RESUMEN
Activating mutations in NRAS account for 20%-30% of melanoma, but despite decades of research and in contrast to BRAF, no effective anti-NRAS therapies have been forthcoming. Here, we identify a previously uncharacterized serine/threonine kinase STK19 as a novel NRAS activator. STK19 phosphorylates NRAS to enhance its binding to its downstream effectors and promotes oncogenic NRAS-mediated melanocyte malignant transformation. A recurrent D89N substitution in STK19 whose alterations were identified in 25% of human melanomas represents a gain-of-function mutation that interacts better with NRAS to enhance melanocyte transformation. STK19D89N knockin leads to skin hyperpigmentation and promotes NRASQ61R-driven melanomagenesis in vivo. Finally, we developed ZT-12-037-01 (1a) as a specific STK19-targeted inhibitor and showed that it effectively blocks oncogenic NRAS-driven melanocyte malignant transformation and melanoma growth in vitro and in vivo. Together, our findings provide a new and viable therapeutic strategy for melanomas harboring NRAS mutations.
Asunto(s)
GTP Fosfohidrolasas/metabolismo , Melanoma/genética , Proteínas de la Membrana/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Línea Celular Tumoral , Transformación Celular Neoplásica , Femenino , Células HEK293 , Humanos , Melanocitos/metabolismo , Melanoma/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Mutación , Fosforilación , Proteínas Proto-Oncogénicas B-raf/metabolismo , Transducción de Señal , Neoplasias Cutáneas/genéticaRESUMEN
Background: Coronary artery calcification (CAC) is a crucial marker for coronary atherosclerosis, and the extent of CAC is closely linked to the incidence and progression of cardiovascular diseases. The interleukin-2 (IL-2) receptor (IL-2R), which plays a critical role in mediating the proliferation and differentiation of immune cells, may also be involved in the development of CAC. The study aimed to investigate the relationship between IL-2R and CAC, with the goal of providing new insights into cardiovascular diseases. Methods: In this study, we enrolled 606 patients diagnosed with coronary artery disease to assess CAC. Based on coronary artery calcification score (CACS), patients were divided into two groups: the non-severe CAC group (CACS ≤ 400 Agatston units, AU) and the severe CAC group (CACS > 400 AU). Results: The results showed that IL-2R levels were significantly higher in patients with severe CAC compared to those with non-severe CAC (383 vs. 352 pg/mL, p = 0.002). Moreover, the level of IL-2R was positively correlated with the severity of CAC, independent of other clinical risk factors. According to Receiver Operating Characteristic (ROC) curve, the IL-2R prediction model demonstrated a good capability in distinguishing severe CAC with the Area Under the Curve (AUC) value of 0.726. Conclusions: Our study suggests that IL-2R is independently associated with the occurrence of severe CAC in coronary artery disease (CAD) patients. Additionally, IL-2R may play a crucial role in the development of advanced atherosclerosis. Consequently, therapeutic strategies targeting the IL-2/IL-2R pathway may be effective in preventing or treating CAD.
RESUMEN
Psoriasis is a chronic inflammatory skin disease mediated by immune and complex genetic factors. The wingless-related integration site (Wnt) signaling pathway plays a critical role in psoriasis, but how the Wnt pathway is regulated in psoriatic skin and whether it can be exploited for therapeutic benefits is unclear. By comparing biopsies from healthy and psoriatic skin, we found that Wnt inhibitory factor 1 (WIF1), an inhibitor of Wnt signaling, showed reduced expression at both mRNA and protein levels in psoriatic skin. We then quantified methylation of the WIF1 gene promoter by DNA methylation sequencing and found that the WIF1 promoter region was hypermethylated. We further showed that recombinant WIF1 injection ameliorates the imiquimod (IMQ) mouse model of psoriasis. We also revealed that treatment with the DNA methylation inhibitor, decitabine, inhibited proliferation of immortalized human keratinocytes (HaCaT) in a psoriasis-like inflammatory environment. Finally, we applied decitabine to the IMQ mouse model and demonstrated that treatment of mice with decitabine ameliorates the disease. Therefore, our study reveals that methylation of the WIF1 gene is associated with the pathogenesis of psoriasis, and suggests that pharmacological targeting of DNA methylation is a potential treatment strategy for psoriasis.
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Psoriasis , Humanos , Animales , Ratones , Decitabina/farmacología , Decitabina/uso terapéutico , Decitabina/metabolismo , Psoriasis/tratamiento farmacológico , Psoriasis/genética , Psoriasis/patología , Piel/patología , Queratinocitos , Metilación de ADN , Imiquimod/uso terapéutico , Regiones Promotoras Genéticas/genética , Ratones Endogámicos BALB C , Modelos Animales de EnfermedadRESUMEN
It was to explore the application value of individualized nursing oriented by solution-focused nursing mode in postoperative nursing of patients with pelvic fractures. 90 patients with ST-segment elevation myocardial infarction (STEMI) undergoing emergency percutaneous coronary intervention (PCI) were enrolled. They were randomly grouped into a control group and an experimental group, with 45 cases in each group. Patients in the general group were treated with conventional treatment, and patients in the enhancement group were treated with high-dose rosuvastatin based on conventional treatment. The experimental group was compared for indicators such as serum inflammatory factors, cardiac function, overall efficacy, and follow-up prognosis before and after the operation. After treatment, the total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in the enhancement group were better as against the control group (P<0.05). Through treatment, the concentration of high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in the enhancement group was lower compared to the general group. The total effective rate of the enhancement group (95.56%) was higher relative to the general group (86.67%) (P<0.05). In patients with STEMI, preoperative intensive statin therapy can improve the efficacy of PCI, and reduce the inflammatory response and the incidence of cardiovascular events.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas , Infarto del Miocardio , Intervención Coronaria Percutánea , Infarto del Miocardio con Elevación del ST , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio con Elevación del ST/tratamiento farmacológico , Infarto del Miocardio con Elevación del ST/cirugía , Proteína C-Reactiva/metabolismo , LDL-Colesterol , Arritmias Cardíacas , Resultado del TratamientoRESUMEN
The melanocortin-1 receptor (MC1R), a G-protein-coupled receptor, has a crucial role in human and mouse pigmentation. Activation of MC1R in melanocytes by α-melanocyte-stimulating hormone (α-MSH) stimulates cAMP signalling and melanin production and enhances DNA repair after ultraviolet irradiation. Individuals carrying MC1R variants, especially those associated with red hair colour, fair skin and poor tanning ability (denoted as RHC variants), are associated with higher risk of melanoma. However, how MC1R activity is modulated by ultraviolet irradiation, why individuals with red hair are more prone to developing melanoma, and whether the activity of RHC variants might be restored for therapeutic benefit are unknown. Here we demonstrate a potential MC1R-targeted intervention strategy in mice to rescue loss-of-function MC1R in MC1R RHC variants for therapeutic benefit by activating MC1R protein palmitoylation. MC1R palmitoylation, primarily mediated by the protein-acyl transferase ZDHHC13, is essential for activating MC1R signalling, which triggers increased pigmentation, ultraviolet-B-induced G1-like cell cycle arrest and control of senescence and melanomagenesis in vitro and in vivo. Using C57BL/6J-Mc1re/eJ mice, in which endogenous MC1R is prematurely terminated, expressing Mc1r RHC variants, we show that pharmacological activation of palmitoylation rescues the defects of Mc1r RHC variants and prevents melanomagenesis. The results highlight a central role for MC1R palmitoylation in pigmentation and protection against melanoma.
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Transformación Celular Neoplásica/metabolismo , Lipoilación , Melanoma/metabolismo , Melanoma/prevención & control , Pigmentación , Receptor de Melanocortina Tipo 1/química , Receptor de Melanocortina Tipo 1/metabolismo , Aciltransferasas/metabolismo , Animales , Femenino , Humanos , Masculino , Melanocitos/metabolismo , Melanoma/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación , Pigmentación/genética , Receptor de Melanocortina Tipo 1/genéticaRESUMEN
The study aimed to explore the correlations of the results of the high-frequency ultrasound evaluation of the brachial artery endothelial dilatation and carotid atherosclerosis with glucose and lipid metabolism, inflammatory cytokines, the severity of coronary artery disease (CAD) and vascular endothelial function in elderly patients. 78 elderly patients with CAD in Beijing Anzhen Hospital were selected. The high-frequency ultrasonography was carried out to observe the flow-mediated dilatation (FMD) and intima-media thickness (IMT) and to analyze their correlations with inflammatory cytokines [C-reactive protein (CRP) and plasminogen activator inhibitor (PAI-1)], endothelial function [nitric oxide (NO) and endothelin-1 (ET-1)], glycolipid metabolism [high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), triglyceride (TG) and fasting blood glucose (FBG)] and the severity of CAD. FMD, NO and HDL-C: patients with single-vesselCAD> those with double-vessel CAD>those with multi-vessel CAD. IMT, CRP, PAI-1, FBG, ET-1, TC and TG: patients with single-vesselCAD< those with double-vessel CAD Asunto(s)
Enfermedades de las Arterias Carótidas
, Enfermedad de la Arteria Coronaria
, Anciano
, Arteria Braquial
, Proteína C-Reactiva
, Arterias Carótidas
, Grosor Intima-Media Carotídeo
, Colesterol
, Citocinas
, Dilatación
, Endotelio Vascular
, Glucosa
, Humanos
, Metabolismo de los Lípidos
, Inhibidor 1 de Activador Plasminogénico
, Triglicéridos
, Ultrasonografía
RESUMEN
Acute statin treatment has been reported to be critical in protecting the cardiac cells against ischemia/reperfusion injury by activating PI3K/Akt signal pathway. In vitro rat myocardial ischemia/reperfusion model, chronic statin treatment led to upregulation of phosphatase and tensin homolog (PTEN). This has been potentially indicated the correlation in PTEN and protective effect of statin on myocardium. In this current study, we evaluated the role of sodium orthovanadate a nonspecific inhibitor to PTEN and its correlation with atorvastatin on protecting myocardium against ischemia/reperfusion injury. We found a long-term statin treatment could increase the PTEN level, and this process was counteracted in the presence of sodium orthovanadate. However, the phosphotyrosine level was not affected by this statin. Besides, this process was mediated by Akt signaling since phosphorylated Akt level was altered by statin and sodium orthovanadate treatment. In a conclusion, this study showed a potential mechanism underlying PTEN-induced attenuation in long-term statin's therapeutic effect, which provided the new insight into the synergic role of PTEN and atorvastatin in protecting cardiac cells against ischemia/reperfusion injury.
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Atorvastatina/efectos adversos , Regulación hacia Abajo/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Daño por Reperfusión Miocárdica/patología , Miocardio/enzimología , Fosfohidrolasa PTEN/biosíntesis , Vanadatos/farmacología , Animales , Atorvastatina/farmacología , Masculino , Daño por Reperfusión Miocárdica/inducido químicamente , Daño por Reperfusión Miocárdica/enzimología , Miocardio/patología , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Programmed cell death protein-1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have remarkable clinical efficacy in the treatment of non-small cell lung cancer (NSCLC); however, the breakdown of immune escape causes a variety of immune-related adverse events (irAEs). With the increasing use of PD-1/PD-L1 inhibitors alone or in combination with other therapies, awareness and management of irAEs have become more important. We aimed to assess the incidence and nature of irAEs associated with PD-1 and PD-L1 inhibitors for NSCLC. METHODS: Articles from the MEDLINE, EMBASE, and Cochrane databases were searched through December 2017. The incidence of overall and organ-specific irAEs was investigated in all clinical trials with nivolumab, pembrolizumab, atezolimumab, durvalumab, and avelumab as single agents for treatment of NSCLC. We calculated the pooled incidence using R software with package Meta. RESULTS: Sixteen trials were included in the meta-analysis: 10 trials with PD-1 inhibitors (3734 patients) and 6 trials with PD-L1 inhibitors (2474 patients). The overall incidence of irAEs was 22% (95% confidence interval [CI], 17-28) for all grades and 4% (95% CI, 2-6) for high-grade irAEs. The frequency of irAEs varied based on drug type and organ, and patients treated with PD-1 inhibitors had an increased rate of any grade and high-grade irAEs compared with patients who received PD-L1 inhibitors. Organ-specific irAEs were most frequently observed in, in decreasing order, the endocrine system, skin, pulmonary tract, and gastrointestinal tract. The total number of patients whose death was attributed to irAEs was 14 (0.34%), and most (79%) of these patients died because of pneumonitis. The median time to the onset of irAEs after the initiation of treatment was 10 weeks (interquartile range, 6-19.5 weeks) and varied depending on the organ system involved. CONCLUSIONS: The specificity of irAEs was closely associated with the mechanism of PD-1/PD-L1 antibodies involved in restarting anticancer immune attacks. Comprehensive understanding, timely detection, and effective management could improve the compliance of patients and guide the interruption of treatment.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/terapia , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Enfermedades del Sistema Endocrino/epidemiología , Inmunoterapia/efectos adversos , Neoplasias Pulmonares/terapia , Anticuerpos Monoclonales/efectos adversos , Antineoplásicos/efectos adversos , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Ensayos Clínicos como Asunto , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/mortalidad , Enfermedades del Sistema Endocrino/etiología , Enfermedades del Sistema Endocrino/mortalidad , Humanos , Inmunidad , Incidencia , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Análisis de SupervivenciaRESUMEN
OBJECTIVES: Recent studies have suggested that the CXCL9, 10, 11/CXCR3 axis is significant in immune regulation and therapeutic efficacy in human cancers; however, its role in pancreatic ductal adenocarcinoma (PDAC) remains unknown. This study serves to evaluate the prognostic prediction value of plasma IFN-γ-inducible chemokines, CXCL9 and CXCL10, in advanced PDAC. METHODS: Two hundred patients with advanced PDAC receiving palliative chemotherapy were retrospectively recruited. The association between Plasma CXCL9/CXCL10 levels and survival time was first analyzed in a test group of 110 patients and then confirmed in a validation group of 90 patients. RESULTS: High levels of CXCL9 and CXCL10 were significantly correlated with longer overall survival (OS) in advanced PDAC patients (314 vs. 136 days for CXCL9, Pâ¯<â¯0.0001, and 374 vs. 163 days for CXCL10, Pâ¯<â¯0.0001, respectively) in the test group, which was consistent with the results derived from the validation group. In addition, high levels of CXCL9 and CXCL10 were associated with longer time to progression (TTP) in patients receiving chemotherapy (100 vs. 60 days for CXCL9, Pâ¯=â¯0.0021, and 104 vs. 67 days for CXCL10, Pâ¯=â¯0.0057, respectively). Multivariate analyses confirmed that CXCL9 and CXCL10 were independent prognostic predictors for OS (hazard ratio [HR]: 0.452, Pâ¯<â¯0.001 for CXCL9; and HR: 0.586, Pâ¯=â¯0.007 for CXCL10, respectively) and TTP (HR: 0.656, Pâ¯=â¯0.015 for CXCL9; and HR: 0.687, Pâ¯=â¯0.040 for CXCL10, respectively). CONCLUSIONS: Plasma CXCL9 and CXCL10 can be used to predict survival of advanced PDAC patients receiving chemotherapy, allowing clinicians to potentially improve treatment outcomes by identifying candidates for aggressive therapy.
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Antineoplásicos/uso terapéutico , Carcinoma Ductal Pancreático/sangre , Quimiocina CXCL10/metabolismo , Quimiocina CXCL9/metabolismo , Interferón gamma/farmacología , Quimiocina CXCL10/sangre , Quimiocina CXCL10/genética , Quimiocina CXCL9/sangre , Quimiocina CXCL9/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas , Estudios Retrospectivos , Neoplasias PancreáticasRESUMEN
BACKGROUND: The first-line agents comprising antihistamines for chronic urticaria, are not completely satisfactory. Tripterygium wilfordii Hook F (TwHF), a Chinese herb, has been developed into several Tripterygium agents and have definite effects on autoimmune and inflammatory diseases. In chronic urticaria, however, their values of practical application remain unclear. The aim of this study was to investigate the efficacy and safety of TwHF in patients with chronic urticaria. METHODS: Several databases were systematically searched including PubMed, Embase, Cochrane Central Register of Controlled Trials, China Network Knowledge Infrastructure, Chinese Scientific Journals Database, Wan Fang Database, and Chinese Biomedicine. Randomized controlled trials comparing antihistamines with TwHF or Tripterygium agents in combination with antihistamines were included. Revman5.3 was utilized to calculate risk ratios (RR) with 95% confidence intervals (CI). This study was registered with PROSPERO, number CRD42018091595. RESULTS: Twenty-one trials with 2565 participants were included in this analysis. Meta-analysis showed that, when antihistamines were combined with TwHF and Tripterygium agents, the curative effect in cases of chronic urticaria was superior to that of antihistamines alone (RR: 1.40; 95% CI: 1.33-1.46). The incidence rates of gastrointestinal disorder (RR: 2.91; 95% CI: 1.70-4.99) and menstrual disorder (RR: 6.00; 95% CI: 1.79-20.13) in drug combination groups were higher than those in controls, while other adverse events were similar between the two groups. After treatment, Dermatology Life Quality Index (RR: 1.23; 95% CI: 1.09-1.40), quality of sleep (RR: 1.50; 95% CI: 1.07-2.12), and daily activity (RR: 1.49; 95% CI: 1.25-1.78) were all improved. Furthermore, drug combination groups demonstrated less relapse (RR: 0.34; 95% CI: 0.25-0.45). CONCLUSIONS: TwHF and Tripterygium agents, in combination with antihistamines, appear to be more effective than antihistamines alone. Nevertheless, adverse events cannot be ignored. Large sample, multi-center, high-quality clinical studies are needed to verify the exact effects and safety of TwHF and Tripterygium agents in treatment of chronic urticaria.
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Antialérgicos , Extractos Vegetales , Tripterygium/química , Urticaria/tratamiento farmacológico , Antialérgicos/efectos adversos , Antialérgicos/uso terapéutico , Enfermedad Crónica , Femenino , Humanos , Masculino , Extractos Vegetales/efectos adversos , Extractos Vegetales/uso terapéuticoRESUMEN
No consensus view has been published on the relationship between the aldosterone synthase gene (CYP11B2) -344C/T polymorphism and left ventricular hypertrophy (LVH) in Chinese Han. We undertook a meta-analysis to investigate the potential association of this polymorphism and left ventricular structure-related phenotypes, including left ventricular mass (LVM), left ventricular mass index (LVMI), left ventricular end systolic diameter (LVESD), left ventricular end diastolic dimension (LVEDD), left ventricular posterior wall thickness (LVPWT), and interventricular septal wall thickness (IVS). Studies in English and Chinese were found based on a systematic search of Medline, Embase, CNKI, and Wanfang databases. The dominant model (TT vs. TC+CC) and homozygote model (TT vs. CC) were selected to examine the association between the -344C/T polymorphism and LVH. The random-effects model was used to pool data. From a total of 3104 participants, despite the investigation of six echocardiographic indicators, we found no significant association between the -344C/T variant and LVH in the whole group and the subgroup analyses by blood pressure. However, in the subgroup of northern Han Chinese, TT genotype had higher LVPWT than CC genotype and TC genotype (pheterogeneity = 0.4, pvalue = 0.04, 95% CI 0.09 (0.00, 0.18)). In addition, no evidence of publication bias was observed. In conclusion, our meta-analysis indicated that subjects with TT genotype might have higher risk of developing LVH in northern Han Chinese.
Asunto(s)
Pueblo Asiatico/genética , Citocromo P-450 CYP11B2/genética , Ventrículos Cardíacos/patología , Hipertrofia Ventricular Izquierda/genética , Presión Sanguínea/genética , Homocigoto , Humanos , Hipertrofia Ventricular Izquierda/fisiopatología , Tamaño de los Órganos/genética , Fenotipo , Polimorfismo de Nucleótido Simple , Regiones Promotoras GenéticasRESUMEN
Objective: This bibliometric analysis and review aimed to examine the current research status and trends in the combination of nutrition and exercise training for sarcopenia. Additionally, it sought to provide researchers with future research directions in this field. Methods: Relevant publications were obtained from the Web of Science Core Collection (WoSCC) database, covering the period from January 1995 to October 2023. The collected publications were analyzed using CiteSpace, VOSviewer, Bibliometrix, and Review Manager. Results: Out of the 2528 retrieved publications, the United States emerged as the leading contributor in terms of publication volume. The University of Texas System was identified as the most productive institution. Luc J C van Loon emerged as the most published author in this field. Analysis of keywords revealed recent hot topics and emerging areas of interest, such as "gut microbiota" and "mechanisms". Upon further evaluation, resistance training (RT) and protein supplementation were identified as the most commonly employed and effective methods. Conclusion: RT and protein supplementation are widely recognized as effective strategies. Future research should focus on investigating the molecular aspects of sarcopenia. Moreover, the potential therapeutic role of gut microbiota in sarcopenia requires further comprehensive investigation in human subjects to establish its correlation.
RESUMEN
Microplastics (MPs) is an emerging pollutant potentially harmful to health. Medical practices using plastic devices, such as percutaneous coronary interventions (PCI), may result in MPs entering into the blood. The purpose of this study was to quantify the effect of PCI on microplastic levels in patients' blood. Laser direct infrared (LDIR) was used to detect MPs in the blood of 23 patients before and after PCI. MPs in the water in which devices used in PCI were washed were also examined. The concentration of MPs in the blood was significantly elevated (93.57 ± 35.95 vs. 4.96 ± 3.40 particles/10 mL of blood, P < 0.001) after PCI compared to before, and the increased MPs were polyamide (PA), polyethylene (PE), polyurethane (PU), and polyethylene terephthalate (PET), which was consistent with the types of MPs detected in the device washing water. The maximum diameter of MPs in blood before PCI was 50 µm, whereas after PCI it was 213 µm, and even 336 µm in device washing water. These findings indicated that PCI will cause MPs to enter the blood, and devices used during PCI were a major source, a range of medical practices that use plastic devices may be a new route for MPs to enter the human body.
Asunto(s)
Microplásticos , Intervención Coronaria Percutánea , Humanos , Microplásticos/análisis , Intervención Coronaria Percutánea/instrumentación , Masculino , Femenino , Anciano , Persona de Mediana Edad , Poliuretanos/químicaRESUMEN
INTRODUCTION: The present study aimed to examine the correlation between serum cytokine levels and the incidence of coronary artery disease (CAD), a leading cause of mortality globally, which is known to have a strong association with inflammatory factors. The study further sought to determine the predictors of CAD to distinguish patients with coronary artery lesions from those suspected of having CAD. METHODS AND RESULTS: In this study, 487 patients who underwent coronary angiography as a result of suspected CAD but without acute myocardial infarction (AMI) were recruited. The serum levels of the cytokines interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17, tumor necrosis factor-α, interferon (IFN)-α, and IFN-γ were measured using a multiplexed particle-based flow cytometric assay technique. The results of the study revealed that the levels of IL-4, IL-12p70, IL-17, IFN-α, and IFN-γ in the CAD group were significantly lower compared to those in the non-CAD group. Multivariate logistic regression analysis indicated that two serum cytokines (IL-4 and IL-17), one protective factor (high-density lipoprotein cholesterol [HDL-C]), and three risk factors (sex, smoking, and diabetes) were independently predictive of CAD. The receiver operating characteristic curve analysis showed that the combined use of these predictors in a multivariate model demonstrated good predictive performance for CAD, as evidenced by an area under the curve value of 0.826. CONCLUSION: The results of the study indicated that serum IL-4 and IL-17 levels serve as independent predictors of CAD. The risk prediction model established in the research, which integrates these serum cytokines (IL-4 and IL-17) with relevant clinical risk factors (gender, smoking, and diabetes) and the protective factor HDL-C, holds the potential to differentiate patients with CAD from those suspected of having CAD but without AMI.
Asunto(s)
Enfermedad de la Arteria Coronaria , Diabetes Mellitus , Infarto del Miocardio , Humanos , Enfermedad de la Arteria Coronaria/complicaciones , Citocinas , Interleucina-17 , Interleucina-4 , Infarto del Miocardio/complicacionesRESUMEN
Basal progenitor cells are crucial for maintaining foregut (the esophagus and forestomach) homeostasis. When their function is dysregulated, it can promote inflammation and tumorigenesis. However, the mechanisms underlying these processes remain largely unclear. Here, we employ genetic mouse models to reveal that Jag1/2 regulate esophageal homeostasis and foregut tumorigenesis by modulating the function of basal progenitor cells. Deletion of Jag1/2 in mice disrupts esophageal and forestomach epithelial homeostasis. Mechanistically, Jag1/2 deficiency impairs activation of Notch signaling, leading to reduced squamous epithelial differentiation and expansion of basal progenitor cells. Moreover, Jag1/2 deficiency exacerbates the deoxycholic acid (DCA)-induced squamous epithelial injury and accelerates the initiation of squamous cell carcinoma (SCC) in the forestomach. Importantly, expression levels of JAG1/2 are lower in the early stages of human esophageal squamous cell carcinoma (ESCC) carcinogenesis. Collectively, our study demonstrates that Jag1/2 are important for maintaining esophageal and forestomach homeostasis and the onset of foregut SCC.
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Carcinogénesis , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Esófago , Homeostasis , Proteína Jagged-1 , Proteína Jagged-2 , Células Madre , Animales , Proteína Jagged-1/metabolismo , Proteína Jagged-1/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/metabolismo , Esófago/patología , Esófago/metabolismo , Células Madre/metabolismo , Ratones , Proteína Jagged-2/metabolismo , Proteína Jagged-2/genética , Humanos , Carcinogénesis/genética , Carcinogénesis/patología , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/metabolismo , Ratones Noqueados , Transducción de Señal , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Receptores Notch/metabolismo , Receptores Notch/genética , Diferenciación Celular , Masculino , FemeninoRESUMEN
The gut microbiota play a pivotal role in human health. Emerging evidence indicates that gut microbes participate in the progression of tumorigenesis through the generation of carcinogenic metabolites. However, the underlying molecular mechanism is largely unknown. In the present study we show that a tryptophan metabolite derived from Peptostreptococcus anaerobius, trans-3-indoleacrylic acid (IDA), facilitates colorectal carcinogenesis. Mechanistically, IDA acts as an endogenous ligand of an aryl hydrocarbon receptor (AHR) to transcriptionally upregulate the expression of ALDH1A3 (aldehyde dehydrogenase 1 family member A3), which utilizes retinal as a substrate to generate NADH, essential for ferroptosis-suppressor protein 1(FSP1)-mediated synthesis of reduced coenzyme Q10. Loss of AHR or ALDH1A3 largely abrogates IDA-promoted tumour development both in vitro and in vivo. It is interesting that P. anaerobius is significantly enriched in patients with colorectal cancer (CRC). IDA treatment or implantation of P. anaerobius promotes CRC progression in both xenograft model and ApcMin/+ mice. Together, our findings demonstrate that targeting the IDA-AHR-ALDH1A3 axis should be promising for ferroptosis-related CRC treatment.
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Neoplasias Colorrectales , Ferroptosis , Microbioma Gastrointestinal , Humanos , Animales , Ratones , Ferroptosis/genética , Carcinogénesis/genética , Transformación Celular Neoplásica , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patologíaRESUMEN
Understanding the heterogeneous intestinal microenvironment is critical to uncover the pathogenesis of inflammatory bowel disease (IBD). Recent advances in single-cell RNA sequencing (scRNA-seq) have identified certain cell types and genes that could contribute to IBD; however, a comprehensively integrated analysis of these scRNA-seq datasets is not yet available. Here we introduce scIBD, a platform for single-cell meta-analysis of IBD with interactive and visualization features, which combines highly curated single-cell datasets in a uniform workflow, enabling identifying rare or less-characterized cell types in IBD and dissecting the commonalities, as well as the differences between ulcerative colitis and Crohn's disease. scIBD also incorporates multifunctional information-including regulon activity, GWAS-implicated risk genes and genes targeted by therapeutics-to infer clinically relevant cell-type specificity. Collectively, scIBD is a user-friendly web-based platform for the community to analyze the transcriptome features and gene regulatory networks associated with the pathogenesis and treatment of IBD at single-cell resolution.
Asunto(s)
Colitis Ulcerosa , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Humanos , Enfermedades Inflamatorias del Intestino/genética , Colitis Ulcerosa/etiología , Enfermedad de Crohn/diagnóstico , TranscriptomaRESUMEN
Inherited genetic variations in the melanocortin-1 receptor (MC1R) responsible for human red hair color (RHC) variants are associated with impaired DNA damage repair and increased melanoma risk. MC1R signaling is critically dependent on palmitoylation, primarily mediated by the protein acyltransferase zinc finger DHHC-type palmitoyltransferase 13 (ZDHHC13). A better understanding of how ZDHHC13 is physiologically activated could help identify approaches to prevent melanomagenesis in redheads. Here, we report that AMP-activated protein kinase (AMPK) phosphorylates ZDHHC13 at S208 to strengthen the interaction between ZDHHC13 and MC1R-RHC, leading to enhanced MC1R palmitoylation in redheads. Consequently, phosphorylation of ZDHHC13 by AMPK increased MC1R-RHC downstream signaling. AMPK activation and MC1R palmitoylation repressed UVB-induced transformation of human melanocytes in vitro and delayed melanomagenesis in vivo in C57BL/6J-MC1R-RHC mice. The importance of AMPK to MC1R signaling was validated in human melanomas where AMPK upregulation correlated with expression of factors downstream from MC1R signaling and with prolonged patient survival. These findings suggest AMPK activation as a promising strategy to reduce melanoma risk, especially for individuals with red hair. SIGNIFICANCE: Phosphorylation of ZDHHC13 by AMPK at S208 promotes MC1R activation and suppresses melanocyte transformation, indicating activation of AMPK as a potential approach to prevent melanoma in people with red hair.