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1.
Metabolomics ; 19(9): 80, 2023 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-37690093

RESUMO

INTRODUCTION: Lung cancer is one of the most malignant cancers and the leading cause of cancer-related deaths worldwide, while acquired chemoresistance would represent a major problem in the treatment of non-small cell lung cancer (NSCLC) because of the reduced treatment effect and increased rates of recurrence. METHODS: To establish the chemoresistant NSCLC cells, doxorubicin was treated to A549 cells over 3 months at gradually increasing concentrations from 0.03 to 0.5 µM. Real-time PCR and Western blotting were employed for investigating mRNA and protein expression of the glutathione peroxidase (GPX) protein family and multidrug resistance protein 1 (MRP1) in A549 and A549/CR cells. We also employed gas chromatography mass-spectrometry and nano electrospray ionization mass-spectrometry coupled with multivariate statistical analysis to characterize the unique metabolic and lipidomic profiles of chemoresistant NSCLC cells in order to identify potential therapeutic targets. RESULTS: Reactive oxygen species levels were decreased, and mRNA and protein levels of GPX2 and multidrug resistance protein 1 (MRP1) were increased in A549/CR. We identified 87 metabolites and intact lipid species in A549 and A549/CR. Among these metabolites, lactic acid, glutamic acid, glycine, proline, aspartic acid, succinic acid, and ceramide, alongside the PC to PE ratio, and arachidonic acid-containing phospholipids were suggested as characteristic features of chemoresistant NSCLC cells (A549/CR). CONCLUSIONS: This study reveals characteristic feature differences between drug-resistance NSCLC cells and their parental cells. We suggest potential therapeutic targets in chemoresistant NSCLC. Our results provide new insight into metabolic and lipidomic alterations in chemoresistant NSCLC. This could be used as fundamental information to develop therapeutic strategies for the treatment of chemoresistant NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Lipidômica , Metabolômica
2.
FASEB J ; 36(2): e22127, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35066937

RESUMO

Lung cancer has the highest incidence and mortality rates among all types of cancer worldwide, and 80%-85% of patients with lung cancer are diagnosed with non-small cell lung cancer (NSCLC), which has 5-year survival rate of only 5% at advanced stages. Development of new therapeutic agents and strategies is required to enhance the treatment efficiency in patients with NSCLC. Metabolic alterations and anticancer effects of plant hormones and their derivatives have not been investigated in NSCLC in vitro and in vivo. The present study investigated the cytotoxic effects of 11 plant hormones and their derivatives against NSCLC cell lines; ortho-topolin riboside (oTR) showed the highest cytotoxicity among all tested compounds against NSCLC cells. Alteration of metabolites and lipids was investigated using gas chromatography-mass spectrometry and nano electrospray ionization-mass spectrometry in oTR-treated NSCLC cells and a xenograft mouse model. oTR reduced amino acid and pyrimidine synthesis in NSCLC cells and xenograft tumors. Moreover, oTR reduced glycolytic function and decreased mitochondrial respiration function by inhibiting glutamine and fatty acid oxidation. Increased levels of phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine species suggested that oTR might act as a fatty acid oxidation inhibitor. In addition, the increased level of phosphatidylserine species implied that phosphatidylserine-mediated apoptosis occurred in oTR-treated NSCLC cells and xenograft tumor. The antiproliferative and apoptotic effects of oTR were mediated by the reduced p-ERK and p-AKT levels and increased cleaved Caspase-3 levels, respectively. This is the first study to investigate the metabolic alterations and anticancer activity of oTR in in vitro and in vivo models of NSCLC. Our results provide basis for the development of oTR-based therapeutic agent for patients with NSCLC.


Assuntos
Antineoplásicos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Citocininas/metabolismo , Neoplasias Pulmonares/metabolismo , Metaboloma/fisiologia , Células A549 , Animais , Apoptose/fisiologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/metabolismo
3.
BMC Plant Biol ; 22(1): 545, 2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36434529

RESUMO

BACKGROUND: Lemna species are cosmopolitan floating plants that have great application potential in the food/feed, pharmaceutical, phytoremediation, biofuel, and bioplastic industries. In this study, the effects of exogenous melatonin (0.1, 1, and 10 µM) on the growth and production of various bioactive metabolites and intact lipid species were investigated in Lemna aequinoctialis culture. RESULTS: Melatonin treatment significantly enhanced the growth (total dry weight) of the Lemna aequinoctialis culture. Melatonin treatment also increased cellular production of metabolites including ß-alanine, ascorbic acid, aspartic acid, citric acid, chlorophyll, glutamic acid, phytosterols, serotonin, and sucrose, and intact lipid species; digalactosyldiacylglycerols, monogalactosyldiacylglycerols, phosphatidylinositols, and sulfoquinovosyldiacylglycerols. Among those metabolites, the productivity of campesterol (1.79 mg/L) and stigmasterol (10.94 mg/L) were the highest at day 28, when 10 µM melatonin was treated at day 7. CONCLUSION: These results suggest that melatonin treatment could be employed for enhanced production of biomass or various bioactive metabolites and intact lipid species in large-scale L. aequinoctialis cultivation as a resource for food, feed, and pharmaceutical industries.


Assuntos
Araceae , Melatonina , Melatonina/farmacologia , Melatonina/metabolismo , Lipidômica , Biodegradação Ambiental , Lipídeos
4.
J Appl Toxicol ; 40(7): 1004-1013, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32084307

RESUMO

Amiodarone is known to induce hepatic injury in some recipients. We applied an untargeted metabolomics approach to identify endogenous metabolites with potential as biomarkers for amiodarone-induced liver injury. Oral amiodarone administration for 1 week in rats resulted in significant elevation of acylcarnitines and phospholipids in the liver. Hepatic short- and medium-chain acylcarnitines were dramatically increased in a dose-dependent manner, while the serum levels of these acylcarnitines did not change substantially. In addition, glucose levels were significantly increased in both the serum and liver. Gene expression profiling showed that the hepatic mRNA levels of Cpt1, Cpt2, and Acat1 were significantly suppressed, whereas those of Acot1, Acly, Acss2, and Acsl3 were increased. These results suggest that hepatic acylcarnitines and glucose levels might be increased due to disruption of mitochondrial function and suppression of glucose metabolism. Perturbation of energy metabolism might be associated with amiodarone-induced hepatotoxicity.


Assuntos
Amiodarona/toxicidade , Biomarcadores/metabolismo , Carnitina/sangue , Carnitina/genética , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Fígado/metabolismo , RNA Mensageiro , Administração Oral , Amiodarona/administração & dosagem , Animais , Variação Genética , Masculino , Metabolômica , Ratos , Ratos Sprague-Dawley
5.
Anal Bioanal Chem ; 411(21): 5423-5436, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31161326

RESUMO

It is necessary to characterize and classify neural stem cells (NSCs) and differentiated cells (DCs) for potential use of NSC to treat neurodegenerative diseases. We therefore performed an analysis of NSCs and DCs using gas chromatography mass spectrometry (GC-MS) and direct infusion mass spectrometry (DI-MS) with elaborate multivariate statistical analysis for the characterization and classification of rat NSCs and DCs. GC-MS and DI-MS detected a total of 92 metabolites and lipids in NSCs and DCs, and the levels of 72 of them differed significantly between NSCs and DCs. The optimal model for partial least squares (PLS) discriminant analysis was constructed by applying 3 and 2 PLS components with a unit-variance scaling method for classifying NSCs and DCs based on the data obtained in the GC-MS and DI-MS analyses, respectively. The obtained results from PCA and PLS-DA suggest that creatinine, lactic acid, lysine, glutamine, glycine, pyroglutamic acid, PG 18:1/20:2, PS 18:0/20:2, PI 18:0/20:3, PC 16:0/20:4, PI 16:0/20:4, and PI 18:1/20:4 were the main contributors that provided distinct characteristics of NSCs and DCs. The results of this study suggest objective and complementary criteria for the characterization and classification of NSCs and DCs for potential clinical applications. Graphical abstract.


Assuntos
Diferenciação Celular , Metabolismo dos Lipídeos , Células-Tronco Neurais/classificação , Células-Tronco Neurais/citologia , Animais , Células Cultivadas , Análise Discriminante , Cromatografia Gasosa-Espectrometria de Massas/métodos , Análise dos Mínimos Quadrados , Espectrometria de Massas/métodos , Análise de Componente Principal , Ratos , Ratos Sprague-Dawley
6.
Chem Biol Interact ; 391: 110900, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38325522

RESUMO

Lung cancer is a highly prevalent and lethal malignancy worldwide, with non-small cell lung cancer (NSCLC) accounting for 85% of cancer-related deaths. In this study, the effects of co-treatment with melatonin and ortho-topolin riboside (oTR) on the cell viability and alteration of metabolites and transcripts were investigated in NSCLC cells using gas chromatography-mass spectrometry (GC-MS) and next-generation sequencing (NGS). The co-treatment of melatonin and oTR exhibited synergistic effects on the reduction of cell viability and alteration of metabolic and transcriptomic profiles in NSCLC cells. We observed that the co-treatment inhibited glycolytic function and mitochondria respiration, and downregulated glycine, serine and threonine metabolism alongside tyrosine metabolism in NSCLC cells. In the glycine, serine and threonine metabolism pathway, the co-treatment resulted in a significant 8.4-fold reduction in the expression level of the SDS gene, which encodes the enzyme responsible for the breakdown of serine to pyruvate. Moreover, co-treatment decreased the gene expression of TH, DDC, and CYP1A1 in tyrosine metabolism. Additionally, we observed that the co-treatment resulted in a significant 146.9-fold reduction in the expression of the DISC1 gene. The alteration in metabolites and transcript expressions might provide information to explain the cytotoxicity of co-treatment of melatonin and oTR in NSCLC cells. Our study presents insights into the synergistic anticancer effect of the co-treatment of melatonin and oTR, which could be a potential future therapeutic strategy for the treatment of NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Citocininas , Neoplasias Pulmonares , Melatonina , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Melatonina/farmacologia , Melatonina/uso terapêutico , Sobrevivência Celular , Metaboloma , Glicina/metabolismo , Glicina/farmacologia , Glicina/uso terapêutico , Serina/metabolismo , Treonina/metabolismo , Tirosina/metabolismo , Linhagem Celular Tumoral
7.
Metabolites ; 13(4)2023 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-37110136

RESUMO

The endogenous factors that control the differentiation of myeloid-derived suppressor cells (MDSCs) are not yet fully understood. The purpose of this study was to find MDSC-specific biomolecules through comprehensive metabolomic and lipidomic profiling of MDSCs from tumor-bearing mice and to discover potential therapeutic targets for MDSCs. Partial least squares discriminant analysis was performed on the metabolomic and lipidomic profiles. The results showed that inputs for the serine, glycine, and one-carbon pathway and putrescine are increased in bone marrow (BM) MDSC compared to normal BM cells. Splenic MDSC showed an increased phosphatidylcholine to phosphatidylethanolamine ratio and less de novo lipogenesis products, despite increased glucose concentration. Furthermore, tryptophan was found to be at the lowest concentration in splenic MDSC. In particular, it was found that the concentration of glucose in splenic MDSC was significantly increased, while that of glucose 6-phosphate was not changed. Among the proteins involved in glucose metabolism, GLUT1 was overexpressed during MDSC differentiation but decreased through the normal maturation process. In conclusion, high glucose concentration was found to be an MDSC-specific feature, and it was attributed to GLUT1 overexpression. These results will help to develop new therapeutic targets for MDSCs.

8.
J Pharm Biomed Anal ; 208: 114449, 2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-34749107

RESUMO

To provide preliminary insights into metabolic and lipidomic characteristics in radioresistant triple-negative breast cancer (TNBC) cells and suggest potential therapeutic targets, we performed a comprehensive metabolic and lipidomic profiling of radioresistant MDA-MB-231 (MDA-MB-231/RR) TNBC cells and their parental cells using gas chromatography-mass spectrometry and nano electrospray ionization-mass spectrometry, followed by multivariate statistical analysis. Buthionine sulfoximine (BSO) and radiation were co-treated to radioresistant TNBC cells. The level of glutathione (GSH) was significantly increased, and the levels of GSH synthesis-related metabolites, such as cysteine, glycine, and glutamine were also increased in MDA-MB-231/RR cells. In contrast, the level of lactic acid was significantly reduced. In addition, reactive oxygen species (ROS) level was decreased in MDA-MB-231/RR cells. In the lipidomic profiles of MDA-MB-231/RR cells, the levels of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were significantly increased, whereas those of most of the phosphatidylinositol species were significantly decreased. BSO sensitized MDA-MB-231/RR cells to radiotherapy, which resulted in decreased GSH level and increased ROS level and apoptosis. Radioresistant TNBC cells showed distinct metabolic and lipidomic characteristics compared to their parental cells. We suggested activated GSH, PC, and PE biosynthesis pathways as potential targets for treating radioresistant TNBC cells. Particularly, enhanced radiosensitivity was achieved by inhibition of GSH biosynthesis in MDA-MB-231/RR cells.


Assuntos
Lipidômica , Neoplasias de Mama Triplo Negativas , Apoptose , Linhagem Celular Tumoral , Humanos , Espécies Reativas de Oxigênio , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
9.
Food Sci Biotechnol ; 31(10): 1325-1334, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35992320

RESUMO

Beyond probiotics, the interest in the application of postbiotics to various fields has been growing. We aimed to develop a novel postbiotic complex (PC) with antibacterial and anti-inflammatory properties. Through antibacterial activity testing against Staphylococcus aureus or Cutibacterium acnes, a PC [a mixture of cell-free supernatants (postbiotics) from probiotic Lactobacillus helveticus (HY7801) and Lactococcus lactis (HY449)] was developed. Anti-inflammatory activity of the PC was investigated using HaCaT keratinocytes treated with S. aureus or C. acnes. PC significantly decreased IL-8 levels and increased hyaluronic acid levels in HaCaT cells cultured with S. aureus or C. acnes. GC-MS based metabolic profiling suggested 2-hydroxyisocaproic acid, hypoxanthine, succinic acid, ornithine, and γ-aminobutyric acid as potential contributing metabolites for the antibacterial and anti-inflammatory effects of PC. The PC developed in this study could be utilized in food, cosmetics, and pharmaceutical products as an alternative or complementary resources of probiotics. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-022-01123-x.

10.
Cancers (Basel) ; 13(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34439333

RESUMO

SQCC is a major type of NSCLC, which is a major cause of cancer-related deaths, and there were no reports regarding the prediction of metastatic potential of lung SQCC by metabolomic and lipidomic profiling. In this study, metabolomic and lipidomic profiling of lung SQCC were performed to predict its metastatic potential and to suggest potential therapeutic targets for the inhibition of lung SQCC metastasis. Human bronchial epithelial cells and four lung SQCC cell lines with different metastatic potentials were analyzed using gas chromatography-mass spectrometry and direct infusion-mass spectrometry. Based on the obtained metabolic and lipidomic profiles, we constructed models to predict the metastatic potential of lung SQCC; glycerol, putrescine, ß-alanine, hypoxanthine, inosine, myo-inositol, phosphatidylinositol (PI) 18:1/18:1, and PI 18:1/20:4 were suggested as characteristic metabolites and intact lipid species associated with lung SQCC metastatic potential. In this study, we established predictive models for the metastatic potential of lung SQCC; furthermore, we identified metabolites and intact lipid species relevant to lung SQCC metastatic potential that may serve as potential therapeutic targets for the inhibition of lung SQCC metastasis.

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