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BACKGROUND: Antineoplastic medications, including doxorubicin, idarubicin, and epirubicin, have been found to adversely affect the heart due to oxidative stress - mitochondrial dysfunction - ferroptosis (ORMFs), which act as contributing attributes to anthracycline-induced cardiotoxicity. To better understand this phenomenon, the time-resolved measurements of ORMFS genes were analyzed in this study. METHODS: The effect of three anthracycline drugs on ORMFs genes was studied using a human 3D cardiac microtissue cell model. Transcriptome data was collected over 14 days at two doses (therapeutic and toxic). WGCNA identified key module-related genes, and functional enrichment analysis investigated the biological processes quantified by ssGSEA, such as immune cell infiltration and angiogenesis. Biopsies were collected from heart failure patients and control subjects. GSE59672 and GSE2965 were collected for validation. Molecular docking was used to identify anthracyclines's interaction with key genes. RESULTS: The ORMFs genes were screened in vivo or in vitro. Using WGCNA, six co-expressed gene modules were grouped, with MEblue emerging as the most significant module. Eight key genes intersecting the blue module with the dynamic response genes were obtained: CD36, CDH5, CHI3L1, HBA2, HSD11B1, OGN, RPL8, and VWF. Compared with control samples, all key genes except RPL8 were down-regulated in vitro ANT treatment settings, and their expression levels varied over time. According to functional analyses, the key module-related genes were engaged in angiogenesis and the immune system pathways. In all ANT-treated settings, ssGSEA demonstrated a significant down-regulation of angiogenesis score and immune cell activity, including Activated CD4 T cell, Immature B cell, Memory B cell, Natural killer cell, Type 1 T helper cell, and Type 2 T helper cell. Molecular docking revealed that RPL8 and CHI3L1 show significant binding affinity for anthracyclines. CONCLUSION: This study focuses on the dynamic characteristics of ORMFs genes in both human cardiac microtissues and cardiac biopsies from ANT-treated patients. It has been highlighted that ORMFs genes may contribute to immune infiltration and angiogenesis in cases of anthracycline-induced cardiotoxicity. A thorough understanding of these genes could potentially lead to improved diagnosis and treatment of the disease.
Asunto(s)
Cardiotoxicidad , Ferroptosis , Simulación del Acoplamiento Molecular , Estrés Oxidativo , Humanos , Estrés Oxidativo/efectos de los fármacos , Ferroptosis/efectos de los fármacos , Ferroptosis/genética , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patología , Mitocondrias Cardíacas/genética , Redes Reguladoras de Genes , Factores de Tiempo , Transcriptoma , Epirrubicina/efectos adversos , Doxorrubicina , Antibióticos Antineoplásicos/efectos adversos , Estudios de Casos y Controles , Idarrubicina , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Perfilación de la Expresión Génica , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Estudios Longitudinales , Antraciclinas/efectos adversos , Regulación de la Expresión Génica , Transducción de SeñalRESUMEN
Objective To evaluate the safety and efficacy of interventional procedure for treating the renal artery aneurysm (RAA).Methods From Jan 2009 to Apr 2014,17 patients,who were diagnosed as RAA and accepted the interventional therapy,were reviewed in our hospital.The mean age in those patients,including 7 males and 10 females,was (46.4±10.3) years old (range from 20 to 67 years old).The related symptoms included backache in 4 cases,abdominal pain in 4 cases,intermittent hematuria in 2 cases,chyluria in one case,oligouria in one case.9 cases were diagnosed as multiple RAA and 8 cases were confirmed as signle cases.In 17 cases,31 aneurysms were found,including 26 true aneurysms,5 pseudoaneurysums,17 sacculated aneurysms,4 spindle-like aneurysms,4 irregular shape aneurysms,4 parenchyma aneurysm and 2 dissecting aneurysm.8 aneurysms located in the main renal artery,19 aneurysms located in the branch of renal artery,4 aneurysums located in the renal parenchyma.Intracavitary coil embolization was used in 4 patients.We carried out parent artery embolization in 3 patients.A combination of the former techniques was performed in 6 cases.Covered stent placement was operated in one case.Combination of the intracavitary coil embolization and nude stent placement were performed in 2 patients.We used two techniques in one patient with multiple artery aneurysms in both sides.Results The interventional treatment of RAAs succeed at the first operation in 16 of 17 patients.17 cases were followed-up from 3 to 53 months (mean 23 months).No severe complications or death cases occurred in this study.Urine occult blood in 3 patients turned to negative after one week.Primary symptoms such as gross hematuria,abdominal pain,lumbodorsalgia,fever vanished or obviously eased after a month.Laboratory tests showed that normal level in SCr,BUN,routine urinalysis 3 months,6 months and 1 year later.No tendency of stent and coil stent shifting was found in 16 patients and the parent arteries were patent in 8 cases,with reexamination bv ultrasonic or computed tomography angiography (CTA).Conclusions Interventional techniques are minimally-invasive,safe and effective methods for treating the RAAs.
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ood long-term efficacy for cirrhosis patients with portal hypertension was a useful treatment for these patients.