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2.
Int J Mol Sci ; 22(6)2021 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-33809931

RESUMEN

The consumption of fish now involves a risk of methylmercury (MeHg) exposure but also provides the benefit of ω-3 polyunsaturated fatty acids (ω-3 PUFAs) such as docosahexaenoic acid (DHA). Some epidemiological studies have suggested that the intake of DHA can alleviate the neurotoxicity of MeHg, but the underlying mechanism is not known. Herein, we observed that pretreatment with 0.1-1 µM DHA suppressed MeHg-induced cytotoxicity in human neuroblastoma (SH-SY5Y) cells and mouse primary neuronal cells. These effects of DHA were canceled in the presence of the retinoid X receptor (RXR) antagonist UVI3003. An RXR agonist, bexarotene, suppressed the cytotoxicity of MeHg. DHA also suppressed the MeHg-induced production of reactive oxygen species (ROS) via an induction of antioxidant genes (catalase and SOD1). Pretreatment with DHA did not change the incorporation of MeHg. We showed previously that in the brain, the intake of DHA increased the level of 19,20-DHDP, which is the metabolite produced by cytochrome P450 and soluble epoxide hydrolase from DHA. In the present study, we observed that 19,20-DHDP also suppressed neurotoxicity from MeHg. These results indicate that DHA and its metabolites have a protective role in MeHg-induced neurotoxicity.


Asunto(s)
Ácidos Docosahexaenoicos/farmacología , Compuestos de Metilmercurio/toxicidad , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Animales , Antioxidantes/farmacología , Línea Celular Tumoral , Células Cultivadas , Ácidos Docosahexaenoicos/análogos & derivados , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Receptores X Retinoide/agonistas
3.
Int J Mol Sci ; 22(6)2021 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-33810024

RESUMEN

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


Asunto(s)
Precondicionamiento Isquémico Miocárdico , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Isquemia Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Adenosina Trifosfato/biosíntesis , Animales , Muerte Celular/efectos de los fármacos , Humanos , Precondicionamiento Isquémico Miocárdico/métodos , Dinámicas Mitocondriales/efectos de los fármacos , Isquemia Miocárdica/tratamiento farmacológico , Isquemia Miocárdica/etiología , Daño por Reperfusión Miocárdica/etiología , Daño por Reperfusión Miocárdica/prevención & control , Miocardio/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Fosforilación Oxidativa/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Regeneración , Transducción de Señal/efectos de los fármacos , Investigación en Medicina Traslacional
4.
Int J Mol Sci ; 22(6)2021 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-33810045

RESUMEN

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


Asunto(s)
Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Asteraceae/química , Lactonas/aislamiento & purificación , Lactonas/farmacología , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos/farmacología , Animales , Antineoplásicos Fitogénicos/química , Apoptosis/efectos de los fármacos , Apoptosis/genética , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Inmunohistoquímica , Lactonas/química , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Melanoma/patología , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Estructura Molecular , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/química , Proteínas Proto-Oncogénicas B-raf/genética , Especies Reactivas de Oxígeno/metabolismo , Sesquiterpenos/química , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
5.
Int J Nanomedicine ; 16: 2555-2568, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33833511

RESUMEN

Introduction: Silver nanoparticles (Ag-NPs) are among the most commonly used nanoparticles in different fields. Zinc nanoparticles (Zn-NPs) are known for their antioxidant effect. This study was designed to investigate the adverse effects of Ag-NPs (50 nm) on the male reproductive system and also the ameliorative effect of Zn-NPs (100 nm) against these harmful effects. Methods: Forty adult male rats were used in this study; they were randomly divided into four equal groups: control group, Ag-NPs group, Zn-NPs group, Ag-NPs + Zn-NPs group. Ag-NPs (50 mg/kg) and/or Zn-NPs (30 mg/kg) were administered orally for 90 days. Results: The results revealed that exposure to Ag-NPs adversely affected sperm motility, morphology, viability, and concentration. Ag-NPs also induced oxidative stress and lipid peroxidation in testicular tissue. The exposure to Ag-NPs decreased serum FSH, LH, and testosterone hormones. Additionally, comet assay revealed DNA degeneration in the testicular tissue of rats exposed to Ag-NPs. Histopathological examination showed various histological alterations in the testes of rats intoxicated with Ag-NPs. Furthermore, co-administration of Zn-NPs ameliorated most of the toxic effects of Ag-NPs via their antioxidative capacity.


Asunto(s)
Infertilidad Masculina/prevención & control , Nanopartículas del Metal/administración & dosificación , Sustancias Protectoras/administración & dosificación , Reproducción , Plata/toxicidad , Testículo/efectos de los fármacos , Zinc/farmacología , Animales , Antioxidantes/farmacología , Infertilidad Masculina/inducido químicamente , Peroxidación de Lípido/efectos de los fármacos , Masculino , Nanopartículas del Metal/química , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/química , Ratas , Ratas Sprague-Dawley , Motilidad Espermática/efectos de los fármacos , Testosterona/metabolismo
6.
J Med Microbiol ; 70(4)2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33830911

RESUMEN

Introduction. Antipathogenic or antivirulence strategy is to target a virulence pathway that is dispensable for growth, in the hope to mitigate the selection for drug resistance.Hypothesis/Gap Statment. Peroxide stress responses are one of the conserved virulence pathways in bacterial pathogens and thus good targets for antipathogenic strategy.Aim. This study aims to identify a new chemical compound that targets OxyR, the peroxide sensor required for the full virulence of the opportunistic human pathogen, Pseudomonas aeruginosa.Methodology. Computer-based virtual screening under consideration of the 'eNTRy' rules and molecular docking were conducted on the reduced form of the OxyR regulatory domain (RD). Selected hits were validated by their ability to phenocopy the oxyR null mutant and modulate the redox cycle of OxyR.Results. We first isolated three robust chemical hits that inhibit OxyR without affecting prototrophic growth or viability. One (compound 1) of those affected the redox cycle of OxyR in response to H2O2 treatment, in a way to impair its function. Compound 1 displayed selective antibacterial efficacy against P. aeruginosa in Drosophila infection model, without antibacterial activity against Staphylococcus aureus.Conclusion. These results suggest that compound 1 could be an antipathogenic hit inhibiting the P. aeruginosa OxyR. More importantly, our study provides an insight into the computer-based discovery of new-paradigm selective antibacterials to treat Gram-negative bacterial infections presumably with few concerns of drug resistance.


Asunto(s)
Antibacterianos/farmacología , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/patogenicidad , Transactivadores/antagonistas & inhibidores , Animales , Drosophila , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Peróxido de Hidrógeno/farmacología , Simulación del Acoplamiento Molecular , Mutación , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/mortalidad , Pseudomonas aeruginosa/genética , Tasa de Supervivencia , Transactivadores/química , Transactivadores/genética , Transactivadores/metabolismo , Virulencia/efectos de los fármacos , Virulencia/genética
7.
Molecules ; 26(6)2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33804228

RESUMEN

Sophora flavescens, also known as Kushen, has traditionally been used as a herbal medicine. In the present study we evaluated the ameliorative effects of kushenol C (KC) from S. flavescens against tBHP (tert-Butyl hydroperoxide)-induced oxidative stress in hepatocellular carcinoma (HEPG2) cells and acetaminophen (APAP)-induced hepatotoxicity in mice. KC pretreatment protected the HEPG2 cells against oxidative stress by reducing cell death, apoptosis and reactive oxygen species (ROS) generation. KC pretreatment also upregulated pro-caspase 3 and GSH (glutathione) as well as expression of 8-Oxoguanine DNA Glycosylase (OGG1) in the HEPG2 cells. The mechanism of action was partly related by KC's activation of Akt (Protein kinase B (PKB)) and Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) in the HepG2 cells. In in vivo investigations, coadministration of mice with KC and APAP significantly attenuated APAP-induced hepatotoxicity and liver damage, as the serum enzymatic activity of aspartate aminotransferase and alanine aminotransferase, as well as liver lipid peroxidation and cleaved caspase 3 expression, were reduced in APAP-treated mice. Coadministration with KC also up-regulated antioxidant enzyme expression and prevented the production of proinflammatory mediators in APAP-treated mice. Taken together, these results showed that KC treatment has potential as a therapeutic agent against liver injury through the suppression of oxidative stress.


Asunto(s)
Acetaminofén/efectos adversos , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/tratamiento farmacológico , Hígado/efectos de los fármacos , Extractos Vegetales/farmacología , Sophora/química , terc-Butilhidroperóxido/efectos adversos , Alanina Transaminasa/metabolismo , Animales , Antioxidantes/fisiología , Aspartato Aminotransferasas/metabolismo , Línea Celular Tumoral , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/metabolismo , Glutatión/metabolismo , Células Hep G2 , Medicina de Hierbas/métodos , Humanos , Peroxidación de Lípido/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos
8.
Int J Nanomedicine ; 16: 2849-2877, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33883895

RESUMEN

Background: Exosomes are endosome-derived nano-sized vesicles that have emerged as important mediators of intercellular communication and play significant roles in various diseases. However, their applications are rigorously restricted by the limited secretion competence of cells. Therefore, strategies to enhance the production and functions of exosomes are warranted. Studies have shown that nanomaterials can significantly enhance the effects of cells and exosomes in intercellular communication; however, how palladium nanoparticles (PdNPs) enhance exosome release in human leukemia monocytic cells (THP-1) remains unclear. Therefore, this study aimed to address the effect of PdNPs on exosome biogenesis and release in THP-1 cells. Methods: Exosomes were isolated by ultracentrifugation and ExoQuickTM and characterized by dynamic light scattering, nanoparticle tracking analysis system, scanning electron microscopy, transmission electron microscopy, EXOCETTM assay, and fluorescence polarization. The expression levels of exosome markers were analyzed via quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Results: PdNP treatment enhanced the biogenesis and release of exosomes by inducing oxidative stress, endoplasmic reticulum stress, apoptosis, and immunomodulation. The exosomes were spherical in shape and had an average diameter of 50-80 nm. Exosome production was confirmed via total protein concentration, exosome counts, acetylcholinesterase activity, and neutral sphingomyelinase activity. The expression levels of TSG101, CD9, CD63, and CD81 were significantly higher in PdNP-treated cells than in control cells. Further, cytokine and chemokine levels were significantly higher in exosomes isolated from PdNP-treated THP-1 cells than in those isolated from control cells. THP-1 cells pre-treated with N-acetylcysteine or GW4869 showed significant decreases in PdNP-induced exosome biogenesis and release. Conclusion: To our knowledge, this is the first study showing that PdNPs stimulate exosome biogenesis and release and simultaneously increase the levels of cytokines and chemokines by modulating various physiological processes. Our findings suggest a reasonable approach to improve the production of exosomes for various therapeutic applications.


Asunto(s)
Apoptosis/efectos de los fármacos , Estrés del Retículo Endoplásmico , Exosomas/metabolismo , Inmunomodulación/efectos de los fármacos , Leucemia/patología , Nanopartículas del Metal/toxicidad , Estrés Oxidativo , Paladio/toxicidad , Acetilcolinesterasa/metabolismo , Acetilcisteína/farmacología , Compuestos de Anilina/farmacología , Antioxidantes/metabolismo , Compuestos de Bencilideno/farmacología , Biomarcadores de Tumor/metabolismo , Caspasas/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Citocinas/metabolismo , Daño del ADN , Estrés del Retículo Endoplásmico/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Leucemia/sangre , Nanopartículas del Metal/ultraestructura , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Tamaño de la Partícula , Esfingomielina Fosfodiesterasa/metabolismo , Células THP-1
9.
Medicine (Baltimore) ; 100(16): e25621, 2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33879733

RESUMEN

ABSTRACT: This study aimed to investigate the effects of the basic treatment for heart failure and sequential treatment with rh-brain natriuretic peptide (rhBNP) alone or the combination of rhBNP and sacubitril/valsartan. Cardiac structure, pulmonary artery pressure, inflammation and oxidative stress in patients with acute heart failure were evaluated.Three hundred patients with acute heart failure were included. According to the random number table method, the patients were divided into 3 groups of 100 patients per group: the standard treatment group (treated with an angiotensin-converting enzyme inhibitor, ß receptor blocker, and corticosteroid antagonist), rhBNP group (basic treatment combined with rhBNP) and sequential treatment group (basic treatment for heart failure combined with rhBNP followed by sacubitril/valsartan). The changes in NT-probrain natriuretic peptide (BNP) levels, cardiac troponin T (cTnT) levels, cardiac structure, pulmonary artery pressure, and the levels inflammatory factors and oxidative stress factors were compared among the 3 groups at 1, 4, 12, and 36 weeks after treatment.The sequential treatment group displayed superior outcomes than the standard treatment group and the rhBNP group in terms of left atrium diameter, left ventricular end diastolic volume, left ventricular ejection fraction, pulmonary artery pressure, NT-proBNP levels, and cTnT levels, which respond to damage to the heart structure and myocardium. This result may be related to the decreased levels of inflammatory factors and the correction of oxidative stress imbalance.Sacubitril/valsartan significantly reduce the serum levels of inflammatory factors in patients with acute heart failure while decreasing the levels of oxidizing factors and increasing the levels of antioxidant factors. These changes may be one of the explanations for the better cardiac structure and better pulmonary artery pressure observed in the sequential treatment group.


Asunto(s)
Aminobutiratos/administración & dosificación , Antagonistas de Receptores de Angiotensina/administración & dosificación , Insuficiencia Cardíaca/tratamiento farmacológico , Péptido Natriurético Encefálico/administración & dosificación , Tetrazoles/administración & dosificación , Enfermedad Aguda , Antagonistas Adrenérgicos beta/administración & dosificación , Anciano , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Presión Arterial/efectos de los fármacos , Biomarcadores/sangre , Combinación de Medicamentos , Quimioterapia Combinada , Femenino , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Antagonistas de Hormonas/administración & dosificación , Humanos , Inflamación , Mediadores de Inflamación/sangre , Masculino , Persona de Mediana Edad , Miocardio/patología , Estrés Oxidativo/efectos de los fármacos , Arteria Pulmonar/fisiopatología , Volumen Sistólico/efectos de los fármacos , Resultado del Tratamiento , Troponina T/sangre
10.
Molecules ; 26(6)2021 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-33799355

RESUMEN

Biocompatible tryptophan-derived copper (1) and zinc (2) complexes with norharmane (ß-carboline) were designed, synthesized, characterized, and evaluated for the potential anticancer activity in vitro and in vivo. The in vitro cytotoxicity of both complexes 1 and 2 were assessed against two cancerous cells: (human breast cancer) MCF7 and (liver hepatocellular cancer) HepG2 cells with a non-tumorigenic: (human embryonic kidney) HEK293 cells. The results exhibited a potentially decent selectivity of 1 against MCF7 cells with an IC50 value of 7.8 ± 0.4 µM compared to 2 (less active, IC50 ~ 20 µM). Furthermore, we analyzed the level of glutathione, lipid peroxidation, and visualized ROS generation to get an insight into the mechanistic pathway and witnessed oxidative stress. These in vitro results were ascertained by in vivo experiments, which also supported the free radical-mediated oxidative stress. The comet assay confirmed the oxidative stress that leads to DNA damage. The histopathology of the liver also ascertained the low toxicity of 1.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Carbolinas/farmacología , Cobre/farmacología , Triptófano/farmacología , Animales , Neoplasias de la Mama/metabolismo , Línea Celular , Línea Celular Tumoral , Ensayo Cometa/métodos , Daño del ADN/efectos de los fármacos , Femenino , Glutatión/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Peroxidación de Lípido/efectos de los fármacos , Células MCF-7 , Estrés Oxidativo/efectos de los fármacos , Ratas , Especies Reactivas de Oxígeno/metabolismo , Zinc/farmacología
11.
Molecules ; 26(7)2021 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-33805024

RESUMEN

Depression and anxiety disorders are widespread diseases, and they belong to the leading causes of disability and greatest burdens on healthcare systems worldwide. It is expected that the numbers will dramatically rise during the COVID-19 pandemic. Established medications are not sufficient to adequately treat depression and are not available for everyone. Plants from traditional medicine may be promising alternatives to treat depressive symptoms. The model organism Chaenorhabditis elegans was used to assess the stress reducing effects of methanol/dichlormethane extracts from plants used in traditional medicine. After initial screening for antioxidant activity, nine extracts were selected for in vivo testing in oxidative stress, heat stress, and osmotic stress assays. Additionally, anti-aging properties were evaluated in lifespan assay. The extracts from Acanthopanax senticosus, Campsis grandiflora, Centella asiatica, Corydalis yanhusuo, Dan Zhi, Houttuynia cordata, Psoralea corylifolia, Valeriana officinalis, and Withaniasomnifera showed antioxidant activity of more than 15 Trolox equivalents per mg extract. The extracts significantly lowered ROS in mutants, increased resistance to heat stress and osmotic stress, and the extended lifespan of the nematodes. The plant extracts tested showed promising results in increasing stress resistance in the nematode model. Further analyses are needed, in order to unravel underlying mechanisms and transfer results to humans.


Asunto(s)
Antidepresivos/farmacología , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/fisiología , Extractos Vegetales/farmacología , Plantas Medicinales/química , Envejecimiento/efectos de los fármacos , Envejecimiento/fisiología , Animales , Antioxidantes/farmacología , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Técnicas de Inactivación de Genes , Respuesta al Choque Térmico/efectos de los fármacos , Longevidad/efectos de los fármacos , Longevidad/genética , Longevidad/fisiología , Mutación , Presión Osmótica/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/química , Especies Reactivas de Oxígeno/metabolismo
12.
Anticancer Res ; 41(4): 1831-1840, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813388

RESUMEN

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


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antibióticos Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Doxorrubicina/farmacología , Silenciador del Gen , Mitocondrias/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Peroxirredoxinas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/enzimología , Adenocarcinoma/genética , Adenocarcinoma/patología , Proteínas Reguladoras de la Apoptosis/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Humanos , Mitocondrias/enzimología , Mitocondrias/patología , Peroxirredoxinas/genética , Transducción de Señal , Neoplasias Gástricas/enzimología , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología
13.
Int J Nanomedicine ; 16: 2461-2475, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33814910

RESUMEN

Aim: To explore the effects of Radix Sophorae Flavescentis carbonisata-based carbon dots (RSFC-CDs) on an ethanol-induced acute gastric ulcer rat model. Methods: The structure, optical properties, functional groups and elemental composition of RSFC-CDs synthesized by one-step pyrolysis were characterized. The gastric protective effects of RSFC-CDs were evaluated and confirmed by applying a rat model of ethanol-induced acute gastric ulcers. The underlying mechanisms were investigated through the nuclear factor-kappa B (NF-κB) signalling pathway and oxidative stress. Results: RSFC-CDs with a diameter ranging from 2-3 nm mainly showed gastric protective effects by reducing the levels of NF-κB, tumour necrosis factor-α (TNF-α), interleukin (IL)-6, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione (GSH), malondialdehyde (MDA) and inducible nitric oxide synthase (iNOS) to inhibit ethanol-induced inflammation and oxidative stress. Conclusion: RSFC-CDs have anti-inflammatory and anti-oxidative effects, making them promising for application in ethanol-induced gastric injury.


Asunto(s)
Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Carbono/química , Medicamentos Herbarios Chinos/uso terapéutico , Sustancias Protectoras/uso terapéutico , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/tratamiento farmacológico , Enfermedad Aguda , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Regulación hacia Abajo/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Etanol/efectos adversos , Interleucina-6/metabolismo , Masculino , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Estrés Oxidativo/efectos de los fármacos , Espectroscopía de Fotoelectrones , Sustancias Protectoras/farmacología , Ratas Sprague-Dawley , Úlcera Gástrica/patología , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia Arriba/efectos de los fármacos
14.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-33802633

RESUMEN

The current study was designed to investigate the protective role of diosmin against cyclophosphamide-induced premature ovarian insufficiency (POI). Female Swiss albino rats received a single intraperitoneal dose of cyclophosphamide (200 mg/kg) followed by 8 mg/kg/day for the next 15 consecutive days either alone or in combination with oral diosmin at 50 or 100 mg/kg. Histopathological examination of ovarian tissues, hormonal assays for follicle stimulating hormone (FSH), estradiol (E2), and anti-Mullerian hormone (AMH), assessment of the oxidative stress status, as well as measurement of the relative expression of miRNA-145 and its target genes [vascular endothelial growth factor B (VEGF-B) and regulator of cell cycle (RGC32)] were performed. Diosmin treatment ameliorated the levels of E2, AMH, and oxidative stress markers. Additionally, both low and high diosmin doses significantly reduced the histopathological alterations and nearly preserved the normal ovarian reserve. MiRNA-145 expression was upregulated after treatment with diosmin high dose. miRNA-145 target genes were over-expressed after both low and high diosmin administration. Based on our findings, diosmin has a dose-dependent protective effect against cyclophosphamide-induced ovarian toxicity in rats.


Asunto(s)
Diosmina/uso terapéutico , Insuficiencia Ovárica Primaria/inducido químicamente , Insuficiencia Ovárica Primaria/tratamiento farmacológico , Animales , Biomarcadores/metabolismo , Peso Corporal/efectos de los fármacos , Caspasa 3/metabolismo , Catalasa/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Colágeno/metabolismo , Ciclofosfamida , Diosmina/farmacología , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Hormonas/sangre , Malondialdehído/sangre , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Tamaño de los Órganos/efectos de los fármacos , Folículo Ovárico/efectos de los fármacos , Folículo Ovárico/crecimiento & desarrollo , Folículo Ovárico/patología , Estrés Oxidativo/efectos de los fármacos , Insuficiencia Ovárica Primaria/sangre , Insuficiencia Ovárica Primaria/patología , Antígeno Nuclear de Célula en Proliferación/metabolismo , Ratas , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo
15.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-33802660

RESUMEN

Proximal tubular (PT) acidosis, which alkalinizes the urinary filtrate, together with Ca2+ supersaturation in PT can induce luminal calcium phosphate (CaP) crystal formation. While such CaP crystals are known to act as a nidus for CaP/calcium oxalate (CaOx) mixed stone formation, the regulation of PT luminal Ca2+ concentration ([Ca2+]) under elevated pH and/or high [Ca2+] conditions are unknown. Since we found that transient receptor potential canonical 3 (TRPC3) knockout (KO; -/-) mice could produce mild hypercalciuria with CaP urine crystals, we alkalinized the tubular pH in TRPC3-/- mice by oral acetazolamide (0.08%) to develop mixed urinary crystals akin to clinical signs of calcium nephrolithiasis (CaNL). Our ratiometric (λ340/380) intracellular [Ca2+] measurements reveal that such alkalization not only upsurges Ca2+ influx into PT cells, but the mode of Ca2+ entry switches from receptor-operated to store-operated pathway. Electrophysiological experiments show enhanced bicarbonate related current activity in treated PT cells which may determine the stone-forming phenotypes (CaP or CaP/CaOx). Moreover, such alkalization promotes reactive oxygen species generation, and upregulation of calcification, inflammation, fibrosis, and apoptosis in PT cells, which were exacerbated in absence of TRPC3. Altogether, the pH-induced alteration of the Ca2+ signaling signature in PT cells from TRPC3 ablated mice exacerbated the pathophysiology of mixed urinary stone formation, which may aid in uncovering the downstream mechanism of CaNL.


Asunto(s)
Acetazolamida/farmacología , Calcio/metabolismo , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/patología , Nefrolitiasis/metabolismo , Nefrolitiasis/patología , Animales , Transporte Biológico/efectos de los fármacos , Calcinosis/complicaciones , Estrés del Retículo Endoplásmico/efectos de los fármacos , Fibrosis , Concentración de Iones de Hidrógeno , Inflamación/patología , Túbulos Renales Proximales/efectos de los fármacos , Ratones , Nefrolitiasis/orina , Estrés Oxidativo/efectos de los fármacos , Canales Catiónicos TRPC/metabolismo , Regulación hacia Arriba/efectos de los fármacos
16.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-33805772

RESUMEN

Sulforaphane, a potent dietary bioactive agent obtainable from cruciferous vegetables, has been extensively studied for its effects in disease prevention and therapy. Sulforaphane potently induces transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated expression of detoxification, anti-oxidation, and immune system-modulating enzymes, and possibly acts as an anti-carcinogenic agent. Several clinical trials are in progress to study the effect of diverse types of cruciferous vegetables and sulforaphane on prostate cancer, breast cancer, lung cancer, atopic asthmatics, skin aging, dermatitis, obesity, etc. Recently, the protective effects of sulforaphane on brain health were also considerably studied, where the studies have further extended to several neurological diseases, including Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, autism spectrum disorder, and schizophrenia. Animal and cell studies that employ sulforaphane against memory impairment and AD-related pre-clinical biomarkers on amyloid-ß, tau, inflammation, oxidative stress, and neurodegeneration are summarized, and plausible neuroprotective mechanisms of sulforaphane to help prevent AD are discussed. The increase in pre-clinical evidences consistently suggests that sulforaphane has a multi-faceted neuroprotective effect on AD pathophysiology. The anti-AD-like evidence of sulforaphane seen in cells and animals indicates the need to pursue sulforaphane research for relevant biomarkers in AD pre-symptomatic populations.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/genética , Isotiocianatos/farmacología , Trastornos de la Memoria/prevención & control , Fármacos Neuroprotectores/farmacología , Sulfóxidos/farmacología , Proteínas tau/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Animales , Biomarcadores/metabolismo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Esquema de Medicación , Evaluación Preclínica de Medicamentos , Regulación de la Expresión Génica , Humanos , Trastornos de la Memoria/genética , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/fisiopatología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Estrés Oxidativo/efectos de los fármacos , Agregado de Proteínas/efectos de los fármacos , Agregado de Proteínas/genética , Proteínas tau/antagonistas & inhibidores , Proteínas tau/metabolismo
17.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33799812

RESUMEN

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


Asunto(s)
Dieta , Suplementos Dietéticos , Micronutrientes/análisis , Mitocondrias/efectos de los fármacos , Obesidad/prevención & control , Animales , Antioxidantes/administración & dosificación , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Humanos , Inflamación/etiología , Inflamación/metabolismo , Inflamación/prevención & control , Masculino , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Mitocondrias/fisiología , Obesidad/etiología , Obesidad/metabolismo , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos
18.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33799869

RESUMEN

The possible cardioprotective effects of translocator protein (TSPO) modulation with its ligand 4'-Chlorodiazepam (4'-ClDzp) in isoprenaline (ISO)-induced rat myocardial infarction (MI) were evaluated, alone or in the presence of L-NAME. Wistar albino male rats (b.w. 200-250 g, age 6-8 weeks) were divided into 4 groups (10 per group, total number N = 40), and certain substances were applied: 1. ISO 85 mg/kg b.w. (twice), 2. ISO 85 mg/kg b.w. (twice) + L-NAME 50 mg/kg b.w., 3. ISO 85 mg/kg b.w. (twice) + 4'-ClDzp 0.5 mg/kg b.w., 4. ISO 85 mg/kg b.w. (twice) + 4'-ClDzp 0.5 mg/kg b.w. + L-NAME 50 mg/kg b.w. Blood and cardiac tissue were sampled for myocardial injury and other biochemical markers, cardiac oxidative stress, and for histopathological evaluation. The reduction of serum levels of high-sensitive cardiac troponin T hs cTnT and tumor necrosis factor alpha (TNF-α), then significantly decreased levels of serum homocysteine Hcy, urea, and creatinine, and decreased levels of myocardial injury enzymes activities superoxide dismutase (SOD) and glutathione peroxidase (GPx) as well as lower grades of cardiac ischemic changes were demonstrated in ISO-induced MI treated with 4'-ClDzp. It has been detected that co-treatment with 4'-ClDzp + L-NAME changed the number of registered parameters in comparison to 4'-ClDzp group, indicating that NO (nitric oxide) should be important in the effects of 4'-ClDzp.


Asunto(s)
Benzodiazepinonas/farmacología , Proteínas Portadoras/metabolismo , Infarto del Miocardio/prevención & control , NG-Nitroarginina Metil Éster/farmacología , Estrés Oxidativo/efectos de los fármacos , Receptores de GABA-A/metabolismo , Animales , Biomarcadores/sangre , Biomarcadores/metabolismo , Inhibidores Enzimáticos/farmacología , Glutatión Peroxidasa/metabolismo , Homocisteína/sangre , Isoproterenol , Masculino , Infarto del Miocardio/inducido químicamente , Infarto del Miocardio/metabolismo , Miocardio/enzimología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Ratas Wistar , Superóxido Dismutasa/metabolismo , Troponina T/sangre , Factor de Necrosis Tumoral alfa/sangre
19.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33801911

RESUMEN

Although epoxyeicosatrienoic acid (EET) analogs have performed well in several acute and chronic kidney disease models, targeted delivery of EET analogs to the kidney can be reasonably expected to reduce the level of drug needed to achieve a therapeutic effect and obviate possible side effects. For EET analog kidney-targeted delivery, we conjugated a stable EET analog to folic acid via a PEG-diamine linker. Next, we compared the kidney targeted EET analog, EET-F01, to a well-studied EET analog, EET-A. EET-A or EET-F01 was infused i.v. and plasma and kidney tissue collected. EET-A was detected in the plasma but was undetectable in the kidney. On the other hand, EET-F01 was detected in the plasma and kidney. Experiments were conducted to compare the efficacy of EET-F01 and EET-A for decreasing cisplatin nephrotoxicity. Cisplatin was administered to WKY rats treated with vehicle, EET-A (10 mg/kg i.p.) or EET-F01 (20 mg/kg or 2 mg/kg i.p.). Cisplatin increased kidney injury markers, viz., blood urea nitrogen (BUN), N-acetyl-ß-(D)-glucosaminidase (NAG), kidney injury molecule-1 (KIM-1), and thiobarbituric acid reactive substances (TBARS). EET-F01 was as effective as EET-A in decreasing BUN, NAG, KIM-1, TBARS, and renal histological injury caused by cisplatin. Despite its almost 2×-greater molecular weight compared with EET-A, EET-F01 was comparably effective in decreasing renal injury at a 10-fold w/w lower dose. EET-F01 decreased cisplatin nephrotoxicity by reducing oxidative stress and inflammation. These data demonstrate that EET-F01 targets the kidney, allows for a lower effective dose, and combats cisplatin nephrotoxicity. In conclusion, we have developed a kidney targeted EET analog, EET-F01, that demonstrates excellent potential as a therapeutic for kidney diseases.


Asunto(s)
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Neoplasias de la Mama/tratamiento farmacológico , Inflamación/prevención & control , Enfermedades Renales/prevención & control , Riñón/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ácido 8,11,14-Eicosatrienoico/química , Ácido 8,11,14-Eicosatrienoico/farmacocinética , Ácido 8,11,14-Eicosatrienoico/farmacología , Animales , Neoplasias de la Mama/patología , Línea Celular Tumoral , Cisplatino , Femenino , Humanos , Inflamación/metabolismo , Riñón/patología , Enfermedades Renales/inducido químicamente , Enfermedades Renales/metabolismo , Masculino , Ratones Desnudos , Ratas Endogámicas WKY , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
20.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33801956

RESUMEN

Diabetes mellitus is a major healthcare problem. It is not only characterized by hyperglycemia and chronic complications, but in longer lasting diabetes and a longer living population, it is also associated with accelerated arterial ageing, which importantly contributes to cardiovascular complications. The accelerated arterial ageing in patients with diabetes should be considered separately from arterial ageing in patients without diabetes. Basic and clinical research have allowed better insight into the mechanisms of arterial ageing. In a simplified mechanistic way, it could be considered that the three tightly connected cornerstone characteristics of arterial ageing in patients with diabetes are: phenotypic presentation as endothelial dysfunction and arterial stiffness, and the underlying basic ageing-facilitating mechanism represented as the impaired expression of genetic longevity pathways. Currently, specific drugs for preventing/treating arterial ageing are not available. Therefore, we aimed to review the capacity of available drugs, particularly antidiabetic drugs, to interfere with the arterial ageing process. In the near future, these characteristics could help to guide therapy in patients with diabetes. Overall, it appears that arterial ageing could become a new target in diabetes. The expanding knowledge regarding the capability of antidiabetic drugs and other available drugs to inhibit/delay arterial aging is therefore essential.


Asunto(s)
Envejecimiento , Arterias/fisiopatología , Enfermedades Cardiovasculares/fisiopatología , Diabetes Mellitus/fisiopatología , Calcificación Vascular/fisiopatología , Rigidez Vascular/fisiología , Arterias/efectos de los fármacos , Arterias/metabolismo , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/metabolismo , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/metabolismo , Humanos , Hipoglucemiantes/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Calcificación Vascular/tratamiento farmacológico , Calcificación Vascular/metabolismo , Rigidez Vascular/efectos de los fármacos
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