RESUMEN
BACKGROUND: Helicobacter pylori (H. pylori) infection causes aberrant DNA methylation and contributes to the risk of gastric cancer (GC). Guanine nucleotide-binding protein subunit beta-4 (GNB4) is involved in various tumorigenic processes. We found an aberrant methylation level of GNB4 in H. pylori-induced GC in our previous bioinformatic analysis; however, its expression and underlying molecular mechanisms are poorly understood. METHODS: The expression, underlying signaling pathways, and clinical significance of GNB4 were analyzed in a local cohort of 107 patients with GC and several public databases. H. pylori infection was induced in in vitro and in vivo models. Methylation-specific PCR, pyrosequencing, and mass spectrometry analysis were used to detect changes in methylation levels. GNB4, TET1, and YAP1 were overexpressed or knocked down in GC cell lines. We performed gain- and loss-of-function experiments, including CCK-8, EdU, colony formation, transwell migration, and invasion assays. Nude mice were injected with genetically manipulated GC cells, and the growth of xenograft tumors and metastases was measured. Real-time quantitative PCR, western blotting, immunofluorescence, immunohistochemistry, chromatin immunoprecipitation, and co-immunoprecipitation experiments were performed to elucidate the underlying molecular mechanisms. RESULTS: GNB4 expression was significantly upregulated in GC and correlated with aggressive clinical characteristics and poor prognosis. Increased levels of GNB4 were associated with shorter survival times. Infection with H. pylori strains 26695 and SS1 induced GNB4 mRNA and protein expression in GC cell lines and mice. Additionally, silencing of GNB4 blocked the pro-proliferative, metastatic, and invasive ability of H. pylori in GC cells. H. pylori infection remarkably decreased the methylation level of the GNB4 promoter region, particularly at the CpG#5 site (chr3:179451746-179451745). H. pylori infection upregulated TET1 expression via activation of the NF-κB. TET binds to the GNB4 promoter region which undergoes demethylation modification. Functionally, we identified that GNB4 induced oncogenic behaviors of tumors via the Hippo-YAP1 pathway in both in vitro and in vivo models. CONCLUSIONS: Our findings demonstrate that H. pylori infection activates the NF-κB-TET1-GNB4 demethylation-YAP1 axis, which may be a potential therapeutic target for GC.
Asunto(s)
Subunidades beta de la Proteína de Unión al GTP , Helicobacter pylori , Neoplasias Gástricas , Humanos , Ratones , Animales , FN-kappa B/genética , FN-kappa B/metabolismo , Helicobacter pylori/metabolismo , Ratones Desnudos , Carcinogénesis/genética , Neoplasias Gástricas/genética , Desmetilación , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Oxigenasas de Función Mixta/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Subunidades beta de la Proteína de Unión al GTP/genética , Subunidades beta de la Proteína de Unión al GTP/metabolismoRESUMEN
Fusarium crown rot (FCR) and sharp eyespot (SE) are serious soil-borne diseases in wheat and its relatives that have been reported to cause wheat yield losses in many areas. In this study, the expression of a cell wall invertase gene, TaCWI-B1, was identified to be associated with FCR resistance through a combination of bulk segregant RNA sequencing and genome resequencing in a recombinant inbred line population. Two bi-parental populations were developed to further verify TaCWI-B1 association with FCR resistance. Overexpression lines and ethyl methanesulfonate (EMS) mutants revealed TaCWI-B1 positively regulating FCR resistance. Determination of cell wall thickness and components showed that the TaCWI-B1-overexpression lines exhibited considerably increased thickness and pectin and cellulose contents. Furthermore, we found that TaCWI-B1 directly interacted with an alpha-galactosidase (TaGAL). EMS mutants showed that TaGAL negatively modulated FCR resistance. The expression of TaGAL is negatively correlated with TaCWI-B1 levels, thus may reduce mannan degradation in the cell wall, consequently leading to thickening of the cell wall. Additionally, TaCWI-B1-overexpression lines and TaGAL mutants showed higher resistance to SE; however, TaCWI-B1 mutants were more susceptible to SE than controls. This study provides insights into a FCR and SE resistance gene to combat soil-borne diseases in common wheat.
Asunto(s)
Fusarium , Triticum , Triticum/genética , Fusarium/fisiología , beta-Fructofuranosidasa/genética , Pared Celular , Enfermedades de las Plantas/genética , Resistencia a la Enfermedad/genéticaRESUMEN
BACKGROUND AND OBJECTIVES: Methylene blue (MB) and carbon nanoparticles (CNs) can be used as a simple method for reverse lymphatic mapping. We investigated whether the two tracers had an impact on the survival of lymph nodes and the function of reconstructed lymph vessels after transplantation, as well as the changes in surrounding related factors. METHODS: The stained lymph nodes were non-vascularized transplanted into the contralateral popliteal fossa in mice. After 4 weeks, the lymphatic recanalization was detected. The samples were harvested for pathological detection and PCR. In addition, the transport ability of the recanalized lymphatics to tumor cells was also explored. RESULTS: Compared with the control group, there was no significant difference of the MB and CNs groups in the drainage function of recanalized lymphatic vessels, the survival of lymph nodes, or the transport capacity to tumor cells. TNF-α and IL-6 were significantly higher in the two tracer groups (**p < 0.01). Besides, the α-SMA was significantly increased in the CNs group (*p < 0.05). CONCLUSIONS: Two tracers have no effect on the survival of transplanted lymph nodes, nor do they affect the drainage ability or tumor cell capture ability of the reconstructed lymphatics, despite improving TNF-α and IL-6 levels and the deposition of CNs.
Asunto(s)
Vasos Linfáticos , Nanopartículas , Animales , Carbono , Fibrosis , Interleucina-6 , Ganglios Linfáticos/patología , Metástasis Linfática/patología , Vasos Linfáticos/patología , Azul de Metileno/farmacología , Ratones , Factor de Necrosis Tumoral alfaRESUMEN
Statins are associated with gastric cancer (GC) risk. The present study aimed to clarify the efficacy of statins on the overall survival (OS) benefits in patients with GC. Publications were retrieved from PubMed, Embase, and the Cochrane Library as of April 2022. Data from the eligible cohort, case-control studies, and randomized control trials (RCTs) were extracted for the meta-analysis. Hazard ratio (HR) and 95% confidence intervals (CI) were used to assess the association between statins users and OS in GC patients. Subgroup analysis was performed based on the study design (prospective vs. retrospective). A total of 6 studies encompassing 5693 GC patients were included. Statins added to the standard treatment prolonged the patient's OS outcome (HR (95% CI): 0.72 (0.53-0.97), p = 0.032; I 2 = 88.0%, p heterogeneity < 0.001). A prospective study did not find any statistically significant difference in OS between statins users vs. nonstatin users (HR (95% CI): 0.92 (0.68-1.26), p = 0.614; I 2 = 11.7%, p heterogeneity = 0.322), whereas the retrospective studies showed prolonged OS in statins users (HR (95% CI): 0.63 (0.42-0.961), p = 0.032; I 2 = 94.6%, p heterogeneity < 0.001). Statin users had significantly improved OS compared to nonstatin users in GC treatment. This long-term survival benefit was only observed in the pooled analysis of retrospective studies but not in prospective studies.
Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas , Neoplasias Gástricas , Estudios de Casos y Controles , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Neoplasias Gástricas/tratamiento farmacológicoRESUMEN
Cold-inducible RNA-binding protein (CIRP) was previously identified as an intracellular stress-response protein, which can respond to a variety of stress conditions by changing its expression and regulating mRNA stability through its binding site on the 3'-UTR of its targeted mRNAs. Recently, extracellular CIRP (eCIRP) was discovered to be present in various inflammatory conditions and could act as a pro-inflammatory factor. Genetic studies have demonstrated a key role for eCIRP in inflammatory conditions that led to the importance of targeting eCIRP in these diseases. Currently, the underlying mechanism of eCIRP-induced inflammation is under intensive investigation and several signalling pathways are being explored. Here, we epitomized various signalling pathways that mediate the pro-inflammatory effects of CIRP and also recapitulated all the CIRP-derived peptides that can block the interaction between CIRP and its receptors in inflammatory setting.
Asunto(s)
Susceptibilidad a Enfermedades , Inflamación/etiología , Inflamación/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Transducción de Señal , Animales , Biomarcadores , Humanos , Inflamación/tratamiento farmacológico , Inflamación/patología , Antígeno 96 de los Linfocitos/metabolismo , Terapia Molecular Dirigida , Complejos Multiproteicos/metabolismo , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/farmacología , Unión Proteica , Proteínas de Unión al ARN/química , Receptores de Interleucina-6/metabolismo , Receptor Toll-Like 2/metabolismo , Receptor Activador Expresado en Células Mieloides 1/metabolismoRESUMEN
BACKGROUND: Gastric cancer (GC) remains an important cancer worldwide. Further understanding of the molecular mechanisms of gastric carcinogenesis will enhance the diagnosis and treatment of GC. METHODS: The expression of DLEU2 and ETS2 was analyzed in several GC cell lines using GEPIA online analyze, qRT-PCR and immunohistochemistry. The biological behavior of GC cells was detected by CCK8, clone formation, transwell, wound healing, western blot, and flow cytometry assay. More in-depth mechanisms were studied. RESULTS: DLEU2 was significantly up-regulated in GC tissues and cell lines. The expression of DLEU2 was significantly associated with pathological grading and TNM stage of GC patients. Furthermore, knockdown of DLEU2 inhibited the proliferation, migration, and invasion of AGS and MKN-45 cells, while overexpression of DLEU2 promoted the proliferation, migration, and invasion of HGC-27 cells. MiR-30a-5p could directly bind to the 3' UTR region of ETS2. Moreover, DLEU2 bound to miR-30a-5p through the same binding site, which facilitated the expression of ETS2. Knockdown of DLEU2 reduced the protein level of intracellular ETS2 and inhibited AKT phosphorylation, while overexpression of DLEU2 induced the expression of ETS2 and the phosphorylation of AKT. ETS2 was highly expressed in GC tissues. The expression of ETS2 was significantly associated with age, pathological grading, and TNM stage. ETS2 overexpression promoted cell proliferation and migration of AGS and MKN-45 cells. Furthermore, ETS2 overexpression rescued cell proliferation and migration inhibition induced by DLEU2 down-regulation and miR-30a-5p up-regulation in AGS and MKN-45 cells. CONCLUSIONS: DLEU2 is a potential molecular target for GC treatment.
RESUMEN
Emodin (1,3,8-trihydroxy-6-methylanthraquinone), as an active ingredient in rhubarb roots and rhizomes, has been reported to possess various pharmacological properties including anti-tumor effects. Recent studies have confirmed that emodin inhibited cell proliferation and induced apoptosis of cancer cells. However, the inhibitory effect of emodin on the migration and invasion of melanoma cells and its underlying mechanism are still unclear. In the study, we observed the impercipient effects of emodin in B16F10 and A375 melanoma cells with strong metastatic abilities, focusing on the functions and mechanisms of migration and invasion of B16F10 and A375 melanoma cells. Cell counting kit-8 (CCK-8), colony formation test and Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining tests confirmed that emodin possessed anti-proliferative and pro-apoptotic activities in B16F10 and A375 cells. The inhibitory effects on the migration and invasion of B16F10 and A375 cells were proved by wound healing assay and Transwell methods. Moreover, immunofluorescence assay approved the decrease in protein expression of matrix metalloproteinas (MMP)-2/-9 by emodin, and Western blot analyses revealed that emodin could increase the Bax/Bcl-2 ratio and inhibit the MMP-2/-9 protein expression and Wnt/ß-catenin pathway in a dose-depended manner. BML-284, as an agonist of Wnt/ß-catenin signaling pathway, reversed the effects of emodin on cell growth, migration and invasion in B16F10 cells. These findings may suggest that emodin treatment can be a promising therapeutic strategy for melanoma with highly metastatic abilities.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Emodina/farmacología , Melanoma/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Rheum/química , Vía de Señalización Wnt , beta Catenina/metabolismo , Antineoplásicos Fitogénicos/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Emodina/uso terapéutico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genes myc , Humanos , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Melanoma/tratamiento farmacológico , Invasividad Neoplásica , Fitoterapia , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Factores de Transcripción TCF/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
The interleukin-21 receptor (IL-21R) can be upregulated in endothelial cells (EC) from ischemic muscles in mice following hind-limb ischemia (HLI), an experimental peripheral arterial disease (PAD) model, blocking this ligand-receptor pathway-impaired STAT3 activation, angiogenesis, and perfusion recovery. We sought to identify mRNA and microRNA transcripts that were differentially regulated following HLI, based on the ischemic muscle having intact, or reduced, IL-21/IL21R signaling. In this comparison, 200 mRNAs were differentially expressed but only six microRNA (miR)/miR clusters (and among these only miR-30b) were upregulated in EC isolated from ischemic muscle. Next, myoglobin-overexpressing transgenic (MgTG) C57BL/6 mice examined following HLI and IL-21 overexpression displayed greater angiogenesis, better perfusion recovery, and less tissue necrosis, with increased miR-30b expression. In EC cultured under hypoxia serum starvation, knock-down of miR-30b reduced, while overexpression of miR-30b increased IL-21-mediated EC survival and angiogenesis. In Il21r-/- mice following HLI, miR-30b overexpression vs. control improved perfusion recovery, with a reduction of suppressor of cytokine signaling 3, a miR-30b target and negative regulator of STAT3. Together, miR-30b appears both necessary and sufficient for IL21/IL-21R-mediated angiogenesis and may present a new therapeutic option to treat PAD if the IL21R is not available for activation.
Asunto(s)
MicroARNs/metabolismo , Neovascularización Fisiológica/genética , Enfermedad Arterial Periférica/genética , Receptores de Interleucina-21/metabolismo , Animales , Supervivencia Celular/genética , Miembro Posterior/patología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Isquemia/genética , Isquemia/patología , Ratones Transgénicos , MicroARNs/genética , Modelos Biológicos , Familia de Multigenes , Mioglobina/metabolismo , Perfusión , Enfermedad Arterial Periférica/patología , Fosforilación , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factor de Transcripción STAT3/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Regulación hacia Arriba/genéticaRESUMEN
BACKGROUND: The circulating level of trimethylamine N-oxide (TMAO) has been reported to be associated with the prognosis of of peripheral arterial disease (PAD) patients. However, the effects of TMAO on neovascularization and perfusion recovery after PAD are not known. METHODS: Unilateral hindlimb ischemia was generated in mice as experimental PAD model, TMAO or 3,3-dimethyl-1-butanol (DMB) were added to the drinking water for these mice. In cultured endothelial cells, TMAO was added to culture medium to assess the effects on cell viability and tube formation under simulated ischemic conditions. RESULTS: In experimental PAD, TMAO treatment increased malondialdehyde (MDA), interleukin (IL)-1ß and IL-6 in the ischemic muscle, impaired perfusion recovery, and decreased capillary density. On the other hand, mice fed with DMB drinking water showed lower TMAO level, interleukin (IL)-1ß and IL-6, and higher vascular endothelial growth factor in the ischemic muscle, and better perfusion recovery after experimental PAD. In cultured endothelial cell, TMAO decreased intracellular nitric oxide, cell viability and tube formation, and increased intracellular reactive oxygen species levels. CONCLUSIONS: TMAO increases oxidative stress and inflammation, and impairs perfusion recovery and angiogenesis in experimental PAD.
Asunto(s)
Miembro Posterior/irrigación sanguínea , Isquemia/sangre , Metilaminas/sangre , Enfermedad Arterial Periférica/sangre , Animales , Circulación Sanguínea , Modelos Animales de Enfermedad , Miembro Posterior/metabolismo , Miembro Posterior/fisiopatología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Isquemia/diagnóstico , Isquemia/metabolismo , Isquemia/fisiopatología , Masculino , Metilaminas/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Neovascularización Fisiológica , Estrés Oxidativo , Enfermedad Arterial Periférica/diagnóstico , Enfermedad Arterial Periférica/metabolismo , Enfermedad Arterial Periférica/fisiopatología , PronósticoRESUMEN
BACKGROUND: Diabetes is a strong risk factor of peripheral arterial disease (PAD), and also leads to impaired perfusion recovery in the ischemic limb, which eventually results in poor outcomes in PAD patients. Sodium Tanshinone IIA Sulfonate (STS), a monomer from herbs, has been shown to improve the outcomes in a variety of ischemic disease including myocardial infarction. However, the effects of STS treatment in PAD is not known. METHODS AND RESULTS: Unilateral femoral artery was ligated in mice as experimental PAD models, STS treatment improved perfusion recovery, increased capillary densities, decreased reactive oxygen species (ROS) level and microRNA-133a (miR-133a) expression in the ischemic hindlimb in diabetic mice; however, STS did not change perfusion recovery in non-diabetic C57BL/6 mice. Ischemic muscle tissue from diabetic mice was harvested 7 days after femoral ligation for biochemical test, STS resulted in reduced malondialdehyde (MDA), and increased GTP cyclohydrolase 1 (GCH1) and cyclic guanine monophosphate (cGMP) levels. In addition, STS treatment increased miR-133a expression in endothelial cells isolated from ischemic muscle tissue of diabetic mice. In endothelial cells cultured in high glucose medium, STS increased tube formation and nitric oxide (NO) production, and reduced cellular ROS level and miR-133a expression under simulated ischemic condition. In addition, GCH1 inhibitor or miR-133a overexpression using exogenous microRNA mimic blunted STS-induced angiogenic effects and ROS neutralization in cultured endothelial cells under hyperglycemic and hypoxic conditions. CONCLUSION: These findings demonstrate STS improves angiogenesis via inhibiting miR-133a expression and increasing GCH-1 protein levels in experimental PAD with diabetes.
Asunto(s)
Hiperglucemia/complicaciones , Isquemia/tratamiento farmacológico , Neovascularización Fisiológica/efectos de los fármacos , Fenantrenos/uso terapéutico , Animales , Diabetes Mellitus Experimental/complicaciones , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/uso terapéutico , Miembro Posterior/irrigación sanguínea , Células Endoteliales de la Vena Umbilical Humana , Humanos , Isquemia/etiología , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/genética , MicroARNs/metabolismo , Enfermedad Arterial Periférica/tratamiento farmacológico , Enfermedad Arterial Periférica/etiología , Fitoterapia , Especies Reactivas de Oxígeno/metabolismo , Salvia miltiorrhizaRESUMEN
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. It contains LM images in figure 2E, which were originally published in Nat. Comm. 6/2015, p. 1-14 (http://doi:10.1038/ncomms8388). Permission to reproduce this figure was not requested nor granted by the authors of the original article for its re-use. The authors of this article would like to apologize to all affected parties.
RESUMEN
The mechanisms of cardiac repair after myocardial infarction (MI) are complicated and not well-understood currently. It is known that exosomes are released from most cells, recognized as new candidates with important roles in intercellular and tissue-level communication. Cells can package proteins and RNA messages into exosome and secret to recipient cells, which regulate gene expression in recipient cells. The research on exosomes in cardiovascular disease is just emerging. It is well-known that exosomes from cardiomyocyte can transfect endothelial cells, stem cells, fibroblasts and smooth muscle cells to induce cellular changes. After myocardial infarction (MI), the exosomes play important roles in local and distant microcommunication. Nowadays, exosomal microRNAs transportation has been found to deliver signals to mediate cardiac repair after MI. However, the exosomes quality and quantities are variable under different pathological conditions. Therefore, we speculate that the monitoring of the quality and quantity of exosomes may serve as diagnosis and prognosis biomarkers of MI, and the study of exosomes will provide insights for the new therapeutics to cardiac remodeling after MI.
Asunto(s)
Exosomas/patología , Infarto del Miocardio/patología , Comunicación Celular/fisiología , Exosomas/metabolismo , Humanos , MicroARNs/metabolismo , Infarto del Miocardio/genética , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patologíaRESUMEN
N6-methyladenosine (m6A) modification is involved in many aspects of gastric cancer (GC). Moreover, m6A and glycolysis-related genes (GRGs) play important roles in immunotherapeutic and prognostic implication of GC. However, GRGs involved in m6A regulation have never been analyzed comprehensively in GC. Herein, the study aims to identify and validate a novel signature based on m6A-related GRGs in GC patients. Therefore, a m6A-related GRGs signature is established, which can predict the survival of patients with GC and remain an independent prognostic factor in multivariate analyses. Clinical significance of the model is well validated in internal cohort and independent validation cohort. In addition, the expression levels of risk model-related GRGs in clinical samples are validated. Consistent with the database results, all model genes are up-regulated in expression except DCN. After regrouping the patients based on this risk model, the study can effectively distinguish between them in respect to immune-cell infiltration microenvironment and immunotherapeutic response. Additionally, candidate drugs targeting risk model-related GRGs are confirmed. Finally, a nomogram combining risk scores and clinical parameters is created, and calibration plots show that the nomogram can accurately predict survival. This risk model can serve as a reliable assessment tool for predicting prognosis and immunotherapeutic responses in GC patients.
Asunto(s)
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Pronóstico , Genes Reguladores , Nomogramas , Inmunoterapia , Microambiente Tumoral/genéticaRESUMEN
Myocardial infarction (MI) leads to progressive left ventricular (LV) dilatation and is associated with interstitial fibrosis in the non-infarcted myocardium. The NF-κB signaling pathway plays an important role in ventricular remodeling after MI. Recent studies have indicated that the anti-malarial agent artemisinin can inhibit NF-κB activation, which may attenuate post-infarct myocardial remodeling. In this study, we investigated the effect of artemisinin on post-infarct myocardial remodeling using a rat model of MI. Adult male Sprague Dawley rats were divided into a sham group (n = 10) and MI groups that were treated either with oral gavage of artemisinin (75 mg/kg/day, n = 20) or vehicle (0.5% carboxymethyl cellulose, n = 20) three times a day for 4 weeks. Each treatment was started at 24 hours after ligation of the left anterior descending coronary artery. Four weeks after MI, the artemisinin-treated group showed a significantly improved survival rate compared with that of the vehicle-treated group (65% vs. 40%, P < 0.05). Although infarct size was similar in both groups, echocardiography showed significant improvements in cardiac function and left ventricular dimensions in the artemisinin-treated group. Moreover, the degree of myocardial fibrosis and elevated levels of fibrosis-related factors [transforming growth factor-ß1, collagen type I, matrix metalloproteinase (MMP)-2 and MMP-9] in the non-infarcted myocardium were remarkably ameliorated by artemisinin (all P < 0.05). Importantly, artemisinin inhibited the NF-κB pathway by blocking IKBα phosphorylation. In conclusion, artemisinin may attenuate post-infarct myocardial remodeling by down-regulating the NF-κB pathway.
Asunto(s)
Artemisininas/uso terapéutico , Regulación hacia Abajo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/fisiopatología , FN-kappa B/metabolismo , Transducción de Señal , Remodelación Ventricular , Animales , Artemisininas/química , Artemisininas/farmacología , Western Blotting , Cardiomegalia/complicaciones , Cardiomegalia/diagnóstico por imagen , Cardiomegalia/patología , Cardiomegalia/fisiopatología , Colágeno Tipo I/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Fibrosis , Hemodinámica/efectos de los fármacos , Proteínas I-kappa B/metabolismo , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/metabolismo , Miocardio/metabolismo , Miocardio/patología , Inhibidor NF-kappaB alfa , Fosforilación/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Análisis de Supervivencia , Factor de Crecimiento Transformador beta1/metabolismo , Ultrasonografía , Remodelación Ventricular/efectos de los fármacosRESUMEN
Background: Platelets (PLT) have a significant effect in promoting cancer progression and hematogenous metastasis. However, the effect of platelet activation-related lncRNAs (PLT-related lncRNAs) in gastric cancer (GC) is still poorly understood. In this study, we screened and validated PLT-related lncRNAs as potential biomarkers for prognosis and immunotherapy in GC patients. Methods: We obtained relevant datasets from the Cancer Genome Atlas (TCGA) and Gene Ontology (GO) Resource Database. Pearson correlation analysis was used to identify PLT-related lncRNAs. By using the univariate, least absolute shrinkage and selection operator (LASSO) Cox regression analyses, we constructed the PLT-related lncRNAs model. Kaplan-Meier survival analysis, univariate, multivariate Cox regression analysis, and nomogram were used to verify the model. The Gene Set Enrichment Analysis (GSEA), drug screening, tumor immune microenvironment analysis, epithelial-mesenchymal transition (EMT), and DNA methylation regulators correlation analysis were performed in the high- and low-risk groups. Patients were regrouped based on the risk model, and candidate compounds and immunotherapeutic responses aimed at GC subgroups were also identified. The expression of seven PLT-related lncRNAs was validated in clinical medical samples using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Results: In this study, a risk prediction model was established using seven PLT-related lncRNAs -(AL355574.1, LINC01697, AC002401.4, AC129507.1, AL513123.1, LINC01094, and AL356417.2), whose expression were validated in GC patients. Kaplan-Meier survival analysis, the receiver operating characteristic (ROC) curve analysis, univariate, multivariate Cox regression analysis verified the accuracy of the model. We screened multiple targeted drugs for the high-risk patients. Patients in the high-risk group had a poorer prognosis since low infiltration of immune killer cells, activation of immunosuppressive pathways, and poor response to immunotherapy. In addition, we revealed a close relationship between risk scores and EMT and DNA methylation regulators. The nomogram based on risk score suggested a good ability to predict prognosis and high clinical benefits. Conclusion: Our findings provide new insights into how PLT-related lncRNAs biomarkers affect prognosis and immunotherapy. Also, these lncRNAs may become potential biomarkers and therapeutic targets for GC patients.
RESUMEN
Water pollution due to heavy metals has become a universal environmental problem. Ni(II) is a common heavy metal ion in polluted wastewater, which has high toxicity and carcinogenicity. In this study, the structure of a calcium-iron layered double hydroxide (Ca-Fe-LDHs) was synthesized and characterized by FTIR, XRD, SEM and XPS. Then, Ni(II) ion was effectively removed by Ca-Fe-LDHs and its mechanism for this materials was described. The maximum adsorption capacity of Ni(II) for Ca-Fe-LDHs was 418.9 mgâ§g-1 when the initial concentration of Ni(II) was 1 g/L. The adsorption and removal of Ni(II) by Ca-Fe-LDHs was attributed to the action of hydroxyl groups on the hydrotalcite, generating surface capture. Ni(OH)2)0.75(H2O)0.16(NiCO3)0.09, Ni(OH)2, NiO, NiSO4 and other precipitates were generated on its surface. And a small amount of Ni-Fe-LDHs was generated through isomorphic transition before hydrolysis. Therefore, surface capture and isomorphic transition enhanced the removal efficiency of Ni(II) with Ca-Fe-LDHs, making Ca-Fe-LDHs as a potential material for effective removal of Ni(II).
RESUMEN
BACKGROUND: Lymph node transfer has been known as a physiologic approach for "curing" lymphedema. The transplantation of methylene blue and carbon nanoparticles stained lymph nodes aims to investigate their impact on the survival of transplanted lymph nodes. METHODS: Four weeks after transplantation, the survival condition of transplanted lymph nodes was detected by the reconnection with lymphatics, reconnected lymphatic function, HE staining, and distribution of B-cells and T-cells. Also, the number of lymphatics (LYVE-1) and blood vessels (CD31) of transplanted lymph nodes was investigated. RESULTS: Reconnected lymphatic function, the number of transplanted lymph nodes of achieving lymphatic reconstruction, and the surviving and potentially surviving ones were close. Besides, the control group (n = 11, CD31: mean = 9.527 ± 1.017, LYVE-1: mean = 21.45 ± 1.780), the methylene blue group (n = 12, CD31: mean = 9.73 ± 0.8998, LYVE-1: mean = 20.67 ± 1.601) and the carbon nanoparticles group (n = 11, CD31:mean = 8.709 ± 1.435, LYVE-1: mean = 19.60 ± 2.268). After calculation, both CD31 and LYVE-1 showed no significant difference statistically among the three groups. CONCLUSIONS: Our findings justify the use of methylene blue and carbon nanoparticles in reverse lymphatic mapping, as they can increase the efficiency of collecting "target lymph nodes" and minimize the iatrogenic injury in the donor area while having no significant adverse effects on the survival condition of transplanted lymph nodes. And this approach is easy to operate and worthy of clinical application and popularization.
Asunto(s)
Azul de Metileno , Nanopartículas , Animales , Carbono/uso terapéutico , Modelos Animales de Enfermedad , Enfermedad Iatrogénica , Ganglios Linfáticos/patología , Ganglios Linfáticos/fisiología , Ganglios Linfáticos/trasplante , Azul de Metileno/uso terapéutico , Ratones , Nanopartículas/uso terapéuticoRESUMEN
Objective: Gastroesophageal adenocarcinoma (GEA) is a high deadly and heterogeneous cancer. RNA N6-methyladenosine (m6A) modification plays a non-negligible role in shaping individual tumour microenvironment (TME) characterizations. However, the landscape and relationship of m6A modification patterns and TME cell infiltration features remain unknown in GEA. Methods: In this study, we examined the TME of GEA using assessments of the RNA-sequencing data focusing on the distinct m6A modification patterns from the public databases. Intrinsic patterns of m6A modification were evaluated for associations with clinicopathological characteristics, underlying biological pathways, tumour immune cell infiltration, oncological outcomes, and treatment responses. The expression of key m6A regulators and module genes was validated by qRT-PCR analysis. Results: We identified two distinct m6A modification patterns of GEA (cluster 1/2 subgroup), and correlated two subgroups with TME cell-infiltrating characteristics. Cluster 2 subgroup correlates with a poorer prognosis, downregulated PD-1 expression, higher risk scores, and distinct immune cell infiltration. In addition, PPI and WGCNA network analysis were integrated to identify key module genes closely related to immune infiltration of GEA to find immunotherapy markers. COL4A1 and COL5A2 in the brown module were significantly correlated to the prognosis, PD-1/L1 and CTLA-4 expression of GEA patients. Finally, a prognostic risk score was constructed using m6A regulator-associated signatures that represented an independent prognosis factor for GEA. Interestingly, COL5A2 expression was linked to the response to anti-PD-1 immunotherapy, m6A regulator expression, and risk score. Conclusion: Our work identified m6A RNA methylation regulators as an important class of players in the malignant progression of GEA and were associated with the complexity of the TME. COL5A2 may be the potential biomarker which contributes to predicting the response to anti-PD-1 immunotherapy and patients' prognosis.
Asunto(s)
Adenocarcinoma , Microambiente Tumoral , Humanos , Metilación , Inmunoterapia , Pronóstico , Factores Inmunológicos , Adenocarcinoma/genética , Adenocarcinoma/terapia , ARN/genéticaRESUMEN
Ghrelin, a 28-aminoacid peptide, was isolated from the human and rat stomach and identified in 1999 as an endogenous ligand for the growth hormone secretagogue-receptor (GHS-R). In addition to stimulating appetite and regulating energy balance, ghrelin and its receptor GHS-R1a have a direct effect on the cardiovascular system. In recent years, it has been shown that ghrelin exerts cardioprotective effects, including the modulation of sympathetic activity and hypertension, enhancement of the vascular activity and angiogenesis, inhibition of arrhythmias, reduction in heart failure and inhibition of cardiac remodeling after myocardial infarction (MI). The cardiovascular protective effect of ghrelin may be associated with anti-inflammation, anti-apoptosis, inhibited sympathetic nerve activation, regulated autophagy, and endothelial dysfunction. However, the molecular mechanisms underlying the effects of ghrelin on the cardiovascular system have not been fully elucidated, and no specific therapeutic agent has been established. It is important to further explore the pharmacological potential of ghrelin pathway modulation for the treatment of cardiovascular diseases.
Asunto(s)
Enfermedades Cardiovasculares/fisiopatología , Ghrelina/fisiología , Arritmias Cardíacas/fisiopatología , Vasos Sanguíneos/fisiología , Ghrelina/metabolismo , Humanos , Miocardio/metabolismo , Neovascularización Fisiológica/fisiologíaRESUMEN
BACKGROUNDS: Experimental and clinical studies have suggested that cell implantation could improve cardiac function after myocardial infarction (MI). However, this technique was limited by decreased engraftment and survival of transplanted cells within the ischemic tissue. The present study was performed to investigate whether implantation of bone marrow-derived mononuclear cells (BMMNCs) encapsulated in hydrogel could increase cell engraftment and help to restore cardiac function of MI rabbits. METHODS: MI was induced in rabbits by coronary artery ligation. One week later, cell culture medium, Dex-PCL-HEMA/PNIPAAm hydrogel, BMMNCs in medium or BMMNCs in hydrogel were injected into the infarcted area of the left ventricle (LV). RESULTS: Increased cell engraftment was observed 48 h after injection when cells were encapsulated in hydrogel; 30 days after treatment, echocardiographic studies showed that injection of BMMNCs in hydrogel preserved LV ejection fraction and attenuated LV dilatation compared with other groups. Histological analysis indicated that injection of BMMNCs in hydrogel enhanced neovascular formation and prevented scar expansion compared with the other groups. CONCLUSION: Injection of hydrogel-encapsulated BMMNCs increased cell engraftment and improved LV function; this technique may serve as an effective approach to restore infarcted myocardium.