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1.
Life Sci ; 251: 117639, 2020 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-32272181

RESUMEN

AIMS: To reduce the dose of arsenic used against human T-cell leukemia/lymphoma and to sensitize cells to drug treatment, we combined arsenic/interferon-alpha (As/IFN-α) with thymoquinone (TQ) in HTLV-I positive (HuT-102 and C91) and HTLV-1 negative (CEM and Jurkat) cell lines. MAIN METHODS: Cells were treated with TQ, As/IFN-α and combinations. Trypan blue and flow cytometry were used to investigate viability and cell cycle effects. Annexin-V staining, rhodamine assay and western blotting were used to determine apoptosis induction and changes in protein expression. Efficacy of single drugs and combinations were tested in adult T-cell leukemia (HuT-102) mouse xenograft model. KEY FINDINGS: TQ/As/IFN-α led to a more pronounced and synergistic time-dependent inhibitory effect on HTLV-I positive cells in comparison to As/IFN-α. While As/IFN-α combination was not effective against CEM or Jurkat cells, the triple combination TQ/As/IFN-α sensitized these two cell lines and led to a pronounced time-dependent inhibition of cell viability. TQ/As/IFN-α significantly induced apoptosis in all four cell lines and disrupted the mitochondrial membrane potential. Apoptosis was confirmed by the cleavage of caspase 3 and poly (ADP-ribose) polymerase (PARP), downregulation of Bcl-2 and XIAP and upregulation of Bax. TQ alone or in combination activated p53 in HTLV-1 positive cell lines. Strikingly, TQ/As/IFN-α resulted in a pronounced significant decrease in tumor volume in HuT-102 xenograft mouse model, as compared to separate treatments or double combination therapy. SIGNIFICANCE: Our results suggest a strong potential for TQ to enhance the drug targeting effects of the standard clinical drugs As and IFN-α against CD4+ malignant T-cells.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Benzoquinonas/farmacología , Supervivencia Celular/efectos de los fármacos , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Arsénico/administración & dosificación , Benzoquinonas/administración & dosificación , Línea Celular Tumoral , Sinergismo Farmacológico , Virus Linfotrópico T Tipo 1 Humano/aislamiento & purificación , Humanos , Interferón-alfa/administración & dosificación , Células Jurkat , Leucemia-Linfoma de Células T del Adulto/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Factores de Tiempo , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Anticancer Res ; 40(4): 1905-1913, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32234879

RESUMEN

BACKGROUND/AIM: Methylsulfonylmethane (MSM) is a natural organic compound that displays anti-inflammatory as well as antioxidant properties. MSM reportedly has potential in inhibition of tumor cells. However, molecular mechanisms underlying the effects of MSM on lung cancer remain unclear. MATERIALS AND METHODS: In this study, the effect of MSM on A549 cells was examined. We focused on the mode of apoptosis induced by MSM and investigated alterations in the integrity of the outer membrane of mitochondria. RESULTS: Our results showed that MSM inhibited viability of A549 cells and changed the shape and permeability of nuclei. In addition, MSM induced G2/M arrest. MSM reduced the mitochondrial membrane potential and contributed to release of cytochrome c from mitochondria to cytoplasm. CONCLUSION: MSM is a potential anticancer agent for the treatment of lung cancer.


Asunto(s)
Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Dimetilsulfóxido/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Sulfonas/farmacología , Células A549 , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Transducción de Señal/efectos de los fármacos
3.
Anticancer Res ; 40(4): 1963-1972, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32234885

RESUMEN

BACKGROUND/AIM: The menadione/ascorbate (M/A) combination has attracted attention due to the unusual ability of pro-vitamin/vitamin combination to kill cancer cells without affecting the viability of normal cells. The aim of this study was to elucidate the role of M/A in targeting cancerous mitochondria. MATERIALS AND METHODS: Several cancer and normal cell lines of the same origin were used. Cells were treated with different concentrations of M/A for 24 h. The cell viability, mitochondrial superoxide, mitochondrial membrane potential, and succinate were analyzed using conventional analytical tests. RESULTS: M/A exhibited a highly specific suppression on cancer cell growth and viability, without adversely affecting the viability of normal cells at concentrations attainable by oral or parenteral administration in vivo. This effect was accompanied by: (i) an extremely high production of mitochondrial superoxide in cancer cells, but not in normal cells; (ii) a significant dose-dependent depolarization of mitochondrial membrane and depletion of oncometabolite succinate in cancer cells. CONCLUSION: The anticancer effect of M/A is related to the induction of severe mitochondrial oxidative stress in cancer cells only. Thus, M/A has a potential to increase the sensitivity and vulnerability of cancer cells to conventional anticancer therapy and immune system.


Asunto(s)
Ácido Ascórbico/farmacología , Mitocondrias/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Vitamina K 3/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/patología , Neoplasias/genética , Neoplasias/patología , Estrés Oxidativo/efectos de los fármacos , Superóxido Dismutasa/genética , Superóxidos/metabolismo
4.
Anticancer Res ; 40(3): 1405-1417, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32132037

RESUMEN

BACKGROUND/AIM: Niclosamide is an antihe-minthic drug that has shown cytotoxic effects on non-small cell lung carcinoma (NSCLC) cells. However, the exact mechanisms underlying the anti-tumour activity of niclosamide in NSCLC cancer cells remains to be defined. The aim of this study was to evaluate the antitumor activity of niclosamide in human A549 and CL1-5 non-small cell lung cancer cells using in vitro and in vivo. MATERIALS AND METHODS: We investigated the effects of niclosamide on cell viability, apoptosis, the mitochondrial membrane potential (MMP; Δϕm), and autophagy and apoptosis-related protein expression in human A549 and CL1-5 non-small cell lung cancer cells. RESULTS: Niclosamide induced mainly caspase-independent apoptosis through apoptosis-inducible factor (AIF) translocation to the nucleus upon mitochondria damage. Moreover, niclosamide-induced autophagy may act as adaptive response against apoptosis. AMPK/AKT/mTOR pathway were involved in niclosamide-induced cell death and autophagy in response to ATP depletion. Furthermore, niclosamide efficiently suppressed tumor growth and induce autophagy in vivo. CONCLUSION: Niclosamide induced apoptosis by activating the intrinsic and caspase-independent pathway in human A549 and CL1-5 non-small cell lung cancer cells. Therefore, niclosamide is a potential candidate for anti-NSCLC therapy.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Niclosamida/farmacología , Células A549 , Adenosina Trifosfato/metabolismo , Adenilato Quinasa/metabolismo , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/patología , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Activación Enzimática/efectos de los fármacos , Humanos , Neoplasias Pulmonares/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Distribución Aleatoria , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
5.
Life Sci ; 248: 117471, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-32112868

RESUMEN

AIMS: This study aimed to explore the protective effects and possible mechanisms of baicalein on Aß25-35-induced toxicity. MAIN METHODS: Thioflavin-T (Th-T) dye was used to determine the effects of baicalein on Aß25-35 aggregation in vitro. PC12 cells were stimulated with Aß25-35, then the effects of baicalein on apoptosis, mitochondrial membrane potential (MMP), adenosine triphosphate (ATP), mitochondrial respiratory complex I, reactive oxygen species (ROS) and nitric oxide (NO) levels were determined. Moreover, LC-MS metabolomics approach was used to detect metabolic changes induced by baicalein in Aß25-35-injured PC12 cells. KEY FINDINGS: The results showed that baicalein could inhibit the aggregation of Aß25-35 in vitro. Furthermore, pretreatment with baicalein significantly prevented Aß25-35-induced cell apoptosis, as manifested by increasing the levels of MMP, ATP and mitochondrial respiratory complex I, decreasing the contents of ROS and NO. LC-MS metabolomics revealed that baicalein can regulate 5 metabolites, mainly involving two metabolic pathways, arginine and proline metabolism, nicotinate and nicotinamide metabolism. SIGNIFICANCE: Our study revealed that baicalein has a protective effect on Aß25-35-induced neurotoxicity in PC12 cells, which may be related to inhibition of apoptosis and metabolic disorders.


Asunto(s)
Péptidos beta-Amiloides/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Flavanonas/farmacología , Mitocondrias/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Fragmentos de Péptidos/antagonistas & inhibidores , Adenosina Trifosfato/biosíntesis , Péptidos beta-Amiloides/toxicidad , Animales , Arginina/metabolismo , Complejo I de Transporte de Electrón/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/metabolismo , Niacina/metabolismo , Niacinamida/metabolismo , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Células PC12 , Fragmentos de Péptidos/toxicidad , Prolina/metabolismo , Agregado de Proteínas/efectos de los fármacos , Ratas , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo
6.
Cell Physiol Biochem ; 54(2): 230-251, 2020 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-32153152

RESUMEN

BACKGROUND/AIMS: Adverse effects of cigarette smoke on health are widely known. Heating rather than combusting tobacco is one of strategies to reduce the formation of toxicants. The sensitive nature of mitochondrial dynamics makes the mitochondria an early indicator of cellular stress. For this reason, we studied the morphology and dynamics of the mitochondrial network in human bronchial epithelial cells (BEAS-2B) exposed to total particulate matter (TPM) generated from 3R4F reference cigarette smoke and from aerosol from a new candidate modified risk tobacco product, the Tobacco Heating System (THS 2.2). METHODS: Cells were subjected to short (1 week) and chronic (12 weeks) exposure to a low (7.5 µg/mL) concentration of 3R4F TPM and low (7.5 µg/mL), medium (37.5 µg/mL), and high (150 µg/mL) concentrations of TPM from THS 2.2. Confocal microscopy was applied to assess cellular and mitochondrial morphology. Cytosolic Ca2+ levels, mitochondrial membrane potential and mitochondrial mass were measured with appropriate fluorescent probes on laser scanning cytometer. The levels of proteins regulating mitochondrial dynamics and biogenesis were determined by Western blot. RESULTS: In BEAS-2B cells exposed for one week to the low concentration of 3R4F TPM and the high concentration of THS 2.2 TPM we observed clear changes in cell morphology, mitochondrial network fragmentation, altered levels of mitochondrial fusion and fission proteins and decreased biogenesis markers. Also cellular proliferation was slowed down. Upon chronic exposure (12 weeks) many parameters were affected in the opposite way comparing to short exposure. We observed strong increase of NRF2 protein level, reorganization of mitochondrial network and activation of the mitochondrial biogenesis process. CONCLUSION: Comparison of the effects of TPMs from 3R4F and from THS 2.2 revealed, that similar extent of alterations in mitochondrial dynamics and biogenesis is observed at 7.5 µg/mL of 3R4F TPM and 150 µg/mL of THS 2.2 TPM. 7 days exposure to the investigated components of cigarette smoke evoke mitochondrial stress, while upon chronic, 12 weeks exposure the hallmarks of cellular adaptation to the stressor were visible. The results also suggest that mitochondrial stress signaling is involved in the process of cellular adaptation under conditions of chronic stress caused by 3R4F and high concentration of THS 2.2.


Asunto(s)
Aerosoles/química , Mitocondrias/metabolismo , Dinámicas Mitocondriales/efectos de los fármacos , Material Particulado/toxicidad , Calcio/metabolismo , Línea Celular , Colorantes Fluorescentes/química , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Microscopía Confocal , Mitocondrias/efectos de los fármacos , Material Particulado/química , Humo/efectos adversos , Factores de Tiempo , Productos de Tabaco/análisis
7.
Chem Biol Interact ; 321: 109031, 2020 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-32142722

RESUMEN

Reactive oxygen species (ROS) is mainly produced as a by-product from electron transport chain (ETC) of mitochondria and effectively eliminated by cellular antioxidants. However, 2-chloroethyl ethyl sulfide (CEES) exposure to keratinocytes declined antioxidant capacity and increased accumulation of ROS triggered alteration of mitochondrial activity and apoptosis is lacking. Our findings demonstrated that the electron leakage from the impaired ETC, leading to the accumulation of ROS was gradually elevating with increasing concentration of CEES exposure, which decline the activity of superoxide dismutase (SOD), manganese SOD (MnSOD) and copper-zinc SOD (Cu-ZnSOD) in keratinocytes. Further, excess accumulation of ROS, decreased the mitochondrial membrane potential (ΔΨm) and increased the mitochondrial mass with increasing dose of CEES. CEES exposure provoked the decrease in expression of transcription factor A mitochondrial (TFAM), augmented mitochondrial DNA (mtDNA) damage and altered the mtDNA-encoded oxidative phosphorylation (OXPHOS) subunits. Moreover, fragmented mtDNA translocated into cytosol, where it activated cGAS-STING and interferon regulatory factor3 (IRF3), coinciding with the increased expression of inflammatory mediators and alteration of cell-to-cell communication markers. Pre-treatment of N-acetyl-l-cysteine (NAC) or L-Nω-nitroarginine methyl ester (NAME), hydralazine hydrochloride (Hyd·HCl) or ERK1/2 or phosphoinositide3-kinase (PI3-K)/Akt inhibitors in keratinocyte cells significantly restored the CEES effect. Our findings suggest that CEES-induced mitochondrial ROS production and accumulation leads to mitochondrial dysfunction and inflammatory response in keratinocytes. However, treatment of antioxidants or ERK1/2 or PI3-K/Akt inhibitors is a novel therapeutic option for the keratinocytes complication.


Asunto(s)
Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Gas Mostaza/análogos & derivados , Especies Reactivas de Oxígeno/metabolismo , Animales , Línea Celular , Sustancias para la Guerra Química/toxicidad , Daño del ADN , ADN Mitocondrial/metabolismo , Humanos , Inflamación/inducido químicamente , Inflamación/metabolismo , Inflamación/patología , Irritantes/toxicidad , Queratinocitos/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Pelados , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/patología , Gas Mostaza/toxicidad , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal/efectos de los fármacos
8.
Chem Biol Interact ; 321: 109044, 2020 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-32151596

RESUMEN

Overconsumption of alcohol could lead to severe liver injury that connects with oxidative stress, apoptosis, and inflammatory response. Previously, we proved that p-coumaric acid prevents ethanol induced reproductive toxicity; however, p-coumaric acid (PCA) on ethanol mediated hepatotoxicity has not been examined yet. In our work, we sought to study the potential of PCA in contradiction of ethanol induced hepatoxicity which linking with MAPKs, apoptosis, oxidative stress, and Nrf2 signaling. Foremost, we found that PCA could protect ethanol induced both L-02 and HepG2 hepatic cells by inhibiting cytotoxicity, ROS production, mitochondrial depolarization, and nuclear fragmentation. Also, in vivo experiments showed that the ethanol increasing the lipid markers (TBARS, CD) and depletes the antioxidants thereby increased phosphorylation of JNK, ERK, and p38 in rat liver tissues. Interestingly, PCA treatments inhibit ethanol exposed lipid markers and depletion of antioxidants, which directs the inhibition of MAPKs activation in rat liver tissues. We also noticed that the PCA protected ethanol induced apoptosis and liver markers by inhibiting the expression of Bax, caspases; AST, ALT, ALS, and LDH in liver tissue. Overall, the ameliorative consequence of PCA on ethanol induced oxidative stress and apoptosis was achieved by suppressing the expression of CYP2E1 and overexpressing Nrf2 and its target protein HO-1 in rat liver tissue. As a result, PCA was marked to be an effective antioxidant with notable hepatoprotection by inhibiting MAPKs and apoptosis signaling via enhancing Nrf2 signaling.


Asunto(s)
Hepatopatías Alcohólicas/metabolismo , Hepatopatías Alcohólicas/prevención & control , Propionatos/farmacología , Animales , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Línea Celular , Modelos Animales de Enfermedad , Etanol/toxicidad , Células Hep G2 , Humanos , Peroxidación de Lípido/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/lesiones , Hígado/metabolismo , Hepatopatías Alcohólicas/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Sustancias Protectoras/farmacología , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos
9.
J Photochem Photobiol B ; 204: 111767, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32006893

RESUMEN

Colon carcinoma is a recurring type of cancer that affects the intestine epithelial with a poor survival rate. It was already proven the anticancer property of hesperidin in various cancers but the bioavailability hesperidin is poor, which hinders the hesperidin usage. In this investigation we synthesized hesperidin loaded Zn2+@ SA/PCT nanocomposites and assessed its anticancer potential against colon cancer (HCT116) cells. Hesperidin loaded Zn2+@ SA/PCT nanocomposites were characterized using Fourier transform infrared (FTIR), X-ray diffraction (XRD), scanning electron microscope (SEM) and transmission electron microscope (TEM) analysis. The drug releasing capacity and cytotoxic property was assessed via drug releasing assay, MTT assay with HCT116 cells. The anticancer potency of hesperidin nanocomposites were evaluated with TUNEL, DAPI staining, reactive oxygen species (ROS) generation assay and it is confirmed with flow cytometry analysis of MMP disruption in colon cancer (HCT116) cell line. Further the immunoblotting analysis of cysteine proteases Caspases 3, 9, PARP, proapoptotic protein Bax and antiapoptotic protein Bcl2 were performed. The results of FTIR, XRD and electroscopic analyses confirmed the synthesized hesperidin nanocomposites accomplish the properties of potent nanodrug and the MTT assay authentically confirmed that the synthesized hesperidin nanocomposite inhibited the HCT116 cell growth, and the results of fluorescent staining proved that the hesperidin nanocomposite induced the apoptotic mediated cell necrosis via promoting the expression of apoptotic proteins thereby induced the apoptosis in colon cancer (HCT116) cells. Hence, it was concluded that the, hesperidin loaded nanocomposites persuasively inhibited proliferation of colon carcinoma cell and induced apoptosis in in vitro condition.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Proliferación Celular/efectos de los fármacos , Hesperidina/química , Nanocompuestos/química , Alginatos/química , Antineoplásicos Fitogénicos/química , Caspasa 3/metabolismo , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Composición de Medicamentos , Liberación de Fármacos , Células HCT116 , Hesperidina/farmacología , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Pectinas/química , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Zinc/química
10.
PLoS One ; 15(2): e0229332, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32092105

RESUMEN

The placenta, a tissue that is metabolically active and rich in mitochondria, forms a critical interface between the mother and developing fetus. Oxidative stress within this tissue, derived from the dysregulation of reactive oxygen species (ROS), has been linked to a number of adverse fetal outcomes. While such outcomes have been associated with mitochondrial dysfunction, the causal role of mitochondrial dysfunction and mitochondrially generated ROS in altering the process of placentation remains unclear. In this study, mitochondrial complex I activity was attenuated using 10 nM rotenone to induce cellular oxidative stress by increasing mitochondrial ROS production in the BeWo choriocarcinoma cell line. Increased mitochondrial ROS resulted in a significant decrease in the transcripts which encode for proteins associated with fusion (GCM1, ERVW-1, and ERVFRD-1) resulting in a 5-fold decrease in the percentage of BeWo fusion. This outcome was associated with increased indicators of mitochondrial fragmentation, as determined by decreased expression of MFN2 and OPA1 along with an increase in a marker of mitochondrial fission (DRP1). Importantly, increased mitochondrial ROS also resulted in a 5.0-fold reduction of human placental lactogen (PL) and a 4.4-fold reduction of insulin like growth factor 2 (IGF2) transcripts; hormones which play an important role in regulating fetal growth. The pre-treatment of rotenone-exposed cells with 5 mM N-acetyl cysteine (NAC) resulted in the prevention of these ROS mediated changes in BeWo function and supports a central role for mitochondrial ROS signaling in the maintenance and function of the materno-fetal interface.


Asunto(s)
Mitocondrias/metabolismo , Hormonas Placentarias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Trofoblastos/metabolismo , Fusión Celular , Células Cultivadas , Femenino , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Potencial de la Membrana Mitocondrial/fisiología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Embarazo , Especies Reactivas de Oxígeno/farmacología , Rotenona/farmacología , Transducción de Señal/efectos de los fármacos , Trofoblastos/efectos de los fármacos
11.
Phytomedicine ; 68: 153148, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32028185

RESUMEN

BACKGROUND: Aloe-emodin (AE) is among the primary bioactive anthraquinones present in traditional Chinese medicinal plants such as Rheum palmatum L. Multidrug resistance protein 2 (ABCC2/ MRP2) is an important efflux transporter of substances associated with cellular oxidative stress. However, the effects of traditional Chinese medicine on this protein remain unclear. PURPOSE: The aim of this research is to study the role of ABCC2 in AE-induced hepatotoxicity. METHODS: The expression of ABCC2 protein and mRNA levels were analyzed by Western-Blotting and qRT-PCR, respectively. The intracellular oxidative stress caused by AE was evaluated by quantifying the levels of intracellular reactive oxygen species, malondialdehyde, glutathione reduced and oxidized glutathione. The levels of adenosine triphosphate, mitochondrial membrane potential and mitochondrial DNA were explored to evaluate the effects of AE on mitochondrial function. The effects of AE on cell apoptosis and cell cycle were detected by flow cytometry. To further clarify the key role of ABCC2 in AE induced cytotoxicity, we used pCI-neo-ABCC2 plasmid to over express ABCC2 protein, and small interfering RNA was used to knockdown ABCC2 in HepG2 cells. Additionally, we investigated the impact of AE on ABCC2 degradation pathway and the hepatotoxic effects of AE in mice. RESULTS: AE was found to inhibit ABCC2 transport activity, downregulate ABCC2 expression and altered intracellular redox balance. Induction of oxidative stress resulted in depletion of intracellular glutathione reduced, mitochondria dysfunction and activation of apoptosis. ABCC2 overexpression significantly reduced AE-induced intracellular oxidative stress and cell death, which was enhanced by ABCC2 knockdown. Furthermore, AE was observed to promote ABCC2 degradation through induction of autophagy and hepatotoxicity was induced in mice by promoting ABCC2 degradation. CONCLUSIONS: The inhibition of ABCC2 is a novel effect of AE that triggers oxidative stress and apoptosis. These findings are helpful in understanding the toxicological effects of AE-containing medicinal plants.


Asunto(s)
Antraquinonas/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Femenino , Células Hep G2 , Humanos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Mitocondrias/efectos de los fármacos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo
12.
Phytomedicine ; 68: 153142, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32045840

RESUMEN

BACKGROUND: The dried heartwood of Caesalpinia sappan L. is traditionally prescribed in the formula of traditional Chinese medicine (TCM) for the treatment of acute myeloid leukemia (AML), while nothing is yet known of the active fractions and the underlying mechanisms. PURPOSE: This study aims to investigate the effect of the ethyl acetate extract of the dried heartwood of Caesalpinia sappan L. (C-A-E) on induction of apoptosis and promotion of differentiation in vitro and anti-AML activity in vivo. STUDY DESIGN/METHODS: The aqueous extract was sequentially separated with solvents of increasing polarity and the active fraction was determined through the inhibition potency. The inhibition of the active fraction on cell viability, proliferation and colony formation was performed in different AML cells. Induction of apoptosis and the promotion of differentiation were further determined. Then, the level of the reactive oxygen species (ROS) and its potential role were assessed. Finally, anti-AML activity was evaluated in NOD/SCID mice. RESULTS: C-A-E exhibited the highest inhibition on the cell viability of HL-60 cells. Meanwhile, C-A-E significantly suppressed the proliferation and the colony formation ability of HL-60 and Kasumi-1 cells. Moreover, C-A-E significantly induced the apoptosis, which was partially reversed by Z-VAD-FMK. C-A-E also reduced the level of mitochondrial membrane potential, promoted the release of cytochrome C, decreased the Bcl-2/Bax ratio, and promoted the cleavage of caspase-9 and -3. In addition, Mdivi-1 (mitochondrial fission blocker) remarkably reduced the apoptosis caused by C-A-E. Meanwhile, C-A-E also induced the expression of Mff and Fis1 and increased the location of Drp1 in mitochondria. Furthermore, C-A-E obviously promoted the differentiation of AML cells characterized by the typic morphological changes, the increased NBT positive cells, as well as the increased CD11b and CD14 levels. Notably, C-A-E significantly enhanced the intracellular ROS level. Moreimportantly, C-A-E-mediated apoptosis and differentiation of HL-60 cells was significantly mitigated by NAC. Additionally, C-A-E also exhibited an obvious anti-AML effect in NOD/SCID mice with the injection of HL-60 cells. CONCLUSIONS: C-A-E exhibited an inhibitory effect on AML cells by inducing mitochondrial apoptosis and promoting differentiation, both of which were highly correlated to the activation of ROS.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Caesalpinia/química , Leucemia Mieloide Aguda/tratamiento farmacológico , Extractos Vegetales/farmacología , Especies Reactivas de Oxígeno/metabolismo , Acetatos/química , Animales , Antineoplásicos Fitogénicos/química , Apoptosis/efectos de los fármacos , Antígeno CD11b/metabolismo , Diferenciación Celular/efectos de los fármacos , Células HL-60 , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Receptores de Lipopolisacáridos/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Endogámicos NOD , Ratones SCID , Ensayos Antitumor por Modelo de Xenoinjerto
13.
Life Sci ; 247: 117425, 2020 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-32057904

RESUMEN

AIMS: Glioma is the most common type of malignant tumor of the nervous system, and aggressiveness and recurrence are major obstacles for treatment. This study is designed to explore the effects of amentoflavone (AF) on glioma, and to investigate the underlying mechanism of the anti-cancer activities of AF. METHODS: Cell morphology was recorded under microscopy. Cell viability and cell death ratio were determined by CCK-8 assay and lactate dehydrogenase (LDH) release assay, respectively. Cell cycle progression was assessed by flow cytometry. The levels of iron, MDA (malondialdehyde), lipid ROS, and GSH (reduced glutathione) were assessed by ELISA kit. The cycle-related proteins, ferroptosis-related protein, autophagy-related protein, and the phosphorylation of AMPK, mTOR and p70S6K were analyzed by western blotting. The autophagic flux was observed by transfecting cells with mRFP-GFP-LC3 plasmids. The xenograft murine models were established to analyze the effects of amentoflavone in vivo. The immunohistochemistry assay was performed to analyze the expression of LC3B, Beclin1, ATG5, ATG7, and ferritin heavy chain (FTH). RESULTS: Our results showed that AF treatment led to reduction in cell viability and cell death. In addition, AF was found to block cell cycle progression in a dose-dependent manner in vitro. Following treatment with AF, the intracellular levels of iron, MDA, and lipid OS were increased, and the levels of GSH and the mitochondrial membrane potential were reduced. In addition, our results showed that AF promoted the autophagic by regulating autophagy-relevant proteins. Our results also showed that the autophagy-induction by AF was associated with regulation of AMPK/mTOR signaling. Mechanistically, the inhibition effects of AF on glioma cell were reversed by DFO, ferreostatin-1 as well as upregulation of FTH. Meanwhile, the FTH levels were increased by compound C and knockdown of ATG7. Moreover, both autophagy inhibitor Baf A1 and knockdown of ATG7 were able to compromising AF-induce ferroptosis and cell death. In vivo, the tumor growth was suppressed by AF in a dose-dependent manner. The level of MDA in the tumor tissue was increased while the level of GSH in tumor tissue was decreased by AF in a dose-dependent manner. Furthermore, the expression of LC3B, Beclin1, ATG5, ATG7 were increased, and the expression of FTH were decreased by AF in a dose-dependent manner in vivo. Conclusion These results demonstrate that AF triggered ferroptosis in autophagy-dependent manner. Our results suggest that AF has the potential to be considered as a novel treatment agent in glioma.


Asunto(s)
Antineoplásicos/uso terapéutico , Autofagia/efectos de los fármacos , Biflavonoides/uso terapéutico , Inhibidores del Citocromo P-450 CYP3A/uso terapéutico , Ferroptosis/efectos de los fármacos , Glioma/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Proteínas Relacionadas con la Autofagia/metabolismo , Beclina-1/metabolismo , Biflavonoides/farmacología , Línea Celular Tumoral , Inhibidores del Citocromo P-450 CYP3A/farmacología , Glioma/metabolismo , Glioma/patología , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas Quinasas/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Serina-Treonina Quinasas TOR/metabolismo
14.
Life Sci ; 248: 117455, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-32088216

RESUMEN

AIMS: Idiopathic scoliosis is a common deformity of the spine that has an especially high incidence rate in adolescents. Some studies have demonstrated a close relationship between idiopathic scoliosis and melatonin deficiency. Our team's previous research showed that melatonin can inhibit the proliferation of osteoblasts, but the mechanism remains unclear. This study aimed to determine the mechanism by which melatonin inhibits the proliferation of osteoblasts. MAIN METHODS: Cell viability experiment, DNA fragment detection and alkaline phosphatase (ALP) activity assays were performed to determine the effects of melatonin on the proliferation, apoptosis and differentiation of osteoblasts. We used immunofluorescence to detect the expression of STIM1 in melatonin-treated osteoblasts. STIM1 interference was achieved using a specific siRNA, and a TRPC inhibitor was used to block the influx of Ca2+. The mRNA expression was determined by RT-qPCR, and protein levels were measured by Western blot. KEY FINDINGS: In this study, we found that melatonin inhibited the proliferation, differentiation and apoptosis of osteoblasts in a concentration-dependent manner. Additional studies showed that melatonin elevated cytosolic calcium levels by upregulation of STIM1, leading to osteoblast apoptosis via the mitochondrial pathway. Finally, we demonstrated that the STIM1-mediated increase in cytosolic calcium levels induced apoptosis through the ERK pathway. SIGNIFICANCE: Melatonin induces mitochondrial apoptosis in osteoblasts by regulating the STIM1/cytosolic calcium elevation/ERK pathway. These basic findings provide a basis for further clinical studies on melatonin as a drug therapeutic for idiopathic scoliosis.


Asunto(s)
Antioxidantes/farmacología , Calcio/metabolismo , Sistema de Señalización de MAP Quinasas , Melatonina/farmacología , Osteoblastos/efectos de los fármacos , Molécula de Interacción Estromal 1/genética , Fosfatasa Alcalina/genética , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Diferenciación Celular/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica , Transporte Iónico/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Osteoblastos/citología , Osteoblastos/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Molécula de Interacción Estromal 1/agonistas , Molécula de Interacción Estromal 1/antagonistas & inhibidores , Molécula de Interacción Estromal 1/metabolismo , Canales Catiónicos TRPC/antagonistas & inhibidores , Canales Catiónicos TRPC/genética , Canales Catiónicos TRPC/metabolismo
15.
Cell Physiol Biochem ; 54(2): 161-179, 2020 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-32045141

RESUMEN

BACKGROUND/AIMS: We performed co-culture experiments between human RPE cells (ARPE-19) and human umbilical vascular endothelial cells (HUVEC) in order to evaluate how anti-VEGF drugs could affect NO release, mitochondrial function, the oxidative status, proliferation and migration of RPE cells through modulation of their cross talk with vascular endothelial cells. METHODS: The co-culture HUVEC/RPE, was exposed to Ranibizumab/Aflibercept in the absence/presence of the NO synthase (NOS) inhibitor, the phosphatidylinositol 3'-kinase (PI3K), the extracellular-signal-regulated kinases 1/2 (ERK1/2) and the p38 mitogen-activated protein kinase (p38 MAPK) blockers. Specific kits were used for cell viability, mitochondrial membrane potential, NO, ROS and GSH production. Western blot was performed for apoptosis markers, NOS isoforms, and others kinases detection. Cell migration was analyzed by scratch assay, whereas cell proliferation and cell cycle through xCELLigence and flow cytometry. RESULTS: In RPE cells co-cultured with HUVEC in physiological conditions, Aflibercept/Ranibizumab increased NO release in a dose and time-dependent way. Opposite results were obtained in peroxidative conditions. Both anti-VEGF agents were able to prevent the fall of cell viability and mitochondrial membrane potential, an effect which was reduced by various inhibitors, and increased cell migration. Aflibercept/Ranibizumab counteracted the changes of apoptosis markers, NOS expression/activation, PI3K and ERK1/2 activation caused by peroxidation. These results were confirmed by cell cycle analysis. CONCLUSION: This study has shown new mechanisms at the basis of protective effects elicited by Aflibercept/Ranibizumab in RPE cells. HUVEC stimulated with Aflibercept/Ranibizumab, could release some paracrine factors that can modulate the RPE cells response in both physiologic and peroxidative conditions.


Asunto(s)
Comunicación Celular/efectos de los fármacos , Ranibizumab/farmacología , Proteínas Recombinantes de Fusión/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Técnicas de Cocultivo , Glutatión/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular , Epitelio Pigmentado de la Retina/citología , Epitelio Pigmentado de la Retina/metabolismo
16.
Chem Biol Interact ; 320: 109005, 2020 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-32109484

RESUMEN

The mortality rates for acute myeloid leukemia are very high, necessitating the search for novel chemotherapeutic candidates. Herein, we investigated the anticancer potential of a new synthetic compound, 2-ethyl-3-methyliden-1-tosyl-2,3-dihydroquinolin-4-(1H)-one (AJ-374) against myeloid leukemia HL-60 cell line. This analog was selected from the small library of synthetic dihydroquinolinones on the basis of its strong antiproliferative activity against HL-60 cells and 30-fold lower cytotoxicity towards healthy HUVEC cells. AJ-374 promoted the arrest of the cells in the subG0/G1 phase of the cell cycle in the first 24 h. Treatment of HL-60 cells with AJ-374 caused an increase in annexin-V positive cells, activation of caspase-8, -9 and -3, dissipation of the mitochondrial membrane potential and enhancement of FAS protein level. Apoptosis induction triggered by this quinolinone was blocked by the pre-treatment of the cells with caspase-8, -9 and -3 inhibitors. The obtained results indicated that AJ-374-induced apoptosis was executed by both, the extrinsic and intrinsic pathways. The cytotoxic activity of AJ-374 was also associated with down-regulation of the mitogen-activated protein kinase (MAPK) pathway and was independent of reactive oxygen species generation. Taken together, these results suggest that AJ-374 exerts a potent anticancer effect on leukemia cells, with a wide safety margin, which makes this analog an attractive drug candidate for further testing.


Asunto(s)
Apoptosis/efectos de los fármacos , Quinolonas/farmacología , Caspasas/genética , Caspasas/metabolismo , Ciclo Celular/efectos de los fármacos , Proliferación Celular , Daño del ADN/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HL-60 , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Estructura Molecular , Quinolonas/química , Especies Reactivas de Oxígeno , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor fas/genética , Receptor fas/metabolismo
17.
PLoS One ; 15(1): e0228024, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31978092

RESUMEN

Abnormal accumulation of acyl-CoA cholesterol acyltransferase-1 (ACAT-1) mediated cholesterol ester has been shown to contribute to cancer progression in various cancers including leukemia, glioma, breast, pancreatic and prostate cancers. However, the significance of ACAT-1 and cholesterol esters (CE) is relatively understudied in ovarian cancer. In this in vitro study, we assessed the expression and contribution of ACAT-1 in ovarian cancer progression. We observed a significant increase in the expression of ACAT-1 and CE levels in a panel of ovarian cancer cell lines (OC-314, SKOV-3 and IGROV-1) compared to primary ovarian epithelial cells (normal controls). To confirm the tumor promoting capacity of ACAT-1, we inhibited ACAT-1 expression and activity by treating our cell lines with an ACAT inhibitor, avasimibe, or by stable transfection with ACAT-1 specific short hairpin RNA (shRNA). We observed significant suppression of cell proliferation, migration and invasion in ACAT-1 knockdown ovarian cancer cell lines compared to their respective controls (cell lines transfected with scrambled shRNA). ACAT-1 inhibition enhanced apoptosis with a concurrent increase in caspases 3/7 activity and decreased mitochondrial membrane potential. Increased generation of reactive oxygen species (ROS) coupled with increased expression of p53 may be the mechanism(s) underlying pro-apoptotic action of ACAT-1 inhibition. Additionally, ACAT-1 inhibited ovarian cancer cell lines displayed enhanced chemosensitivity to cisplatin treatment. These results suggest ACAT-1 may be a potential new target for the treatment of ovarian cancer.


Asunto(s)
Progresión de la Enfermedad , Neoplasias Ováricas/enzimología , Neoplasias Ováricas/patología , Esterol O-Aciltransferasa/metabolismo , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ésteres del Colesterol/metabolismo , Cisplatino/farmacología , Femenino , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Invasividad Neoplásica , ARN Interferente Pequeño/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Esterol O-Aciltransferasa/antagonistas & inhibidores , Ensayo de Tumor de Célula Madre
18.
Life Sci ; 242: 117248, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-31899224

RESUMEN

Diabetic nephropathy is the most common long-term complication of diabetes mellitus. The Methylglyoxal (MGO) production is mainly by metabolic pathways, such as lipolysis and glycolysis, its increases in the DM enhances oxidative stress and plays a crucial role in the diabetic nephrotic pathogenesis. Phosphocreatine (PCr) can improve lipopolysaccharide, ox-LDL-induced atherosclerosis, and alleviate vascular endothelial cell injury in diabetes. The aim of our present study is to examine the potential role of phosphocreatine (PCr) as a molecule protects against diabetes-induced Kidney Injury in-vitro and in-vivo through ERK/Nrf2/HO-1 signaling pathway. NRK-52E cells treatment with PCr obviously suppressed MGO-induced change of viability, apoptosis, coupled with decreased Bax/Bcl-2ratio, casapse-9 and caspase-3expressions. We determined the generation of reactive oxygen species (ROS) using membrane permeable fluorescent probe DCFH-DA as well as intracellular calcium by flow cytometry. ERK, Nrf2 and HO-1 expressions were determined by Western blot. PCr pretreatment significantly returned the oxidative stress enzymes to normal condition in-vitro and in-vivo. PCr pretreatment significantly reduced apoptosis, calcium and ROS production, induced by MGO, in NRK-52E cells. Moreover, pretreatment with PCr significantly inhibited cleaved caspase-3, cleaved caspase-9 and p-ERK expressions, while increased Nrf-2 and HO-1 expressions. Furthermore, PCr pretreatment significantly decreased p-ERK expression of MGO-induced injury in NRK-52E cells transfected with p-ERK cDNA. In conclusion, the renal protective effect of PCr in-vitro and in-vivo depends on suppressing apoptosis and ROS generation through ERK mediated Nrf-2/HO-1 pathway, suggesting that PCr may be a novel therapeutic candidate for the diabetic nephropathy treatment.


Asunto(s)
Nefropatías Diabéticas/prevención & control , Hemo Oxigenasa (Desciclizante)/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Fosfocreatina/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Western Blotting , Calcio/metabolismo , Línea Celular , Diabetes Mellitus Experimental/complicaciones , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo
19.
Chemosphere ; 248: 126009, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32000039

RESUMEN

Cadmium (Cd) is a widespread environment contaminant due to the development of electroplating and metallurgical industry. Cd can be enriched by organisms via food chain, causing the enlarged environmental problems and posing threats to the health of humans. Polydatin (PD), a natural stilbenoid compound derived from Polygonum cuspidatum, shows pronouncedly curative effect on oxidative damage. In this work, the protective effects of PD on oxidative damage induced by Cd in Musca domestica (housefly) larvae were evaluated. The larvae were exposed to Cd and/or PD, subsequently, the oxidative stress status, mitochondria activity, oxidative phosphorylation efficiency, and survival rate were assessed. Cd exposure generated significant increases of malondialdehyde (MDA), reactive oxygen species (ROS) and 8-hydroxy-2-deoxyguanosine (8-oxoG) in the housefly larvae, causing mitochondrial dysfunction and survival rate decline. Interestingly, pretreatment with PD exhibited obviously mitochondrial protective effects in the Cd-exposed larvae, as evidenced by reduced MDA, ROS and 8-oxoG levels, and increased activities of superoxide dismutase (SOD), mitochondrial electron transfer chain, and mitochondrial membrane potential, as well as respiratory control ratio. These results suggested that PD could attenuate Cd-induced damage via maintaining redox balance, stimulating SOD activity, and regulating mitochondria activity in housefly larvae. As a natural polyphenolic chemical, PD can act as a potential candidate compounds to relieve Cd injury.


Asunto(s)
Cadmio/toxicidad , Moscas Domésticas/fisiología , Superóxido Dismutasa/metabolismo , Animales , Glucósidos , Moscas Domésticas/efectos de los fármacos , Humanos , Larva/metabolismo , Malondialdehído/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/metabolismo , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Estilbenos
20.
Int J Occup Environ Med ; 11(1): 41-52, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31905194

RESUMEN

BACKGROUND: Arsenic, an environmental pollutant, is a carcinogenic metalloid and also an anticancer agent. OBJECTIVE: To evaluate the toxicity of arsenic nanoparticles in rat hepatocytes. METHODS: Freshly isolated rat hepatocytes were exposed to 0, 20, 40, and 100 µM of arsenic nanoparticles and its bulk counterpart. Their viability, reactive oxygen species level, glutathione depletion, mitochondrial and lysosomal damage, and apoptosis were evaluated. RESULTS: By all concentrations, lysosomal damage and apoptosis were clearly evident in hepatocytes exposed to arsenic nanoparticles. Evaluation of mitochondria and lysosomes revealed that lysosomes were highly damaged. CONCLUSION: Exposure to arsenic nanoparticles causes apoptosis and organelle impairment. The nanoparticles have potentially higher toxicity than the bulk arsenic. Lysosomes are highly affected. It seems that, instead of mitochondria, lysosomes are the first target organelles involved in the toxicity induced by arsenic nanoparticles.


Asunto(s)
Apoptosis/efectos de los fármacos , Arsénico/toxicidad , Hepatocitos/efectos de los fármacos , Lisosomas/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Nanopartículas/toxicidad , Animales , Células Cultivadas , Glutatión/metabolismo , Hepatocitos/citología , Humanos , Masculino , Mitocondrias/patología , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo
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