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1.
Chemosphere ; 250: 126416, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32380589

RESUMEN

The flavonoid metal-insecticide magnesium-hesperidin complex (MgHP) has recently been considered as a novel insecticide to replace some persistent pesticides. However, it is important to evaluate its action on non-target species, mainly those living in an aquatic environment, as these ecosystems are the final receptors of most chemicals. Reactive oxygen species, antioxidant and oxidative stress biomarkers, genotoxicity as well as cell cycle was evaluated in the liver cell line from zebrafish (Danio rerio; ZF-L) exposed to 0, 0.1, 1, 10, 100 and 1000 ng mL-1 MgHP. MgHP affected cell stability by increasing reactive oxygen species (ROS) in both exposure times (24 and 96 h) at high concentrations. Catalase (CAT) activity decreased after 24 h exposure, and glutathione and metallothionein values increased, avoiding the lipid peroxidation. Genotoxicity increased as MgHP concentration increased, after 24 h exposure, exhibiting nuclear abnormalities; it was recovered after 96 h exposure, evidencing possible stimulation of DNA repair mechanisms. The alteration in the cell cycle (increasing in the Sub-G1 phase and decreasing in the S-phase) was associated with chromosomal instability. In conclusion, the responses of ROS and the antioxidant defense system depended on MgHP concentration and time exposure, while DNA exhibited some instability after 24 h exposure, which was recovered after 96 h.


Asunto(s)
Ciclo Celular/efectos de los fármacos , Insecticidas/toxicidad , Hígado/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Animales , Antioxidantes/metabolismo , Línea Celular , Daño del ADN , Relación Dosis-Respuesta a Droga , Ecotoxicología/métodos , Biomarcadores Ambientales/efectos de los fármacos , Glutatión/metabolismo , Hesperidina/química , Hesperidina/toxicidad , Insecticidas/administración & dosificación , Insecticidas/química , Peroxidación de Lípido/efectos de los fármacos , Hígado/citología , Hígado/metabolismo , Magnesio/química , Pruebas de Mutagenicidad/métodos , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Especies Reactivas de Oxígeno/metabolismo , Contaminantes Químicos del Agua/química , Pez Cebra
2.
Anticancer Res ; 40(5): 2549-2557, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32366399

RESUMEN

BACKGROUND/AIM: Sonodynamic cancer therapy is based on the preferential uptake and/or retention of a sonosensitizing drug (sonosensitizer) in tumor tissues and the subsequent activation of the drug by ultrasound irradiation. In the present study, we investigated the sonodynamically-induced antitumoral effect with functionalized carbon nanotubes, such as poly-ethylene glycol-modified carbon nanotubes (PEG-modified CNTs). MATERIALS AND METHODS: Antitumor effects were evaluated using histological observation and assessing tumor growth following sonodynamic exposure to PEG-modified CNTs. RESULTS: The combined treatment of 100 µM PEG-modified CNT and ultrasound induced a 2-fold cytotoxicity. Sodium azide, which quenches singlet oxygen, significantly inhibited ultrasonication induced cell damage in the presence of PEG-modified CNTs. This suggests that singlet oxygen produced by the combined use of PEG-modified CNTs and ultrasound is involved in the induction of antitumoral effects. The destruction of tumor tissue was observed with the ultrasonic treatment in combination with PEG-modified CNTs, while neither the treatment with PEG-modified CNTs alone nor ultrasound alone caused any necrosis. CONCLUSION: These results indicate that PEG-modified CNT functions as a sonosensitizer and is effective for sonochemical treatment of solid tumors.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Nanotubos de Carbono , Polietilenglicoles , Ondas Ultrasónicas , Animales , Antineoplásicos/aislamiento & purificación , Línea Celular Tumoral , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Estructura Molecular , Nanotubos de Carbono/química , Polietilenglicoles/química , Especies Reactivas de Oxígeno/metabolismo , Sarcoma 180 , Terapia por Ultrasonido , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Chem Biol Interact ; 323: 109075, 2020 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-32229109

RESUMEN

The use of orchids in herbal medicine has a very long history. Dendrobium species are known to produce a variety of secondary metabolites such as phenanthrens, bibenzyls, fluorenones and sesquiterpenes, and alkaloids and are responsible for their wide variety of medicinal properties. For decades, bibenzyls, which are the main bioactive components derived from Dendrobium species, have been subjected to extensive investigation as likely candidates for cancer treatment. The present study was undertaken to investigate the effect of moscatilin, a bibenzyl derivative from the orchid Dendrobium loddigesii on human melanoma cells. In A375 cells compound moscatilin showed a clear dose-response relationship in the range of 6.25-50 µM concentrations. In addition, we demonstrated an apoptotic response after treatment of cancer cells with this bibenzyl compound at 6.25 and 12.5 µM concentrations that probably involves PTEN activity, inhibition of Hsp70 expression and reactive oxygen species production. Alternatively, the inhibition of the caspase cascade at higher concentrations, 25 and 50 µM, correlated with additional reactive oxygen species increase, probably switched the mode of moscatilin-induced cell death from apoptosis to necrosis.


Asunto(s)
Apoptosis/efectos de los fármacos , Compuestos de Bencilo/uso terapéutico , Dendrobium/química , Melanoma/tratamiento farmacológico , Melanoma/patología , Compuestos de Bencilo/química , Compuestos de Bencilo/farmacología , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ADN de Neoplasias/metabolismo , Glutatión/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Humanos , L-Lactato Deshidrogenasa/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteína X Asociada a bcl-2/metabolismo
4.
Medicine (Baltimore) ; 99(17): e19848, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32332640

RESUMEN

Xiakemycin A (XKA), a new antibiotic in the pyranonaphthoquinone family, shows antitumor activity. However, the type of cell death induced by XKA remains elusive. In this study, we aim to investigate the type of death induced by XKA in hepatic cancer.The apoptotic features, such as chromatic agglutination, reactive oxygen species generation and membrane potential of mitochondria, in HepG2 cells treated by XKA were measured by Hoechst 33342 staining and flow cytometry. Apoptosis of HepG2 cells treated with XKA was determined by Annexin V-FITC/propidium iodide double staining and Western blot analysis, respectively.XKA had a significant dose-dependent elevation of chromatic agglutination, reactive oxygen species generation, Annexin V and propidium iodide staining, decrease of membrane potential. Meanwhile, in apoptotic HepG2 cells induced by XKA, robust increment was noticed in p53 expression, cleavage of PARP, caspase-3, and caspase-9.XKA showed potent inhibitory effects on the proliferation of HepG2 cells. Such phenomenon may be related to activation of the apoptotic pathway.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/patología , Naftoquinonas/farmacología , Anexina A5/metabolismo , Carcinoma Hepatocelular/tratamiento farmacológico , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Daño del ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células Hep G2 , Humanos , Potenciales de la Membrana/efectos de los fármacos , Mitocondrias Hepáticas/fisiología , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Propidio/metabolismo , Especies Reactivas de Oxígeno/metabolismo
5.
J Appl Oral Sci ; 28: e20190519, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32348444

RESUMEN

Natural products have emerged as a rich source of bioactive compounds for adjunctive treatments of many infectious and inflammatory conditions, including periodontitis. Among the monoterpenes with significant biological properties, there is the perillyl alcohol (POH), which can be found in several essential oils and has shown immunomodulatory properties in recent studies, which may be interesting in the treatment of non-neoplastic inflammatory disorders. Objective To determine the antibacterial and immune modulatory activities of the POH. Methodology The minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of the POH for two significant Gram-negative periodontal pathogens were determined by macrodilution and subculture, respectively. Cell proliferation and cytotoxicity in RAW 264.7 macrophages were determined by Trypan Blue and mitochondrial enzymatic activity assay. The modulation of reactive oxygen species (ROS) was analyzed by flow cytometry and expression of TNF and arginase-1 by real-time PCR. Results The POH was effective against P. gingivalis (ATCC 33277) and F. nucleatum (ATCC 25586) with MIC= MBC=1600 µM. No cytotoxicity up to 100 µM was observed on macrophages. The cell proliferation was inhibited from 48 hours at 100 µM (p<0.05) and 250 µM (p<0.01). The POH increased ROS production at both 10 µM and 100 µM (p<0.05) in unstimulated cells. The PMA-induced ROS production was not affected by POH, whereas 100 µM significantly reduced lipopolysaccharide-induced (LPS-induced) ROS. The expression of TNF was not affected by POH in unstimulated cells or in cells polarized to M1 phenotype, whereas both concentrations of POH reduced (p<0.05) the expression of arginase-1 in M2-polarized macrophages. Conclusion The POH has antibacterial activity against periodontal pathogens and reduced proliferation of murine macrophages without significant cytotoxicity at concentrations up to 100 µM. In addition, the POH reduced the LPS-induced ROS and the expression of arginase-1 in M2-polarized macrophages.


Asunto(s)
Antibacterianos/farmacología , Fusobacterium nucleatum/efectos de los fármacos , Macrófagos/efectos de los fármacos , Monoterpenos/farmacología , Porphyromonas/efectos de los fármacos , Especies Reactivas de Oxígeno/análisis , Animales , Arginasa/análisis , Productos Biológicos/farmacología , Proliferación Celular/efectos de los fármacos , Citometría de Flujo , Fusobacterium nucleatum/crecimiento & desarrollo , Expresión Génica , Lipopolisacáridos/farmacología , Macrófagos/metabolismo , Ratones , Pruebas de Sensibilidad Microbiana , Porphyromonas/crecimiento & desarrollo , Células RAW 264.7 , Especies Reactivas de Oxígeno/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Reproducibilidad de los Resultados , Factores de Tiempo , Factor de Necrosis Tumoral alfa/análisis
6.
Tumour Biol ; 42(4): 1010428320914477, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32342732

RESUMEN

Triple-negative breast cancers are the most aggressive subtypes with poor prognosis due to lack of targeted cancer therapy. Recently, we reported an association of A-kinase anchor protein 4 expression with various clinico-pathological parameters of breast cancer patients. In this context, we examined the effect of knockdown of A-kinase anchor protein 4 on cell cycle, apoptosis, cellular proliferation, colony formation, migration, and invasion in triple-negative breast cancer cells. We also examined the synergistic cytotoxic effect of paclitaxel on A-kinase anchor protein 4 downregulated triple-negative breast cancer cells. Knockdown of A-kinase anchor protein 4 resulted in significant reduction in cellular growth and migratory abilities. Interestingly, we also observed enhanced cell death in A-kinase anchor protein 4 downregulated cells treated with paclitaxel. Knockdown of A-kinase anchor protein 4 in cell cycle resulted in G0/G1 phase arrest. Knockdown of A-kinase anchor protein 4 also led to increased reactive oxygen species generation as a result of upregulation of NOXA and CHOP. In addition, levels of cyclins, cyclin-dependent kinases, anti-apoptotic molecules, and mesenchymal markers were reduced in A-kinase anchor protein 4 downregulated cells. Moreover, downregulation of A-kinase anchor protein 4 also caused tumor growth reduction in in vivo studies. These data together suggest that A-kinase anchor protein 4 downregulation inhibits various malignant properties and enhances the cytotoxic effect of paclitaxel, and this combinatorial approach could be useful for triple-negative breast cancer treatment.


Asunto(s)
Proteínas de Anclaje a la Quinasa A/deficiencia , Neoplasias de la Mama Triple Negativas/genética , Proteínas de Anclaje a la Quinasa A/genética , Proteínas de Anclaje a la Quinasa A/metabolismo , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Biomarcadores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Modelos Animales de Enfermedad , Femenino , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Humanos , Inmunofenotipificación , Ratones , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Paclitaxel/farmacología , Especies Reactivas de Oxígeno/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Ensayos Antitumor por Modelo de Xenoinjerto
7.
Life Sci ; 250: 117599, 2020 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-32234491

RESUMEN

Chemotherapeutic antibiotic doxorubicin belongs to the anthracycline class, slaughters not only the cancer cells but also non-cancerous cells even in the non-targeted organs thereby resulting in the toxicity. The liver is primarily involved in the process of detoxification and this mini-review we focused mainly to investigate the molecular mechanisms heading hepatotoxicity caused due to doxorubicin administration. The alterations in the doxorubicin treated liver tissue include vacuolation of hepatocytes, degeneration of hepatocyte cords, bile duct hyperplasia and focal necrosis. About the literature conducted, hepatotoxicity caused by doxorubicin has been explained by estimating the levels of liver serum biomarkers, ROS production, antioxidant enzymes, lipid peroxidation, and mitochondrial dysfunction. The liver serum biomarkers such as ALT and AST, elated levels of free radicals inducing oxidative stress characterized by a surge in Nrf-2, FOXO-1 and HO-1 genes and diminution of anti-oxidant activity characterized by a decline in SOD, GPx, and CAT genes. The augmented levels of SGOT, SGPT, LDH, creatine kinase, direct and total bilirubin levels also reveal the toxicity in the hepatic tissue due to doxorubicin treatment. The molecular insight of hepatotoxicity is mainly due to the production of ROS, ameliorated oxidative stress and inflammation, deteriorated mitochondrial production and functioning, and enhanced apoptosis. Certain substances such as extracts from medicinal plants, natural products, and chemical substances have been shown to produce an alleviating effect against the doxorubicin-induced hepatotoxicity are also discussed.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/fisiopatología , Doxorrubicina/efectos adversos , Hígado/efectos de los fármacos , Adenosina Trifosfato/metabolismo , Animales , Antioxidantes/metabolismo , Apoptosis , Fragmentación del ADN , Células Hep G2 , Hepatocitos/efectos de los fármacos , Humanos , Inflamación , Peroxidación de Lípido/efectos de los fármacos , Malondialdehído/metabolismo , Mitocondrias/metabolismo , Estrés Oxidativo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Extractos Vegetales/farmacología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal
8.
Life Sci ; 250: 117598, 2020 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-32243927

RESUMEN

AIMS: To investigate if autonomic dysregulation is exacerbated in female rats, subjected to diabetes mellitus (DM), via a paradoxical estrogen (E2)-evoked provocation of neuroinflammation/injury of the hypothalamic paraventricular nucleus (PVN). MAIN METHODS: We measured cardiac autonomic function and conducted subsequent PVN neurochemical studies, in DM rats, and their respective controls, divided as follows: male, sham operated (SO), ovariectomized (OVX), and OVX with E2 supplementation (OVX/E2). KEY FINDINGS: Autonomic dysregulation, expressed as sympathetic dominance (higher low frequency, LF, band), only occurred in DM E2-replete (SO and OVX/E2) rats, and was associated with higher neuronal activity (c-Fos) and higher levels of TNFα and phosphorylated death associated protein kinase-3 (p-DAPK3) in the PVN. These proinflammatory molecules likely contributed to the heightened PVN oxidative stress, injury and apoptosis. The PVN of these E2-replete DM rats also exhibited upregulations of estrogen receptors, ERα and ERß, and proinflammatory adenosine A1 and A2a receptors. SIGNIFICANCE: The E2-dependent autonomic dysregulation likely predisposes DM female rats and women to hypersensitivity to cardiac dysfunction. Further, upregulations of proinflammatory mediators including adenosine A1 and A2 receptors, TNFα and DAPK3, conceivably explain the paradoxical hypersensitivity of DM females to PVN inflammation/injury and the subsequent autonomic dysregulation in the presence of E2.


Asunto(s)
Sistema Nervioso Autónomo/fisiopatología , Diabetes Mellitus Experimental/complicaciones , Estrógenos/farmacología , Cardiopatías/fisiopatología , Hipotálamo/fisiopatología , Inflamación/patología , Animales , Apoptosis , Proteínas Quinasas Asociadas a Muerte Celular/metabolismo , Complicaciones de la Diabetes/fisiopatología , Femenino , Corazón/efectos de los fármacos , Frecuencia Cardíaca , Masculino , Estrés Oxidativo , Núcleo Hipotalámico Paraventricular/metabolismo , Fosforilación , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Receptor de Adenosina A1/metabolismo , Receptor de Adenosina A2A/metabolismo , Factores Sexuales , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia Arriba
9.
Anticancer Res ; 40(4): 2025-2032, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32234893

RESUMEN

BACKGROUND/AIM: The winemaking procedure results in the generation of stems, a by-product that is harmful to the environment. Concomitantly, stems are rich in polyphenols and, hence, they are putatively beneficial for human health. MATERIALS AND METHODS: In this study, the grape stem extracts derived from three native Greek vine varieties, namely Mavrodaphne, Muscat and Rhoditis were examined for their chemical composition and antioxidant and antimutagenic properties using a battery of in vitro biomarkers. RESULTS: All extracts are rich in polyphenols. Moreover, they exhibit potent antioxidant and antimutagenic properties with the extract of Mavrodaphne being the strongest in reducing the DPPH• and O2 -• radicals and the Fe3+ and in protecting plasmid DNA from peroxyl radical-induced oxidative modification. CONCLUSION: Therefore, although they are serious pollutants, grape stems contain phytochemicals with important biological properties and can be used as (ingredients of) bio-functional foods to improve certain aspects of human health.


Asunto(s)
Antioxidantes/farmacología , ADN/efectos de los fármacos , Polifenoles/farmacología , Vitis/química , ADN/metabolismo , Daño del ADN/efectos de los fármacos , Grecia , Humanos , Oxidación-Reducción , Extractos Vegetales/química , Extractos Vegetales/farmacología , Tallos de la Planta/química , Plásmidos/efectos de los fármacos , Plásmidos/metabolismo , Polifenoles/química , Especies Reactivas de Oxígeno/metabolismo
10.
Chem Biol Interact ; 322: 109056, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-32198084

RESUMEN

Cytochrome P450 (P450) 2E1 is the major P450 enzyme involved in ethanol metabolism. That role is shared with two other enzymes that oxidize ethanol, alcohol dehydrogenase and catalase. P450 2E1 is also involved in the bioactivation of a number of low molecular weight cancer suspects, as validated in vivo in mouse models where cancers could be attenuated by deletion of Cyp2e1. P450 2E1 does not have a role in global production of reactive oxygen species but localized roles are possible, e.g. in mitochondria. The structures, conformations, and catalytic mechanisms of P450 2E1 have some unusual features among P450s. The concentration of hepatic P450 varies ≥10-fold among humans, possibly in part due to single nucleotide variants. The level of P450 2E1 may have relevance in the rates of oxidation of drugs, particularly acetaminophen and anesthetics.


Asunto(s)
Citocromo P-450 CYP2E1/metabolismo , Neoplasias/patología , Acetaminofén/química , Acetaminofén/metabolismo , Animales , Carcinógenos/química , Carcinógenos/metabolismo , Citocromo P-450 CYP2E1/deficiencia , Citocromo P-450 CYP2E1/genética , Etanol/química , Etanol/metabolismo , Humanos , Cinética , Mitocondrias/metabolismo , Neoplasias/metabolismo , Especies Reactivas de Oxígeno/metabolismo
11.
Life Sci ; 250: 117531, 2020 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-32151691

RESUMEN

AIMS: To investigate the protective effects and mechanism of semaglutide on exercise-induced myocardial injury. MAIN METHODS: Effects of semaglutide on lipopolysaccharide (LPS)-induced oxidative stress injuries and inflammatory response were assessed in H9c2 cell via MTT assay and Western blot. Quiet control group, over training group and three doses of semaglutide treated overtraining groups were subjected to the swimming training with increasing load for consecutive 10 weeks. Immediately after the last training, the body weight, myocardial morphological changes, injury markers and inflammatory response related proteins of the model rats were analyzed. KEY FINDINGS: Semaglutide at three concentrations in LPS treated H9c2 cells significantly increased the survival rate and inhibited the apoptosis of cardiomyocytes. Moreover, semaglutide activated AMPK pathway, improve autophagy and inhibited reactive oxygen species production in LPS treated H9C2 cells. In vivo results further revealed that chronic treatment of semaglutide induced significant increase in myocardial injury markers. The pathological histology analysis results showed that semaglutide ameliorated myocardial morphological changes, reduced area of lipid accumulation and significantly decreased the expression levels of NF-κB, TNF-α and IL-1ß. SIGNIFICANCE: Semaglutide exert the protective effects on exercise-induced cardiomyopathy by activating AMPK pathway, increasing autophagy, reducing the production of ROS and inflammation-related proteins.


Asunto(s)
Péptidos Similares al Glucagón/farmacología , Lesiones Cardíacas/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Miocardio/patología , Estrés Oxidativo/efectos de los fármacos , Condicionamiento Físico Animal/efectos adversos , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Apoptosis , Línea Celular , Supervivencia Celular , Citocinas/metabolismo , Lesiones Cardíacas/prevención & control , Interleucina-1beta/metabolismo , Lípidos/química , Lipopolisacáridos , Masculino , FN-kappa B/metabolismo , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
12.
Life Sci ; 249: 117518, 2020 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-32147432

RESUMEN

AIMS: The objectives of the present study were to investigate the mechanisms of Ninj-1 regulation in TNFα-activated human endothelial cells (HEC), and to test if Amlodipine (AML) ameliorates the inflammatory stress by decreasing Ninj-1 expression. MAIN METHODS: TNFα-activated HEC with/without AML (0.1 µM and 1 µM) were used. TNFα-receptor 1 (TNFR1) was silenced and inhibitors for oxidative stress (N-acetyl cysteine), endoplasmic reticulum stress (salubrinal, 4-phenyl butyric acid), or NF-kB (Bay 11-7085) and p38 MAPK (SB203580) were used. Levels of Ninj-1, TNFR1, monocyte adhesion, endoplasmic reticulum stress (ERS) sensors, NADPH oxidase- and mitochondria-derived oxidative species were evaluated. KEY FINDINGS: The novel findings that we report here are: (i) silencing the endothelial TNFR1 leads to decreased Ninj-1 expression and diminished monocyte adhesion; (ii) increased oxidative stress, ERS and NF-kB activation enhance Ninj-1 expression and monocyte adhesion; (iii) up-regulation of endothelial Ninj-1 expression stimulates monocytes adhesion to TNFα - activated HEC; (iv) AML diminishes monocyte adhesion by reducing Ninj-1 expression through mechanisms involving the decrease of NADPH oxidase and mitochondria-dependent oxidative stress, ERS and NF-kB. In addition, AML alleviates apoptosis by reducing the pro-apoptotic CHOP expression and re-establishing the mitochondrial transmembrane potential. SIGNIFICANCE: The results of the present study suggest that Ninj-1 and the proteins involved in its regulation can be considered therapeutic targets for the alleviation of inflammation- dependent disorders. In addition, we demonstrate that some of the benefic effects of AML can be achieved through regulation of Ninj-1.


Asunto(s)
Amlodipino/farmacología , Moléculas de Adhesión Celular Neuronal/fisiología , Adhesión Celular/fisiología , Monocitos/citología , Factores de Crecimiento Nervioso/fisiología , Receptores Tipo I de Factores de Necrosis Tumoral/fisiología , Factor de Necrosis Tumoral alfa/fisiología , Regulación hacia Arriba , Vasodilatadores/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Silenciador del Gen , Células Endoteliales de la Vena Umbilical Humana , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , NADPH Oxidasas/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/genética
13.
Gene ; 745: 144623, 2020 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-32222530

RESUMEN

Metformin and cisplatin have been widely studied as antitumor agents. However, the effect of metformin combined with cisplatin has not been investigated in colorectal cancer (CRC) cells. This study was aimed to explore the effect of metformin or/and cisplatin on cell viability, apoptosis, and the related signaling pathways in CRC SW480 and SW620 cells. We found that metformin or cisplatin inhibited cell viability of SW480 and SW620 cells in a concentration- and time-dependent manner. Furthermore, metformin combined with cisplatin obviously inhibited cell viability, decreased colony formation, induced apoptosis, mediated cleavage of caspase-9, caspase-3 and PARP, activated mitochondrial membrane potential, downregulated Mcl-1 and Bcl-2 expression, upregulated Bak and Bax expression, and increased reactive oxygen species (ROS) production, compared to the individual agent in SW480 and SW620 cells, which were attenuated by N-acetyl-L-cysteine (NAC), a ROS scavenger. Moreover, NAC could recover the downregulation of p-PI3K and p-Akt treated with combination of metformin and cisplatin, which subsequently activated the PI3K/Akt signaling pathway. Taken together, our results demonstrated that metformin enhanced the sensitivity of CRC cells to cisplatin through ROS-mediated PI3K/Akt signaling pathway.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Cisplatino/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Metformina/farmacología , Transducción de Señal/efectos de los fármacos , Acetilcisteína/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Supervivencia Celular/efectos de los fármacos , Cisplatino/uso terapéutico , Neoplasias Colorrectales/patología , Resistencia a Antineoplásicos/efectos de los fármacos , Células HCT116 , Humanos , Metformina/uso terapéutico , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo
14.
Int J Nanomedicine ; 15: 1643-1659, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32210558

RESUMEN

Purpose: Aseptic loosening is a major complication after total joint replacement. Reactive oxygen species generated by local tissue cells and liberated from implant surfaces have been suggested to cause implant failures. Surface modification of titanium (Ti)-based implants with proanthocyanidins (PAC) is a promising approach for the development of anti-oxidant defense mechanism to supplement the mechanical functions of Ti implants. In this study, a controlled PAC release system was fabricated on the surface of Ti substrates using the layer-by-layer (LBL) assembly. Materials and Methods: Polyethyleneimine (PEI) base layer was fabricated to enable layer-by-layer (LBL) deposition of hyaluronic acid/chitosan (HA/CS) multi-layers without or with the PAC. Surface topography and wettability of the fabricated HA/CS-PAC substrates were characterized by scanning electron microscopy (SEM), atomic force microscopy (AFM), Fourier-transform infrared spectroscopy (FTIR) and contact angle measurement. PAC release profiles were investigated using drug release assays. MC3T3-E1 pre-osteoblast cells were used to assess the osteo-inductive effects of HA/CS-PAC substrates under conditions H2O2-induced oxidative stress in vitro. A rat model of femoral intramedullary implantation evaluated the osseo-integration and osteo-inductive potential of the HA/CS-PAC coated Ti implants in vivo. Results: SEM, AFM, FTIR and contact angle measurements verified the successful fabrication of Ti surfaces with multi-layered HA/CS-PAC coating. Drug release assays revealed controlled and sustained release of PAC over 14 days. In vitro, cell-based assays showed high tolerability and enhanced the osteogenic potential of MC3T3-E1 cells on HA/CS-PAC substrates when under conditions of H2O2-induced oxidative stress. In vivo evaluation of femoral bone 14 days after femoral intramedullary implantation confirmed the enhanced osteo-inductive potential of the HA/CS-PAC coated Ti implants. Conclusion: Multi-layering of HA/CS-PAC coating onto Ti-based surfaces by the LBL deposition significantly enhances implant osseo-integration and promotes osteogenesis under conditions of oxidative stress. This study provides new insights for future applications in the field of joint arthroplasty.


Asunto(s)
Antioxidantes/farmacología , Osteogénesis/efectos de los fármacos , Proantocianidinas/farmacología , Prótesis e Implantes , Titanio/farmacología , Animales , Apoptosis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Quitosano/química , Liberación de Fármacos , Femenino , Ácido Hialurónico/química , Peróxido de Hidrógeno/farmacología , Espacio Intracelular/metabolismo , Ratones , Oseointegración/efectos de los fármacos , Osteoblastos/citología , Osteoblastos/efectos de los fármacos , Polietileneimina/química , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Humectabilidad , Microtomografía por Rayos X
15.
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
16.
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
17.
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
18.
Int J Nanomedicine ; 15: 1349-1361, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32184590

RESUMEN

Background: Impaired wound healing might be associated with many issues, especially overactive of reactive oxygen species (ROS), deficiency of blood vessels and immature of epidermis. N-acetylcysteine (NAC), as an antioxidant, could solve these problems by inhibiting overreactive of ROS, promoting revascularization and accelerating re-epithelialization. How to deliver NAC in situ with a controllable releasing speed still remain a challenge. Materials and Methods: In this study, we combined collagen (Col) with N-acetylcysteine to perform the characteristics of sustained release and chemically crosslinked Col/NAC composite with polyamide (PA) nanofibers to enhance the mechanical property of collagen and fabricated this multi-layered scaffold (PA-Col/NAC scaffold). The physical properties of the scaffolds such as surface characteristics, water absorption and tensile modulus were tested. Meanwhile, the ability to promote wound healing in vitro and in vivo were investigated. Results: These scaffolds were porous and performed great water absorption. The PA-Col/NAC scaffold could sustainably release NAC for at least 14 days. After cell implantation, PA-Col/NAC scaffold showed better cell proliferation and cell migration than the other groups. In vivo, PA-Col/NAC scaffolds could promote wound healing best among all the groups. Conclusion: The multi-layered scaffolds could obviously accelerate the process of wound healing and exert better and prolonged effects.


Asunto(s)
Acetilcisteína/farmacología , Colágeno/química , Depuradores de Radicales Libres/farmacología , Nylons/química , Repitelización/efectos de los fármacos , Andamios del Tejido/química , Cicatrización de Heridas/efectos de los fármacos , Animales , Antioxidantes/farmacología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Preparaciones de Acción Retardada , Masculino , Nanofibras/química , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo
19.
Life Sci ; 250: 117570, 2020 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-32205088

RESUMEN

Accidental exposure to ionizing radiation is a serious concern to human life. Studies on the mitigation of side effects following exposure to accidental radiation events are ongoing. Recent studies have shown that radiation can activate several signaling pathways, leading to changes in the metabolism of free radicals including reactive oxygen species (ROS) and nitric oxide (NO). Cellular and molecular mechanisms show that radiation can cause disruption of normal reduction/oxidation (redox) system. Mitochondria malfunction following exposure to radiation and mutations in mitochondria DNA (mtDNA) have a key role in chronic oxidative stress. Furthermore, exposure to radiation leads to infiltration of inflammatory cells such as macrophages, lymphocytes and mast cells, which are important sources of ROS and NO. These cells generate free radicals via upregulation of some pro-oxidant enzymes such as NADPH oxidases, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Epigenetic changes also have a key role in a similar way. Other mediators such as mammalian target of rapamycin (mTOR) and peroxisome proliferator-activated receptor (PPAR), which are involved in the normal metabolism of cells have also been shown to regulate cell death following exposure to radiation. These mechanisms are tissue specific. Inhibition or activation of each of these targets can be suggested for mitigation of radiation injury in a specific tissue. In the current paper, we review the cellular and molecular changes in the metabolism of cells and ROS/NO following exposure to radiation. Furthermore, the possible strategies for mitigation of radiation injury through modulation of cellular metabolism in irradiated organs will be discussed.


Asunto(s)
Estrés Oxidativo/efectos de la radiación , Traumatismos por Radiación/metabolismo , Animales , Ciclooxigenasa 2/metabolismo , ADN Mitocondrial/genética , Epigénesis Genética , Humanos , Inflamación , Linfocitos/citología , Mastocitos/citología , Ratones , Mitocondrias/efectos de la radiación , Mutación , NADPH Oxidasas/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Oxidación-Reducción , Radiación Ionizante , Especies Reactivas de Oxígeno/metabolismo
20.
Emerg Microbes Infect ; 9(1): 639-650, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32192413

RESUMEN

Acinetobacter baumannii, a Gram-negative opportunistic pathogen, is a leading cause of hospital- and community-acquired infections. Acinetobacter baumannii can rapidly acquire diverse resistance mechanisms and undergo genetic modifications that confer resistance and persistence to all currently used clinical antibiotics. In this study, we found exogenous L-lysine sensitizes Acinetobacter baumannii, other Gram-negative bacteria (Escherichia coli and Klebsiella pneumoniae) and a Gram-positive bacterium (Mycobacterium smegmatis) to aminoglycosides. Importantly, the combination of L-lysine with aminoglycosides killed clinically isolated multidrug-resistant Acinetobacter baumannii and persister cells. The exogenous L-lysine can increase proton motive force via transmembrane chemical gradient, resulting in aminoglycoside acumination that further accounts for reactive oxygen species production. The combination of L-lysine and antibiotics highlights a promising strategy against bacterial infection.


Asunto(s)
Acinetobacter baumannii/efectos de los fármacos , Aminoglicósidos/farmacología , Antibacterianos/farmacología , Lisina/farmacología , Acinetobacter baumannii/metabolismo , Ciclo del Ácido Cítrico , Farmacorresistencia Bacteriana Múltiple , Sinergismo Farmacológico , Escherichia coli/efectos de los fármacos , Concentración de Iones de Hidrógeno , Klebsiella pneumoniae/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Mycobacterium smegmatis/efectos de los fármacos , Fuerza Protón-Motriz/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo
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