RESUMEN
Allergic rhinitis (AR) is an immunoglobulin E-mediated type 2 inflammation of the nasal mucosa that is mainly driven by type 2 helper T cells (Th2) and type 2 innate lymphoid cells (ILC2s). CD226 is a costimulatory molecule associated with inflammatory response and is mainly expressed on T cells, natural killer cells, and monocytes. This study is aimed at elucidating the role of CD226 in allergic inflammatory responses in murine AR using global and CD4+ T cell-specific Cd226 knockout (KO) mice. AR nasal symptoms were assessed based on the frequency of nose rubbing and sneezing. Hematoxylin and eosin and periodic acid-Schiff staining and quantitative real-time PCR methods were used to determine eosinophils, goblet cells, and ILC2-associated mRNA levels in the nasal tissues of mice. CD226 levels on ILC2s were detected using flow cytometry, and an immunofluorescence double staining assay was employed to determine the number of ILC2s in the nasal mucosa. The results showed that global Cd226 KO mice, but not CD4+ T cell-specific Cd226 KO mice, exhibited attenuated AR nasal symptoms. Eosinophil recruitment, goblet cell proliferation, and Th2-inflammatory cytokines were significantly reduced, which resulted in the alleviation of allergic and inflammatory responses. ILC2s in the murine nasal mucosa expressed higher levels of CD226 after ovalbumin stimulation, and CD226 deficiency led to a reduction in the proportion of nasal ILC2s and ILC2-related inflammatory gene expression. Hence, the effect of CD226 on the AR mouse model may involve the regulation of ILC2 function rather than CD4+ T cells.
Asunto(s)
Inmunidad Innata , Rinitis Alérgica , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Linfocitos/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Mucosa Nasal/metabolismo , Ovalbúmina , Rinitis Alérgica/metabolismo , Células Th2/metabolismoRESUMEN
In the past two decades, miRNAs have been demonstrated to play critical roles in development and progression of malignant diseases. To identify the role and mechanism of miRNA are urgent for the application of miRNA-based therapeutics in cancers. MiR-205 is a conserved miRNA from the invertebrate to mammalian species. Previous studies showed a large body of evidence to demonstrate the oncogenic or tumor suppressive role of it in different types of cancers. Our aim here is to clarify the role and novel mechanism of miR-205 in solid tumors. In the present study, we found that a high level of miR-205 is an independent biomarker for favorable prognosis in LIHC, HNSCC and LUSC. In the functional experiment, we stably expressed miR-205 in tumor cell lines derived from above mentioned cancers. The result showed that overexpression of miR-205 significantly inhibits cancer cell proliferation. Mechanistically, we identified that the lysophosphatidylcholine acyltransferase-1 (LPCAT1) is a novel target of miR-205 in multiple cancer cells. Furthermore, we found that LPCAT1 is required for sustained proliferation of cancer cells and a high level of it is closely associated with poor prognosis in clinical patients. Collectively, we revealed the important prognostic value of a miR-205-LPCAT1 axis in multiple cancers and highlighted an essential role of LPCAT1 in miR-205-regulated cancer cell proliferation. All these discoveries make a miR-205-LPCAT1 axis to shed light upon a potential therapeutic target in cancer treatment.
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1-Acilglicerofosfocolina O-Aciltransferasa/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Neoplasias/genética , Línea Celular Tumoral , Proliferación Celular , Progresión de la Enfermedad , Humanos , Neoplasias/diagnóstico , PronósticoRESUMEN
Surgical management of spontaneous hypertensive brainstem hemorrhage remains a challenge for neurosurgeons, especially when the hemorrhage is located the ventral brainstem. Recently endoscopic endonasal approach has been applied for resection of ventral brainstem lesions, though no published literature has explored its utility in treating brainstem hemorrhage. Here we reported a successful evacuation of severe hypertensive brainstem hemorrhage through endoscopic endonasal transclival approach. A 37 years-old male with a 5-year history of uncontrolled hypertension was brought to the Emergency Department with sudden vomiting, limb convulsions, and loss of consciousness for 2âhours. Computed tomography demonstrated a hemorrhage measuring 2.5â×â2.2âcm in the ventral midbrain and pontine. He presented with a Glasgow coma scale (GCS) score of 3 and disrupted vitals, and was intubated in the Emergency Department. Considering the ventral location of the hemorrhage and the need for emergent surgical decompression, an endoscopic endonasal approach was applied. Evacuation of the brainstem hemorrhage was achieved and his spontaneous respiration improved immediately after surgery. He was weaned off the ventilator and extubated on postoperative day 1, along with an improved GCS score of 5 (E2V1M2). At 1 month postoperatively his GCS score improved to 11 (E4V2M5) and he is currently under rehabilitation. Endoscopic endonasal approach is a feasible alternative for emergent surgery of ventrally located brainstem hemorrhage in carefully selected cases by providing direct visualization of the area and a good working angle, which facilitate evacuation of the hemorrhage with minimal damage to the brainstem.
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Hemorragia Cerebral/cirugía , Hipertensión/complicaciones , Mesencéfalo/cirugía , Nariz , Puente/cirugía , Adulto , Hemorragia Cerebral/etiología , Escala de Coma de Glasgow , Humanos , Masculino , Neuroendoscopía , Convulsiones/etiologíaRESUMEN
Soluble guanylate cyclase (sGC) is a heterodimer composed of α and ß subunits. The loss of sGCß1 has been implicated in several vascular and nonvascular diseases. Our analysis showed that higher levels of sGCß1 in breast cancer tissues are correlated with greater survival probability than lower sGCß1 levels. However, there is no information on sGC regulation by epigenetic mechanisms. We examined the role of histone deacetylase (HDAC) inhibitors in regulating sGCα1 and -ß1 expression in human breast cancer MDA-MB-231 and MDA-MB-468 cell lines. The class I HDAC inhibitors increased the expression of sGCß1 more than sGCα1. Transient overexpression of HDAC3, but not HDAC1 or HDAC2, significantly reduced sGCß1 mRNA. Chromatin immunoprecipitation assay confirmed an enhanced binding of HDAC3 to the sGCß1 proximal promoter, which could be reversed by panobinostat (LBH-589) treatment. Mutations at the CCAAT binding sequence, a major element regulating sGCß1 expression, markedly reduced the efficacy of LBH-589 in augmenting sGCß1 promoter activity. LBH-589 markedly enhanced the binding of nuclear transcription factor Y, subunit α, to the sGCß1 promoter (CCAAT binding sequence). In summary, HDAC3 is an endogenous antagonist of sGCß1 expression. Inhibition of HDAC3 with targeted therapy could benefit treatment of the diseases associated with sGCß1 down-regulation and/or deficiency such as cancer and several vascular-related diseases.-Sotolongo, A., Mónica, F. Z., Kots, A., Xiao, H., Liu, J., Seto, E., Bian, K., Murad, F. Epigenetic regulation of soluble guanylate cyclase (sGC) ß1 in breast cancer cells.
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Neoplasias de la Mama/metabolismo , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica/fisiología , Histona Desacetilasas/metabolismo , Guanilil Ciclasa Soluble/metabolismo , Acetilación , Factor de Unión a CCAAT/genética , Factor de Unión a CCAAT/metabolismo , Línea Celular Tumoral , Femenino , Glioma , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/genética , Humanos , Regiones Promotoras Genéticas , Guanilil Ciclasa Soluble/genéticaRESUMEN
It has been reported since late 1970 that magnetic field interacts strongly with biological systems. Cold atmospheric plasma (CAP) has also been widely studied over the past few decades in physics, biology, and medicine. In this study, we propose a novel idea to combine static magnetic field (SMF) with CAP as a tool for cancer therapy. Breast cancer cells and wild type fibroblasts were cultured in 96-well plates and treated by CAP with or without SMF. Breast cancer cells MDA-MB-231 showed a significant decrease in viability after direct plasma treatment with SMF (compared to only plasma treatment). In addition, cancer cells treated by the CAP-SMF-activated medium (indirect treatment) also showed viability decrease but was slightly weaker than the direct plasma-SMF treatment. By integrating the use of SMF and CAP, we were able to discover their advantages that have yet to be utilized. Bioelectromagnetics. 38:53-62, 2017. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Campos Magnéticos , Gases em Plasma/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , HumanosRESUMEN
AIM: We have shown that rutaecarpine extracted from the dried fruit of Chinese herb Evodia rutaecarpa (Juss) Benth (Wu Zhu Yu) promotes glucose consumption and anti-inflammatory cytokine expression in insulin-resistant primary skeletal muscle cells. In this study we investigated whether rutaecarpine ameliorated the obesity profiles, lipid abnormality, glucose metabolism and insulin resistance in rat model of hyperlipidemia and hyperglycemia. METHODS: Rats fed on a high-fat diet for 8 weeks, followed by injection of streptozotocin (30 mg/kg, ip) to induce hyperlipidemia and hyperglycemia. One week after streptozotocin injection, the fat-fed, streptozotocin-treated rats were orally treated with rutaecarpine (25 mg·kg(-1)·d(-1)) or a positive control drug metformin (250 mg·kg(-1)·d(-1)) for 7 weeks. The body weight, visceral fat, blood lipid profiles and glucose levels, insulin sensitivity were measured. Serum levels of inflammatory cytokines were analyzed. IRS-1 and Akt/PKB phosphorylation, PI3K and NF-κB protein levels in liver tissues were assessed; pathological changes of livers and pancreases were examined. Glucose uptake and AMPK/ACC2 phosphorylation were studied in cultured rat skeletal muscle cells in vitro. RESULTS: Administration of rutaecarpine or metformin significantly decreased obesity, visceral fat accumulation, water consumption, and serum TC, TG and LDL-cholesterol levels in fat-fed, streptozotocin-treated rats. The two drugs also attenuated hyperglycemia and enhanced insulin sensitivity. Moreover, the two drugs significantly decreased NF-κB protein levels in liver tissues and plasma TNF-α, IL-6, CRP and MCP-1 levels, and ameliorated the pathological changes in livers and pancreases. In addition, the two drugs increased PI3K p85 subunit levels and Akt/PKB phosphorylation, but decreased IRS-1 phosphorylation in liver tissues. Treatment of cultured skeletal muscle cells with rutaecarpine (20-180 µmol/L) or metformin (20 µmol/L) promoted the phosphorylation of AMPK and ACC2, and increased glucose uptake. CONCLUSION: Rutaecarpine ameliorates hyperlipidemia and hyperglycemia in fat-fed, streptozotocin-treated rats via regulating IRS-1/PI3K/Akt signaling pathway in liver and AMPK/ACC2 signaling pathway in skeletal muscles.
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Hiperglucemia/tratamiento farmacológico , Hiperlipidemias/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Hipolipemiantes/uso terapéutico , Alcaloides Indólicos/uso terapéutico , Quinazolinas/uso terapéutico , Animales , Grasas de la Dieta/administración & dosificación , Hiperglucemia/inducido químicamente , Hiperglucemia/metabolismo , Hiperlipidemias/inducido químicamente , Hiperlipidemias/metabolismo , Hipoglucemiantes/farmacología , Hipolipemiantes/farmacología , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Células Musculares/efectos de los fármacos , Células Musculares/metabolismo , Músculo Esquelético/citología , Músculo Esquelético/metabolismo , Páncreas/efectos de los fármacos , Páncreas/patología , Ratas Sprague-Dawley , Transducción de Señal , EstreptozocinaRESUMEN
OBJECTIVE: To systematically study various surgical approaches for treating complex hypopharyngeal and/or laryngotracheal stenoses at a variety of sites and levels. PATIENTS AND METHODS: We retrospectively analyzed the treatment of 17 patients with severe and complex hypopharyngeal and/or laryngotracheal stenosis at various sites and levels of severity. All of the 17 patients initially had a tracheostomy. Thirteen had failed the previous laser lysis and/or dilation treatment. Given the high severity and complexity of stenosis, all of these patients were treated by open surgical reconstruction techniques using repairing grafts (flaps), followed by stenting. RESULTS: Thirteen of 17 patients had successful decannulation 1-8 months post-operation and had stable airway and adequate vocal and swallow function. Two patients with complex hypopharyngeal and esophageal stenosis had unsuccessful decannulation. Follow-up was lost in 1 patient with complex hypopharyngeal and esophageal stenosis and 1 patient with original hypopharyngeal stenosis and recurrent thoracotracheal stenosis. CONCLUSION: Despite the failure by the regular treatments using laser lysis and/or dilation therapy, severe and complex hypopharyngeal and/or laryngotracheal stenosis may be successfully treated by variable open surgical reconstruction techniques using different grafts (flaps) depending on the site and severity of the stenosis.
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Laringoestenosis/cirugía , Terapia por Láser/métodos , Procedimientos de Cirugía Plástica/métodos , Complicaciones Posoperatorias/cirugía , Colgajos Quirúrgicos , Estenosis Traqueal/cirugía , Adolescente , Adulto , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Laringoplastia/métodos , Laringoestenosis/etiología , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Factores de Tiempo , Estenosis Traqueal/etiología , Resultado del Tratamiento , Adulto JovenRESUMEN
The classification of molecular subtypes of breast cancer improves the prognostic accuracy and therapeutic benefits in clinic. However, because of the complexity of breast cancer, more biomarkers and functional molecules need to be explored. Here, analyzing the data in a huge cohort of breast cancer patients, we found that Topoisomerase II alpha (TOP2a), an important target of chemotherapy is a biomarker for prognosis in luminal type breast cancer patients, but not in basal like or HER2 positive breast cancer patients. We identified that miR-139, a previous reported anti-metastatic microRNA targets 3'-untranslated region (3'UTR) of TOP2a mRNA. Further more, we revealed that the forced expression of miR-139 reduces the TOP2a expression at both mRNA and protein levels. And our functional experiments showed that the ectopic expression of miR-139 remarkably inhibits proliferation in luminal type breast cancer cells, while exogenous TOP2a expression could rescue inhibition of cell proliferation mediated by miR-139. Collectively, our present study demonstrates the miR-139-TOP2a regulatory axis is important for proliferation in luminal type breast cancer cells. This functional link may help us to further understand the specificity of subtypes of breast cancer and optimize the strategy of cancer treatment.
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Antígenos de Neoplasias/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular , ADN-Topoisomerasas de Tipo II/metabolismo , Proteínas de Unión al ADN/metabolismo , MicroARNs/fisiología , Antígenos de Neoplasias/genética , Neoplasias de la Mama/enzimología , Línea Celular Tumoral , ADN-Topoisomerasas de Tipo II/genética , Proteínas de Unión al ADN/genética , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Proteínas de Unión a Poli-ADP-RibosaRESUMEN
Garcinia Linn. plants having rich natural xanthones and benzophenones with anti-inflammatory activity attracted a great deal of attention to discover and develop them as potential drug candidates. Through screening targeting nitric oxide accumulation in stimulated macrophage, we found that 1,3,5,7-tetrahydroxy-8-isoprenylxanthone (TIE) had potential anti-inflammatory effect. To understand how TIE elicits its anti-inflammatory activity, we uncovered that it significantly inhibits the production of nitric oxide (NO) and prostaglandin E2 (PGE2) in LPS/IFNγ-stimulated RAW264.7 cells. In further study, we showed that TIE reduced the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), two key molecules responsible for the production of NO and PGE2 during inflammation progress. Additionally, TIE also suppressed the expression of inflammatory cytokines IL-6, IL-12, and TNF-α. TIE-led suppression in iNOS, COX-2, and cytokines production were probably the consequence of TIE's capability to block ERK and p38MAPK signaling pathway. Moreover, TIE blocked activation of nuclear factor-kappa B (NF-κB) as well as NF-κB regulation of miR155 expression. Our study suggests that TIE may represent as a potential therapeutic agent for the treatment of inflammatory diseases.
Asunto(s)
Antiinflamatorios/farmacología , Garcinia/química , Macrófagos/efectos de los fármacos , Extractos Vegetales/química , Xantonas/farmacología , Animales , Supervivencia Celular , Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Inflamación , Interleucina-6/metabolismo , Lipopolisacáridos/química , Ratones , FN-kappa B/metabolismo , Óxido Nítrico/química , Óxido Nítrico Sintasa de Tipo II/metabolismo , Células RAW 264.7 , Transducción de Señal , Xantonas/aislamiento & purificación , Xantonas/uso terapéuticoRESUMEN
Macrophages are heterogeneous and diversified, and can be polarized into different phenotypes in various microenvironments and physiological or pathological conditions. Major macrophage subpopulations including classically activated(M1) and alternatively activated(M2) macrophages, which represent different surface receptors, secret different cytokines and chemokines, are regulated by different signal paths of transcriptions and epigenetic levels, and play distinctive roles in tumor progress. TCMs may improve the microenvironment by regulating phenotype polarization of macrophages. So far, specific biomarkers and polarized molecules mechanisms generated through the macrophage polarization approach are still unclear. In this article, we merely summarize the advance in domestic and foreign studies on phenotype polarization of macrophages and regulatory mechanisms and look into the future of intervention with TCMs.
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Macrófagos/fisiología , Medicina Tradicional China , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Animales , Polaridad Celular , Humanos , FenotipoRESUMEN
To study the mechanisms of total flavonoid from Glycyrrhizae Radix et Rhizoma (TFGR) and its ingredient isoliquiritigenin (ISL) on their regulation of M2 phenotype polarization of macrophages. IL-4 (60 µg x L(-1)) induced RAW264.7 cells for 6 h to establish the M2 macrophage model. TFGR and ISL restrained breast cancer cells migration with the aid of M2 macrophages in vitro. TFGR and ISL inhibited gene and protein expression of Arg-1, up-regulated gene of HO-1 and protein expression of iNOS, enhanced the expression of microRNA 155 and its target gene SHIP1, meanwhile down-regulated.the phosphorylation of STAT3 and STAT6. So TFGR and ISL were the bioactive fraction and ingredient in Glycyrrhizae Radix et Rhizoma to reverse M2 phenotype macrophages polarization. TFGR and ISL inhibited the promotion of M2 macrophages to breast cancer cells migration in vitro, STAT signal pathways and miR155 were partly involved.
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Chalconas/farmacología , Flavonoides/farmacología , Glycyrrhiza/química , Macrófagos/efectos de los fármacos , Animales , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Polaridad Celular/efectos de los fármacos , Interleucina-4/genética , Interleucina-4/metabolismo , Macrófagos/citología , Macrófagos/metabolismo , Ratones , Células RAW 264.7 , Rizoma/químicaRESUMEN
Despite a regain of interest recently in ERK3 kinase signaling, the molecular regulations of both ERK3 gene expression and protein kinase activity are still largely unknown. While it is shown that disruption of ERK3 gene causes neonatal lethality, cell type-specific functions of ERK3 signaling remain to be explored. In this study, we report that ERK3 gene expression is upregulated by cytokines through c-Jun in endothelial cells; c-Jun binds to the ERK3 gene and regulates its transcription. We further reveal a new role for ERK3 in regulating endothelial cell migration, proliferation and tube formation by upregulating SRC-3/SP-1-mediated VEGFR2 expression. The underlying molecular mechanism involves ERK3-stimulated formation of a transcriptional complex involving coactivator SRC-3, transcription factor SP-1 and the secondary coactivator CBP. Taken together, our study identified a molecular regulatory mechanism of ERK3 gene expression and revealed a previously unknown role of ERK3 in regulating endothelial cell functions.
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Células Endoteliales de la Vena Umbilical Humana/enzimología , Proteína Quinasa 6 Activada por Mitógenos/metabolismo , Neovascularización Fisiológica , Coactivador 3 de Receptor Nuclear/metabolismo , Factor de Transcripción Sp1/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Sitios de Unión , Proteína de Unión a CREB/metabolismo , Movimiento Celular , Proliferación Celular , Regulación Enzimológica de la Expresión Génica , Células HeLa , Humanos , Proteína Quinasa 6 Activada por Mitógenos/genética , Coactivador 3 de Receptor Nuclear/genética , Regiones Promotoras Genéticas , Interferencia de ARN , Transducción de Señal , Factor de Transcripción Sp1/genética , Factores de Tiempo , Transcripción Genética , Transfección , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia Arriba , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genéticaRESUMEN
Recent studies report that a conflict between information from the visual system and vestibular system is one of the main reasons for induction of motion sickness (MS). We may be able to clarify the integration mechanism of visual and vestibular information using an animal model with a visual defect, the retinal degeneration fast (rdf) mouse, and the role of vestibular information in the pathogenesis of MS. The rdf mice and wild-type Kunming mice were subjected to rotary stimulation to induce MS. Conditioned taste anorexia to saccharin solution and behavior score were used to observe the differences in MS sensitivity between two types of mice. The decrease in intake of saccharin solution and the behavior score in rdf mice were greater than those in normal mice. After rotatory stimulation, the reduction of intake mass and the behavior score were greater in rdf mice compared to those of normal mice. The rdf mice were more sensitive to rotation than normal mice. We conclude that visual information plays a role in the pathogenesis of MS. Visual information and vestibular information impact each other and integrate through certain channels in the central nervous system in mice.
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Mareo por Movimiento/fisiopatología , Degeneración Retiniana/fisiopatología , Animales , Anorexia , Condicionamiento Psicológico , Modelos Animales de Enfermedad , Ingestión de Líquidos , Masculino , Ratones , Mareo por Movimiento/etiología , Estimulación Física/efectos adversos , Rotación/efectos adversos , Sacarina , Índice de Severidad de la Enfermedad , Factores de TiempoRESUMEN
The broad role of nitric oxide (NO) and cyclic GMP in biochemistry and biology as important messenger molecules is evident from the numerous publications in this research field. NO and cGMP have been known as components of the key signaling pathway in regulating numerous processes such as vascular dilation, blood pressure, neurotransmission, cardiovascular function, and renal function. In spite of almost 150,000 publications with nitric oxide and cyclic GMP, there are few publications regarding the effects of these messenger molecules on gene regulation, cell differentiation and cell proliferation. Our research data with embryonic stem cells and several cancer cell lines suggest that nitric oxide, its receptor soluble guanylyl cyclase (sGC) and sGC's product cyclic GMP can regulate the processes of proliferation and differentiation. Furthermore, we have found that undifferentiated stem cells and some malignant tumors such as human glioma have decreased levels of sGC and translocation of the sGCß1 subunit to the nucleus. We propose that sGC and cyclic GMP function as tumor suppressors. An understanding of the mechanisms of the translocation of the sGCß1 subunit into the nucleus and the possible regulation of gene expression of NO and/or cyclic CMP could lead to novel and innovative approaches to cancer therapy and stem cell proliferation and differentiation.
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Investigación Biomédica/tendencias , Sistema Cardiovascular/fisiopatología , Neoplasias/fisiopatología , Óxido Nítrico/metabolismo , GMP Cíclico/metabolismo , Guanilato Ciclasa/metabolismo , Humanos , Receptores Citoplasmáticos y Nucleares/metabolismo , Transducción de Señal , Guanilil Ciclasa SolubleRESUMEN
The biologic endogenous production of cGMP was reported in the 1960s and followed by the demonstration of guanylyl cyclase activity and the isoforms of soluble and membrane-bound guanylyl cyclases. During the same period, cGMP specific phosphodiesterases also was discovered. Murad's lab established link between the endothelium derived relaxation factor (EDRF) and elevated cGMP concentration in the vascular system. October 12, 1998, the Nobel Assembly awarded the Nobel Prize in Medicine or Physiology to scientists Robert Furchgott, Louis Ignarro, and Ferid Murad for their discoveries concerning nitric oxide (NO) as a signaling molecule in the cardiovascular system. In contrast with the short research history of the enzymatic synthesis of NO, the introduction of nitrate-containing compounds for medicinal purposes marked its 150th anniversary in 1997. Glyceryl trinitrate (nitroglycerin; GTN) is the first compound of this category. Alfred Nobel (the founder of the Nobel Prize) himself had suffered from angina pectoris and was prescribed nitroglycerin for his chest pain while he refused to take due to the induction of headaches. Almost a century after its first chemical use, research in the nitric oxide and 3',5'-cyclic guanosine monophosphate (NO/cGMP) pathway has dramatically expanded and the role of NO/cGMP in physiology and pathology has been extensively studied. Soluble guanylyl cyclase (sGC) is the receptor for NO. The α1ß1 heterodimer is the predominant isoform of sGC that is obligatory for catalytic activity. NO binds to the ferrous (Fe(2+)) heme at histidine 105 of the ß1 subunit and leads to an increase in sGC activity and cGMP production of at least 200-fold. In this chapter, we reviewed the studies of sGC-cGMP signaling in cell proliferation; introduced our work of targeting sGC-cGMP signaling for cancer therapy; and explored the role of sGC-cGMP signaling in the chromatin-microenvironment.
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GMP Cíclico/metabolismo , Guanilato Ciclasa/metabolismo , Neoplasias , Transducción de Señal/fisiología , Microambiente Tumoral/fisiología , Animales , Humanos , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/terapiaRESUMEN
Cisplatin is a first-line anticancer drug widely used in clinic. However, its resistance reduces its efficacy. With a non-specific cell cycle, cisplatin's main targets are nucleophilic protein, DNA and RNA in cells. Among cisplatin's multi-factorial resistance mechanisms, abnormal expression of transport protein, intracellular detoxification enhancement, DNA repair capacity increase and apoptosis blocking are the main mechanisms. Because traditional Chinese medicines (TCMs) have unique advantages in cancer treatment, their combination with cisplatin can improve the efficacy. In this paper, the authors summarized the advance in studies on cisplatin's resistance and the combination of TCMs and cisplatin in recent years.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Medicina Tradicional China/métodos , Neoplasias/tratamiento farmacológico , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Cisplatino/administración & dosificación , Medicamentos Herbarios Chinos/administración & dosificación , Humanos , Medicina Tradicional China/tendencias , Neoplasias/patología , Neoplasias/terapiaRESUMEN
Stroke is one of the major diseases that threaten human health, early diagnosis and treatment are very important for stroke. Carotid intima-media thickness (CIMT) is measured noninvasively to diagnosis stroke, and it is a independent predictor for stroke because its thickening can timely predict the incidence and development of stroke. As an important predictor of cardiovascular disease, more and more attention is played on CIMT. In this review, we will make a summary on the important role of CIMT in stroke and the mechanisms of carotid intima-media thickening in stroke as well as the potential use of traditional Chinese medicine in treating carotid intima-media thickening.
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Medicamentos Herbarios Chinos/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/fisiopatología , Animales , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/fisiopatología , Grosor Intima-Media Carotídeo , Humanos , Accidente Cerebrovascular/diagnósticoRESUMEN
It is now well established that inflammation plays an important role in the development of numerous chronic metabolic diseases including insulin resistance (IR) and type 2 diabetes (T2DM). Skeletal muscle is responsible for 75% of total insulin-dependent glucose uptake; consequently, skeletal muscle IR is considered to be the primary defect of systemic IR development. Our pre- vious study has shown that rutaecarpine (Rut) can benefit blood lipid profile, mitigate inflammation, and improve kidney, liver, pan- creas pathology status of T2DM rats. However, the effects of Rut on inflammatory cytokines in the development of IR-skeletal muscle cells have not been studied. Thus, our objective was to investigate effects of Rut on inflammatory cytokines interleukiri (IL)-1, IL-6 and tumor necrosis factor (TNF)-α in insulin resistant primary skeletal muscle cells (IR-PSMC). Primary cultures of skeletal muscle cells were prepared from 5 neonate SD rats, and the primary rat skeletal muscle cells were identified by cell morphology, effect of ru- taecarpine on cell proliferation by MTT assay. IR-PSMC cells were induced by palmitic acid (PA), the glucose concentration was measured by glucose oxidase and peroxidase (GOD-POD) method. The effects of Rut on inflammatory cytokines IL-1, IL-6 and TNF-α in IR-PSMC cells were tested by enzyme-linked immunosorbent assay (ELISA) kit. The results show that the primary skeletal muscle cells from neonatal rat cultured for 2-4 days, parallel alignment regularly, and cultured for 7 days, cells fused and myotube formed. It was shown that Rut in concentration 0-180. 0 µmol x L(-1) possessed no cytotoxic effect towards cultured primary skeletal muscle cells. However, after 24 h exposure to 0.6 mmol x L(-1) PA, primary skeletal muscle cells were able to induce a state of insulin resistance. The results obtained indicated significant decrease (P < 0.05 to P < 0.001) IL-1, IL-6 and TNF-α production by cultured IR-PSMC cells when incubating 24 hours with Rut, beginning from 20 to 180.0 µmol x L(-1). IL-1, IL-6 and TNF-α in the Rut treated groups were dose-dependently decreased compared with that in the IR-PSMC control group. Our results demonstrated that the Rut promoted glucose consumption and improved insulin resistance possibly through suppression of inflammatory cytokines in the IR-PSMC cells.
Asunto(s)
Citocinas/metabolismo , Alcaloides Indólicos/farmacología , Resistencia a la Insulina , Músculo Esquelético/citología , Músculo Esquelético/efectos de los fármacos , Quinazolinas/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Femenino , Glucosa/metabolismo , Inflamación/metabolismo , Masculino , Músculo Esquelético/metabolismo , RatasRESUMEN
The oncogenic potential of chromosome 8q22 copy number gain in liver cancer remains to be depicted. Here, we report that ZNF706, encoded by a gene mapped to chromosome 8q22, is a C2H2-type zinc finger protein. However, the biological function and mechanism of ZNF706 have been poorly investigated. Clinically, ZNF706 expression was elevated in hepatocellular carcinoma (HCC), and high ZNF706 expression was associated with unfavorable survival in HCC patients. Functional experiments revealed that ZNF706 knockdown inhibited HCC progression both in vitro and in vivo. RNA sequencing (RNA-seq) and chromatin immunoprecipitation-based deep sequencing (ChIP-seq) revealed that mechanistically, ZNF706 is a crucial ferroptosis regulator and that SLC7A11 is a critical target of ZNF706. In addition, ZNF706 knockdown inhibited SLC7A11 expression, increased lipid peroxidation, and promoted ferroptosis. Further analysis revealed that ZNF706 is a novel direct target transcriptionally activated by MYC in HCC cells. Importantly, MYC depletion reduced SLC7A11-mediated redox homeostasis, and this effect was reversed by ZNF706 reexpression. Collectively, our data demonstrate that ZNF706 is a potential oncogene in liver cancer and functions as a ferroptosis regulator by modulating SLC7A11 expression, constituting a potential therapeutic target for HCC.
RESUMEN
OBJECTIVE: To examine the anti-inflammatory mechanism of total flavonoids of Glycyrrhizae Radix et Rhizoma (TFGR) and its ingredient on IFN-gamma and LPS-induced macrophage RAW264.7. METHOD: Solvent extraction and macroporous resin enrichment were adopted for preparing ethanol extracts of Glycyrrhizae Radix et Rhizoma, components and total flavonoids. Ultraviolet spectroscopy was used to determine the content of total flavonoids. An IFN-gamma and LPS-induced cell inflammatory model was established. Griess reaction was used for detecting the effect of extracts at all levels and flavonoid monomers on nitrite content in cell culture supernatant. FRAP was used for measuring anti-oxidation capacity. RT-PCR was used for determining the effect of TFGR and isoliquiritigenins on intracellular inducible nitric oxide synthase iNOS, COX-2, IL-6 and PPAR-gamma. Western blot was used for detecting the effect of TFGR and isoliquiritigenins on iNOS, COX-2 and MAPK signal transduction pathways. RESULT: Compared with other extracts, ethyl acetate fractions from Glycyrrhizae Radix et Rhizoma showed the highest inhibition ratio on nitrite content at the same concentration. After being enriched with macroporous resin, TFGR (60. 08% of liquiritin) of ethyl acetate extracts from Glycyrrhizae Radix et Rhizoma showed dose-dependence, and inhibited the nitrite content in cell culture supernatant, which was superior to ethyl acetate extracts, and had the protective effect on post-stimulated cell activity, with a stronger total anti-oxidation than other extracts. TFGR inhibited iNOS, IL-6 mRNA, protein expressions of iNOS, COX-2 and IL-6. Isoliquiritigenin, a flavonoid monomer, could inhibited iNOS, COX-2 gene and protein expression and gene expressions of IL-1beta and IL-6, and upside-regulated gene expression of PPAR-gamma. CONCLUSION: Activity-oriented extraction suggests that ethyl acetate fractions from Glycyrrhizae Radix et Rhizoma is one of components with anti-inflammatory activity. TFGR obtained by enriching the active component showed dose-dependence, and inhibited the nitrite content in cell culture supernatant. The anti-inflammatory effect is partially achieved by regulating ERK signal pathway and inhibiting iNOS and COX-2 gene and protein expressions through extracellular signals of mitogen activated protein kinases (MAPKs). Specifically, isoliquiritigenin may be a component with TFGR anti-inflammatory activity.