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1.
Molecules ; 26(7)2021 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-33917607

RESUMEN

ß-sitosterol (SIT), the most abundant bioactive component of vegetable oil and other plants, is a highly potent antidiabetic drug. Our previous studies show that SIT controls hyperglycemia and insulin resistance by activating insulin receptor and glucose transporter 4 (GLUT-4) in the adipocytes of obesity induced type 2 diabetic rats. The current research was undertaken to investigate if SIT could also exert its antidiabetic effects by circumventing adipocyte induced inflammation, a key driving factor for insulin resistance in obese individuals. Effective dose of SIT (20 mg/kg b.wt) was administered orally for 30 days to high fat diet and sucrose induced type-2 diabetic rats. Metformin, the conventionally used antidiabetic drug was used as a positive control. Interestingly, SIT treatment restores the elevated serum levels of proinflammatory cytokines including leptin, resistin, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) to normalcy and increases anti-inflammatory adipocytokines including adiponectin in type 2 diabetic rats. Furthermore, SIT decreases sterol regulatory element binding protein-1c (SREBP-1c) and enhances Peroxisome Proliferator-activated receptor-γ (PPAR-γ) gene expression in adipocytes of diabetic rats. The gene and protein expression of c-Jun-N-terminal kinase-1 (JNK1), inhibitor of nuclear factor kappa-B kinase subunit beta (IKKß) and nuclear factor kappa B (NF-κB) were also significantly attenuated in SIT treated groups. More importantly, SIT acts very effectively as metformin to circumvent inflammation and insulin resistance in diabetic rats. Our results clearly show that SIT inhibits obesity induced insulin resistance by ameliorating the inflammatory events in the adipose tissue through the downregulation of IKKß/NF-κB and c-Jun-N-terminal kinase (JNK) signaling pathway.


Asunto(s)
Adipocitos/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Regulación hacia Abajo , Quinasa I-kappa B/metabolismo , Inflamación/tratamiento farmacológico , Resistencia a la Insulina , Obesidad/complicaciones , Sitoesteroles/uso terapéutico , Adipocitos/efectos de los fármacos , Adipoquinas/sangre , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Animales , Peso Corporal/efectos de los fármacos , Citocinas/sangre , Citocinas/genética , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Dieta Alta en Grasa , Regulación hacia Abajo/efectos de los fármacos , Conducta Alimentaria , Inflamación/sangre , Inflamación/metabolismo , Inflamación/patología , Mediadores de Inflamación/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Simulación del Acoplamiento Molecular , FN-kappa B/metabolismo , Obesidad/sangre , PPAR gamma/genética , PPAR gamma/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Sitoesteroles/farmacología , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Sacarosa , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genética
2.
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
3.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-33802775

RESUMEN

Silver nanoparticles (AgNPs) are the one of the most extensively used nanomaterials. The strong antimicrobial properties of AgNPs have led to their use in a wide range of medical and consumer products. Although the neurotoxicity of AgNPs has been confirmed, the molecular mechanisms have not been extensively studied, particularly in immature organisms. Based on information gained from previous in vitro studies, in the present work, we examine whether ionotropic NMDA glutamate receptors contribute to AgNP-induced neurotoxicity in an animal model of exposure. In brains of immature rats subjected to a low dose of AgNPs, we identified ultrastructural and molecular alterations in the postsynaptic region of synapses where NMDA receptors are localized as a multiprotein complex. We revealed decreased expression of several NMDA receptor complex-related proteins, such as GluN1 and GluN2B subunits, scaffolding proteins PSD95 and SynGAP, as well as neuronal nitric oxide synthase (nNOS). Elucidating the changes in NMDA receptor-mediated molecular mechanisms induced by AgNPs, we also identified downregulation of the GluN2B-PSD95-nNOS-cGMP signaling pathway which maintains LTP/LTD processes underlying learning and memory formation during development. This observation is accompanied by decreased density of NMDA receptors, as assessed by a radioligand binding assay. The observed effects are reversible over the post-exposure time. This investigation reveals that NMDA receptors in immature rats are a target of AgNPs, thereby indicating the potential health hazard for children and infants resulting from the extensive use of products containing AgNPs.


Asunto(s)
Encéfalo/metabolismo , Ácido Glutámico/metabolismo , Nanopartículas del Metal/toxicidad , Receptores de N-Metil-D-Aspartato/metabolismo , Plata/toxicidad , Animales , Encéfalo/efectos de los fármacos , Encéfalo/ultraestructura , GMP Cíclico/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Femenino , Ligandos , Masculino , Nanopartículas del Metal/ultraestructura , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo I/metabolismo , Subunidades de Proteína/metabolismo , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Sinapsis/ultraestructura
4.
Anticancer Res ; 41(4): 1921-1926, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813397

RESUMEN

BACKGROUND/AIM: Methionine addiction is a general and fundamental hallmark of cancer due to the excess use of methionine for transmethylation reactions, termed the "Hoffman Effect". Methionine addiction has been shown to be a highly-effective target for cancer therapy by methionine restriction with oral recombinant methioninase (o-rMETase) in preclinical studies, including patient- derived orthotopic xenograft (PDOX) mouse models of cancer. A clinical study of o-rMETase as a supplement showed a 70% reduction of PSA levels in a patient with bone-metastatic prostate cancer. MATERIALS AND METHODS: In the present study, two advanced prostate-cancer patients took o-rMETase as a supplement for approximately one month. RESULTS: One of the patients taking o-rMETase showed a 38% reduction of PSA levels and the second patient showed a 20% PSA reduction. CONCLUSION: o-rMETase shows promise for treating patients with advanced prostate cancer.


Asunto(s)
Liasas de Carbono-Azufre/administración & dosificación , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/tratamiento farmacológico , Administración Oral , Anciano de 80 o más Años , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Progresión de la Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Terapia de Reemplazo Enzimático , Humanos , Masculino , Metionina/sangre , Metionina/efectos de los fármacos , Persona de Mediana Edad , Proyectos Piloto , Antígeno Prostático Específico/efectos de los fármacos , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/patología , Proteínas Recombinantes/administración & dosificación
5.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-33806354

RESUMEN

The loss of skeletal muscle mass (muscle atrophy or wasting) caused by aging, diseases, and injury decreases quality of life, survival rates, and healthy life expectancy in humans. Although long non-coding RNAs (lncRNAs) have been implicated in skeletal muscle formation and differentiation, their precise roles in muscle atrophy remain unclear. In this study, we used RNA-sequencing (RNA-Seq) to examine changes in the expression of lncRNAs in four muscle atrophy conditions (denervation, casting, fasting, and cancer cachexia) in mice. We successfully identified 33 annotated lncRNAs and 18 novel lncRNAs with common expression changes in all four muscle atrophy conditions. Furthermore, an analysis of lncRNA-mRNA correlations revealed that several lncRNAs affected small molecule biosynthetic processes during muscle atrophy. These results provide novel insights into the lncRNA-mediated regulatory mechanism underlying muscle atrophy and may be useful for the identification of promising therapeutic targets.


Asunto(s)
Atrofia Muscular/genética , ARN Largo no Codificante/genética , ARN Mensajero/genética , Animales , Caquexia/genética , Modelos Animales de Enfermedad , Regulación hacia Abajo , Ayuno/metabolismo , Expresión Génica , Humanos , Ratones , Ratones Endogámicos C57BL , Desnervación Muscular , Músculo Esquelético/metabolismo , Atrofia Muscular/etiología , RNA-Seq , Restricción Física , Regulación hacia Arriba
6.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-33802702

RESUMEN

Our previous study demonstrated that the glutathione S-transferase Mu 5 (GSTM5) gene is highly CpG-methylated in bladder cancer cells and that demethylation by 5-aza-dC activates GSTM5 gene expression. The aim of the present study was to investigate the role of GSTM5 in bladder cancer. The levels of GSTM5 gene expression and DNA methylation were analyzed in patients with bladder cancer, and functional studies of GSTM5 were conducted using GSTM5 overexpression in cultured bladder cancer cells. Clinical analysis revealed that the GSTM5 mRNA expression was lower in bladder cancer tissues than in normal tissues and that the level of GSTM5 DNA methylation was higher in bladder cancer tissues than in normal urine pellets. Overexpression of GSTM5 decreased cell proliferation, migration and colony formation capacity. Glutathione (GSH) assay results indicated that cellular GSH concentration was decreased by GSTM5 expression and that GSH supplementation reversed the decrease in proliferation and migration of cells overexpressing GSTM5. By contrast, a GSH synthesis inhibitor significantly decreased 5637 cell GSH levels, survival and migration. Furthermore, GSTM5 overexpression inhibited the adhesion of cells to the extracellular matrix protein fibronectin. To elucidate the effect of GSTM5 on anticancer drugs used to treat bladder cancer, cellular viability was compared between cells with or without GSTM5 overexpression. GSTM5-overexpressed cells showed no significant change in the cytotoxicity of cisplatin or mitomycin C in 5637, RT4 and BFTC 905 cells. Though a degree of resistance to doxorubicin was noted in 5637 cells overexpressing GSTM5, no such resistance was observed in RT4 and BFTC 905 cells. In summary, GSTM5 plays a tumor suppressor role in bladder cancer cells without significantly affecting chemoresistance to cisplatin and mitomycin C, and the cellular GSH levels highlight a key mechanism underlying the cancer inhibition effect of GSTM5. These findings suggest that low gene expression and high DNA methylation levels of GSTM5 may act as tumor markers for bladder cancer.


Asunto(s)
Antineoplásicos/metabolismo , Biomarcadores de Tumor/metabolismo , Glutatión Transferasa/metabolismo , Neoplasias de la Vejiga Urinaria/enzimología , Adulto , Anciano , Anciano de 80 o más Años , Butionina Sulfoximina/farmacología , Adhesión Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Cisplatino/farmacología , Metilación de ADN/efectos de los fármacos , Metilación de ADN/genética , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Doxorrubicina/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glutatión/metabolismo , Glutatión Transferasa/genética , Humanos , Masculino , Persona de Mediana Edad , Mitomicina/farmacología , Regiones Promotoras Genéticas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Caracteres Sexuales , Neoplasias de la Vejiga Urinaria/genética
7.
Int J Mol Sci ; 22(6)2021 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-33803511

RESUMEN

Rhizoctonia solani is the causer of black scurf disease on potatoes and is responsible for high economical losses in global agriculture. In order to increase the limited knowledge of the plants' molecular response to this pathogen, we inoculated potatoes with R. solani AG3-PT isolate Ben3 and carried out RNA sequencing with total RNA extracted from potato sprouts at three and eight days post inoculation (dpi). In this dual RNA-sequencing experiment, the necrotrophic lifestyle of R. solani AG3-PT during early phases of interaction with its host has already been characterised. Here the potato plants' comprehensive transcriptional response to inoculation with R. solani AG3 was evaluated for the first time based on significantly different expressed plant genes extracted with DESeq analysis. Overall, 1640 genes were differentially expressed, comparing control (-Rs) and with R. solani AG3-PT isolate Ben3 inoculated plants (+Rs). Genes involved in the production of anti-fungal proteins and secondary metabolites with antifungal properties were significantly up regulated upon inoculation with R. solani. Gene ontology (GO) terms involved in the regulation of hormone levels (i.e., ethylene (ET) and jasmonic acid (JA) at 3 dpi and salicylic acid (SA) and JA response pathways at 8 dpi) were significantly enriched. Contrastingly, the GO term "response to abiotic stimulus" was down regulated at both time points analysed. These results may support future breeding efforts toward the development of cultivars with higher resistance level to black scurf disease or the development of new control strategies.


Asunto(s)
Interacciones Huésped-Patógeno/genética , Enfermedades de las Plantas/inmunología , Enfermedades de las Plantas/microbiología , Rhizoctonia/fisiología , Solanum tuberosum/genética , Solanum tuberosum/microbiología , Transcripción Genética , Regulación hacia Abajo/genética , Regulación de la Expresión Génica de las Plantas , Ontología de Genes , Genes de Plantas , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Enfermedades de las Plantas/genética , Análisis de Componente Principal , ARN Mensajero/genética , ARN Mensajero/metabolismo , Solanum tuberosum/inmunología , Transcriptoma/genética , Regulación hacia Arriba/genética
8.
Nat Commun ; 12(1): 2047, 2021 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-33824349

RESUMEN

Human chromosome 9p21.3 is susceptible to inactivation in cell immortalization and diseases, such as cancer, coronary artery disease and type-2 diabetes. Although this locus encodes three cyclin-dependent kinase (CDK) inhibitors (p15INK4B, p14ARF and p16INK4A), our understanding of their functions and modes of action is limited to the latter two. Here, we show that in vitro p15INK4B is markedly stronger than p16INK4A in inhibiting pRb1 phosphorylation, E2F activity and cell-cycle progression. In mice, urothelial cells expressing oncogenic HRas and lacking p15INK4B, but not those expressing HRas and lacking p16INK4A, develop early-onset bladder tumors. The potency of CDKN2B/p15INK4B in tumor suppression relies on its strong binding via key N-terminal residues to and inhibition of CDK4/CDK6. p15INK4B also binds and inhibits enolase-1, a glycolytic enzyme upregulated in most cancer types. Our results highlight the dual inhibition of p15INK4B on cell proliferation, and unveil mechanisms whereby p15INK4B aberrations may underpin cancer and non-cancer conditions.


Asunto(s)
Ciclo Celular , Cromosomas de los Mamíferos/genética , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/metabolismo , Glucólisis , Aerobiosis , Secuencia de Aminoácidos , Animales , Unión Competitiva , Cruzamiento , Carcinogénesis/metabolismo , Carcinogénesis/patología , Línea Celular Tumoral , Proliferación Celular , Cruzamientos Genéticos , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/química , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Quinasas Ciclina-Dependientes/metabolismo , Regulación hacia Abajo , Femenino , Humanos , Enlace de Hidrógeno , Masculino , Ratones Transgénicos , Modelos Moleculares , Oncogenes , Penetrancia , Fosfopiruvato Hidratasa/metabolismo , Dominios Proteicos , Proteínas Proto-Oncogénicas p21(ras) , Homología Estructural de Proteína , Neoplasias de la Vejiga Urinaria/patología , Urotelio/metabolismo
9.
Science ; 372(6537)2021 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-33795428

RESUMEN

T cell exhaustion limits immune responses against cancer and is a major cause of resistance to chimeric antigen receptor (CAR)-T cell therapeutics. Using murine xenograft models and an in vitro model wherein tonic CAR signaling induces hallmark features of exhaustion, we tested the effect of transient cessation of receptor signaling, or rest, on the development and maintenance of exhaustion. Induction of rest through enforced down-regulation of the CAR protein using a drug-regulatable system or treatment with the multikinase inhibitor dasatinib resulted in the acquisition of a memory-like phenotype, global transcriptional and epigenetic reprogramming, and restored antitumor functionality in exhausted CAR-T cells. This work demonstrates that rest can enhance CAR-T cell efficacy by preventing or reversing exhaustion, and it challenges the notion that exhaustion is an epigenetically fixed state.


Asunto(s)
Dasatinib/farmacología , Epigénesis Genética , Inmunoterapia Adoptiva , Receptores Quiméricos de Antígenos/metabolismo , Linfocitos T/inmunología , Animales , Línea Celular Tumoral , Citotoxicidad Inmunológica , Regulación hacia Abajo , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Epigenoma , Femenino , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Proteínas del Grupo de Alta Movilidad/metabolismo , Humanos , Memoria Inmunológica , Activación de Linfocitos , Factor de Unión 1 al Potenciador Linfoide/metabolismo , Masculino , Ratones , Neoplasias Experimentales/terapia , Dominios Proteicos , Estabilidad Proteica , Receptores Quiméricos de Antígenos/química , Receptores Quiméricos de Antígenos/inmunología , Transducción de Señal , Linfocitos T/metabolismo , Transcripción Genética , Ensayos Antitumor por Modelo de Xenoinjerto
10.
Int J Nanomedicine ; 16: 2461-2475, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33814910

RESUMEN

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


Asunto(s)
Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Carbono/química , Medicamentos Herbarios Chinos/uso terapéutico , Sustancias Protectoras/uso terapéutico , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/tratamiento farmacológico , Enfermedad Aguda , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Regulación hacia Abajo/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Etanol/efectos adversos , Interleucina-6/metabolismo , Masculino , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Estrés Oxidativo/efectos de los fármacos , Espectroscopía de Fotoelectrones , Sustancias Protectoras/farmacología , Ratas Sprague-Dawley , Úlcera Gástrica/patología , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia Arriba/efectos de los fármacos
11.
Int J Nanomedicine ; 16: 2803-2818, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33880025

RESUMEN

Background: Circular RNAs (circRNAs) have been identified as key factors in the development of hepatocellular carcinoma (HCC). However, the role and potential molecular mechanism of circRNAs in HCC remain largely unclear. In addition, exosomes are known as important messengers of the cross-talk between tumor cells and immune cells, while the role of extracellular circRNAs in the cell-to-cell communication of tumor cells and immune cells remains not unclear. Methods: The level of hsa_circ_0074854 in HCC cell lines and HCC cell-derived exosomes was assessed using RT-qPCR assay. In addition, CCK-8 and transwell assays were used to determine the viability, migration and invasion of HCC cells. Results: Hsa_circ_0074854 expression was upregulated in HCC tissues and HCC cell lines. Additionally, hsa_circ_0074854 knockdown was found to inhibit HCC growth in vitro and in vivo. Mechanistically, hsa_circ_0074854 knockdown inhibited the migration and invasion of HCC cells via interacting with human antigen R (HuR) to reduce its stability. Furthermore, hsa_circ_0074854 can be transferred from HCC cells to macrophages via exosomes. Exosomes with downregulated hsa_circ_0074854 suppressed macrophage M2 polarization, which in turn suppressing migration and invasion of HCC cells both in vitro and in vivo. Conclusion: Downregulation of hsa_circ_0074854 suppresses the migration and invasion in hepatocellular carcinoma via interacting with HuR and via suppressing exosomes-mediated macrophage M2 polarization. Collectively, these findings may help to understand the diagnosis and treatment of HCC.


Asunto(s)
Carcinoma Hepatocelular/genética , Movimiento Celular/genética , Polaridad Celular , Regulación hacia Abajo , Proteína 1 Similar a ELAV/metabolismo , Exosomas/metabolismo , Macrófagos/patología , ARN Circular/metabolismo , Animales , Apoptosis/genética , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular/genética , Regulación hacia Abajo/genética , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Macrófagos/metabolismo , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Unión Proteica , ARN Circular/genética
12.
Mol Med Rep ; 23(6)2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33899115

RESUMEN

Esophageal cancer (EC) is one of the most malignant and lethal digestive­related tumors worldwide. However, acquired drug resistance is a major obstacle concerning anticancer chemotherapy. An increasing number of studies have reported that microRNAs (miRNAs/miRs) are implicated in regulating the sensitivity of drug resistance in esophageal squamous cell carcinoma (ESCC). The aim of the present study was to investigate the role of miR­106b­3p in the sensitivity of cisplatin for ESCC. Initially, reverse transcription­quantitative polymerase chain reaction (RT­qPCR) was performed to analyze miR­106b­3p and protein­glutamine γ­glutamyltransferase E (TGM3) expression levels in ESCC and non­tumor adjacent tissues. By using bioinformatics software TargetScan, TGM3 was predicted to be a potential downstream target of miR­106­3p. Following verification that TGM3 was a downstream target of miR­106b­3p by the dual­luciferase reporter assay, the effects of miR­106b­3p transfection on KYSE30 cell viability and apoptosis following treatment with cisplatin were confirmed using Cell Counting Kit­8 and flow cytometry assays, respectively. The results revealed that miR­106b­3p levels were upregulated, whereas TMG3 levels were downregulated in ESCC tissues. Dual­luciferase reporter assays confirmed that miR­106b­3p negatively regulated TGM3 expression by binding to its 3'UTR sequence. It was also shown that inhibition of miR­106b­3p could enhance the anti­proliferative effects, while promoting the apoptotic effects of cisplatin in the KYSE30 cell line by targeting TGM3. In conclusion, the present study demonstrated that downregulation of miR­106b­3p may increase the sensitivity of KYSE30 cell to cisplatin by targeting TGM3.


Asunto(s)
Resistencia a Antineoplásicos , Neoplasias Esofágicas/genética , MicroARNs/metabolismo , Transglutaminasas/genética , Regiones no Traducidas 3' , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Regulación hacia Abajo , Neoplasias Esofágicas/metabolismo , Humanos , MicroARNs/genética , Transglutaminasas/metabolismo
13.
Physiol Rep ; 9(7): e14843, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33904656

RESUMEN

Hypoadiponectinemia is speculated to play a key role in the relationship between obesity and COVID-19 respiratory failure. However, only one study has examined adiponectin levels in COVID-19 patients, and none have investigated adiponectin levels strictly in patients with acute respiratory failure. In this study, we performed a retrospective case-control study of adipokine levels in patients with acute respiratory failure caused by either COVID-19 or other viral/bacterial source. All patients with COVID-19 respiratory failure in the University of Virginia Biorepository and Tissue Research database were included. We also selected patients with non-COVID-19 infectious respiratory failure from the same biorepository to serve as a comparison cohort. Plasma adipokine levels were measured on three occasions during the first 72 hours of hospitalization. Twelve patients with COVID-19 respiratory failure and 17 patients with other infectious respiratory failure were studied. Adiponectin levels were significantly lower in patients with COVID-19 respiratory failure, even after adjustment for age, sex, BMI, and other covariates. In conclusion, adiponectin levels appear to be reduced in COVID-19 respiratory failure. Larger studies are needed to confirm this report.


Asunto(s)
Adiponectina/sangre , /sangre , Anciano , Biomarcadores/sangre , Bases de Datos Factuales , Regulación hacia Abajo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Tiempo
14.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-33802796

RESUMEN

RNA-binding proteins (RBPs) are key elements involved in post-transcriptional regulation. Ataxin-2 (ATXN2) is an evolutionarily conserved RBP protein, whose function has been studied in several model organisms, from Saccharomyces cerevisiae to the Homo sapiens. ATXN2 interacts with poly(A) binding proteins (PABP) and binds to specific sequences at the 3'UTR of target mRNAs to stabilize them. CTC-Interacting Domain3 (CID3) and CID4 are two ATXN2 orthologs present in plant genomes whose function is unknown. In the present study, phenotypical and transcriptome profiling were used to examine the role of CID3 and CID4 in Arabidopsis thaliana. We found that they act redundantly to influence pathways throughout the life cycle. cid3cid4 double mutant showed a delay in flowering time and a reduced rosette size. Transcriptome profiling revealed that key factors that promote floral transition and floral meristem identity were downregulated in cid3cid4 whereas the flowering repressor FLOWERING LOCUS C (FLC) was upregulated. Expression of key factors in the photoperiodic regulation of flowering and circadian clock pathways, were also altered in cid3cid4, as well as the expression of several transcription factors and miRNAs encoding genes involved in leaf growth dynamics. These findings reveal that ATXN2 orthologs may have a role in developmental pathways throughout the life cycle of plants.


Asunto(s)
Proteínas de Arabidopsis/metabolismo , Arabidopsis/crecimiento & desarrollo , Arabidopsis/efectos de la radiación , Ataxina-2/química , Luz , Proteínas de Unión al ARN/metabolismo , Homología de Secuencia de Aminoácido , Proteínas de Arabidopsis/genética , Regulación hacia Abajo/genética , Flores/genética , Flores/fisiología , Flores/efectos de la radiación , Regulación de la Expresión Génica de las Plantas , Redes Reguladoras de Genes , Mutación/genética , Hojas de la Planta/genética , Hojas de la Planta/crecimiento & desarrollo , Proteínas de Unión al ARN/genética , Transcriptoma/genética
15.
Eur Rev Med Pharmacol Sci ; 25(7): 3122-3131, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33877681

RESUMEN

OBJECTIVE: Transcriptome data related to severe acute respiratory syndrome-related coronavirus 2 (a novel coronavirus discovered in 2019, SARS-CoV-2) in GEO database were downloaded. Based on the data, influence of SARS-CoV-2 on human cells was analyzed and potential therapeutic compounds against the SARS-CoV-2 were screened. MATERIALS AND METHODS: R package "DESeq2" was used for differential gene analysis on the data of cells infected or non-infected with SARS-CoV-2. The "ClusterProfiler" package was used for GO functional annotation and KEGG pathway enrichment analysis of the differentially expressed genes (DEGs). A protein-protein interaction (PPI) network of the DEGs was constructed through STRING website, and the key subset in the PPI network was identified after visualization by Cytoscape software. Connectivity Map (CMap) database was used to screen known compounds that caused genomic change reverse to that caused by SARS-CoV-2. RESULTS: By intersecting DEGs in two datasets, a total of 145 DEGs were screened out, among which 136 genes were upregulated and 9 genes were downregulated in SARS-CoV-2-infected cells. Functional enrichment analyses revealed that these genes were mainly associated with the pathways involved in viral infection, inflammatory response, and immunity. The CMap research found that there were three compounds with a median_tau_score less than -90, namely triptolide, tivozanib and daunorubicin. CONCLUSIONS: SARS-CoV-2 can cause abnormal changes in a large number of molecules and related signaling pathways in human cells, among which IL-17 and TNF signaling pathways may play a key role in pathogenic process of SARS-CoV-2. Here, three compounds that may be effective for the treatment of SARS-CoV-2 were screened, which would provide new options for improving treatment of patients infected with SARS-CoV-2.


Asunto(s)
/tratamiento farmacológico , Descubrimiento de Drogas , Perfilación de la Expresión Génica , Bases de Datos Genéticas , Bases de Datos Farmacéuticas , Daunorrubicina , Diterpenos , Regulación hacia Abajo , Compuestos Epoxi , Ontología de Genes , Redes Reguladoras de Genes , Humanos , Terapia Molecular Dirigida , Fenantrenos , Compuestos de Fenilurea , Mapas de Interacción de Proteínas , Quinolinas , Transducción de Señal/genética , Regulación hacia Arriba
16.
Sci Rep ; 11(1): 8570, 2021 04 21.
Artículo en Inglés | MEDLINE | ID: mdl-33883570

RESUMEN

Although a defective vitamin D endocrine system has been widely suspected to be associated in SARS-CoV-2 pathobiology, the status of the vitamin D endocrine system and vitamin D-modulated genes in lung cells of patients infected with SARS-CoV-2 remains unknown. To understand the significance of the vitamin D endocrine system in SARS-CoV-2 pathobiology, computational approaches were applied to transcriptomic datasets from bronchoalveolar lavage fluid (BALF) cells of such patients or healthy individuals. Levels of vitamin D receptor, retinoid X receptor, and CYP27A1 in BALF cells of patients infected with SARS-CoV-2 were found to be reduced. Additionally, 107 differentially expressed, predominantly downregulated genes, as potentially modulated by vitamin D endocrine system, were identified in transcriptomic datasets from patient's cells. Further analysis of differentially expressed genes provided eight novel genes with a conserved motif with vitamin D-responsive elements, implying the role of both direct and indirect mechanisms of gene expression by the dysregulated vitamin D endocrine system in SARS-CoV-2-infected cells. Protein-protein interaction network of differentially expressed vitamin D-modulated genes were enriched in the immune system, NF-κB/cytokine signaling, and cell cycle regulation as top predicted pathways that might be affected in the cells of such patients. In brief, the results presented here povide computational evidence to implicate a dysregulated vitamin D endocrine system in the pathobiology of SARS-CoV-2 infection.


Asunto(s)
Líquido del Lavado Bronquioalveolar/química , Biología Computacional/métodos , Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes , Vitamina D/metabolismo , Células A549 , Estudios de Casos y Controles , Línea Celular , Colestanotriol 26-Monooxigenasa/genética , Bases de Datos Genéticas , Regulación hacia Abajo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mapas de Interacción de Proteínas , Receptores de Calcitriol/genética , Receptores X Retinoide/genética
18.
Medicine (Baltimore) ; 100(14): e25270, 2021 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-33832090

RESUMEN

ABSTRACT: Del-1 has been linked to the pathogenesis of various cancers, including breast cancer. However, the regulation of Del-1 expression remains unclear. We previously reported the interaction between microRNA-137 (miR-137) and the Del-1 gene. In this study, we investigated miR-496 and miR-137 as regulators of Del-1 expression in triple negative breast cancer (TNBC). Del-1 mRNA and miR-496 were measured by quantitative PCR in breast cancer cells (MDA-MB-231, MCF7, SK-BR3, and T-47D) and tissues from 30 patients with TNBC. The effects of miR-496 on cell proliferation, migration, and invasion were determined with MTT, wound healing, and Matrigel transwell assays, respectively. In MDA-MB-231 cells, miR-496 levels were remarkably low and Del-1 mRNA levels were higher than in other breast cancer cell lines. Luciferase reporter assays revealed that miR-496 binds the 3'-UTR of Del-1 and Del-1 expression is downregulated by miR-496 mimics. Furthermore, miR-496 inhibited the proliferation, migration, and invasion of MDA-MB-231 cells. The effects of miR-496 on cell proliferation were additive with those of miR-137, another miRNA that regulates Del-1 expression. Moreover, in the 30 TNBC specimens, miR-496 was downregulated (P < .005) and the levels of Del-1 in the plasma were significantly elevated as compared with in normal controls (P = .0142). The Cancer Genome Atlas (TCGA) data showed the correlation of miR-496 expression with better overall survival in patients with early TNBC. In in silico and in vitro analyses, we showed that Del-1 is a target of miR-496 in TNBC and thereby affects cancer progression. Our findings suggest that miR-496 and miR-137 additively target Del-1 and act as modulating factors in TNBC. They are potentially new biomarkers for patients with TNBC.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , MicroARNs/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Proteínas de Unión al Calcio , Moléculas de Adhesión Celular , Línea Celular Tumoral , Proliferación Celular , Regulación hacia Abajo , Femenino , Humanos , MicroARNs/genética , Invasividad Neoplásica/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología
19.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 52(2): 188-193, 2021 Mar.
Artículo en Chino | MEDLINE | ID: mdl-33829690

RESUMEN

Objective: To analyze the correlation between connexin 43 (Cx43) and the expression of P16 and P21, aging-related proteins, and to investigate the possible role of Cx43 in the development of cell senescence with an aging model prepared by D-galactose (D-gal) intervention in the vascular smooth muscle cells (VSMCs) of guinea pig spiral modiolar artery (SMA). Methods: The VSMCs of guinea pig SMA were cultured with the adhesion method, and the markers of VSMCs were detected with immunofluorescence technique. The experiment has a control group, a D-gal group, and a group that received D-gal and gap junction agonist AAP10 intervention, hereafter referred to as the AAP10 group. Cell Counting Kit-8 (CCK-8) was used to check VSMC activity and to determine the concentration and duration of D-gal intervention. The mRNA expression of Cx43 in each group was checked with qRT-PCR. The expression of Cx43, P16 and P21 proteins in each group was examined with the Western blot. The expression and distribution of P16 and P21 proteins were examined with immunofluorescence assay. Results: Immunofluorescence results showed that the positive expression rate of cell actin (α-SM-actin) was over 90%. CCK-8 results showed that the optimal concentration of D-gal intervention was 30 mg/mL and the intervention duration was 48 h. qRT-PCR test showed that the mRNA expression of Cx43 in VSMCs in the D-gal group was significantly lower than that in the control group ( P<0.01), while it is higher in the AAP10 group than that of the D-gal group ( P<0.01); Western blot assay showed that the Cx43 expression level in VSMCs in the D-gal group was significantly lower than that in the control group ( P<0.01) and the expression of P16 and P21 was significantly higher than that in the control group ( P<0.01), the expression of Cx43 protein in AAP10 group was significantly up-regulated compared with that in the D-gal group ( P<0.01), while the expression of P16 and P21 was down-regulated significantly ( P<0.01); The results of immunofluorescence showed that P16 and P21 were mainly expressed in the cell nucleus. Semi-quantitative analysis of fluorescence intensity showed that the level of P16 and P21 protein in the D-gal group was significantly higher than that in the control group, and the fluorescence intensity of AAP10 group was significantly lower than that in the D-gal group ( P<0.01). Conclusion: Up-regulation of Cx43 expression can reverse the D-gal-induced abnormal expression of P16 and P21, two aging-related proteins, in SMA. It is suggested that Cx43 on SMA may be involved in D-gal-induced cell senescence, which provides a theoretical basis and possible intervention target for the delay of cell senescence.


Asunto(s)
Conexina 43 , Músculo Liso Vascular , Animales , Arterias , Senescencia Celular , Conexina 43/genética , Conexina 43/metabolismo , Regulación hacia Abajo , Cobayas , Miocitos del Músculo Liso/metabolismo
20.
Nat Commun ; 12(1): 2183, 2021 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-33846348

RESUMEN

Here we show that FTO as an N6-methyladenosine (m6A) RNA demethylase is degraded by selective autophagy, which is impaired by low-level arsenic exposure to promote tumorigenesis. We found that in arsenic-associated human skin lesions, FTO is upregulated, while m6A RNA methylation is downregulated. In keratinocytes, chronic relevant low-level arsenic exposure upregulated FTO, downregulated m6A RNA methylation, and induced malignant transformation and tumorigenesis. FTO deletion inhibited arsenic-induced tumorigenesis. Moreover, in mice, epidermis-specific FTO deletion prevented skin tumorigenesis induced by arsenic and UVB irradiation. Targeting FTO genetically or pharmacologically inhibits the tumorigenicity of arsenic-transformed tumor cells. We identified NEDD4L as the m6A-modified gene target of FTO. Finally, arsenic stabilizes FTO protein through inhibiting p62-mediated selective autophagy. FTO upregulation can in turn inhibit autophagy, leading to a positive feedback loop to maintain FTO accumulation. Our study reveals FTO-mediated dysregulation of mRNA m6A methylation as an epitranscriptomic mechanism to promote arsenic tumorigenicity.


Asunto(s)
Adenosina/análogos & derivados , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Arsénico/toxicidad , Autofagia , Carcinogénesis/genética , Adenosina/metabolismo , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Animales , Autofagia/efectos de los fármacos , Autofagia/genética , Secuencia de Bases , Carcinogénesis/efectos de los fármacos , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/patología , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Epidermis/metabolismo , Ontología de Genes , Células HEK293 , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Ratones , FN-kappa B/metabolismo , Ubiquitina-Proteína Ligasas Nedd4/metabolismo , Estabilidad Proteica/efectos de los fármacos , Estabilidad del ARN/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteína Sequestosoma-1/metabolismo , Transcriptoma/genética , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genética , Vacuolas/efectos de los fármacos , Vacuolas/metabolismo , Vacuolas/ultraestructura
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