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1.
Int J Mol Sci ; 22(6)2021 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-33803555

RESUMEN

In this study, detailed information on hepatocellular carcinoma (HCC) cells (HepG-2, SMMC-7721, and HuH-7) and normal human liver cell L02 treated by ferrocene derivatives (compounds 1, 2 and 3) is provided. The cell viability assay showed that compound 1 presented the most potent and selective anti-HCC activity. Further mechanism study indicated that the proliferation inhibition effect of compound 1 was associated with the cycle arrest at the G0/G1 phase and downregulation of cyclin D1/CDK4. Moreover, compound 1 could induce apoptosis in HCC cells by loss of mitochondrial membrane potential (ΔΨm), accumulation of reactive oxygen species (ROS), decrease in Bcl-2, increase in BAX and Bad, translocation of Cytochrome c, activation of Caspase-9, -3, and cleavage of PARP. These results indicated that compound 1 would be a promising candidate against HCC through G0/G1 cell cycle arrest-related proliferation inhibition and mitochondrial pathway-dependent apoptosis.


Asunto(s)
Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/patología , Compuestos Ferrosos/farmacología , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Neoplasias Hepáticas/patología , Metalocenos/farmacología , Mitocondrias/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Citocromos c/metabolismo , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Modelos Biológicos , Especies Reactivas de Oxígeno/metabolismo , Fase de Descanso del Ciclo Celular/efectos de los fármacos
2.
Anticancer Res ; 41(4): 1831-1840, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813388

RESUMEN

BACKGROUND/AIM: Peroxiredoxin V (Prx V) plays crucial roles in cellular apoptosis and proliferation in various cancer cells by regulating the cellular reactive oxygen species (ROS) levels. MATERIALS AND METHODS: Here, we examined the possible regulatory effects of Prx V on doxorubicin (DOX)-induced cellular apoptosis and its mechanisms in the human gastric adenocarcinoma cell line (AGS cells). RESULTS: Our findings suggest that Prx V knockdown may significantly increase the DOX-induced apoptosis by aggravating intracellular ROS accumulation. We also found that DOX-induced mitochondrial ROS levels and membrane permeability were significantly higher in short hairpin Prx V cells than in mock cells, and these phenomena were dramatically reversed by ROS scavenger treatment. Prx V knockdown also significantly upregulated the cleaved caspase 9, 3, and B-cell lymphoma 2 (Bcl2)-associated agonist of cell death/Bcl2 protein expression levels, suggesting that Prx V knockdown activates mitochondria-dependent apoptotic signaling pathways. CONCLUSION: Taken together, this study suggests that Prx V may be a strong molecular target for gastric cancer (GC) chemotherapy, and further elucidates the role of Prx V in oxidative stress-induced cell apoptosis.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antibióticos Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Doxorrubicina/farmacología , Silenciador del Gen , Mitocondrias/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Peroxirredoxinas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/enzimología , Adenocarcinoma/genética , Adenocarcinoma/patología , Proteínas Reguladoras de la Apoptosis/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Humanos , Mitocondrias/enzimología , Mitocondrias/patología , Peroxirredoxinas/genética , Transducción de Señal , Neoplasias Gástricas/enzimología , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología
3.
Int J Mol Sci ; 22(5)2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33804447

RESUMEN

Interleukin (IL)-1ß is an important pro-inflammatory cytokine in the progression of osteoarthritis (OA), which impairs mitochondrial function and induces the production of nitric oxide (NO) in chondrocytes. The aim was to investigate if blockade of NO production prevents IL-1ß-induced mitochondrial dysfunction in chondrocytes and whether cAMP and AMP-activated protein kinase (AMPK) affects NO production and mitochondrial function. Isolated human OA chondrocytes were stimulated with IL-1ß in combination with/without forskolin, L-NIL, AMPK activator or inhibitor. The release of NO, IL-6, PGE2, MMP3, and the expression of iNOS were measured by ELISA or Western blot. Parameters of mitochondrial respiration were measured using a seahorse analyzer. IL-1ß significantly induced NO release and mitochondrial dysfunction. Inhibition of iNOS by L-NIL prevented IL-1ß-induced NO release and mitochondrial dysfunction but not IL-1ß-induced release of IL-6, PGE2, and MMP3. Enhancement of cAMP by forskolin reduced IL-1ß-induced NO release and prevented IL-1ß-induced mitochondrial impairment. Activation of AMPK increased IL-1ß-induced NO production and the negative impact of IL-1ß on mitochondrial respiration, whereas inhibition of AMPK had the opposite effects. NO is critically involved in the IL-1ß-induced impairment of mitochondrial respiration in human OA chondrocytes. Increased intracellular cAMP or inhibition of AMPK prevented both IL-1ß-induced NO release and mitochondrial dysfunction.


Asunto(s)
Condrocitos/efectos de los fármacos , Inflamación/prevención & control , Interleucina-1beta/farmacología , Mitocondrias/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Osteoartritis de la Rodilla/prevención & control , Células Cultivadas , Condrocitos/metabolismo , Condrocitos/patología , Femenino , Humanos , Inflamación/etiología , Inflamación/metabolismo , Inflamación/patología , Masculino , Persona de Mediana Edad , Mitocondrias/metabolismo , Mitocondrias/patología , FN-kappa B/genética , FN-kappa B/metabolismo , Osteoartritis de la Rodilla/inducido químicamente , Osteoartritis de la Rodilla/metabolismo , Osteoartritis de la Rodilla/patología
4.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-33802591

RESUMEN

Mitochondrial apoptosis is one of the main mechanisms for cancer cells to overcome chemoresistance. Hexokinase 2 (HK2) can resist cancer cell apoptosis by expressing on mitochondria and binding to voltage-dependent anion channel 1 (VDAC1). We previously reported that peroxisome proliferator-activated receptor coactivator 1 α (PGC1α) is highly expressed in ovarian cancer cisplatin-resistant cells. However, the underlying mechanism remains unclear. Therefore, we evaluated the interaction between PGC1α and HK2 in ovarian cancer cisplatin-resistant cells. We found that the knockdown of PGC1α promotes the apoptosis of ovarian cancer cisplatin-resistant cells and increases their sensitivity to cisplatin. In addition, we found that the knockdown of PGC1α affects the mitochondrial membrane potential and the binding of HK2 and VDAC1. As the heat shock protein 70 (HSP70) family can help protein transport, we detected it and found that PGC1α can promote HSP70 gene transcription. Furthermore, HSP70 can promote an increase of HK2 expression on mitochondria and an increase of binding to VDAC1. Based on these results, PGC1α may reduce apoptosis through the HSP70/HK2/VDAC1 signaling pathway, thus promoting cisplatin resistance of ovarian cancer. These findings provide strong theoretical support for PGC1α as a potential therapeutic target of cisplatin resistance in ovarian cancer.


Asunto(s)
Cisplatino/farmacología , Resistencia a Antineoplásicos/fisiología , Mitocondrias/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Transducción de Señal/efectos de los fármacos , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Femenino , Proteínas del Choque Térmico HSP72/metabolismo , Hexoquinasa/metabolismo , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Potencial de la Membrana Mitocondrial/fisiología , Mitocondrias/efectos de los fármacos , Transducción de Señal/fisiología , Canal Aniónico 1 Dependiente del Voltaje/metabolismo
5.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-33806369

RESUMEN

Isothiazolinone (IT) biocides are potent antibacterial substances commonly used as preservatives or disinfectants, and 2-n-Octyl-4-isothiazolin-3-one (OIT; octhilinone) is a common IT biocide that is present in leather products, glue, paints, and cleaning products. Although humans are exposed to OIT through personal and industrial use, the potentially deleterious effects of OIT on human health are still unknown. To investigate the effects of OIT on the vascular system, which is continuously exposed to xenobiotics through systemic circulation, we treated brain endothelial cells with OIT. OIT treatment significantly activated caspase-3-mediated apoptosis and reduced the bioenergetic function of mitochondria in a bEnd.3 cell-based in vitro blood-brain barrier (BBB) model. Interestingly, OIT significantly altered the thiol redox status, as evidenced by reduced glutathione levels and protein S-nitrosylation. The endothelial barrier function of bEnd.3 cells was significantly impaired by OIT treatment. OIT affected mitochondrial dynamics through mitophagy and altered mitochondrial morphology in bEnd.3 cells. N-acetyl cysteine significantly reversed the effects of OIT on the metabolic capacity and endothelial function of bEnd.3 cells. Taken together, we demonstrated that the alteration of the thiol redox status and mitochondrial damage contributed to OIT-induced BBB dysfunction, and we hope that our findings will improve our understanding of the potential hazardous health effects of IT biocides.


Asunto(s)
Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Desinfectantes/toxicidad , Tiazoles/toxicidad , Acetilcisteína/farmacología , Animales , Antioxidantes/farmacología , Barrera Hematoencefálica/patología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Muerte Celular/efectos de los fármacos , Línea Celular , Desinfectantes/antagonistas & inhibidores , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Metabolismo Energético/efectos de los fármacos , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/patología , Proteolisis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Compuestos de Sulfhidrilo/metabolismo , Tiazoles/antagonistas & inhibidores , Proteínas de Uniones Estrechas/metabolismo
6.
Nat Commun ; 12(1): 1980, 2021 03 31.
Artículo en Inglés | MEDLINE | ID: mdl-33790300

RESUMEN

The majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. Mitochondrial abnormalities have also been reported, but the contribution of type I IFN exposure to these changes is unknown. Here, we show downregulation of mitochondria-derived genes and mitochondria-associated metabolic pathways in IFN-High patients from transcriptomic analysis of CD4+ and CD8+ T cells. CD8+ T cells from these patients have enlarged mitochondria and lower spare respiratory capacity associated with increased cell death upon rechallenge with TCR stimulation. These mitochondrial abnormalities can be phenocopied by exposing CD8+ T cells from healthy volunteers to type I IFN and TCR stimulation. Mechanistically these 'SLE-like' conditions increase CD8+ T cell NAD+ consumption resulting in impaired mitochondrial respiration and reduced cell viability, both of which can be rectified by NAD+ supplementation. Our data suggest that type I IFN exposure contributes to SLE pathogenesis by promoting CD8+ T cell death via metabolic rewiring.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Perfilación de la Expresión Génica/métodos , Interferón Tipo I/inmunología , Lupus Eritematoso Sistémico/inmunología , Adulto , Anciano , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/metabolismo , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Femenino , Humanos , Interferón Tipo I/metabolismo , Interferón Tipo I/farmacología , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/metabolismo , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Redes y Vías Metabólicas/genética , Persona de Mediana Edad , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Mitocondrias/metabolismo , Adulto Joven
7.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-33800867

RESUMEN

During tissue injury events, the innate immune system responds immediately to alarms sent from the injured cells, and the adaptive immune system subsequently joins in the inflammatory reaction. The control mechanism of each immune reaction relies on the orchestration of different types of T cells and the activators, antigen-presenting cells, co-stimulatory molecules, and cytokines. Mitochondria are an intracellular signaling organelle and energy plant, which supply the energy requirement of the immune system and maintain the system activation with the production of reactive oxygen species (ROS). Extracellular mitochondria can elicit regenerative effects or serve as an activator of the immune cells to eliminate the damaged cells. Recent clarification of the cytosolic escape of mitochondrial DNA triggering innate immunity underscores the pivotal role of mitochondria in inflammation-related diseases. Human mesenchymal stem cells could transfer mitochondria through nanotubular structures to defective mitochondrial DNA cells. In recent years, mitochondrial therapy has shown promise in treating heart ischemic events, Parkinson's disease, and fulminating hepatitis. Taken together, these results emphasize the emerging role of mitochondria in immune-cell-mediated tissue regeneration and ageing.


Asunto(s)
Envejecimiento/inmunología , Células Presentadoras de Antígenos/inmunología , Subgrupos de Linfocitos B/inmunología , Mitocondrias/fisiología , Regeneración/inmunología , Subgrupos de Linfocitos T/inmunología , Inmunidad Adaptativa , Animales , Citocinas/fisiología , ADN/metabolismo , ADN Mitocondrial/metabolismo , Reposicionamiento de Medicamentos , Péptido 1 Similar al Glucagón/agonistas , Homeostasis , Humanos , Inmunidad Innata , Inflamación , Péptidos y Proteínas de Señalización Intercelular/fisiología , Lupus Eritematoso Sistémico/tratamiento farmacológico , Metformina/farmacología , Metformina/uso terapéutico , Mitocondrias/efectos de los fármacos , Proteínas Mitocondriales/fisiología , Especies Reactivas de Oxígeno/metabolismo , Inmunología del Trasplante , Heridas y Traumatismos/inmunología , Heridas y Traumatismos/fisiopatología
8.
Int J Mol Sci ; 22(6)2021 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-33810024

RESUMEN

Pharmacologic cardiac conditioning increases the intrinsic resistance against ischemia and reperfusion (I/R) injury. The cardiac conditioning response is mediated via complex signaling networks. These networks have been an intriguing research field for decades, largely advancing our knowledge on cardiac signaling beyond the conditioning response. The centerpieces of this system are the mitochondria, a dynamic organelle, almost acting as a cell within the cell. Mitochondria comprise a plethora of functions at the crossroads of cell death or survival. These include the maintenance of aerobic ATP production and redox signaling, closely entwined with mitochondrial calcium handling and mitochondrial permeability transition. Moreover, mitochondria host pathways of programmed cell death impact the inflammatory response and contain their own mechanisms of fusion and fission (division). These act as quality control mechanisms in cellular ageing, release of pro-apoptotic factors and mitophagy. Furthermore, recently identified mechanisms of mitochondrial regeneration can increase the capacity for oxidative phosphorylation, decrease oxidative stress and might help to beneficially impact myocardial remodeling, as well as invigorate the heart against subsequent ischemic insults. The current review highlights different pathways and unresolved questions surrounding mitochondria in myocardial I/R injury and pharmacological cardiac conditioning.


Asunto(s)
Precondicionamiento Isquémico Miocárdico , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Isquemia Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Adenosina Trifosfato/biosíntesis , Animales , Muerte Celular/efectos de los fármacos , Humanos , Precondicionamiento Isquémico Miocárdico/métodos , Dinámicas Mitocondriales/efectos de los fármacos , Isquemia Miocárdica/tratamiento farmacológico , Isquemia Miocárdica/etiología , Daño por Reperfusión Miocárdica/etiología , Daño por Reperfusión Miocárdica/prevención & control , Miocardio/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Fosforilación Oxidativa/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Regeneración , Transducción de Señal/efectos de los fármacos , Investigación en Medicina Traslacional
9.
Int J Mol Sci ; 22(6)2021 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-33810045

RESUMEN

Melanoma is a highly metastatic disease with an increasing rate of incidence worldwide. It is treatment refractory and has poor clinical prognosis; therefore, the development of new therapeutic agents for metastatic melanoma are urgently required. In this study, we created a lung-seeking A375LM5IF4g/Luc BRAFV600E mutant melanoma cell clone and investigated the bioefficacy of a plant sesquiterpene lactone deoxyelephantopin (DET) and its novel semi-synthetic derivative, DETD-35, in suppressing metastatic A375LM5IF4g/Luc melanoma growth in vitro and in a xenograft mouse model. DET and DETD-35 treatment inhibited A375LM5IF4g/Luc cell proliferation, and induced G2/M cell-cycle arrest and apoptosis. Furthermore, A375LM5IF4g/Luc exhibited clonogenic, metastatic and invasive abilities, and several A375LM5IF4g/Luc metastasis markers, N-cadherin, MMP2, vimentin and integrin α4 were significantly suppressed by treatment with either compound. Interestingly, DET- and DETD-35-induced Reactive Oxygen Species (ROS) generation and glutathione (GSH) depletion were found to be upstream events important for the in vitro activities, because exogenous GSH supplementation blunted DET and DETD-35 effects on A375LM5IF4g/Luc cells. DET and DETD-35 also induced mitochondrial DNA mutation, superoxide production, mitochondrial bioenergetics dysfunction, and mitochondrial protein deregulation. Most importantly, DET and DETD-35 inhibited lung metastasis of A375LM5IF4g/Luc in NOD/SCID mice through inhibiting pulmonary vascular permeability and melanoma cell (Mel-A+) proliferation, angiogenesis (VEGF+, CD31+) and EMT (N-cadherin) in the tumor microenvironment in the lungs. These findings indicate that DET and DETD-35 may be useful in the intervention of lung metastatic BRAFV600E mutant melanoma.


Asunto(s)
Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Asteraceae/química , Lactonas/aislamiento & purificación , Lactonas/farmacología , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos/farmacología , Animales , Antineoplásicos Fitogénicos/química , Apoptosis/efectos de los fármacos , Apoptosis/genética , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Inmunohistoquímica , Lactonas/química , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Melanoma/patología , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Estructura Molecular , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/química , Proteínas Proto-Oncogénicas B-raf/genética , Especies Reactivas de Oxígeno/metabolismo , Sesquiterpenos/química , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
10.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33799812

RESUMEN

Obesity and associated metabolic disturbances, which have been increasing worldwide in recent years, are the consequences of unhealthy diets and physical inactivity and are the main factors underlying non-communicable diseases (NCD). These diseases are now responsible for about three out of five deaths worldwide, and it has been shown that they depend on mitochondrial dysfunction, systemic inflammation and oxidative stress. It was also demonstrated that several nutritional components modulating these processes are able to influence metabolic homeostasis and, consequently, to prevent or delay the onset of NCD. An interesting combination of nutraceutical substances, named DMG-gold, has been shown to promote metabolic and physical wellness. The aim of this research was to investigate the metabolic, inflammatory and oxidative pathways modulated by DMG-gold in an animal model with diet-induced obesity. Our data indicate that DMG-gold decreases the metabolic efficiency and inflammatory state and acts as an antioxidant and detoxifying agent, modulating mitochondrial functions. Therefore, DMG-gold is a promising candidate in the prevention/treatment of NCD.


Asunto(s)
Dieta , Suplementos Dietéticos , Micronutrientes/análisis , Mitocondrias/efectos de los fármacos , Obesidad/prevención & control , Animales , Antioxidantes/administración & dosificación , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Humanos , Inflamación/etiología , Inflamación/metabolismo , Inflamación/prevención & control , Masculino , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Mitocondrias/fisiología , Obesidad/etiología , Obesidad/metabolismo , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos
11.
Nat Commun ; 12(1): 2284, 2021 04 16.
Artículo en Inglés | MEDLINE | ID: mdl-33863904

RESUMEN

Drug resistance is a major obstacle to the treatment of most human tumors. In this study, we find that dual-specificity phosphatase 16 (DUSP16) regulates resistance to chemotherapy in nasopharyngeal carcinoma, colorectal cancer, gastric and breast cancer. Cancer cells expressing higher DUSP16 are intrinsically more resistant to chemotherapy-induced cell death than cells with lower DUSP16 expression. Overexpression of DUSP16 in cancer cells leads to increased resistance to cell death upon chemotherapy treatment. In contrast, knockdown of DUSP16 in cancer cells increases their sensitivity to treatment. Mechanistically, DUSP16 inhibits JNK and p38 activation, thereby reducing BAX accumulation in mitochondria to reduce apoptosis. Analysis of patient survival in head & neck cancer and breast cancer patient cohorts supports DUSP16 as a marker for sensitivity to chemotherapy and therapeutic outcome. This study therefore identifies DUSP16 as a prognostic marker for the efficacy of chemotherapy, and as a therapeutic target for overcoming chemoresistance in cancer.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Fosfatasas de Especificidad Dual/metabolismo , Mitocondrias/efectos de los fármacos , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/metabolismo , Neoplasias/terapia , Adulto , Anciano , Anciano de 80 o más Años , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Fraccionamiento Celular , Línea Celular Tumoral , Quimioterapia Adyuvante , Cisplatino/farmacología , Cisplatino/uso terapéutico , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos , Fosfatasas de Especificidad Dual/análisis , Femenino , Técnicas de Silenciamiento del Gen , Técnicas de Inactivación de Genes , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones , Persona de Mediana Edad , Mitocondrias/metabolismo , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/análisis , Neoplasias/mortalidad , Neoplasias/patología , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína X Asociada a bcl-2/metabolismo
12.
Int J Mol Sci ; 22(4)2021 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-33671212

RESUMEN

Lysophosphatidic acid (LPA) species are a family of bioactive lipids that transmit signals via six cognate G protein-coupled receptors, which are required for brain development and function of the nervous system. LPA affects the function of all cell types in the brain and can display beneficial or detrimental effects on microglia function. During earlier studies we reported that LPA treatment of microglia induces polarization towards a neurotoxic phenotype. In the present study we investigated whether these alterations are accompanied by the induction of a specific immunometabolic phenotype in LPA-treated BV-2 microglia. In response to LPA (1 µM) we observed slightly decreased mitochondrial respiration, increased lactate secretion and reduced ATP/ADP ratios indicating a switch towards aerobic glycolysis. Pathway analyses demonstrated induction of the Akt-mTOR-Hif1α axis under normoxic conditions. LPA treatment resulted in dephosphorylation of AMP-activated kinase, de-repression of acetyl-CoA-carboxylase and increased fatty acid content in the phospholipid and triacylglycerol fraction of BV-2 microglia lipid extracts, indicating de novo lipogenesis. LPA led to increased intracellular amino acid content at one or more time points. Finally, we observed LPA-dependent generation of reactive oxygen species (ROS), phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf2), upregulated protein expression of the Nrf2 target regulatory subunit of glutamate-cysteine ligase and increased glutathione synthesis. Our observations suggest that LPA, as a bioactive lipid, induces subtle alterations of the immunometabolic program in BV-2 microglia.


Asunto(s)
Aminoácidos/metabolismo , Glucólisis/efectos de los fármacos , Lipogénesis/efectos de los fármacos , Lisofosfolípidos/farmacología , Microglía/metabolismo , Nucleótidos de Adenina/metabolismo , Aerobiosis/efectos de los fármacos , Animales , Antioxidantes/metabolismo , Línea Celular , Respiración de la Célula/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Ácidos Grasos/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ácido Láctico/metabolismo , Redes y Vías Metabólicas/efectos de los fármacos , Ratones , Microglía/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Modelos Biológicos , Factor 2 Relacionado con NF-E2/metabolismo , Fosfocreatina/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo
13.
Methods Mol Biol ; 2265: 81-89, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33704707

RESUMEN

Cancer cells have deregulated metabolism that can contribute to the unique metabolic makeup of the tumor microenvironment. This can be variable between patients, and it is important to understand these differences since they potentially can affect therapy response. Here we discuss a method of processing and assaying metabolism from direct ex vivo murine and human tumor samples using seahorse extracellular flux analysis. This provides real-time profiling of oxidative versus glycolytic metabolism and can help infer the metabolic status of the tumor microenvironment.


Asunto(s)
Melanoma/metabolismo , Análisis de Flujos Metabólicos/métodos , Mitocondrias/metabolismo , Consumo de Oxígeno , Animales , Técnicas de Cultivo de Célula/métodos , Humanos , Análisis de Flujos Metabólicos/instrumentación , Ratones , Mitocondrias/efectos de los fármacos , Oxidación-Reducción , Fosforilación Oxidativa/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Microambiente Tumoral
14.
Int J Mol Sci ; 22(4)2021 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-33672594

RESUMEN

High alcohol intake results in the accumulation of non-oxidative ethanol metabolites such as fatty acid ethyl esters (FAEEs) in the pancreas. High FAEE concentrations mediate pancreatic acinar cell injury and are associated with alcoholic pancreatitis. Treatment with ethanol and the fatty acid palmitoleic acid (EtOH/POA) increased the levels of palmitoleic acid ethyl ester and induced zymogen activation and cytokine expression in pancreatic acinar cells. EtOH/POA induces nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated reactive oxygen species (ROS) production and pancreatic acinar cell injury. Lycopene, a bright-red carotenoid, is a potent antioxidant due to its high number of conjugated double bands. This study aimed to investigate whether lycopene inhibits the EtOH/POA-induced increase in ROS production, zymogen activation, and expression of the inflammatory cytokine IL-6 in EtOH/POA-stimulated pancreatic acinar AR42J cells. EtOH/POA increased the ROS levels, NADPH oxidase and NF-κB activities, zymogen activation, IL-6 expression, and mitochondrial dysfunction, which were inhibited by lycopene. The antioxidant N-acetylcysteine and NADPH oxidase 1 inhibitor ML171 suppressed the EtOH/POA-induced increases in ROS production, NF-κB activation, zymogen activation, and IL-6 expression. Therefore, lycopene inhibits EtOH/POA-induced mitochondrial dysfunction, zymogen activation, and IL-6 expression by suppressing NADPH oxidase-mediated ROS production in pancreatic acinar cells.


Asunto(s)
Células Acinares/patología , Inflamación/patología , Licopeno/farmacología , Estrés Oxidativo/efectos de los fármacos , Páncreas Exocrino/patología , Acetilcisteína/farmacología , Células Acinares/efectos de los fármacos , Adenosina Trifosfato/metabolismo , Animales , Línea Celular , ADN/metabolismo , Inhibidores Enzimáticos/farmacología , Precursores Enzimáticos/metabolismo , Etanol , Ácidos Grasos Monoinsaturados , Interleucina-6/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , NADPH Oxidasas/metabolismo , FN-kappa B/metabolismo , Unión Proteica/efectos de los fármacos , Ratas , Especies Reactivas de Oxígeno/metabolismo
15.
Int J Mol Sci ; 22(4)2021 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-33672606

RESUMEN

Oxidative stress, mitochondrial dysfunction, and neuroinflammation are strongly associated with the pathogenesis of Parkinson's disease (PD), which suggests that anti-oxidative and anti-inflammatory compounds might provide an alternative treatment for PD. Here, we evaluated the neuroprotective effects of evernic aid (EA), which was screened from a lichen library provided by the Korean Lichen Research Institute at Sunchon National University. EA is a secondary metabolite generated by lichens, including Ramalina, Evernia, and Hypogymnia, and several studies have described its anticancer, antifungal, and antimicrobial effects. However, the neuroprotective effects of EA have not been studied. We found that EA protected primary cultured neurons against 1-methyl-4-phenylpyridium (MPP+)-induced cell death, mitochondrial dysfunction, and oxidative stress, and effectively reduced MPP+-induced astroglial activation by inhibiting the NF-κB pathway. In vivo, EA ameliorated MPTP-induced motor dysfunction, dopaminergic neuronal loss, and neuroinflammation in the nigrostriatal pathway in C57BL/6 mice. Taken together, our findings demonstrate that EA has neuroprotective and anti-inflammatory effects in PD models and suggest that EA is a potential therapeutic candidate for PD.


Asunto(s)
Antiinflamatorios/uso terapéutico , Hidroxibenzoatos/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Antiinflamatorios/farmacología , Apoptosis/efectos de los fármacos , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Astrocitos/patología , Células Cultivadas , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Evaluación Preclínica de Medicamentos , Hidroxibenzoatos/química , Hidroxibenzoatos/farmacología , Líquenes/química , Masculino , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Actividad Motora/efectos de los fármacos , FN-kappa B/metabolismo , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Transducción de Señal/efectos de los fármacos
16.
Ecotoxicol Environ Saf ; 214: 112078, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33676053

RESUMEN

It is well known that the dairy cow production is very sensitive to environmental factors, including high temperature, high humidity and radiant heat sources. High temperature-induced heat stress is the main environmental factor that causes oxidative stress and apoptosis, which affects the development of mammary glands in dairy cows. Dihydromyricetin (DMY) is a nature flavonoid compound extracted from Ampelopsis grossedentata; it has been shown to have various pharmacological functions, such as anti-inflammation, antitumor and liver protection. The present study aims to evaluate the protective effect of DMY on heat stress-induced dairy cow mammary epithelial cells (DCMECs) apoptosis and explore the potential mechanisms. The results show that heat stress triggers heat shock response and reduces cell viability in DCMECs; pretreatment of DCMECs with DMY (25 µM) for 12 h significantly alleviates the negative effects of heat stress on cells. DMY can provide cytoprotective effects by suppressing heat stress-caused mitochondrial membrane depolarization and mitochondrial dysfunction, Bax and Caspase 3 activity, and modulation of oxidative enzymes, thereby preventing ROS production and apoptosis in DCMECs. Importantly, DMY treatment could attenuate heat stress-induced mitochondrial fragmentation through mediating the expression of mitochondrial fission and fusion-related genes, including Dynamin related protein 1 (Drp1), Mitochondrial fission 1 protein (Fis1), and Mitofusin1, 2 (Mfn1, 2). Above all, our findings demonstrate that DMY could protect DCMECs against heat stress-induced injury through preventing oxidative stress, the imbalance of mitochondrial fission and fusion, which provides useful evidence that DMY can be a promising therapeutic drug for protecting heat stress-induced mammary glands injury and mastitis.


Asunto(s)
Flavonoles/farmacología , Respuesta al Choque Térmico/efectos de los fármacos , Sustancias Protectoras/farmacología , Animales , Apoptosis/efectos de los fármacos , Bovinos , Supervivencia Celular/efectos de los fármacos , Dinaminas , Células Epiteliales/efectos de los fármacos , Femenino , Mitocondrias/efectos de los fármacos , Dinámicas Mitocondriales/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos
17.
Int J Nanomedicine ; 16: 2071-2085, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33727814

RESUMEN

Background: Radiation therapy remains an important treatment modality in cancer therapy, however, resistance is a major problem for treatment failure. Elevated expression of glutathione is known to associate with radiation resistance. We used glutathione overexpressing small cell lung cancer cell lines, SR3A-13 and SR3A-14, established by transfection with γ-glutamylcysteine synthetase (γ-GCS) cDNA, as a model for investigating strategies of overcoming radiation resistance. These radiation-resistant cells exhibit upregulated human copper transporter 1 (hCtr1), which also transports cisplatin. This study was initiated to investigate the effect and the underlying mechanism of iron-platinum nanoparticles (FePt NPs) on radiation sensitization in cancer cells. Materials and Methods: Uptakes of FePt NPs in these cells were studied by plasma optical emission spectrometry and transmission electron microscopy. Effects of the combination of FePt NPs and ionizing radiation were investigated by colony formation assay and animal experiment. Intracellular reactive oxygen species (ROS) were assessed by using fluorescent probes and imaged by a fluorescence-activated-cell-sorting caliber flow cytometer. Oxygen consumption rate (OCR) in mitochondria after FePt NP and IR treatment was investigated by a Seahorse XF24 cell energy metabolism analyzer. Results: These hCtr1-overexpressing cells exhibited elevated resistance to IR and the resistance could be overcome by FePt NPs via enhanced uptake of FePt NPs. Overexpression of hCtr1 was responsible for the increased uptake/transport of FePt NPs as demonstrated by using hCtr1-transfected parental SR3A (SR3A-hCtr1-WT) cells. Increased ROS and drastic mitochondrial damages with substantial reduction of oxygen consumption rate were observed in FePt NPs and IR-treated cells, indicating that structural and functional insults of mitochondria are the lethal mechanism of FePt NPs. Furthermore, FePt NPs also increased the efficacy of radiotherapy in mice bearing SR3A-hCtr1-WT-xenograft tumors. Conclusion: These results suggest that FePt NPs can potentially be a novel strategy to improve radiotherapeutic efficacy in hCtr1-overexpressing cancer cells via enhanced uptake and mitochondria targeting.


Asunto(s)
Aleaciones/farmacología , Transportador de Cobre 1/metabolismo , Hierro/farmacología , Nanopartículas del Metal/química , Mitocondrias/metabolismo , Neoplasias/metabolismo , Platino (Metal)/farmacología , Tolerancia a Radiación , Aerobiosis , Animales , Línea Celular Tumoral , Respiración de la Célula/efectos de los fármacos , Glutatión/metabolismo , Humanos , Nanopartículas del Metal/ultraestructura , Ratones SCID , Mitocondrias/efectos de los fármacos , Mitocondrias/ultraestructura , Modelos Biológicos , Tolerancia a Radiación/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Resultado del Tratamiento , Rayos X
18.
Int J Mol Sci ; 22(4)2021 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-33670495

RESUMEN

Mercury is one of the detrimental toxicants that can be found in the environment and exists naturally in different forms; inorganic and organic. Human exposure to inorganic mercury, such as mercury chloride, occurs through air pollution, absorption of food or water, and personal care products. This study aimed to investigate the effect of HgCl2 on cell viability, cell cycle, apoptotic pathway, and alters of the transcriptome profiles in human non-small cell lung cancer cells, H1299. Our data show that HgCl2 treatment causes inhibition of cell growth via cell cycle arrest at G0/G1- and S-phase. In addition, HgCl2 induces apoptotic cell death through the caspase-3-independent pathway. Comprehensive transcriptome analysis using RNA-seq indicated that cellular nitrogen compound metabolic process, cellular metabolism, and translation for biological processes-related gene sets were significantly up- and downregulated by HgCl2 treatment. Interestingly, comparative gene expression patterns by RNA-seq indicated that mitochondrial ribosomal proteins were markedly altered by low-dose of HgCl2 treatment. Altogether, these data show that HgCl2 induces apoptotic cell death through the dysfunction of mitochondria.


Asunto(s)
Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/genética , Caspasa 3/genética , Perfilación de la Expresión Génica/métodos , Neoplasias Pulmonares/genética , Cloruro de Mercurio/farmacología , Apoptosis/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Caspasa 3/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ontología de Genes , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Mitocondrias/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética
19.
Ecotoxicol Environ Saf ; 215: 112129, 2021 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-33740486

RESUMEN

Avermectin (AVM), as a biological insecticide, is widely used in agriculture and forestry production globally. However, inhalation of AVM may pose a risk, and the lung is the direct target, but the cytotoxicity of AVM on human lung cells is still unclear. Here, we attempted to elucidate the cytotoxic effect and molecular mechanism of AVM on human lung A549 cells. The results indicated that AVM inhibits cell proliferation, and enhances programmed cell death (apoptosis and autophagy). In addition, we found the AVM-treated cells showed an obvious drop in mitochondrial membrane potential and LC3-I/II, increased ROS production, DNA double-strand breaks, caspase-3/9 activated, PARP cleaved, cytochrome c and Bax/Bcl-2 content rise. The results showed that AVM induced mitochondria-related apoptosis and autophagy in lung A549 cells. These results indicate that AVM can pose a potential threat to human health by inducing DNA damage and programmed cell death.


Asunto(s)
Insecticidas/toxicidad , Ivermectina/análogos & derivados , Células A549 , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Citocromos c/metabolismo , Daño del ADN/efectos de los fármacos , Humanos , Ivermectina/toxicidad , Pulmón/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2
20.
Molecules ; 26(4)2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33672072

RESUMEN

Calcium (Ca2+) dependent signaling circuit plays a critical role in influenza A virus (IAV) infection. The 8-O-(E-p-methoxycinnamoyl)harpagide (MCH) exhibits pharmacological activities that exert neuroprotective, hepatoprotective, anti-inflammatory and other biological effects. However, not have reports of antiviral effects. To investigate the antiviral activity of MCH on IAV-infected human lung cells mediated by calcium regulation. We examined the inhibitory effect of MCH on IAV infections and measured the level of viral proteins upon MCH treatment using Western blotting. We also performed molecular docking simulation with MCH and IAV M2 protein. Finally, we analyzed MCH's suppression of intracellular calcium and ROS (reactive oxygen species) in IAV-infected human lung cells using a flow cytometer. The results shown that MCH inhibited the infection of IAV and increased the survival of the infected human lung cells. The levels of IAV protein M1, M2, NS1 and PA were inhibited in MCH-treated human lung cells compared to that in infected and untreated cells. Also, docking simulation suggest that MCH interacted with M2 on its hydrophobic wall (L40 and I42) and polar amino acids (D44 and R45), which formed intermolecular contacts and were a crucial part of the channel gate along with W41. Lastly, MCH inhibited IAV infection by reducing intracellular calcium and mitochondrial Ca2+/ROS levels in infected human lung cells. Taken together, these data suggest that MCH inhibits IAV infection and increases the survival of infected human lung cells by suppressing calcium levels. These results indicate that MCH is useful for developing IAV treatments.


Asunto(s)
Antivirales/farmacología , Calcio/metabolismo , Virus de la Influenza A/efectos de los fármacos , Espacio Intracelular/metabolismo , Glicósidos Iridoides/farmacología , Piranos/farmacología , Células A549 , Antivirales/uso terapéutico , Humanos , Gripe Humana/tratamiento farmacológico , Gripe Humana/virología , Canales Iónicos/metabolismo , Glicósidos Iridoides/química , Glicósidos Iridoides/uso terapéutico , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Simulación del Acoplamiento Molecular , Piranos/química , Piranos/uso terapéutico , Proteínas de la Matriz Viral
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