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1.
Oncol Rep ; 47(3)2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35039878

RESUMO

Therapeutic approaches that target the metabolism of tumor cells have been a popular research topic in recent years. Previous studies have demonstrated that glycolysis inhibitors reduce the proliferation of non­small cell lung cancer (NSCLC) cells by interfering with the aerobic glycolytic pathway. However, the mitochondrial oxidative phosphorylation (OXPHOS) pathway in tumor cells has also been implicated in lung cancer metabolism. Metformin, a known inhibitor of mitochondrial OXPHOS, has been indicated to reduce NSCLC morbidity and mortality in clinical studies. The present article reviewed the therapeutic effects of metformin against NSCLC, both as a single agent and combined with other anticancer treatments, in order to provide a theoretical basis for its clinical use in adjuvant therapy for NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Glicólise/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Metformina/farmacologia , Mitocôndrias/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quimioterapia Combinada , Humanos , Hipoglicemiantes/farmacologia
2.
World J Microbiol Biotechnol ; 38(2): 34, 2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-34989900

RESUMO

Formic acid is a representative small molecule acid in lignocellulosic hydrolysate that can inhibit the growth of Saccharomyces cerevisiae cells during alcohol fermentation. However, the mechanism of formic acid cytotoxicity remains largely unknown. In this study, RNA-Seq technology was used to study the response of S. cerevisiae to formic acid stress at the transcriptional level. Scanning electron microscopy and Fourier transform infrared spectroscopy were conducted to observe the surface morphology of yeast cells. A total of 1504 genes were identified as being differentially expressed, with 797 upregulated and 707 downregulated genes. Transcriptomic analysis showed that most genes related to glycolysis, glycogen synthesis, protein degradation, the cell cycle, the MAPK signaling pathway, and redox regulation were significantly induced under formic acid stress and were involved in protein translation and synthesis amino acid synthesis genes were significantly suppressed. Formic acid stress can induce oxidative stress, inhibit protein biosynthesis, cause cells to undergo autophagy, and activate the intracellular metabolic pathways of energy production. The increase of glycogen and the decrease of energy consumption metabolism may be important in the adaptation of S. cerevisiae to formic acid. In addition, formic acid can also induce sexual reproduction and spore formation. This study through transcriptome analysis has preliminarily reveal the molecular response mechanism of S. cerevisiae to formic acid stress and has provided a basis for further research on methods used to improve the tolerance to cell inhibitors in lignocellulose hydrolysate.


Assuntos
Formiatos/farmacologia , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Transcriptoma , Ciclo Celular , Tolerância a Medicamentos , Metabolismo Energético , Fermentação , Perfilação da Expressão Gênica/métodos , Regulação Fúngica da Expressão Gênica , Glicólise , Lignina , Estresse Oxidativo/efeitos dos fármacos , Biossíntese de Proteínas , RNA-Seq , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Estresse Fisiológico/genética
3.
J Toxicol Sci ; 47(1): 13-18, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34987137

RESUMO

The liver microphysiological system (MPS) model is an in-vitro culture method that mimics physiological blood flow, which enhances basal cellular functions. However, the liver MPS model has not been tested in the preclinical stage because of its obscure utility. It can overcome the major problem of conventional systems-rapid loss of mitochondrial activity in cultured hepatocytes due to limited oxygen supply-by supplying oxygen to cultured hepatocytes using a perfusion device. In this study, we developed a new perfusion culture system that can detect mitochondrial toxicity. Primary mouse hepatocytes were cultured under perfusion condition for 48 hr. The hepatocytes showed increased oxygen consumption and reduced lactate release. These results indicated that the ATP-production pathway was switched from glycolysis to mitochondrial oxidative phosphorylation in the perfusion culture system. Furthermore, ATP levels were considerably reduced in the perfusion culture system after exposure to phenformin, a mitochondrial complex I inhibitor. To summarize, the perfusion culture system could improve the mitochondrial activity in primary mouse hepatocytes, and thus, has potential implications in the detection of mitochondrial toxicity.


Assuntos
Hepatócitos , Fosforilação Oxidativa , Animais , Células Cultivadas , Glicólise , Fígado/metabolismo , Camundongos , Consumo de Oxigênio , Perfusão
4.
Eur J Radiol ; 146: 110107, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34922117

RESUMO

PURPOSE: The 2-fluorodeoxyglucose positron emission tomography/computed tomography (2-[18F]FDG PET/CT) is used for the evaluation of response to immunotherapy in malignant melanoma. Here, we evaluated the prognostic value of various metabolic parameters in baseline and different time points after therapy. METHODS: In this retrospective study, 51 metastatic melanoma patients, who had received immunotherapy, were included. Patients with baseline and two follow-up 2-[18F]FDG PET/CT studies (3 and 6 months after therapy) were selected. Multiple metabolic parameters and tumor-to-background ratios (TBRs) were extracted and correlated with OS. RESULTS: The 3- and 5-year OS rates were 49% and 43.1%, respectively. On baseline 2-[18F]FDG PET/CT, only standardized uptake value corrected for lean body mass (SULmax and SULpeak), as well as most of the TBRs were predictive for 3- and 5-year OS rates. Metabolic tumor volume (MTV), total lesion glycolysis (TLG), and most of the TBRs were predictive on both follow-up studies. Also, the changes in values of MTV, TLG and most of the TBRs from the baseline to the 3-month and 6- month follow-up studies were prognostic. On multivariate analysis, all of the most predictive parameters for OS were derived from the 3-month follow-up study. The ratio of TBRmean to the mediastinum was the best factor (cutoff value of 2.15, sensitivity of 88.5% and specificity of 68.0% for 3-year survival). CONCLUSION: Metabolic parameters derived from 2-[18F]FDG PET/CT are valuable tools for the prediction of 3- and 5-year OS rates in metastatic melanoma patients undergoing immunotherapy. The 3-month follow-up 2-[18F]FDG PET/CT is of particular importance in this regard.


Assuntos
Melanoma , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Fluordesoxiglucose F18 , Seguimentos , Glicólise , Humanos , Imunoterapia , Melanoma/diagnóstico por imagem , Melanoma/terapia , Prognóstico , Estudos Retrospectivos , Carga Tumoral
5.
Endocrinology ; 163(1)2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34614512

RESUMO

Estrogen and estrogen receptor (ER) play a fundamental role in breast cancer. To support the rapid proliferation of ER+ breast cancer cells, estrogen increases glucose uptake and reprograms glucose metabolism. Meanwhile, estrogen/ER activates the anticipatory unfolded protein response (UPR) preparing cancer cells for the increased protein production required for subsequent cell proliferation. Here, we report that thioredoxin-interacting protein (TXNIP) is an important regulator of glucose metabolism in ER+ breast cancer cells, and estrogen/ER increases glucose uptake and reprograms glucose metabolism via activating anticipatory UPR and subsequently repressing TXNIP expression. In 2 widely used ER+ breast cancer cell lines, MCF7 and T47D, we showed that MCF7 cells express high TXNIP levels and exhibit mitochondrial oxidative phosphorylation (OXPHOS) phenotype, while T47D cells express low TXNIP levels and display aerobic glycolysis (Warburg effect) phenotype. Knockdown of TXNIP promoted glucose uptake and Warburg effect, while forced overexpression of TXNIP inhibited glucose uptake and Warburg effect. We further showed that estrogen represses TXNIP expression and activates UPR sensor inositol-requiring enzyme 1 (IRE1) via ER in the breast cancer cells, and IRE1 activity is required for estrogen suppression of TXNIP expression and estrogen-induced cell proliferation. Our study suggests that TXNIP is involved in estrogen-induced glucose uptake and metabolic reprogramming in ER+ breast cancer cells and links anticipatory UPR to estrogen reprogramming glucose metabolism.


Assuntos
Neoplasias da Mama/metabolismo , Proteínas de Transporte/metabolismo , Estrogênios/metabolismo , Glucose/metabolismo , Resposta a Proteínas não Dobradas/fisiologia , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Endorribonucleases/metabolismo , Feminino , Glicólise , Humanos , Metabolismo dos Lipídeos , Células MCF-7 , Mitocôndrias/metabolismo , Organoides/metabolismo , Fosforilação Oxidativa , Fenótipo , RNA Interferente Pequeno/metabolismo , Receptores de Estrogênio/metabolismo
6.
Anticancer Res ; 42(1): 589-598, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34969768

RESUMO

BACKGROUND/AIM: We previously identified KS40008 (4-(3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzene-1,2-diol), a novel inhibitor of dual-specificity tyrosine phosphorylation-regulated kinase family (DYRK) 1A/B, which exhibited high enzymatic activity and cell proliferation-inhibitory effects in colorectal cancer (CRC) cell lines. In the present study, we aimed to elucidate the antitumor mechanisms of KS40008. MATERIALS AND METHODS: To assess the cytotoxicity of KS40008, we utilized a human cell line and organoid model and performed a CCK-8 assay and real-time cell analysis. Mitochondrial function was determined through mitochondrial staining, mito-stress test, and glycolysis test. In addition, we investigated the mechanisms of cancer cell death induced by KS40008 through immunoblotting, real-time quantitative polymerase chain reaction, reactive oxygen species staining, and immunofluorescence staining. RESULTS: KS40008 exhibited significant cytotoxicity in CRC and non-CRC cell lines, and organoid models compared to 5-fluorouracil, a conventional chemotherapeutic drug. Moreover, KS40008-induced inhibition of DYRK1A/B led to mitochondrial dysfunction and endoplasmic reticulum stress, promoting autophagic cancer cell death. CONCLUSION: KS40008 exerts antitumor activity through the inhibition of DYRK1A/B. Here, we demonstrated a mechanism by which KS40008 affects endoplasmic reticulum stress-mediated autophagy through the induction of mitochondrial stress, leading to cytotoxicity in CRC.


Assuntos
Morte Celular Autofágica/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Proteínas Tirosina Quinases/genética , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Reprogramação Celular/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/genética , Fluoruracila/farmacologia , Glicólise/efeitos dos fármacos , Humanos , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos , Proteínas Tirosina Quinases/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Life Sci ; 289: 120233, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34921865

RESUMO

Tributyltin (TBT), an endocrine disruptor is used globally in agribusiness and industries as biocides, heat stabilizers, and in chemical catalysis. It is known for its deleterious effects on bone by negatively impacting the functions of osteoblasts, osteoclasts and mesenchymal stem cells. However, the impact of TBT on the metabolomics profile in bone is not yet studied. Here, we demonstrate alterations in chemical metabolomics profiles measured by solid state 1H nuclear magnetic resonance (1H NMR) spectroscopy in zebrafish bone following tributyltin (TBT) treatment. TBT of 0, 100, 200, 300, 400 and 500 µg/L were exposed to zebrafish. From this, zebrafish bone has subjected for further metabolomics profiling. Samples were measured via one-dimensional (1D) solvent -suppressed and T2- filtered methods with in vivo zebrafish metabolites. A dose dependent alteration in the metabolomics profile was observed and results indicated a disturbed aminoacid metabolism, TCA cycle, and glycolysis. We found a significant alteration in the levels of glutamate, glutamine, glutathione, trimethylamine N-oxide (TMAO), and other metabolites. This investigation hints us the deleterious effects of TBT on zebrafish bone enabling a comprehensive understanding of metabolomics profile and is expected to play a crucial role in understanding the deleterious effects of various endocrine disruptor on bone.


Assuntos
Osso e Ossos/metabolismo , Disruptores Endócrinos/toxicidade , Metabolômica , Ressonância Magnética Nuclear Biomolecular , Compostos de Trialquitina/toxicidade , Peixe-Zebra/metabolismo , Aminoácidos/metabolismo , Animais , Ciclo do Ácido Cítrico/efeitos dos fármacos , Glicólise/efeitos dos fármacos
8.
Environ Pollut ; 295: 118708, 2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-34929209

RESUMO

Benzene is a common environmental carcinogen that induces leukemia. Studies suggest that metabolic disorder has a relationship with the toxicity of benzene. Pyruvate kinase M2 (PKM2) is a key rate-limiting enzyme in glycolysis. However, the upstream and downstream regulatory mechanisms of PKM2 in benzene-induced hematotoxicity and the therapeutic effects of targeting PKM2 in vivo are unclear. This study aims to provide insights into the new mechanism of benzene-induced hematotoxicity and reveal the therapeutic significance of targeting PKM2. Herein, we demonstrated that PKM2-dependent glycolysis contributes to benzene-induced hematotoxicity by regulating inflammation reaction. Mechanistically, acetylated proteomics revealed that 1,4-benzoquinone (1,4-BQ) induced acetylation of PKM2 at position K66, and this modification contributed to the increase of PKM2 expression and can be inhibited by inhibition of acetyltransferase GCN5. Meanwhile, the elevated PKM2 was shown to prompt the activation of nuclear phosphorylated Stat3 (p-Stat3) and IL17A. Clinically, pharmacological inhibition of PKM2 alleviated the blood toxicity induced by benzene, which was mainly characterized by an increase in routine blood parameters and improvement of hematopoietic imbalance. Besides, elevated PKM2 is a promising biomarker in people occupationally exposed to benzene. Overall, we identified PKM2/p-Stat3/IL-17A axis participates in the hematotoxicity of benzene, and targeting PKM2 has certain therapeutic implications in hematologic diseases.


Assuntos
Benzeno , Piruvato Quinase , Acetilação , Benzeno/toxicidade , Glicólise , Humanos , Inflamação/induzido quimicamente , Interleucina-17 , Piruvato Quinase/metabolismo , Fator de Transcrição STAT3/metabolismo
9.
Ecotoxicol Environ Saf ; 229: 113098, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34952379

RESUMO

Chronic exposure to arsenic has been associated with a variety of cancers with the mechanisms undefined. Arsenic exposure causes alterations in metabolites in bio-samples. Recent research progress on cancer biology suggests that metabolic reprogramming contributes to tumorigenesis. Therefore, metabolic reprogramming provides a new clue for the mechanisms of arsenic carcinogenesis. In the present manuscript, we review the latest findings in reprogramming of glucose, lipids, and amino acids in response to arsenic exposure. Most studies focused on glucose reprogramming and found that arsenic exposure enhanced glycolysis. However, in vivo studies observed "reverse Warburg effect" in some cases due to the complexity of the disease evolution and microenvironment. Arsenic exposure has been reported to disturb lipid deposition by inhibiting lipolysis, and induce serine-glycine one-carbon pathway. As a dominant mechanism for arsenic toxicity, oxidative stress is considered to link with metabolism reprogramming. Few studies analyzed the causal relationship between metabolic reprogramming and arsenic-induced cancers. Metabolic alterations may vary with exposure doses and periods. Identifying metabolic alterations common among humans and experiment models with human-relevant exposure characteristics may guide future investigations.


Assuntos
Arsênio , Neoplasias , Arsênio/toxicidade , Carcinogênese , Transformação Celular Neoplásica , Glicólise , Humanos , Neoplasias/induzido quimicamente , Microambiente Tumoral
10.
Methods Mol Biol ; 2343: 57-70, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34473315

RESUMO

Phosphoglycerate kinase 1 (PGK1) is the first enzyme in glycolysis to generate a molecule of ATP in the conversion of 1,3-bisphosphoglycerate (1,3-BPG) to 3-phosphoglycerate (3-PG). In addition to the role of glycolysis, PGK-1 acts as a polymerase alpha cofactor protein, with effects on the tricarboxylic acid cycle, DNA replication and repair. Posttranslational modifications such as methylation, phosphorylation, and acetylation have been seen to activate PGK1 in cancer. High levels of intracellular PGK1 are associated with tumorigenesis and progression, and chemoradiotherapy resistance. However, high levels of extracellular PGK1 suppress angiogenesis and subsequently counteract cancer malignancy. Here we have summarized the current knowledge on the mechanisms and effects of PGK1 in various tumor types and evaluated its potential prognostic and therapeutic value in cancer. The data summarized here aims at providing molecular information and new ideas of employing natural products to combat cancer associated with PGK1.


Assuntos
Neoplasias , Fosfoglicerato Quinase , Carcinogênese , Glicólise , Humanos , Neoplasias/genética , Fosfoglicerato Quinase/genética , Fosfoglicerato Quinase/metabolismo , Fosforilação
11.
J Hazard Mater ; 422: 126859, 2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-34449335

RESUMO

Phytoremediation is a cost-effective and environmentally-friendly method to treat cadmium (Cd) contaminated soils, however, there is still a lack of safe disposal methods of harvested hyperaccumulators. In this study, by integrating glycolysis and pyrolysis, we investigated the possibility of bioproduct production and Cd collection from the hyperaccumulator Sedum alfredii. By means of acid-alkali pretreatment, the degree of cellulose polymerization was reduced by 36.24% while the surface accessibility was increased by 115.80%, resulting in a bioethanol yield of 9.29%. Meanwhile, 99.22% of total Cd of biomass could be reclaimed by collecting H2SO4-pretreatment waste. The saccharification residue was subsequently modified by NaOH-pretreatment-filtrate and converted into biochar at 500 °C which possessed a maximum Cd2+ sorption capacity of 60.52 mg g-1 based on the Langmuir model. Furthermore, sustainability analysis indicated that the economic input of this process is acceptable when considering its good environmental benefits. Taken together, our study provides a strategy for simultaneous bioethanol and biochar production during Cd collection from the hyperaccumulator S. alfredii, which could be a promising alternative for the suitable treatment of metal-enriched plants.


Assuntos
Sedum , Poluentes do Solo , Biodegradação Ambiental , Cádmio/análise , Glicólise , Raízes de Plantas/química , Pirólise , Poluentes do Solo/análise
12.
Gene ; 809: 146012, 2022 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-34655719

RESUMO

Cancer cells rewire metabolic pathways as they demand more ATP and building blocks for proliferation. Glucose is the most consumed nutrient by cancer cells and metabolized to lactate even in the presence of oxygen. This phenomenon is called 'aerobic glycolysis'. Also, glucose level is found lower in tumor environment. Leukemia is characterized by abnormal proliferation of hematopoietic cells. STAT3 a transcription factor and an oncogene is upregulated in many tumor types. Despite its well-defined functions, STAT3 has also been proposed as a metabolic regulator. In this study, we aimed to determine the role STAT3 activation in glucose limitation, in leukemia cell lines. K562, NB-4 and HL-60 cells were found sensitive to glucose limitation. In low glucose conditions, total and nuclear STAT3 protein was decreased in all cells. In mitochondria, S727 phosphorylated STAT3 (mitochondrial form) was determined slightly increased in K562 and NB-4 cells. On the other side, ectopically STAT3 expressing cells had increased glucose consumption and less proliferated in low glucose medium. This data suggests that aerobic glycolysis might be upregulated upon STAT3 expression in leukemia cells, in glucose limitation. Furthermore, in this study, it was found that GLUT3 expressing cells did not reduce STAT3 expression in low glucose medium. GLUT3 was previously determined as a molecular marker for cell sensitivity to glucose limitation, therefore, it could be hypothesized as GLUT3 expressing cells might not need to alter STAT3 expression in low glucose level. Overall, our data suggest that leukemia cells rewire glucose metabolism via STAT3 expression in glucose limitation. Elucidating pathways that cause differential phosphorylation of STAT3 and its interaction with other energy regulating pathways in cellular response to glucose limitation might be beneficial to design new drug targets such as STAT3 inhibitors for leukemia treatment.


Assuntos
Glucose/metabolismo , Leucemia/metabolismo , Fator de Transcrição STAT3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Meios de Cultura/química , Regulação para Baixo , Regulação Leucêmica da Expressão Gênica , Transportador de Glucose Tipo 3/metabolismo , Glicólise/fisiologia , Células HL-60 , Humanos , Células K562 , Leucemia/genética , Leucemia/patologia , Mitocôndrias/metabolismo , Fator de Transcrição STAT3/genética
13.
BMC Vet Res ; 17(1): 382, 2021 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-34895222

RESUMO

BACKGROUND: Malignant melanoma in dogs is considered to be largely resistant to conventional chemotherapy, although responses to carboplatin have been documented. Invasion and early metastasis are common features of certain melanoma subtypes that contribute to tumour progression despite aggressive local and systemic therapy. Upregulation of the PI3K/AKT/mTOR pathway has been observed in canine malignant melanoma and may represent a potential target for therapy. Rapamycin (sirolimus) and everolimus are commercially available small molecule inhibitors that target mTOR and therefore may have anticancer activity in canine melanoma. It was hypothesized that there is synergism between rapamycin or everolimus and platinum chemotherapy, and that combination drug treatment would inhibit target/downstream proteins involved in cell viability/proliferation and increase cell death in canine melanoma cells. It was further hypothesized that rapamycin or everolimus would impact metabolism by reducing glycolysis in these cells. Four canine melanoma cell lines were treated in vitro with rapamycin and everolimus as sole treatment or combined with carboplatin. Cell viability, apoptosis, target modulation, and glycolytic metabolism were evaluated by crystal violet colourimetric assay, Annexin V/PI flow cytometry, western blotting, and Seahorse bioanalyzer, respectively. RESULTS: When combined with carboplatin chemotherapy, rapamycin or everolimus treatment was overall synergistic in reducing cell viability. Carboplatin-induced apoptosis was noted at 72 h after treatment compared to the vehicle control. Levels of phosphorylated mTOR were reduced by rapamycin and everolimus in all four cell lines, but activation of the downstream protein p70S6K was not consistently reduced by treatment in two of the cell lines. Both mTOR inhibitors decreased the extracellular acidification rate of canine melanoma cells, indicating reduced cancer cell glycolytic activity. CONCLUSIONS: Inhibition of mTOR by rapalogs, such as rapamycin and everolimus combined with carboplatin chemotherapy may have activity in canine melanoma. Future mechanistic investigation is warranted, including in vivo assessment of this combination therapy.


Assuntos
Carboplatina , Doenças do Cão , Everolimo , Melanoma , Sirolimo , Animais , Apoptose/efeitos dos fármacos , Carboplatina/farmacologia , Carboplatina/uso terapêutico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Doenças do Cão/tratamento farmacológico , Cães , Quimioterapia Combinada/veterinária , Everolimo/farmacologia , Everolimo/uso terapêutico , Glicólise/efeitos dos fármacos , Melanoma/tratamento farmacológico , Melanoma/veterinária , Sirolimo/farmacologia , Sirolimo/uso terapêutico
14.
Cells ; 10(12)2021 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-34944072

RESUMO

BACKGROUND: Tissue-resident macrophages have mixed developmental origins. They derive in variable extent from yolk sac (YS) hematopoiesis during embryonic development. Bone marrow (BM) hematopoietic progenitors give rise to tissue macrophages in postnatal life, and their contribution increases upon organ injury. Since the phenotype and functions of macrophages are modulated by the tissue of residence, the impact of their origin and developmental paths has remained incompletely understood. METHODS: In order to decipher cell-intrinsic macrophage programs, we immortalized hematopoietic progenitors from YS and BM using conditional HoxB8, and carried out an in-depth functional and molecular analysis of differentiated macrophages. RESULTS: While YS and BM macrophages demonstrate close similarities in terms of cellular growth, differentiation, cell death susceptibility and phagocytic properties, they display differences in cell metabolism, expression of inflammatory markers and inflammasome activation. Reduced abundance of PYCARD (ASC) and CASPASE-1 proteins in YS macrophages abrogated interleukin-1ß production in response to canonical and non-canonical inflammasome activation. CONCLUSIONS: Macrophage ontogeny is associated with distinct cellular programs and immune response. Our findings contribute to the understanding of the regulation and programming of macrophage functions.


Assuntos
Medula Óssea/patologia , Inflamação/patologia , Macrófagos/patologia , Saco Vitelino/patologia , Animais , Diferenciação Celular/genética , Proliferação de Células , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Glicólise , Células HEK293 , Células-Tronco Hematopoéticas/patologia , Proteínas de Homeodomínio/metabolismo , Humanos , Inflamassomos/metabolismo , Camundongos Endogâmicos C57BL , Fagocitose , Proteoma/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Transcriptoma/genética
15.
Biomolecules ; 11(12)2021 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-34944395

RESUMO

A number of aggressive human malignant tumors are characterized by an intensified glycolytic rate, over-expression of lactic acid dehydrogenase A (LDHA), and subsequent lactate accumulation, all of which contribute toward an acidic peri-cellular immunosuppressive tumor microenvironment (TME). While recent focus has been directed at how to inhibit LDHA, it is now becoming clear that multiple isozymes of LDH must be simultaneously inhibited in order to fully suppress lactic acid and halt glycolysis. In this work we explore the biochemical and genomic consequences of an applied triple LDH isozyme inhibitor (A, B, and C) (GNE-140) in MDA-MB-231 triple-negative breast cancer cells (TNBC) cells. The findings confirm that GNE-140 does in fact, fully block the production of lactic acid, which also results in a block of glucose utilization and severe impedance of the glycolytic pathway. Without a fully functional glycolytic pathway, breast cancer cells continue to thrive, sustain viability, produce ample energy, and maintain mitochondrial potential (ΔΨM). The only observable negative consequence of GNE-140 in this work, was the attenuation of cell division, evident in both 2D and 3D cultures and occurring in fully viable cells. Of important note, the cytostatic effects were not reversed by the addition of exogenous (+) lactic acid. While the effects of GNE-140 on the whole transcriptome were mild (12 up-regulated differential expressed genes (DEGs); 77 down-regulated DEGs) out of the 48,226 evaluated, the down-regulated DEGS collectively centered around a loss of genes related to mitosis, cell cycle, GO/G1-G1/S transition, and DNA replication. These data were also observed with digital florescence cytometry and flow cytometry, both corroborating a G0/G1 phase blockage. In conclusion, the findings in this work suggest there is an unknown element linking LDH enzyme activity to cell cycle progression, and this factor is completely independent of lactic acid. The data also establish that complete inhibition of LDH in cancer cells is not a detriment to cell viability or basic production of energy.


Assuntos
Citostáticos/farmacologia , Ácido Láctico/metabolismo , Piridonas/farmacologia , Tiofenos/farmacologia , Neoplasias de Mama Triplo Negativas/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Glicólise , Ensaios de Triagem em Larga Escala , Humanos , Ácido Láctico/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Microambiente Tumoral/efeitos dos fármacos
16.
Int J Mol Sci ; 22(24)2021 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-34948132

RESUMO

The microenvironment plays a vital role in tumor progression, and hypoxia is a typical microenvironment feature in nearly all solid tumors. In this study, we focused on elucidating the effect of canagliflozin (CANA), a new class of antidiabetic agents, on hepatocarcinoma (HCC) tumorigenesis under hypoxia, and demonstrated that CANA could significantly inhibit hypoxia-induced metastasis, angiogenesis, and metabolic reprogramming in HCC. At the molecular level, this was accompanied by a reduction in VEGF expression level, as well as a reduction in the epithelial-to-mesenchymal transition (EMT)-related proteins and glycolysis-related proteins. Next, we focused our study particularly on the modulation of HIF-1α by CANA, which revealed that CANA decreased HIF-1α protein level by inhibiting its synthesis without affecting its proteasomal degradation. Furthermore, the AKT/mTOR pathway, which plays an important role in HIF-1α transcription and translation, was also inhibited by CANA. Thus, it can be concluded that CANA decreased metastasis, angiogenesis, and metabolic reprogramming in HCC by inhibiting HIF-1α protein accumulation, probably by targeting the AKT/mTOR pathway. Based on our results, we propose that CANA should be evaluated as a new treatment modality for liver cancer.


Assuntos
Canagliflozina/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Glicólise/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/genética , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Camundongos SCID , Metástase Neoplásica , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Serina-Treonina Quinases TOR/genética , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Biomolecules ; 11(12)2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34944532

RESUMO

It has been considered that proline dehydrogenase/proline oxidase (PRODH/POX) is involved in antineoplastic activity of metformin (MET). The aim of this study is identification of key metabolites of glycolysis, pentose phosphate pathway (PPP), tricarboxylic acids (TCA), urea cycles (UC) and some amino acids in MET-treated MCF-7 cells and PRODH/POX-knocked out MCF-7 (MCF-7crPOX) cells. MCF-7crPOX cells were generated by using CRISPR-Cas9. Targeted metabolomics was performed by LC-MS/MS/QqQ. Expression of pro-apoptotic proteins was evaluated by Western blot. In the absence of glutamine, MET treatment or PRODH/POX-knock out of MCF-7 cells contributed to similar inhibition of glycolysis (drastic increase in intracellular glucose and pyruvate) and increase in the utilization of phospho-enol-pyruvic acid, glucose-6-phosphate and some metabolites of TCA and UC, contributing to apoptosis. However, in the presence of glutamine, MET treatment or PRODH/POX-knock out of MCF-7 cells contributed to utilization of some studied metabolites (except glucose), facilitating pro-survival phenotype of MCF-7 cells in these conditions. It suggests that MET treatment or PRODH/POX-knock out induce similar metabolic effects (glucose starvation) and glycolysis is tightly linked to glutamine metabolism in MCF-7 breast cancer cells. The data provide insight into mechanism of anticancer activity of MET as an approach to further studies on experimental breast cancer therapy.


Assuntos
Neoplasias da Mama/metabolismo , Glutamina/metabolismo , Metabolômica/métodos , Metformina/farmacologia , Prolina Oxidase/genética , Apoptose , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Cromatografia Líquida , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Inativação de Genes , Glicólise/efeitos dos fármacos , Humanos , Células MCF-7 , Via de Pentose Fosfato/efeitos dos fármacos , Espectrometria de Massas em Tandem , Ácidos Tricarboxílicos/metabolismo , Ureia/metabolismo
18.
Cell Rep ; 37(6): 109920, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34731648

RESUMO

It is urgent to develop disease models to dissect mechanisms regulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we derive airway organoids from human pluripotent stem cells (hPSC-AOs). The hPSC-AOs, particularly ciliated-like cells, are permissive to SARS-CoV-2 infection. Using this platform, we perform a high content screen and identify GW6471, which blocks SARS-CoV-2 infection. GW6471 can also block infection of the B.1.351 SARS-CoV-2 variant. RNA sequencing (RNA-seq) analysis suggests that GW6471 blocks SARS-CoV-2 infection at least in part by inhibiting hypoxia inducible factor 1 subunit alpha (HIF1α), which is further validated by chemical inhibitor and genetic perturbation targeting HIF1α. Metabolic profiling identifies decreased rates of glycolysis upon GW6471 treatment, consistent with transcriptome profiling. Finally, xanthohumol, 5-(tetradecyloxy)-2-furoic acid, and ND-646, three compounds that suppress fatty acid biosynthesis, also block SARS-CoV-2 infection. Together, a high content screen coupled with transcriptome and metabolic profiling reveals a key role of the HIF1α-glycolysis axis in mediating SARS-CoV-2 infection of human airway epithelium.


Assuntos
COVID-19/metabolismo , Glicólise/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pulmão/metabolismo , Organoides/metabolismo , Animais , Linhagem Celular , Chlorocebus aethiops , Células Epiteliais/metabolismo , Células HEK293 , Humanos , Células-Tronco Pluripotentes/metabolismo , SARS-CoV-2/patogenicidade , Transcriptoma/fisiologia , Células Vero
19.
Pestic Biochem Physiol ; 179: 104961, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34802511

RESUMO

As a typical glycolytic inhibitor, 3-bromopyruvate (3-BrPA) has been extensively studied in cancer therapy in recent decades. However, few studies focused on 3-BrPA in regulating the growth and development of insects, and the relationship and regulatory mechanism between glycolysis and chitin biosynthesis remain largely unknown. The Hyphantria cunea, named fall webworm, is a notorious defoliator, which caused a huge economic loss to agriculture and forestry. Here, we investigated the effects of 3-BrPA on the growth and development, glycolysis, carbohydrate homeostasis, as well as chitin synthesis in H. cunea larvae. To elucidate the action mechanism of 3-BrPA on H. cunea will provide a new insight for the control of this pest. The results showed that 3-BrPA dramatically restrained the growth and development of H. cunea larvae and resulted in larval lethality. Meanwhile, we confirmed that 3-BrPA caused a significant decrease in carbohydrate, adenosine triphosphate (ATP), pyruvic acid (PA), and triglyceride (TG) levels by inhibiting glycolysis in H. cunea larvae. Further studies indicated that 3-BrPA significantly affected the activities of hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), glucose 6-phosphate dehydrogenase (G6PDH) and trehalase, as well as expressions of the genes related to glycolysis, resulting in carbohydrate homeostasis disorder. Moreover, it was found that 3-BrPA enhanced 20-hydroxyecdysone (20E) signaling by upregulating HcCYP306A1 and HcCYP314A1, two critical genes in 20E synthesis pathway, and accelerated chitin synthesis by upregulating transcriptional levels of genes in the chitin synthesis pathway in H. cunea larvae. Taken together, our findings provide a novel insight into the mechanism of glycolytic inhibitor in regulating the growth and development of insects, and lay a foundation for the potential application of glycolytic inhibitors in pest control as well.


Assuntos
Carboidratos , Glicólise , Animais , Homeostase , Larva , Piruvatos
20.
Sensors (Basel) ; 21(22)2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34833506

RESUMO

The aim of this study was to apply biosensors in the assessment of meat quality. The research was carried out on 20 samples of the Longissimus muscle obtained from pork of Polish Landrace and Polish Large White hybrids of fattening pigs. In the samples, 48 h after slaughter pH values, color parameters in the CIE system (L* a* b*), the volume of natural drip loss and intramuscular fat content were measured. The commercially available biosensor Accutrend Plus was used to measure glucose, triglycerides and lactic acid in meat juice. Significant (p ≤ 0.05) relationships between glucose, triglycerides, lactic acid levels and pork quality characteristics, i.e., pH (r = -0.62; r = -0.78; r = -0.68 respectively), natural drip loss and (r = 0.57; r = 0.58; r = 0.49), color parameters as L*, a* and b* (r = from 0.47 to 0.79) were demonstrated. The study showed a negative correlation between the intramuscular fat content and acidification of muscle tissue (r = -0.49), and a positive one with the brightness of color (r = 0.46). The results of the canonical analysis show that the measurement of all three metabolites in muscle juice allows the evaluation of the technological quality of meat with an accuracy of 86.54% (Rc = 0.93, p < 0.01).


Assuntos
Técnicas Biossensoriais , Glicólise , Animais , Ácido Láctico , Carne/análise , Músculo Esquelético , Suínos
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