in Jgamma1. The data supports a model wherein Lck's targeting, but not its kinase activity, is altered by PLC-γ1, possibly through Lck Tyr192 phosphorylation and increased association of the kinase with protein scaffolds SLP-76 and TSAd.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Retroalimentação Fisiológica/fisiologia , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo , Fosfolipase C gama/metabolismo , Fosfoproteínas/fisiologia , Receptores de Antígenos de Linfócitos T/fisiologia , Humanos , Células Jurkat , Fosforilação , Proteínas Tirosina Quinases/metabolismo , Transdução de Sinais , Tirosina/metabolismo , Proteína-Tirosina Quinase ZAP-70/metabolismo
3.
Biosci Biotechnol Biochem ; 81(12): 2301-2306, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29050519

RESUMO

Long non-coding RNA (lncRNA) plasmacytoma variant translocation 1(PVT1) was aberrantly expressed in various cancers and is associated with tumor prognosis. Here, we aim to investigate its function in prostate cancer. Small interfering RNA against PVT1 was transfected into prostate cancer cell lines and cell growth and apoptosis were analyzed. Our results showed that PVT1 was overexpressed in prostate cancer tissues and cells. Higher levels of PVT1 indicated poorer overall survival and disease-free survival. A significant association was found between PVT1 expression and tumor stage. Besides, PVT1 knockdown significantly inhibited prostate cancer growth in vivo and in vitro and promoted cell apoptosis. PVT1 knockdown also significantly upregulated the expression of cleaved caspase-3 and cleaved caspase-9, but downregulated the expression of c-Myc in prostate cancer cell lines. Our results suggest that PVT1 played an oncogenic role in prostate cancer and could be used as a potential biomarker for diagnosis of prostate cancer.


Assuntos
Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , RNA Longo não Codificante/genética , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Técnicas de Silenciamento de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Próstata/genética , RNA Longo não Codificante/metabolismo , Regulação para Cima
4.
Oncoscience ; 8: 120-133, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34926717

RESUMO

Colorectal cancer is the third most common form of cancer diagnosed and the third leading class for cancer-related deaths. Given the prevalence of colon cancer worldwide, further insight into developing novel and effective prevention and treatment strategies are warranted. The family of plant pigments known as the anthocyanins has been identified with a variety of health benefits including chemopreventive and therapeutic effects. A limitation to current clinical applications of anthocyanins is the high doses that are required. In order to overcome this limitation, we tested the active moiety, anthocyanidins for chemopreventive and therapeutic effects against colorectal cancer in vivo and in vitro. Treatment with native anthocyanidin mixture (Anthos) from bilberry yielded significant antiproliferative activity against colon cancer cells. Anthos treatment led to significant reductions in polyp and tumor counts in vivo. Reduced Src and EGFR phosphorylation was observed with Anthos treatment, which correlated with downstream targets such as PD-L1 and modulation of the colon inflammatory environment. These results provide a promising outlook on the impact of berry Anthos for the treatment and prevention of familial adenomatous polyposis and colorectal cancer. Results from this study also provide novel mechanistic insight into the chemopreventive and therapeutic activities of Anthos.

5.
Cancer Prev Res (Phila) ; 13(1): 41-52, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31796466

RESUMO

Diets rich in fat, smoking, as well as exposure to environmental pollutants and dysbiosis of gut microbiota, increase the risk of developing colorectal cancer. Much progress has been made in combating colorectal cancer. However, options for chemoprevention from environmental insult and dysbiosis of gut microbiota remain elusive. We investigated the influence of berry-derived anthocyanidins (Anthos), with and without encapsulating them in bovine milk-derived exosomes (ExoAnthos), on the chemoprevention of bacteria-driven colon tumor development. Anthos and ExoAnthos treatment of colon cancer cells showed dose-dependent decreases in cell viability. Calculated selectivity index (SI) values for Anthos and ExoAnthos suggest that both treatments selectively targeted cancer over normal colon cells. In addition, ExoAnthos treatment yielded higher SI values than Anthos. Anthos and ExoAnthos treatment of ApcMin/+ mice inoculated with enterotoxigenic Bacteriodes fragilis (ETBF) bacteria led to significant decreases in colon tumor numbers over mice receiving vehicle treatments. Western blot analysis of normal colon, colon tumor, and liver tissue lysates showed that mice inoculated with ETBF featured increased expression of phase I enzymes in normal colon tissue and decreased expression of phase II enzymes in liver tissue. Treatment with the Anthos and ExoAnthos reverted the modulation of phase I and phase II enzymes, respectively; no significant changes in phase II enzyme expression occurred in colon tumor tissue. Treatment of HCT-116 cells with the ubiquitous carcinogen, benzo[a]pyrene (B[a]P) led to similar modulation of phase I and II enzymes, which was partially mitigated by treatment with Anthos. These results provide a promising outlook on the impact of berry Anthos for prevention and treatment of bacteria- and B[a]P-driven colorectal cancer.


Assuntos
Antocianinas/administração & dosagem , Neoplasias do Colo/prevenção & controle , Disbiose/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Neoplasias Experimentais/prevenção & controle , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Antocianinas/isolamento & purificação , Bacteroides fragilis/patogenicidade , Benzo(a)pireno/toxicidade , Carcinogênese/induzido quimicamente , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinógenos/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/microbiologia , Colo/patologia , Neoplasias do Colo/etiologia , Portadores de Fármacos/química , Disbiose/metabolismo , Disbiose/microbiologia , Disbiose/patologia , Exossomos/química , Frutas/química , Microbioma Gastrointestinal/fisiologia , Células HCT116 , Células HT29 , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Camundongos , Leite/citologia , Neoplasias Experimentais/etiologia , Vaccinium myrtillus/química
6.
Cancer Lett ; 393: 94-102, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28202351

RESUMO

Over the last two decades, berries and berry bioactives, particularly anthocyanins and their aglycones anthocyanidins (Anthos) have demonstrated excellent anti-oxidant, anti-proliferative, apoptotic and anti-inflammatory properties. However, their physicochemical and pharmacokinetic limitations such as, low permeability, and poor oral bioavailability are considered as unfavorable properties for development as drugs. Therefore there is a need to develop systems for efficient systemic delivery and robust bioavailability. In this study we prepared nano-formulation of bilberry-derived Anthos using exosomes harvested from raw bovine milk. Exosomal formulation of Anthos enhanced antiproliferative and anti-inflammatory effects compared with the free Anthos against various cancer cells in vitro. Our data also showed significantly enhanced therapeutic response of exosomal-Anthos formulation compared with the free Anthos against lung cancer tumor xenograft in nude mice. The Anthos showed no signs of gross or systemic toxicity in wild-type mice. Thus, exosomes provide an effective alternative for oral delivery of Anthos that is efficacious, cost-effective, and safe, and this regimen can be developed as a non-toxic, widely applicable therapeutic agent.


Assuntos
Antocianinas/farmacologia , Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Portadores de Fármacos , Exossomos/química , Leite/química , Células A549 , Administração Oral , Animais , Antocianinas/química , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Composição de Medicamentos , Feminino , Células HCT116 , Humanos , Células MCF-7 , Masculino , Camundongos Nus , Leite/toxicidade , Nanopartículas , Fatores de Tempo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
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