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1.
Chem Biol Interact ; 341: 109454, 2021 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-33798505

RESUMEN

Doxycycline has been used as antibiotic since the 1960s. Recently, studies have shown that doxycycline is neuroprotective in models of neurodegenerative diseases and brain injuries, mainly due to anti-inflammatory and anti-apoptotic effects. However, it is not known if doxycycline has neurotrophic potential, which is relevant, considering the role of axonal degeneration at the early stages of neurodegeneration in Alzheimer's disease, Amyotrophic Lateral Sclerosis and Parkinson's disease as well as in normal aging. Axons are preceded by the formation of neurites, the hallmark of the neuronal differentiation induced by neurotrophins like NGF. Therefore, the modulation of neurotrophin receptors aimed at formation and regeneration of axons has been proposed as a strategy to delay the progression of neurodegeneration and has gained relevance as new techniques for early diagnosis arise. Based on these premises, we investigated the potential of doxycycline to mimic the effects of Nerve Growth Factor (NGF) with focus on the signaling pathways and neuronal modulators of neurite initiation, growth and branching. We used PC12 cells, a neuronal model widely employed to study the neurotrophic pathways and mechanisms induced by NGF. Results showed that doxycycline induced neurite outgrowth via activation of the trkA receptor and the downstream signaling pathways, PI3K/Akt and MAPK/ERK, without inducing the expression of NGF. Doxycycline also increased the expression of GAP-43, synapsin I and NF200, proteins involved in axonal and synaptic plasticity. Altogether, these data demonstrate, for the first time, the neurotrophic potential of doxycycline, which might be useful to restore the neuronal connectivity lost at the initial phase of neurodegeneration.


Asunto(s)
Antibacterianos/farmacología , Doxiciclina/farmacología , Factor de Crecimiento Nervioso/metabolismo , Animales , Carbazoles/farmacología , Supervivencia Celular/efectos de los fármacos , Proteína GAP-43/metabolismo , Alcaloides Indólicos/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Factor de Crecimiento Nervioso/farmacología , Proteínas de Neurofilamentos/metabolismo , Proyección Neuronal/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Células PC12 , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Receptor trkA/antagonistas & inhibidores , Receptor trkA/metabolismo , Transducción de Señal/efectos de los fármacos , Sinapsinas/metabolismo
2.
Nat Commun ; 12(1): 2284, 2021 04 16.
Artículo en Inglés | MEDLINE | ID: mdl-33863904

RESUMEN

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


Asunto(s)
Biomarcadores de Tumor/metabolismo , Fosfatasas de Especificidad Dual/metabolismo , Mitocondrias/efectos de los fármacos , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/metabolismo , Neoplasias/terapia , Adulto , Anciano , Anciano de 80 o más Años , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Fraccionamiento Celular , Línea Celular Tumoral , Quimioterapia Adyuvante , Cisplatino/farmacología , Cisplatino/uso terapéutico , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos , Fosfatasas de Especificidad Dual/análisis , Femenino , Técnicas de Silenciamiento del Gen , Técnicas de Inactivación de Genes , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones , Persona de Mediana Edad , Mitocondrias/metabolismo , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/análisis , Neoplasias/mortalidad , Neoplasias/patología , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína X Asociada a bcl-2/metabolismo
3.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33802228

RESUMEN

The biosynthesis pathway of melanin is a series of oxidative reactions that are catalyzed by melanin-related proteins, including tyrosinase (TYR), tyrosinase-related protein-1 (TRP-1), and tyrosinase-related protein-2 (TRP-2). Reagents or materials with antioxidative or free radical-scavenging activities may be candidates for anti-melanogenesis. 3,4-Dihydroxybenzalacetone (DBL) is a polyphenol isolated from fungi, such as Phellinus obliguus (Persoon) Pilat and P. linteus. In this study, we investigated the effects and mechanisms of DBL on antioxidation and melanogenesis in murine melanoma cells (B16F10) and human epidermal melanocytes (HEMs). The results indicated that DBL scavenged 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl radicals, and exhibited potent reducing power, indicating that it displays strong antioxidative activity. DBL also inhibited the expression of TYR, TRP-1, TRP-2, and microphthalmia-related transcription factor (MITF) in both the cells. In addition, DBL inhibited hyperpigmentation in B16F10 and HEMs by regulating the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA), v-akt murine thymoma viral oncogene homolog (AKT)/glycogen synthase kinase 3 beta (GSK3ß), and mitogen-activated protein kinase kinase (MEK)/extracellular regulated protein kinase (ERK) signaling pathways. DBL not only shortened dendritic melanocytes but also inhibited premelanosome protein 17 (PMEL17) expression, slowing down the maturation of melanosome transportation. These results indicated that DBL promotes anti-melanogenesis by inhibiting the transportation of melanosomes. Therefore, DBL is a potent antioxidant and depigmenting agent that may be used in whitening cosmetics.


Asunto(s)
Ácidos Cafeicos/farmacología , Regulación hacia Abajo/efectos de los fármacos , Epidermis/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Melanocitos/metabolismo , Melanosomas/metabolismo , Línea Celular Tumoral , Humanos , Sistema de Señalización de MAP Quinasas/genética , Melanosomas/genética
4.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-33802409

RESUMEN

Novel 1,8-naphthyridine-2-carboxamide derivatives with various substituents (HSR2101-HSR2113) were synthesized and evaluated for their effects on the production of pro-inflammatory mediators and cell migration in lipopolysaccharide (LPS)-treated BV2 microglial cells. Among the tested compounds, HSR2104 exhibited the most potent inhibitory effects on the LPS-stimulated production of inflammatory mediators, including nitric oxide (NO), tumor necrosis factor-α, and interleukin-6. Therefore, this compound was chosen for further investigation. We found that HSR2104 attenuated levels of inducible NO synthase and cyclooxygenase 2 in LPS-treated BV2 cells. In addition, it markedly suppressed LPS-induced cell migration as well as the generation of intracellular reactive oxygen species (ROS). Moreover, HSR2104 abated the LPS-triggered nuclear translocation of nuclear factor-κB (NF-κB) through inhibition of inhibitor kappa Bα phosphorylation. Furthermore, it reduced the expressions of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) in LPS-treated BV2 cells. Similar results were observed with TAK242, a specific inhibitor of TLR4, suggesting that TLR4 is an upstream regulator of NF-κB signaling in BV2 cells. Collectively, our findings demonstrate that HSR2104 exhibits anti-inflammatory and anti-migratory activities in LPS-treated BV2 cells via the suppression of ROS and TLR4/MyD88/NF-κB signaling pathway. Based on our observations, HSR2104 may have a beneficial impact on inflammatory responses and microglial cell migration involved in the pathogenesis of various neurodegenerative disorders.


Asunto(s)
Antiinflamatorios/farmacología , Movimiento Celular/efectos de los fármacos , Factor 88 de Diferenciación Mieloide/metabolismo , FN-kappa B/metabolismo , Naftiridinas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Receptor Toll-Like 4/metabolismo , Animales , Células Cultivadas , Ciclooxigenasa 2/metabolismo , Mediadores de Inflamación/farmacología , Lipopolisacáridos/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Microglía/efectos de los fármacos , Microglía/metabolismo , Óxido Nítrico/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo
5.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-33803075

RESUMEN

Methamphetamine is, worldwide, one of the most consumed drugs of abuse. One important side effect is neurodegeneration leading to a decrease in life expectancy. The aim of this paper was to check whether the drug affects one of the receptors involved in neurodegeneration/neuroprotection events, namely the adenosine A2A receptor (A2AR). First, we noticed that methamphetamine does not affect A2A functionality if the receptor is expressed in a heterologous system. However, A2AR becomes sensitive to the drug upon complexes formation with the cannabinoid CB1 receptor (CB1R) and the sigma 1 receptor (σ1R). Signaling via both adenosine A2AR and cannabinoid CB1R was affected by methamphetamine in cells co-expressing the two receptors. In striatal primary cultures, the A2AR-CB1R heteromer complex was detected and methamphetamine not only altered its expression but completely blocked the A2AR- and the CB1R-mediated activation of the mitogen activated protein kinase (MAPK) pathway. In conclusion, methamphetamine, with the participation of σ1R, alters the expression and function of two interacting receptors, A2AR, which is a therapeutic target for neuroprotection, and CB1R, which is the most abundant G protein-coupled receptor (GPCR) in the brain.


Asunto(s)
Antagonistas del Receptor de Adenosina A2/farmacología , Cuerpo Estriado/metabolismo , Metanfetamina/farmacología , Neuronas/metabolismo , Receptor de Adenosina A2A/metabolismo , Receptor Cannabinoide CB1/metabolismo , Receptores sigma/metabolismo , Animales , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Células HEK293 , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones
6.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-33803239

RESUMEN

Previously, we demonstrated the expression of apelin and G-protein-coupled receptor APJ in human placenta cell lines as well as its direct action on placenta cell proliferation and endocrinology. The objective of this study was to examine the effect of apelin on placenta apoptosis in BeWo cells and villous explants from the human third trimester of pregnancy. The BeWo cells and villous explants were incubated with apelin (2 and 20 ng/mL) alone or with staurosporine for 24 to 72 h. First, we analysed the dose- and time-dependent effect of apelin on the expression of apoptotic factors on the mRNA level by real-time PCR and on the protein level using Western blot. Next, we checked caspase 3 and 7 activity by Caspase-Glo 3/7, DNA fragmentation by the Cell Death Detection ELISA kit and oxygen consumption by the MitoXpress-Xtra Oxygen Consumption assay. We found that apelin increased the expression of pro-survival and decreased proapoptotic factors on mRNA and protein levels in both BeWo cells and villous explants. Additionally, apelin inhibited caspase 3 and 7 activity and DNA fragmentation in staurosporine-induced apoptosis as also attenuated oxidative stress by increasing extracellular oxygen consumption. The antiapoptotic effect of apelin in BeWo cells was mediated by the APJ receptor and mitogen-activated protein kinase (ERK1/2/MAP3/1) and protein kinase B (AKT). The obtained results showed the antiapoptotic effect of apelin on trophoblast cells, suggesting its participation in the development of the placenta.


Asunto(s)
Apelina/farmacología , Apoptosis/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Placenta/metabolismo , Tercer Trimestre del Embarazo , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Línea Celular Tumoral , Quinasas MAP Reguladas por Señal Extracelular , Femenino , Humanos , Embarazo , Proteínas Gestacionales/metabolismo
7.
Int J Mol Sci ; 22(4)2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33669855

RESUMEN

Colitis is a multifactorial disorder that mostly occurs in the gastrointestinal tract. Despite improvements in mucosal inflammation research, little is known regarding the small bioactive molecules that are beneficial for regulating T cells and colon cell activity. 6,7,4'-trihydroxyflavanone (THF) is a flavanone that possesses anti-osteoclastogenesis activity and exerts protective effects against methamphetamine-induced immunotoxicity. Whether THF mitigates intestinal inflammation by regulating T cells and colon cell activity remains unknown. In the present study, Jurkat and HT-29 cells were used for in vitro experiments, and dextran sulfate sodium (DSS)-induced colitis model in mice was used for in vivo experiment. We observed that THF did not have a negative effect on the viability of Jurkat and HT-29 cells. Quantitative PCR and Western blot analysis revealed that THF regulates the activity of Jurkat cells and HT-29 cells via the NFκB and MAPK pathways under stimulated conditions. In the DSS-induced colitis model, oral administration of THF attenuated the manifestations of DSS-induced colitis, including a reduction in body weight, shrinkage of the colon, and enhanced expression of pro-inflammatory cytokines in the colon and mesenteric lymph nodes. These data suggest that THF alleviates DSS-induced colitis by modulating the activity of T cells and colon cells in vivo.


Asunto(s)
Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colon/inmunología , Colon/patología , Flavanonas/uso terapéutico , Sustancias Protectoras/uso terapéutico , Linfocitos T/inmunología , Administración Oral , Animales , Peso Corporal/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Colitis/inmunología , Citocinas/metabolismo , Sulfato de Dextran , Modelos Animales de Enfermedad , Femenino , Flavanonas/administración & dosificación , Flavanonas/química , Flavanonas/farmacología , Células HT29 , Humanos , Inflamación/patología , Intestinos/patología , Células Jurkat , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones Endogámicos C57BL , Sustancias Protectoras/farmacología , Linfocitos T/efectos de los fármacos , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células Th17/efectos de los fármacos , Células Th17/inmunología , Factor de Transcripción ReIA/metabolismo
8.
Int J Nanomedicine ; 16: 1993-2011, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33727811

RESUMEN

Background: Even with considerable improvement in treatment of epithelial ovarian cancer achieved in recent years, an increasing chemotherapy resistance and disease 5-year relapse is recorded for a majority part of patients that encourages the search for better therapeutic options. Gold nanoparticles (Au NPs) due to plethora of unique physiochemical features are thoroughly tested as drug delivery, radiosensitizers, as well as photothermal and photodynamic therapy agents. Importantly, due to highly controlled synthesis, it is possible to obtain nanomaterials with directed size and shape. Methods: In this work, we developed novel elongated-type gold nanoparticles in the shape of nanopeanuts (AuP NPs) and investigated their cytotoxic potential against ovarian cancer cells SKOV-3 using colorimetric and fluorimetric methods, Western blot, flow cytometry, and fluorescence microscopy. Results: Peanut-shaped gold nanoparticles showed high anti-cancer activity in vitro against SKOV-3 cells at doses of 1-5 ng/mL upon 72 hours treatment. We demonstrate that AuP NPs decrease the viability and proliferation capability of ovarian cancer cells by triggering cell apoptosis and autophagy, as evidenced by flow cytometry and Western blot analyses. The overproduction of reactive oxygen species (ROS) was noted to be a critical mediator of AuP NPs-mediated cell death. Conclusion: These data indicate that gold nanopeanuts might be developed as nanotherapeutics against ovarian cancer.


Asunto(s)
Apoptosis , Autofagia , Oro/química , Nanopartículas del Metal/química , Neoplasias Ováricas/patología , Especies Reactivas de Oxígeno/metabolismo , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/metabolismo , Arachis , Autofagia/efectos de los fármacos , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Nanopartículas del Metal/toxicidad , Nanopartículas del Metal/ultraestructura , Neoplasias Ováricas/tratamiento farmacológico , Oxidación-Reducción
9.
Nat Commun ; 12(1): 1536, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33750776

RESUMEN

Hyperactivation of the MAPK signaling pathway motivates the clinical use of MAPK inhibitors for BRAF-mutant melanomas. Heterogeneity in differentiation state due to epigenetic plasticity, however, results in cell-to-cell variability in the state of MAPK dependency, diminishing the efficacy of MAPK inhibitors. To identify key regulators of such variability, we screen 276 epigenetic-modifying compounds, individually or combined with MAPK inhibitors, across genetically diverse and isogenic populations of melanoma cells. Following single-cell analysis and multivariate modeling, we identify three classes of epigenetic inhibitors that target distinct epigenetic states associated with either one of the lysine-specific histone demethylases Kdm1a or Kdm4b, or BET bromodomain proteins. While melanocytes remain insensitive, the anti-tumor efficacy of each inhibitor is predicted based on melanoma cells' differentiation state and MAPK activity. Our systems pharmacology approach highlights a path toward identifying actionable epigenetic factors that extend the BRAF oncogene addiction paradigm on the basis of tumor cell differentiation state.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Epigenómica/métodos , Melanoma/metabolismo , Dependencia del Oncogén , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Femenino , Histona Demetilasas/metabolismo , Humanos , Histona Demetilasas con Dominio de Jumonji/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Melanocitos/metabolismo , Melanoma/genética , Ratones , Ratones Desnudos , Mutación , Dependencia del Oncogén/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/genética , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
10.
Int J Mol Sci ; 22(4)2021 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-33670044

RESUMEN

Kallmann syndrome is the result of innate genetic defects in the fibroblast growth factor (FGF) regulated signaling network causing diminished signal transduction. One of the rare mutations associated with the syndrome alters the Sprouty (Spry)4 protein by converting the serine at position 241 into a tyrosine. In this study, we characterize the tyrosine Spry4 mutant protein in the primary human embryonic lung fibroblasts WI-38 and osteosarcoma-derived cell line U2OS. As demonstrated in a cell signaling assay, Spry4 gains the capability of inhibiting FGF, but not epithelial growth factor (EGF)-induced signaling as a consequence of the tyrosine substitution. Additionally, migration of normal embryonic lung fibroblasts and osteosarcoma-derived cells is potently inhibited by the tyrosine Spry4 variant, while an effect of the wildtype Spry4 protein is hardly measureable. Concerning cell proliferation, the unaltered Spry4 protein is ineffective to influence the WI-38 cells, while the mutated Spry4 protein decelerates the cell doubling. In summary, these data emphasize that like the other mutations associated with Kallmann syndrome the described Spry4 mutation creates a hyperactive version of a selective inhibitory molecule and can thereby contribute to a weakened FGF signaling. Additionally, the study pinpoints a Spry4 variation expanding the applicability of Spry4 in a potential cancer therapy.


Asunto(s)
Factor 2 de Crecimiento de Fibroblastos/farmacología , Péptidos y Proteínas de Señalización Intracelular/genética , Síndrome de Kallmann/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Línea Celular , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Factor de Crecimiento Epidérmico/farmacología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Pulmón/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Osteosarcoma/patología , Fosforilación/efectos de los fármacos , Transducción de Señal , Tirosina/metabolismo
11.
Cell Rep ; 35(1): 108940, 2021 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-33784499

RESUMEN

SARS-CoV-2 has currently precipitated the COVID-19 global health crisis. We developed a medium-throughput drug-screening system and identified a small-molecule library of 34 of 430 protein kinase inhibitors that were capable of inhibiting the SARS-CoV-2 cytopathic effect in human epithelial cells. These drug inhibitors are in various stages of clinical trials. We detected key proteins involved in cellular signaling pathways mTOR-PI3K-AKT, ABL-BCR/MAPK, and DNA-damage response that are critical for SARS-CoV-2 infection. A drug-protein interaction-based secondary screen confirmed compounds, such as the ATR kinase inhibitor berzosertib and torin2 with anti-SARS-CoV-2 activity. Berzosertib exhibited potent antiviral activity against SARS-CoV-2 in multiple cell types and blocked replication at the post-entry step. Berzosertib inhibited replication of SARS-CoV-1 and the Middle East respiratory syndrome coronavirus (MERS-CoV) as well. Our study highlights key promising kinase inhibitors to constrain coronavirus replication as a host-directed therapy in the treatment of COVID-19 and beyond as well as provides an important mechanism of host-pathogen interactions.


Asunto(s)
Antivirales/farmacología , Daño del ADN , Isoxazoles/farmacología , Pirazinas/farmacología , Replicación Viral/efectos de los fármacos , Células A549 , Animales , /patología , Chlorocebus aethiops , Evaluación Preclínica de Medicamentos , Células HEK293 , Células HeLa , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Coronavirus del Síndrome Respiratorio de Oriente Medio/metabolismo , Células Vero
12.
Chem Biol Interact ; 339: 109432, 2021 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-33684387

RESUMEN

Mitochondrial dependent oxidative stress (OS) and subsequent cell death are considered as the major cytotoxicity caused by Triethylene glycol dimethacrylate (TEGDMA), a commonly monomer of many resin-based dental composites. Under OS microenvironment, autophagy serves as a cell homeostatic mechanism and maintains redox balance through degradation or turnover of cellular components in order to promote cell survival. However, whether autophagy is involved in the mitochondrial oxidative damage and apoptosis induced by TEGDMA, and the cellular signaling pathways underlying this process remain unclear. In the present study, we demonstrated that TEGDMA induced mouse preodontoblast cell line (mDPC6T) dysfunctional mitochondrial oxidative response. In further exploring the underlying mechanisms, we found that TEGDMA impaired autophagic flux, as evidenced by increased LC3-II expression and hindered p62 degradation, thereby causing both mitochondrial oxidative damage and cell apoptosis. These results were further verified by treatment with chloroquine (autophagy inhibitor) and rapamycin (autophagy promotor). More importantly, we found that the JNK/MAPK pathway was the key upstream regulator of above injury process. Collectively, our finding firstly demonstrated that TEGDMA induced JNK-dependent autophagy, thereby promoting mitochondrial dysfunction-associated oxidative damage and apoptosis in preodontoblast.


Asunto(s)
Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Polietilenglicoles/farmacología , Ácidos Polimetacrílicos/farmacología , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Cloroquina/farmacología , Ratones , Proteínas Asociadas a Microtúbulos/metabolismo , Oxidación-Reducción/efectos de los fármacos , Proteínas de Unión al ARN/metabolismo , Transducción de Señal/efectos de los fármacos , Sirolimus/farmacología
13.
Int J Mol Med ; 47(4)2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33649779

RESUMEN

Oxidative stress serves a key role in doxorubicin (DOX)­induced cardiotoxicity. The peptide Szeto­Schiller (SS)31 is an efficacious antioxidant with the capacity to reduce mitochondrial reactive oxygen species (ROS) levels and scavenge free radicals. Although SS31 is involved in the pathophysiological process of various cardiovascular diseases, the role of SS31 in DOX­induced cardiotoxicity remains unclear. To explore the effects of SS31 in DOX­induced cardiotoxicity, the present study first constructed DOX­induced cardiotoxicity models, in which H9c2 cells were incubated with 1 µM DOX for 24 h and C57BL/6 mice were administered DOX (20 mg/kg cumulative dose). The results of various assays in these models demonstrated that SS31 exhibited a cardioprotective effect in vitro and in vivo by attenuating the level of ROS, stabilizing the mitochondrial membrane potential and ameliorating myocardial apoptosis as well as fibrosis following treatment with DOX. Mechanistically, the results of the present study revealed that the p38 MAPK signaling pathway was inhibited by SS31 in DOX­treated H9c2 cells, which was associated with the cardioprotective function of SS31. In addition, P79350, a selective agonist of p38 MAPK, reversed the protective effects of SS31. Taken together, these results demonstrated the effects of SS31 on ameliorating DOX­induced cardiotoxicity and indicated its potential as a drug for the treatment of DOX­induced cardiotoxicity.


Asunto(s)
Cardiotónicos/uso terapéutico , Doxorrubicina/toxicidad , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Miocardio/patología , Oligopéptidos/uso terapéutico , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Animales , Antioxidantes/uso terapéutico , Apoptosis/efectos de los fármacos , Cardiotoxicidad/tratamiento farmacológico , Cardiotoxicidad/prevención & control , Fibrosis Endomiocárdica/tratamiento farmacológico , Fibrosis Endomiocárdica/prevención & control , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fosforilación/efectos de los fármacos , Ratas , Especies Reactivas de Oxígeno/metabolismo
14.
Int J Mol Sci ; 22(5)2021 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-33669069

RESUMEN

Osteoclasts, bone-specified multinucleated cells produced by monocyte/macrophage, are involved in numerous bone destructive diseases such as arthritis, osteoporosis, and inflammation-induced bone loss. The osteoclast differentiation mechanism suggests a possible strategy to treat bone diseases. In this regard, we recently examined the in vivo impact of kalkitoxin (KT), a marine product obtained from the marine cyanobacterium Moorena producens (previously Lyngbya majuscula), on the macrophage colony-stimulating factor (M-CSF) and on the receptor activator of nuclear factor κB ligand (RANKL)-stimulated in vitro osteoclastogenesis and inflammation-mediated bone loss. We have now examined the molecular mechanism of KT in greater detail. KT decreased RANKL-induced bone marrow-derived macrophages (BMMs) tartrate-resistant acid phosphatase (TRAP)-multinucleated cells at a late stage. Likewise, KT suppressed RANKL-induced pit area and actin ring formation in BMM cells. Additionally, KT inhibited several RANKL-induced genes such as cathepsin K, matrix metalloproteinase (MMP-9), TRAP, and dendritic cell-specific transmembrane protein (DC-STAMP). In line with these results, RANKL stimulated both genes and protein expression of c-Fos and nuclear factor of activated T cells (NFATc1), and this was also suppressed by KT. Moreover, KT markedly decreased RANKL-induced p-ERK1/2 and p-JNK pathways at different time points. As a result, KT prevented inflammatory bone loss in mice, such as bone mineral density (BMD) and osteoclast differentiation markers. These experiments demonstrated that KT markedly inhibited osteoclast formation and inflammatory bone loss through NFATc1 and mitogen-activated protein kinase (MAPK) signaling pathways. Therefore, KT may have potential as a treatment for destructive bone diseases.


Asunto(s)
Resorción Ósea/tratamiento farmacológico , Lípidos/uso terapéutico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Factores de Transcripción NFATC/metabolismo , Osteoclastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Tiazoles/uso terapéutico , Actinas/genética , Actinas/metabolismo , Animales , Densidad Ósea/efectos de los fármacos , Resorción Ósea/metabolismo , Catepsina K/genética , Catepsina K/metabolismo , Supervivencia Celular , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Quinasas Janus/metabolismo , Lípidos/farmacología , Lipopolisacáridos/toxicidad , Sistema de Señalización de MAP Quinasas/genética , Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Factor Estimulante de Colonias de Macrófagos/metabolismo , Factor Estimulante de Colonias de Macrófagos/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos ICR , Factores de Transcripción NFATC/genética , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Osteoclastos/metabolismo , Osteogénesis/genética , Fosforilación , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ligando RANK/antagonistas & inhibidores , Ligando RANK/metabolismo , Ligando RANK/farmacología , Fosfatasa Ácida Tartratorresistente/genética , Fosfatasa Ácida Tartratorresistente/metabolismo , Tiazoles/farmacología
15.
Int J Mol Sci ; 22(4)2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33671948

RESUMEN

Alveolar bone loss, the major feature of periodontitis, results from the activation of osteoclasts, which can consequently cause teeth to become loose and fall out; the development of drugs capable of suppressing excessive osteoclast differentiation and function is beneficial for periodontal disease patients. Given the difficulties associated with drug discovery, drug repurposing is an efficient approach for identifying alternative uses of commercially available compounds. Here, we examined the effects of PF-3845, a selective fatty acid amide hydrolase (FAAH) inhibitor, on receptor activator of nuclear factor kappa B ligand (RANKL)-mediated osteoclastogenesis, its function, and the therapeutic potential for the treatment of alveolar bone destruction in experimental periodontitis. PF-3845 significantly suppressed osteoclast differentiation and decreased the induction of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) and the expression of osteoclast-specific markers. Actin ring formation and osteoclastic bone resorption were also reduced by PF-3845, and the anti-osteoclastogenic and anti-resorptive activities were mediated by the suppression of phosphorylation of rapidly accelerated fibrosarcoma (RAF), mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase, (ERK) and nuclear factor κB (NF-κB) inhibitor (IκBα). Furthermore, the administration of PF-3845 decreased the number of osteoclasts and the amount of alveolar bone destruction caused by ligature placement in experimental periodontitis in vivo. The present study provides evidence that PF-3845 is able to suppress osteoclastogenesis and prevent alveolar bone loss, and may give new insights into its role as a treatment for osteoclast-related diseases.


Asunto(s)
Pérdida de Hueso Alveolar/tratamiento farmacológico , Amidohidrolasas/antagonistas & inhibidores , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , FN-kappa B/metabolismo , Osteogénesis/efectos de los fármacos , Periodontitis/tratamiento farmacológico , Piperidinas/farmacología , Piperidinas/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéutico , Animales , Resorción Ósea/tratamiento farmacológico , Células Cultivadas , Modelos Animales de Enfermedad , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Osteoclastos/metabolismo , Ligando RANK/metabolismo , Resultado del Tratamiento
16.
Ecotoxicol Environ Saf ; 214: 112057, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33662786

RESUMEN

Cigarette smoking has been considered as an independent risk factor for colorectal cancer (CRC) initiation and progression. In this study, we found that cigarette smoking was significantly associated with poor CRC differentiation (P = 0.040). Since studies have indicated that poorly differentiated tumors are more aggressive and metastasize earlier, leading to poorer prognosis; and cancer stem cells (CSCs) are largely responsible for tumor differentiation state, here we observed that the exposure of nicotine-derived 4-(methylnitrosamino)- 1-(3-pyridyl)- 1-butanone (NNK) promoted cell sphere formation and the expression of the stem cell markers, CD44, OCT4, C-MYC and NANOG in HCT8 and DLD-1 cells. Further colony formation assay, CCK-8 assay and tumor-bearing experiment showed that NNK exposure significantly increased the proliferative and growth ability of CRC cells. In mechanism, we found that NNK-activated ERK1/2 played an important role in enrichment of CRC stem cells and the up-regulation of DUSP4, a major negative regulator of ERK1/2. Moreover, DUSP4 up-regulation was essential for maintaining NNK-activated ERK1/2 in an appropriate level, which was an required event for NNK-induced stemness enrichment of CRC cells. Taken together, our findings provided a possible mechanistic insight into cigarette smoking-induced CRC progression.


Asunto(s)
Nicotina/toxicidad , Nitrosaminas/toxicidad , Carcinógenos , Línea Celular Tumoral , Neoplasias Colorrectales , Fosfatasas de Especificidad Dual/metabolismo , Células Epiteliales/efectos de los fármacos , Retroalimentación , Humanos , Receptores de Hialuranos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteína Quinasa 3 Activada por Mitógenos , Fosfatasas de la Proteína Quinasa Activada por Mitógenos , Células Madre Neoplásicas/metabolismo
17.
Arch Biochem Biophys ; 701: 108752, 2021 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-33675811

RESUMEN

Hearing loss caused by ototoxic drugs is a kind of acquired hearing loss. Cisplatin is one of the most commonly used drugs and its main action sites are hair cells (HCs). Sorcin is a drug-resistant calcium-binding protein belonging to the small penta-EF-hand protein family. Sorcin is highly expressed in many tissues, including bone, heart, brain, lung, and skin tissues. Single-cell RNA sequencing showed that sorcin was expressed in the outer HCs of mice, but its role remained unknown. We also found that sorcin was highly expressed in the cytoplasm of cochlear HCs and HEI-OC1 cells. After cisplatin injury, the expression of sorcin in HCs and HEI-OC1 cells decreased significantly. SiRNA transfection technology was used to knock down the expression of sorcin. The results showed that the number of apoptotic cells, the expression of cleaved caspased-3, and the expression of Bax increased while the anti-apoptotic factor Bcl-2 decreased in the siRNA-Sorcin + CIS group. The observed increase in apoptosis was related to the increase of reactive oxygen species (ROS) and the destruction of the mitochondrial membrane potential (MMP). Finally, we found that the downregulated sorcin worked by activating the P-ERK1/2 signaling pathway. Overall, this study showed that sorcin can be used as a new target to prevent the ototoxicity of platinum drugs.


Asunto(s)
Apoptosis/efectos de los fármacos , Proteínas de Unión al Calcio/biosíntesis , Cisplatino/efectos adversos , Células Ciliadas Auditivas/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ototoxicidad/metabolismo , Animales , Apoptosis/genética , Proteínas de Unión al Calcio/genética , Caspasa 3/genética , Caspasa 3/metabolismo , Línea Celular , Cisplatino/farmacología , Técnicas de Silenciamiento del Gen , Células Ciliadas Auditivas/patología , Sistema de Señalización de MAP Quinasas/genética , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Potencial de la Membrana Mitocondrial/genética , Ratones , Ototoxicidad/genética , Ototoxicidad/patología , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismo
18.
Int J Mol Sci ; 22(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652742

RESUMEN

Impressic acid (IPA), a lupane-type triterpenoid from Acanthopanax koreanum, has many pharmacological activities, including the attenuation of vascular endothelium dysfunction, cartilage destruction, and inflammatory diseases, but its influence on atopic dermatitis (AD)-like skin lesions is unknown. Therefore, we investigated the suppressive effect of IPA on 2,4-dinitrochlorobenzene (DNCB)-induced AD-like skin symptoms in mice and the underlying mechanisms in cells. IPA attenuated the DNCB-induced increase in the serum concentrations of IgE and thymic stromal lymphopoietin (TSLP), and in the mRNA levels of thymus and activation regulated chemokine(TARC), macrophage derived chemokine (MDC), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-13 (IL-13), tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) in mice. Histopathological analysis showed that IPA reduced the epidermal/dermal thickness and inflammatory and mast cell infiltration of ear tissue. In addition, IPA attenuated the phosphorylation of NF-κB and IκBα, and the degradation of IκBα in ear lesions. Furthermore, IPA treatment suppressed TNF-α/IFN-γ-induced TARC expression by inhibiting the NF-κB activation in cells. Phosphorylation of extracellular signalregulated protein kinase (ERK1/2) and the signal transducer and activator of transcription 1 (STAT1), the upstream signaling proteins, was reduced by IPA treatment in HaCaT cells. In conclusion, IPA ameliorated AD-like skin symptoms by regulating cytokine and chemokine production and so has therapeutic potential for AD-like skin lesions.


Asunto(s)
Dermatitis Atópica/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , FN-kappa B/metabolismo , Factor de Transcripción STAT1/metabolismo , Triterpenos/uso terapéutico , Animales , Línea Celular , Citocinas/metabolismo , Dermatitis Atópica/metabolismo , Dermatitis Atópica/patología , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Fosforilación/efectos de los fármacos , Piel/efectos de los fármacos , Piel/metabolismo , Piel/patología
19.
Mol Med Rep ; 23(5)2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33760179

RESUMEN

Burn wounds present an evolutionary progression, in which the initial wound tissue deepens and expands following thermal injury. Progressive tissue damage in the zone of stasis may worsen burn injury, which is associated with oxidative stress and secondary apoptosis, and worsen the prognosis of patients with burn wounds. The mitochondrial apoptotic pathway is involved in receiving oxidative signals and regulating tissue apoptosis. Previously, Abnormal Savda Munziq (ASMq), a natural compound of traditional Uyghur Medicine, which includes ten types of herb, has been reported to exhibit a number of effects, including anti­inflammatory, antioxidative and anti­apoptotic activities. The present study demonstrated that ASMq protected against early burn wound progression following thermal injury in rats; this effect may be mediated by its ability to attenuate oxidative stress­induced mitochondria­associated apoptosis. The present study may provide a novel therapeutic method to prevent early burn wound progression following burn injury.


Asunto(s)
Quemaduras/tratamiento farmacológico , Mitocondrias/efectos de los fármacos , Heridas y Traumatismos/tratamiento farmacológico , Animales , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Quemaduras/genética , Quemaduras/patología , Modelos Animales de Enfermedad , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Medicina Tradicional/métodos , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Ratas , Proteínas Quinasas S6 Ribosómicas 90-kDa/genética , Cicatrización de Heridas/efectos de los fármacos , Heridas y Traumatismos/genética , Heridas y Traumatismos/patología , Proteína Letal Asociada a bcl/genética
20.
Molecules ; 26(4)2021 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-33670520

RESUMEN

Uncaria tomentosa is a medicinal plant native to Peru that has been traditionally used in the treatment of various inflammatory disorders. In this study, the effectiveness of U. tomentosa as an anti-cancer agent was assessed using the growth and survival of B16-BL6 mouse melanoma cells. B16-BL6 cell cultures treated with both ethanol and phosphate-buffered saline (PBS) extracts of U. tomentosa displayed up to 80% lower levels of growth and increased apoptosis compared to vehicle controls. Treatment with ethanolic extracts of Uncaria tomentosa were much more effective than treatment with aqueous extracts. U. tomentosa was also shown to inhibit B16-BL6 cell growth in C57/bl mice in vivo. Mice injected with both the ethanolic and aqueous extracts of U. tomentosa showed a 59 ± 13% decrease in B16-BL6 tumour weight and a 40 ± 9% decrease in tumour size. Histochemical analysis of the B16-BL6 tumours showed a strong reduction in the Ki-67 cell proliferation marker in U. tomentosa-treated mice and a small, but insignificant increase in terminal transferase dUTP nick labelling (TUNEL) staining. Furthermore, U. tomentosa extracts reduced angiogenic markers and reduced the infiltration of T cells into the tumours. Collectively, the results in this study concluded that U. tomentosa has potent anti-cancer activity that significantly inhibited cancer cells in vitro and in vivo.


Asunto(s)
Apoptosis , Uña de Gato/química , Melanoma Experimental/patología , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Células 3T3 NIH , Fosforilación/efectos de los fármacos , Extractos Vegetales/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Carga Tumoral/efectos de los fármacos
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