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1.
Chem Biol Interact ; 320: 109026, 2020 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-32112863

RESUMEN

Leishmaniasis is a widespread tropical infection caused by different species of Leishmania protozoa. Many of the available drugs against the disease are toxic and in certain cases parasite drug resistance is developed. The discovery of drugs for the treatment of leishmaniasis is a pressing concern. In the present work, we describe in vitro studies of the phenolic compound methyl gallate (MG) against Leishmania (Leishmania) amazonensis and its possible mechanisms of action. The in vitro activity of MG was assayed against L. amazonensis (promastigotes, axenic amastigotes, and intramacrophagic amastigotes). Cytotoxicity tests were performed with J774A.1 macrophages and THP-1 cell derived macrophages. To evaluate mechanisms of action, we analyzed cellular TNF-α, IL-12, IFN-γ, IL-10, IL-6, NO, ROS levels, arginase activity, and structural mechanisms (phagocytic and lysosomal activities) involving macrophage activation. Meglumine antimoniate and amphotericin B were used as reference drugs. It was observed that MG effectively inhibited the growth of both promastigote (IC50 5.71 µM) and amastigote-like forms (EC50 5.39 µM), with much higher selectivity indexes than the reference drugs, being more benign towards J774A.1 macrophages than meglumine antimoniate and amphotericin B, at 1631- and 70.92-fold respectively, with respect to the promastigote form. Additionally, MG proved to be even more active against intracellular amastigotes of the parasite (EC50 4.24 µM). Our results showed that antileishmania activity was associated with increased TNF-α, IL-12, NO and ROS levels, as well as decreased IL-6 and decreased arginase activity. In addition, MG induced increased phagocytic capability, and lysosomal volume in macrophages; structural parameters of microbicidal activity. Taken together, our results suggest that MG may be a promising candidate for new drug development against leishmaniasis.


Asunto(s)
Antiprotozoarios/farmacología , Ácido Gálico/análogos & derivados , Leishmania/efectos de los fármacos , Anfotericina B/farmacología , Antiprotozoarios/química , Ácido Gálico/efectos adversos , Ácido Gálico/química , Ácido Gálico/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Macrófagos/efectos de los fármacos , Antimoniato de Meglumina/farmacología , Estructura Molecular , Especies Reactivas de Oxígeno
2.
Chem Biol Interact ; 318: 108969, 2020 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-32007422

RESUMEN

Methylmercury (MeHg) is a neurotoxicant that poses risk to human health and the environment, while glutamate homeostasis is necessary for the proper functioning of the brain. We have previously shown an increase in oxidative stress after cockroach exposure to diet containing monosodium glutamate (MSG), both separately and combined with a low dose of methylmercury. We herein seek to corroborate these findings by quantifying the expression levels of certain antioxidant genes in Nauphoeta cinerea exposed to MeHg and MSG. Cockroaches were fed with the basal diet alone, basal diet +2% NaCl, basal diet +2% MSG; basal diet +0.125 mg/g MeHg, basal diet +0.125 mg/g MeHg +2% NaCl; and basal diet +0.125 mg/g MeHg +2% MSG for 21 days and mRNA from head homogenate was used to quantify the expression of antioxidant genes such as glutathione-s-transferase (GstS, GstT, GstD), thioredoxin (Trx1, Trx2, Trx5), peroxiredoxin (prx4), superoxide dismutase (Sod), catalase (Cat). MeHg, NaCl and MSG alone downregulated mRNA levels of GstS and Trx5, in contrast, co-exposure of MeHg + MSG, upregulated these genes. MeHg + NaCl upregulated the mRNA levels of Cat and Sod but these genes were downregulated by NaCl alone. MeHg + NaCl and MeHg + MSG upregulated GstD and GstT. MeHg alone upregulated the transcription levels of Trx1, Trx2 and Prx4. The disruptions in the transcription levels of various genes by MeHg and MSG, reinforce the toxicity of these neurotoxicants. In general, the data suggest their additive effects and support the use of N. cinerea as a model for toxicological studies.


Asunto(s)
Antioxidantes/metabolismo , Cucarachas/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Compuestos de Metilmercurio/toxicidad , Glutamato de Sodio/toxicidad , Animales , Regulación hacia Abajo/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Regulación hacia Arriba/efectos de los fármacos
3.
Chem Biol Interact ; 318: 108971, 2020 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-32017913

RESUMEN

Pulpal infection is one of the most common causes of dental emergency admission. Tooth pain due to infection caused by gram-negative bacteria is the main manifestation of this sort of dental problem. The GPR173 signaling pathway is a highly conserved G-protein-coupled receptor that mediates neurological and reproductive function. In this study, we found that GPR173 was fairly expressed in isolated human dental pulp cells, and its expression was reduced in response to pro-inflammatory lipopolysaccharide (LPS) treatment. The activation of GPR173 by its ligand Phoenixin-20 reduced LPS-induced cytotoxicity, as revealed by a reduction in the release of LDH. Additionally, Phoenixin-20 suppressed LPS-induced release of pro-inflammatory cytokines and inflammatory mediators, including IL-6, MCP-1, VCAM-1, and ICAM-1, as well as MMP-2 and MMP-9. Mechanistically, we showed the suppressive action of Phoenixin-20 on LPS-induced activation of TLR-4 and Myd88 as well as the activation of the NF-κB pathway. Collectively, our study demonstrates that the GPR173 signaling pathway is an important mediator of LPS-induced inflammation, and the activation of GPR173 by its natural ligand Phoenixin-20 exhibits robust anti-inflammatory effects in dental pulp cells, suggesting that GPR173 is an interesting target molecule in the development of pulp cell-based therapies.


Asunto(s)
Pulpa Dental/citología , Inflamación/inducido químicamente , Lipopolisacáridos/toxicidad , Péptidos/farmacología , Células Cultivadas , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inflamación/metabolismo , Inflamación/prevención & control , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo
4.
Chem Biol Interact ; 318: 108978, 2020 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-32044341

RESUMEN

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) accumulates in human body, probably influencing adipocyte differentiation and causing various toxic effects, including wasting syndrome. Recently, orientin, a phenolic compound abundant in natural health products, has been shown to have antioxidant properties. We investigated the protective effects of orientin against TCDD-induced adipocyte dysfunction and its underlying mechanisms. In this study, orientin suppressed TCDD-induced loss of lipid accumulation. Orientin inhibited TCDD-driven decreases in the levels of peroxisome proliferator-activated receptor γ and adiponectin. Orientin also reduced TCDD-induced prostaglandin E2, and cytosolic phospholipase A2α levels, and increased TCDD-inhibited peroxisome proliferator-activated receptor gamma coactivator 1-alpha levels in 3T3-L1 adipocytes. TCDD reduced the levels of insulin receptor substrate 1 and glucose transporter 4, and decreased insulin-stimulated glucose uptake activity; however, orientin diminished these TCDD-induced effects. These results suggest that orientin may have beneficial effects on the prevention of TCDD-induced wasting syndrome and type II diabetes mellitus accompanied by insulin resistance.


Asunto(s)
Adipocitos/efectos de los fármacos , Adipogénesis/efectos de los fármacos , Flavonoides/farmacología , Glucósidos/farmacología , Insulina/metabolismo , Dibenzodioxinas Policloradas/toxicidad , Transducción de Señal/efectos de los fármacos , Células 3T3-L1 , Animales , Dinoprostona , Regulación de la Expresión Génica/efectos de los fármacos , Glucosa/metabolismo , Ratones
5.
Chem Biol Interact ; 317: 108965, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-32001260

RESUMEN

Endocrine therapies (e.g. tamoxifen and aromatase inhibitors) targeting estrogen action are effective in decreasing mortality of breast cancer. However, their efficacy is limited by intrinsic and acquired resistance. Our previous study demonstrated that overexpression of a histone methyltransferase NSD2 drives tamoxifen resistance in breast cancer cells and that NSD2 is a potential biomarker of tamoxifen resistant breast cancer. Here, we found that DZNep, an indirect inhibitor of histone methyltransferases, potently induces the degradation of NSD2 protein and inhibits the expression of NSD2 target genes (HK2, G6PD, GLUT1 and TIGAR) involved in the pentose phosphate pathway (PPP). DZNep treatment of tamoxifen-resistant breast cancer cells and xenograft tumors also strongly inhibits tumor growth and the cancer cell survival through decreasing cell production of NADPH and glutathione (GSH) and invoking elevated ROS to cause apoptosis. These findings suggest that DZNep-like agents can be developed to target NSD2 histone methyltransferase for effective treatment of tamoxifen-resistant breast cancer.


Asunto(s)
Adenosina/análogos & derivados , N-Metiltransferasa de Histona-Lisina/metabolismo , Metiltransferasas/antagonistas & inhibidores , Proteínas Represoras/metabolismo , S-Adenosilhomocisteína/metabolismo , Adenosina/farmacología , Antígenos Ly , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , N-Metiltransferasa de Histona-Lisina/genética , Homeostasis , Humanos , Oxidación-Reducción , Proteolisis/efectos de los fármacos , Especies Reactivas de Oxígeno , Proteínas Represoras/genética , Tamoxifeno , Activador de Plasminógeno de Tipo Uroquinasa
6.
Chem Biol Interact ; 317: 108959, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-32001261

RESUMEN

The isoquinoline 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI) has been studied due to its multitarget properties, such as modulation of GABAergic and glutamatergic systems, antioxidant, and anti-inflammatory. This study investigated the contribution of oxidative stress, nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase (HO-1) signaling, and the cholinergic system to the anti-amnesic action of FDPI in mice. Adult male Swiss mice received FDPI for 5 days (5-25 mg/kg, i.g.); the animals received scopolamine (1 mg/kg, i.p) from day 3-5. The vehicle-control group was carried out. Afterward, mice performed object recognition tests (ORTs). Scopolamine induced amnesia and cholinergic dysfunction by increasing the acetylcholinesterase (AChE) activity and content, decreasing the muscarinic M1 receptor levels in the prefrontal cortex and hippocampus of mice. This study reveals that scopolamine altered oxidative stress parameters differently in the prefrontal cortex and hippocampus of mice. Whereas the prefrontal cortex was susceptible to oxidative stress, none of the parameters evaluated was altered in the hippocampus of scopolamine-treated mice. FDPI at doses of 10 and 25 mg/kg had an anti-amnesic effect in the ORT tests. FDPI 10 mg/kg reversed the increase in the AChE activity and content, oxidative stress parameters, and modulated Nrf2/HO-1 signaling in the prefrontal cortex of scopolamine-exposed mice. Pearson's correlation analyses reinforced the contribution of the prefrontal cortical cholinergic system, oxidative stress as well as Nrf2/HO-1 signaling in the anti-amnesic effect of FDPI. Considering FDPI effects on the hippocampus, it was effective against the cholinergic dysfunction, AChE activity and content, and M1 receptor levels, which collectively could contribute to its anti-amnesic effect.


Asunto(s)
Amnesia/prevención & control , Hemo-Oxigenasa 1/metabolismo , Proteínas de la Membrana/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Quinolinas/farmacología , Amnesia/inducido químicamente , Animales , Conducta Animal/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Hemo-Oxigenasa 1/genética , Proteínas de la Membrana/genética , Ratones , Actividad Motora/efectos de los fármacos , Factor 2 Relacionado con NF-E2/genética , Estrés Oxidativo , Corteza Prefrontal/efectos de los fármacos , Escopolamina/toxicidad , Transducción de Señal
7.
Chem Biol Interact ; 317: 108966, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-32004531

RESUMEN

Titanium dioxide nanoparticles (TiO2-NPs) are widely used in the food industry, cosmetics, personal care and paints among others. Through occupational exposure and daily consumption, and because of their small size, TiO2-NPs can enter the body through different routes such as oral, dermal and inhalation, and accumulate in multiple organs including the brain. TiO2-NPs cause severe damage to many cell types, however their effects in the central nervous system remain largely unexplored. Therefore, in the present study we determined the cytotoxic effect of TiO2-NPs on rat astrocytes. We tested the oxidant properties of TiO2-NPs through DTT depletion, and measured oxidative stress-induced damage in mitochondria, through oxidation of 2,7-dichlorodihydrofluorescein diacetate (H2DCFDA) and loss of mitochondrial membrane potential (ΔΨm) with Mitotracker Green FM. We further examined oxidative stress-derived responses such as IκB-α degradation by Western Blot, NF-κB translocation by EMSA, autophagy induction by LC3-II levels, and expression of the inflammasome protein NLRP3. TiO2-NPs showed high oxidant properties and induced strong oxidative stress in astrocytes following their internalization, causing mitochondrial damage detected by ΔΨm loss. Responses against oxidative damage such as NF-κB translocation and autophagy were induced and NLRP3 protein expression was downregulated, indicating lower inflammasome-mediated responses in astrocytes. These results support TiO2-NPs cytotoxicity in astrocytes, cells that play key roles in neuronal homeostasis and their dysfunction can lead to neurological disorders including cognitive impairment and memory loss.


Asunto(s)
Astrocitos/efectos de los fármacos , Autofagia/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Estrés Oxidativo/efectos de los fármacos , Animales , Animales Recién Nacidos , Astrocitos/metabolismo , Células Cultivadas , Regulación hacia Abajo , Nanopartículas del Metal , Inhibidor NF-kappaB alfa/metabolismo , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Ratas , Ratas Wistar , Titanio
8.
Chem Biol Interact ; 317: 108972, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-32017914

RESUMEN

BACKGROUND: Heart failure (HF) is an epidemic disease with increased incidence annually. It has been reported that taurine can improve cardiac function. This study investigated the cardioprotective effects of taurine in pressure-loaded HF mice and elucidated the possible mechanism. METHODS: HF models were established by transverse aortic constriction (TAC). Animals were treated with either taurine for 9 weeks and/or the SIRT1 inhibitor EX527 (5 mg/kg/day, every 2days) after TAC operation. Cardiac function and geometry were revealed by echocardiography. Myocardial hypertrophy and fibrosis were assessed using Fluorescent wheat germ agglutinin (WGA) staining and Masson's trichrome staining. Western blot and RT-PCR were performed to elucidate the expression of target proteins and genes respectively. Apoptosis in cardiomyocytes was detected by TUNEL staining. Myocardial oxidative stress was assessed by detecting the concentration of myocardial super oxidative dismutase (SOD) and malonyldialdehyde (MDA) and reactive oxygen species (ROS). Taurine concentrations and NAD+/NADH ratio were determined by taurine and NAD+/NADH assay kit. RESULTS: Taurine notably relieved cardiac dysfunction after TAC. The mechanisms were attributed to reduced myocyte hypertrophy and fibrosis, and alleviated apoptosis and oxidative stress. Meanwhile, taurine increased NAD+/NADH ratio,promoted the expression of SIRT1 and suppressed p53 acetylation. However, EX-527(inhibitor of SIRT1) decreased NAD+/NADH ratio and increased acetyl-p53 levels, and abolished the cardioprotective effects of taurine on mice subjected to TAC and increased apoptosis and oxidative stress. CONCLUSION: The mechanism responsible for cardiac-protective effects of taurine in HF induced by pressure overload is associated with the activation of the SIRT1-p53 pathway.


Asunto(s)
Miocitos Cardíacos/efectos de los fármacos , Presión , Sirtuina 1/metabolismo , Taurina/farmacología , Proteína p53 Supresora de Tumor/metabolismo , Animales , Aorta/patología , Apoptosis/efectos de los fármacos , Carbazoles/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Ligadura , Masculino , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo , Sirtuina 1/genética , Proteína p53 Supresora de Tumor/genética
9.
Cell Physiol Biochem ; 54(1): 142-159, 2020 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-32028545

RESUMEN

BACKGROUND/AIMS: It is well established that oxidative stress and inflammation are common pathogenic features of retinal degenerative diseases. ITH12674 is a novel compound that induces the transcription factor Nrf2; in so doing, the molecule exhibits anti-inflammatory, and antioxidant properties, and affords neuroprotection in rat cortical neurons subjected to oxidative stress. We here tested the hypothesis that ITH12674 could slow the retinal degeneration that causes blindness in rd10 mice, a model of retinitis pigmentosa. METHODS: Animals were intraperitoneally treated with 1 or 10 mg/Kg ITH12674 or placebo from P16 to P30. At P30, retinal functionality and visual acuity were analyzed by electroretinography and optomotor test. By immunohistochemistry we quantified the photoreceptor rows and analyzed their morphology and connectivity. Oxidative stress and inflammatory state was studied by Western blot, and microglia reactivity was monitored by flow cytometry. The blood-brain barrier permeation of ITH12674 was evaluated using a PAMPA-BBB assay. RESULTS: In rd10 mice treated with 10 mg/Kg of the compound, the following changes were observed (with respect to placebo): (i) a decrease of vision loss with higher scotopic a- and b-waves; (ii) increased visual acuity; (iii) preservation of cone photoreceptors morphology, as well as their synaptic connectivity; (iv) reduced expression of TNF-α and NF-κB; (v) increased expression of p38 MAPK and Atg12-Atg5 complex; and (vi) decreased CD11c, MHC class II and CD169 positive cell populations. CONCLUSION: These data support the view that a Nrf2 inducer compound may arise as a new therapeutic strategy to combat retinal neurodegeneration. At present, we are chemically optimising compound ITH12674 with the focus on improving its neuroprotective potential in retinal neurodegenerative diseases.


Asunto(s)
Isotiocianatos/uso terapéutico , Melatonina/análogos & derivados , Factor 2 Relacionado con NF-E2/agonistas , Retinitis Pigmentosa/tratamiento farmacológico , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Modelos Animales de Enfermedad , Electrorretinografía , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Isotiocianatos/química , Isotiocianatos/farmacología , Masculino , Melatonina/química , Melatonina/farmacología , Melatonina/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/metabolismo , Células Fotorreceptoras/efectos de los fármacos , Células Fotorreceptoras/patología , Retina/efectos de los fármacos , Retina/metabolismo , Retinitis Pigmentosa/metabolismo , Retinitis Pigmentosa/patología , Factor de Necrosis Tumoral alfa/metabolismo , Agudeza Visual/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
10.
Life Sci ; 248: 117452, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-32088214

RESUMEN

AIMS: The aim of this study was to elucidate the signaling pathway involved in the anti-aging effect of tropisetron and to clarify whether it affects mitochondrial oxidative stress, apoptosis and inflammation in the aging mouse brain by upregulating Sirtuin 1 or silent information regulator 1 (SIRT1). MATERIALS AND METHODS: Aging was induced by d-galactose (DG) at the dose of 200 mg/kg body weight/day subcutaneously injected to male mice for six weeks. Tropisetron was simultaneously administered intraperitoneally once a day at three various doses (1, 3 and 5 mg/kg body weight). Oxidative stress and mitochondrial dysfunction markers were evaluated. Nitric oxide (NO) and pro-inflammatory cytokines levels including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were studied. Besides, the expressions of apoptosis-associated genes (Bax and Bcl-2) and the aging-related gene (SIRT1) were determined by the real time polymerase chain reaction (RT-PCR). In addition, histopathological alterations were assessed. KEY FINDINGS: Tropisetron reversed the induction of oxidative damage, mitochondrial dysfunction and overproduction of inflammatory mediators induced by DG in the brain tissue. In addition, tropisetron suppressed DG-induced apoptosis and found to significantly elevate SIRT1 gene expression. Besides, tropisetron could markedly alleviate DG-induced abnormal changes in the brain morphology. SIGNIFICANCE: Tropisetron exhibited anti-aging effects in the context of DG-induced senescence in mouse brain through various pathways. Our results suggest that tropisetron may attenuate DG-induced brain aging via SIRT1 signaling activation.


Asunto(s)
Envejecimiento/efectos de los fármacos , Antioxidantes/farmacología , Encéfalo/efectos de los fármacos , Antagonistas del Receptor de Serotonina 5-HT3/farmacología , Sirtuina 1/genética , Tropisetrón/farmacología , Envejecimiento/genética , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Encéfalo/metabolismo , Encéfalo/patología , Esquema de Medicación , Galactosa/efectos adversos , Regulación de la Expresión Génica/efectos de los fármacos , Inflamación , Inyecciones Intraperitoneales , Inyecciones Subcutáneas , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Sirtuina 1/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismo
11.
Life Sci ; 248: 117464, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-32097667

RESUMEN

AIMS: The present study was carried out to investigate the influences of Selenium/Zinc-Enriched probiotics (SeZnP) on growth performance, serum enzyme activity, antioxidant capability, inflammatory factors and gene expression associated with Wistar rats inflated under high ambient thermal-stress. MAIN METHODS: Sixty male rates with six-weeks of age were randomly allocated into five groups (12 per group) and fed basal diet (Control), basal diet supplemented with probiotics (P), Zinc-Enriched probiotics (ZnP, 100 mg/L), Selenium-Enriched Probiotics (SeP, 0.3 mg/L) and Selenium/Zinc-Enriched probiotics (SeZnP, 0.3 mg + 100 mg/L). The experiment lasted 30 days. Blood and Tissues samples were taken to investigate serum enzyme activity, antioxidants capability and inflammatory factors by using of commercial kits and antioxidant, heat shock and inflammatory related molecules expressions were determined by qRT-PCR. KEY FINDINGS: Data analysis revealed that thermal stress significantly increased the level of Aspartate-aminotransferase, Alanine-aminotransferase, Lactate-dehydrogenase, Creatine-kinase, blood urea nitrogen, Creatinine and Alkaline phosphatase compared to P, ZnP, SeP or SeZnP groups (P < 0.01). However, supplementation of ZnP, SeP, and SeZnP significantly enhanced glutathione content, glutathione-peroxidase & superoxide-dismutase activity, and decreased malondialdehyde content (P < 0.05). Moreover, the concentration of IL-2, IL-6 and IL-8 were significantly increased while IL-10 was significantly decreased (P < 0.05). Furthermore, the expression of GPx1 and SOD1 genes were significantly increased, but COX-2, iNOS, HSP70 and 90 mRNA levels were significantly decreased (P < 0.05). Finally, the highest influence of the mentioned parameters was observed in SeZnP supplemented group. SIGNIFICANCE: Our study suggests that SeZnP supplementation serves as possible and best nutritive than ZnP or SeP for Wistar rats raising under high ambient temperature.


Asunto(s)
Antioxidantes/administración & dosificación , Suplementos Dietéticos , Regulación de la Expresión Génica/efectos de los fármacos , Respuesta al Choque Térmico/efectos de los fármacos , Probióticos/administración & dosificación , Selenio/administración & dosificación , Zinc/administración & dosificación , Alanina Transaminasa/genética , Alanina Transaminasa/metabolismo , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/metabolismo , Animales , Aspartato Aminotransferasas/genética , Aspartato Aminotransferasas/metabolismo , Nitrógeno de la Urea Sanguínea , Creatina Quinasa/genética , Creatina Quinasa/metabolismo , Creatinina/metabolismo , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Glutatión/metabolismo , Glutatión Peroxidasa/genética , Glutatión Peroxidasa/metabolismo , Proteínas HSP70 de Choque Térmico/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Respuesta al Choque Térmico/genética , L-Lactato Deshidrogenasa/genética , L-Lactato Deshidrogenasa/metabolismo , Masculino , Malondialdehído/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ratas , Ratas Wistar , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo
12.
Ann Hematol ; 99(3): 431-441, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32006153

RESUMEN

Macrophages are characterized by phenotypical and functional heterogeneity. In different microenvironments, macrophages can polarize into two types: classically activated macrophages (M1) or alternatively activated macrophages (M2). M1 macrophages are a well-known bacteriostatic macrophage, and conversely, M2 macrophages may play an important role in tumor growth and tissue remodeling. M1 macrophages have been reported to have high intracellular iron stores, while M2 macrophages contain lower intracellular iron. It has been well-described that disturbances of iron homeostasis are associated with altered immune function. Thus, it is important to investigate if chronic iron overload is capable of polarizing macrophages. Human monocytic leukemia THP-1 cells were maintained in culture medium that contained 100 µM ferrous sulfate heptahydrate (FeSO4) (I-THP-1) and differentiated into THP-1-derived macrophages (I-TDMs) by induction with phorbol 12-myristate 13-acetate (PMA). We characterized that I-TDMs not only enhanced the surface expression of CD163 and CD206 but also increased arginase and decreased iNOS protein expression. I-TDMs enhanced pSTAT6 expression and decreased pSTAT1 and NF-κB expressions. Furthermore, the gene expression profile of I-TDMs was comparable with M2 macrophages by performing human oligonucleotide DNA microarray analysis. Finally, functional assays demonstrated I-TDMs secreted higher levels of IL-10 but not M1 cytokines. Additionally, the conditional medium of I-TDMs had enhanced migration and increased invasion of A375 melanoma cells which was similar to the characteristics of tumor-associated macrophages. Taken together, we demonstrated that THP-1-derived macrophages polarized to a phenotype of M2-like characteristics when subjected to chronic iron overload.


Asunto(s)
Movimiento Celular/inmunología , Sobrecarga de Hierro/inmunología , Macrófagos/inmunología , Monocitos/inmunología , Movimiento Celular/efectos de los fármacos , Compuestos Ferrosos/efectos adversos , Compuestos Ferrosos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Humanos , Sobrecarga de Hierro/inducido químicamente , Sobrecarga de Hierro/patología , Macrófagos/patología , Monocitos/patología , Células THP-1 , Acetato de Tetradecanoilforbol/farmacología
13.
Chem Biol Interact ; 317: 108943, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-31926917

RESUMEN

Epidemiological studies have shown that cigarette smoking is beneficial in ulcerative colitis and that nicotine may be responsible for this effect. However, the mechanism remains unclear. In a previous study, nicotine was found to induce autophagy in intestinal cells. Here, we evaluated the effect of nicotine-induced autophagy in a dextran sodium sulfate (DSS)-induced colitis mouse model. C57BL/6 adult male mice drank DSS water solution freely for seven consecutive days, and then tap water was administered. The effect of nicotine treatment was examined in the DSS model, including colon length, disease severity, histology of the colon tissue, and inflammation levels. Moreover, autophagy levels were detected by Western blot analysis (LC3II/LC3I, p62, and beclin-1). The levels of DSS-induced colitis were significantly decreased following nicotine treatment. The disease activity score, body weight, histologic damage scores, and the level of colonic inflammatory factors of nicotine-treated mice all decreased compared to those of the control mice. Additionally, nicotine enhanced the expression of LC3II/LC3I and beclin-1 but decreased the p62 protein level. Inhibiting autophagy by 3-MA attenuated the protective effects of nicotine on colitis. Additionally, both in vitro and in vivo experiments showed changes in AMPK-mTOR-P70S6K during this process. These results suggest that nicotine improved colitis by regulating autophagy and provided a protective effect against DSS-induced colitis.


Asunto(s)
Adenilato Quinasa/metabolismo , Autofagia/efectos de los fármacos , Colitis/prevención & control , Nicotina/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Adenina/análogos & derivados , Adenina/farmacología , Adenilato Quinasa/genética , Animales , Colitis/inducido químicamente , Sulfato de Dextran/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Proteínas Quinasas S6 Ribosómicas 70-kDa/genética , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Serina-Treonina Quinasas TOR/genética
14.
Chem Biol Interact ; 317: 108942, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-31930969

RESUMEN

Pulmonary hypertension (PH) is distal pulmonary arterial remodelling and is mainly due to the abnormal proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs). Apigenin, a natural dietary flavonoid, is a promising PH preventive agent that inhibits PASMC proliferation and induces apoptosis. In this study, we investigated the biological effects of apigenin on PH. PH was induced in male Sprague-Dawley rats by chronic hypoxia exposure. Administration of apigenin prevented the development of PH, hypoxia-induced right ventricular hypertrophy and pulmonary arterial remodelling and prevented the progression of established PH in this model. Moreover, treatment with apigenin induced mitochondria-dependent apoptosis. To explore the underlying mechanisms, the mitochondrial membrane potential (Δψm) and the mitochondria-dependent apoptosis factors cytochrome C, BAX, Bcl-2, cleaved caspase 3, and cleaved caspase 9 were analysed. These results confirmed that apigenin induces mitochondria-dependent apoptosis in hypoxic PASMCs to protect against PH. In addition, treatment with apigenin reversed hypoxia-induced inhibition of KV1.5 expression both in vivo and in vitro. The KV1.5 inhibitor diphenyl phosphine oxide-1 (DPO-1) abrogated apigenin-induced mitochondria-dependent apoptosis in hypoxic PASMCs, suggesting that KV1.5 is implicated in apigenin-induced mitochondria-dependent apoptosis. Furthermore, functional studies revealed that apigenin activated mitochondria-dependent apoptosis by modulation of hypoxia-induced factor 1α (HIF-1α) signalling. Together, our study shows that apigenin attenuates PH via inhibiting the HIF-1α-KV1.5 channel pathway to induce PASMC mitochondria-dependent apoptosis.


Asunto(s)
Apigenina/uso terapéutico , Apoptosis/efectos de los fármacos , Hipertensión Pulmonar/tratamiento farmacológico , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Mitocondrias/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Animales , Proliferación Celular , Supervivencia Celular/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Hipertensión Pulmonar/complicaciones , Hipoxia/complicaciones , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Canal de Potasio Kv1.5/genética , Canal de Potasio Kv1.5/metabolismo , Masculino , Miocitos del Músculo Liso/fisiología , Arteria Pulmonar/citología , Ratas , Ratas Sprague-Dawley
15.
Chem Biol Interact ; 317: 108945, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-31935363

RESUMEN

Liver fibrosis is a common pathological consequence of liver injury, which increases liver failure-related morbidity and mortality. Hence, anti-fibrotic treatment is urgently needed. Oxidative stress plays a pivotal role in the progression of liver fibrosis. Thus, targeting ROS may be an effective strategy for liver fibrosis treatment. In this study, we investigated four benzoquinones derivatives, including 5-isopropyl-2-methyl-1,4-benzoquinone (TQ), 2-tert-butyl-1,4-benzoquinone (tBu-Q) 2,5-dimethyl-p-benzoquinone (Dime-Q) and p-benzoquinone (Ph-Q), as well as the evaluation of their antioxidant activity and anti-fibrotic effects on activated hepatic stellate cells and TAA-induced mice. Electrochemical analysis showed that all compounds possessed antioxidant property. The result was first confirmed by in vitro experiments, which revealed potential anti-fibrotic activity of all four compounds at the cellular level. Benzoquinone derivatives act as ROS-scavenging molecules, which modulated the TLR4-CD14 signaling pathway to inhibit the expression of procaspase-1 and IL-1ß in cells, induced apoptosis via a mitochondrial pathway by upregulating the ratio of Bax/Bcl-2 and by activating caspase-3, as well as inhibited the expression of the anti-apoptotic proteins FLIP and XIAP in activated LX-2 cells. In addition, a TAA (Thioacetamide)-induced mouse model was used to further validate the results. Treatment with benzoquinone derivatives significantly decreased the levels of liver injury markers and lipid peroxidation caused by excessive ROS, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and malondialdehyde (MDA). Moreover, treatment with benzoquinone derivatives significantly inhibited extracellular matrix (ECM) deposition and downregulated the mRNA and protein expression of liver fibrosis markers, such as collagen I, alpha-smooth muscle actin (α-SMA), and TIMP-1. In summary, these results indicate that benzoquinone derivatives may act as potential therapeutic drugs against liver fibrosis.


Asunto(s)
Antioxidantes/farmacología , Benzoquinonas/farmacología , Células Estrelladas Hepáticas/efectos de los fármacos , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/tratamiento farmacológico , Tioacetamida/toxicidad , Actinas/genética , Actinas/metabolismo , Animales , Biomarcadores , Línea Celular , Supervivencia Celular/efectos de los fármacos , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Inflamación/metabolismo , Inflamación/prevención & control , Masculino , Ratones , Ratones Endogámicos BALB C , Estrés Oxidativo , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-1/metabolismo
16.
Chem Biol Interact ; 317: 108944, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-31935364

RESUMEN

Bone mesenchymal stem cells (BMSCs) are a well-known donor graft source due to their potential for self-renewal and differentiation into multi-lineage cell types, including osteoblasts that are critical for fracture healing. Fasudil (FAS), a Rho kinase inhibitor, has been proven to induce the differentiation of bone marrow stem cells (BMSCs) into neuron-like cells. However, its role in the osteogenesis of BMSCs remain uncertain. Herein, we for the first time studied the effects of FAS on osteogenic differentiation in a mouse fracture model and further explored the involved mechanisms in mouse BMSCs. The results showed that FAS stimulated bone formation in the fracture mouse model. Additionally, at 30 µM, FAS significantly promotes alkaline phosphatase activity, mineralization, and the expression of osteogenic markers COL-1, RUNX2 and OCN in murine BMSCs. Blocking of P38 by SB202190 significantly reversed the effects of FAS, in vitro, suggesting that P38, but not ERK or JNK activation is required for FAS-induced osteogenesis. Collectively, our results indicate that FAS may be a promising agent for promoting fracture healing.


Asunto(s)
1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , Células de la Médula Ósea/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/farmacología , Animales , Biomarcadores , Proliferación Celular/efectos de los fármacos , Femenino , Fracturas Óseas , Regulación de la Expresión Génica/efectos de los fármacos , Imidazoles/farmacología , Células Madre Mesenquimatosas , Ratones , Osteogénesis/efectos de los fármacos , Fosforilación , Piridinas/farmacología
17.
Chem Biol Interact ; 317: 108940, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-31935365

RESUMEN

Type 2 diabetes is associated with oxidative stress and low-grade inflammation resulting in endothelial dysfunction (ED). This study determined to explore the protective effects of berry-derived anthocyanins (AC) with potent antioxidant and anti-inflammatory activities in human diabetic endothelial cells upon oxidative and inflammatory stressors. Cultured healthy human aortic endothelial cells (HAEC) and diabetic human aortic endothelial cells (D-HAEC) exposed to oxidative stress by hydrogen peroxide (H2O2, 75 µM) and lipopolysaccharide (LPS, 1 µg/mL) as an inflammatory inducer before treatment with AC (50 µl/ml). The results from cytotoxicity assays showed that AC had no significant effects in cell viability (P-value < 0.0001), and exposure to H2O2 75 µM had a less toxic effect (P-value < 0.05). Although, AC significantly decreased H2O2-induced cytotoxicity and oxidative stress in both HAEC and D-HAEC cell lines (P-value < 0.0001), no positive impact of AC was found on the GSSG/GSH ratios (P-value < 0.05). Exposure to the LPS increased the production of IL-6 in both HAEC and D-HAEC cell lines (P-value < 0.0001), whereas AC treatment reduced LPS-induced IL-6 production in both cell lines with a more robust impact on D-HAEC (P-value < 0.0001). While LPS increased inflammasome assembling and caspase-1 activation, AC treatment inhibited caspase-1 activation in D-HAEC (P ≤ 0.05). This study indicated that berry anthocyanins reduced oxidative stress and inflammation via the inhibition of the NF-ƙB signaling pathway, which contributes to mitigating the diabetes-induced up-regulation of NF-ƙB.


Asunto(s)
Antocianinas/farmacología , Aorta/citología , Citoprotección/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Inflamación/inducido químicamente , Estrés Oxidativo/efectos de los fármacos , Antocianinas/química , Antocianinas/farmacocinética , Caspasa 1/genética , Caspasa 1/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Citocinas/genética , Citocinas/metabolismo , Diabetes Mellitus Tipo 2 , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Peróxido de Hidrógeno/administración & dosificación , Peróxido de Hidrógeno/toxicidad , Inflamación/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Estructura Molecular , Especies Reactivas de Oxígeno
18.
Chem Biol Interact ; 317: 108947, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-31968208

RESUMEN

Inflammatory responses play a remarkable role in the mechanisms of acute and chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis and lung cancer. Currently, there is a resurgence in the use of drugs from natural sources for various ailments as potent therapeutics. Berberine, an alkaloid prominent in the Chinese traditional system of medicine has been reported to exert therapeutic properties in various diseases. Nevertheless, the number of studies focusing on the curative potential of berberine in inflammatory diseases involving the respiratory system is limited. In this review, we have attempted to discuss the reported anti-inflammatory properties of berberine that function through several pathways such as, the NF-κB, ERK1/2 and p38 MAPK pathways which affect several pro-inflammatory cytokines in the pathophysiological processes involved in chronic respiratory diseases. This review would serve to provide valuable information to researchers who work in this field and a new direction in the field of drug discovery with respect to respiratory diseases.


Asunto(s)
Berberina/farmacología , Inflamación/tratamiento farmacológico , Enfermedades Respiratorias/tratamiento farmacológico , Antiinflamatorios/farmacología , Enfermedad Crónica , Regulación de la Expresión Génica/efectos de los fármacos , Humanos
19.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 51(1): 7-12, 2020 Jan.
Artículo en Chino | MEDLINE | ID: mdl-31950782

RESUMEN

Objective: To study the effects of genistein (GEN) on reproductive system in prepubertal male rats. Methods: Thirty SPF-rated male SD rats were randomly divided into control group (Con group), low-dose group (G1 group) and high-dose group (G2 group), with 10 rats in each group. Corn oil, 150 mg/kg and 300 mg/kg GEN dissolved in corn oil of equal volume were respectively administered every day and weighed the next day. After 6 weeks, the rats were sacrificed, and the testis, epididymis and prostate were dissected, and organ coefficients were calculated. Histopathological changes of testis was observed. The number of sperm was counted and the rate of sperm malformation was calculated. The concentrations of serum testosterone and estradiol were detected by radioimmunoassay. The protein phosphatase 2, regulatory subunit B, gamma (PPP2R2C) protein expression in testicular tissue was detected by immunofluorescence assay. The mRNA and protein expression levels of PPP2R2C and cyclin dependent protein kinases 2 (CDK2) in rat testis were detected by real-time quantitative fluorescence PCR (RT-qPCR) and Western blot, respectively. The protein phosphatase 2A (PP2A) activity in testicular tissue was detected by immunoprecipitation. Results: There were no statistically significant differences in body mass, sperm number, serum estradiol and PP2A enzyme activity among the groups ( P>0.05). The pathological structure of testicular in G2 group was disordered. Sperm abnormality rate in G1 and G2 groups was higher than that in Con group ( P<0.05). Serum testosterone concentration in G2 group was lower than that in Con group ( P<0.05). The expression of PPP2R2C and CDK2 in G2 group was higher than that in Con group ( P<0.05), but the protein level was lower than that in Con group ( P<0.05). PPP2R2C protein was expressed in testicular tissue in each group. Conclusion: Long-term exposure to high dose (300 mg/kg) GEN during prepuberty may cause adverse effects on reproductive function in adult male rats. Further investigation is needed to determine whether PPP2R2C-PP2A-CDK2 phosphorylation pathway affects reproductive system in rats.


Asunto(s)
Genisteína , Genitales Masculinos , Animales , Estradiol/sangre , Regulación de la Expresión Génica/efectos de los fármacos , Genisteína/farmacología , Genitales Masculinos/efectos de los fármacos , Masculino , Fitoestrógenos/farmacología , Ratas , Ratas Sprague-Dawley , Recuento de Espermatozoides , Espermatozoides/efectos de los fármacos , Testículo/efectos de los fármacos , Testículo/enzimología , Testosterona/sangre
20.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 51(1): 13-17, 2020 Jan.
Artículo en Chino | MEDLINE | ID: mdl-31950783

RESUMEN

Objective: To investigate the effects of Akkermansia muciniphila ( A. muciniphila) on the proliferation, apoptosis and insulin secretion of rat pancreatic islet cell tumor cells (INS-1). Methods: INS-1 cells were divided into three groups, normal, repair, and protect groups, and subsequently every group was subjected with A. muciniphila metabolites, live A. muciniphilaorpasteurized A. muciniphila for 48 h. A group that did not treat with anything was set as blank control. After intervention, the cell viability was determined by MTT method, the insulin secretion level stimulated by glucose was determined by ELISA, the expressions of the genes involved in insulin secretion and apoptosis were tested by qRT-PCR, and the expression of apoptosis related protein Bax was evaluated by Western blot. Results: There was no significant change in INS-1 cell morphology after co-incubation with 3 types of A. Muciniphila interventions for 48 h. The proliferative activity of INS-1 cells was decreased in the repair group that treated with live A. muciniphila than that of control ( P<0.005). A. muciniphila intervention had no effect on insulin secretion in INS-1 cells in normal, repair or protection group ( P>0.05). A. muciniphila secretions promoted the expression of glucose transporter 2 ( Glut2) in 3 groups and the expression of glucokinase ( GCK) in repair group ( P<0.05). The expression of Baxof the INS-1 cell in the normal group was decreased after intervented with 3 kinds of A. muciniphila intervention materials ( P<0.001).The expression of Bax gene of the INS-1 cell in the repair group that treated with dead A. muciniphilawas decreased ( P<0.05). The expression of Bax protein of INS-1 cells that treated with A. muciniphila interventions was decreased. Conclusion: A. muciniphila can promote the expression of insulin secretion-related genes in INS-1 cells, inhibit the expression of apoptotic genes and apoptosis protein Bax.This research provides a new direction for applying A. muciniphila in improving type 2 diabetes.


Asunto(s)
Adenoma de Células de los Islotes Pancreáticos , Apoptosis , Diabetes Mellitus Tipo 2 , Secreción de Insulina , Probióticos , Verrucomicrobia , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular , Regulación de la Expresión Génica/efectos de los fármacos , Glucosa/farmacología , Secreción de Insulina/efectos de los fármacos , Ratas , Verrucomicrobia/fisiología
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