RESUMEN
The liver plays a crucial role in maintaining systemic iron homeostasis by secreting hepcidin, which is essential for coordinating iron levels in the body. Imbalances in iron homeostasis are associated with various clinical disorders related to iron deficiency or iron overload. Despite the clinical significance, the mechanisms underlying how hepatocytes sense extracellular iron levels to regulate hepcidin synthesis and iron storage are not fully understood. In this study, we identified Foxo1, a well-known regulator of macronutrient metabolism, that translocates to the nucleus of hepatocytes in response to high-iron feeding, holo-transferrin, and BMP6 treatment. Furthermore, Foxo1 plays a crucial role in mediating hepcidin induction in response to both iron and BMP signals by directly interacting with evolutionally conserved Foxo binding sites within the hepcidin promoter region. These binding sites were found to colocalize with Smad-binding sites. To investigate the physiological relevance of Foxo1 in iron metabolism, we generated mice with hepatocyte-specific deletion of Foxo1. These mice exhibited reduced hepatic hepcidin expression and serum hepcidin levels, accompanied by elevated serum iron and liver non-heme iron concentrations. Moreover, high-iron diet further exacerbated these abnormalities in iron metabolism in mice lacking hepatic Foxo1. Conversely, hepatocyte-specific Foxo1 overexpression increased hepatic hepcidin expression and serum hepcidin levels, thereby ameliorating iron overload in a murine model of hereditary hemochromatosis (Hfe-/- mice). In summary, our study identifies Foxo1 is a critical regulator of hepcidin and systemic iron homeostasis. Targeting Foxo1 may offer therapeutic opportunities for managing conditions associated with aberrant iron metabolism.
RESUMEN
BACKGROUND AND AIMS: Stanford type A aortic dissection (AD) is a degenerative aortic remodelling disease marked by an exceedingly high mortality without effective pharmacologic therapies. Smooth muscle cells (SMCs) lining tunica media adopt a range of states, and their transformation from contractile to synthetic phenotypes fundamentally triggers AD. However, the underlying pathomechanisms governing this population shift and subsequent AD, particularly at distinct disease temporal stages, remain elusive. METHODS: Ascending aortas from nine patients undergoing ascending aorta replacement and five individuals undergoing heart transplantation were subjected to single-cell RNA sequencing. The pathogenic targets governing the phenotypic switch of SMCs were identified by trajectory inference, functional scoring, single-cell regulatory network inference and clustering, regulon, and interactome analyses and confirmed using human ascending aortas, primary SMCs, and a ß-aminopropionitrile monofumarate-induced AD model. RESULTS: The transcriptional profiles of 93 397 cells revealed a dynamic temporal-specific phenotypic transition and marked elevation of the activator protein-1 (AP-1) complex, actively enabling synthetic SMC expansion. Mechanistically, tumour necrosis factor signalling enhanced AP-1 transcriptional activity by dampening mitochondrial oxidative phosphorylation (OXPHOS). Targeting this axis with the OXPHOS enhancer coenzyme Q10 or AP-1-specific inhibitor T-5224 impedes phenotypic transition and aortic degeneration while improving survival by 42.88% (58.3%-83.3% for coenzyme Q10 treatment), 150.15% (33.3%-83.3% for 2-week T-5224), and 175.38% (33.3%-91.7% for 3-week T-5224) in the ß-aminopropionitrile monofumarate-induced AD model. CONCLUSIONS: This cross-sectional compendium of cellular atlas of human ascending aortas during AD progression provides previously unappreciated insights into a transcriptional programme permitting aortic degeneration, highlighting a translational proof of concept for an anti-remodelling intervention as an attractive strategy to manage temporal-specific AD by modulating the tumour necrosis factor-OXPHOS-AP-1 axis.
Asunto(s)
Enfermedades de la Aorta , Disección Aórtica , Benzofenonas , Isoxazoles , Enfermedades Vasculares , Humanos , Factor de Transcripción AP-1 , Aminopropionitrilo , Estudios Transversales , Disección Aórtica/genética , Enfermedades de la Aorta/patología , Enfermedades Vasculares/patología , Miocitos del Músculo Liso/patología , Miocitos del Músculo Liso/fisiología , Factores de Necrosis TumoralRESUMEN
Carrier-phase noise limits both the performance and the maximum operation range of coherent LiDAR. To address this issue, we propose a carrier-phase-noise-canceled LiDAR based on an auxiliary interferometer and adaptive filters. Compared to previous methods, this approach is calibration-free and offers higher compensation accuracy, as well as applicability of dynamic target detection. Experiments of range-Doppler imaging for stationary targets and rotating extended targets have been performed, and the detection results close to the theoretical resolution were obtained at the round trip distance to the target beyond 981 times and 106 times coherence length, respectively.
RESUMEN
Nasopharyngeal Carcinoma (NC) refers to the malignant tumor that occurs at the top and side walls of the nasopharyngeal cavity. The NC incidence rate always dominates the first among the malignant tumors of the ear, nose and throat, and mainly occurs in Asia. NC cases are mainly concentrated in southern provinces in China, with about 4 million existing NC. With the pollution of environment and pickled diet, and the increase of life pressure, the domestic NC incidence rate has reached 4.5-6.5/100000 and is increasing year by year. It was reported that the known main causes of NC include hereditary factor, genetic mutations, and EB virus infection, common clinical symptoms of NC include nasal congestion, bloody mucus, etc. About 90% of NC is highly sensitive to radiotherapy which is regard as the preferred treatment method; However, for NC with lower differentiation, larger volume, and recurrence after treatment, surgical resection and local protons and heavy ions therapy are also indispensable means. According to reports, the subtle heterogeneity and diversity exists in some NC, with about 80% of NC undergone radiotherapy and about 25% experienced recurrence and death within five years after radiotherapy in China. Therefore, screening the NC population with suspected recurrence after concurrent chemoradiotherapy may improve survival rates in current clinical decision-making.
NC is one of the prevalent malignancies of the head and neck region with poor prognosis. The aim of this study is to establish a predictive model for assessing NC prognosis using clinical and MR radiomics data.
Asunto(s)
Quimioradioterapia , Neoplasias Nasofaríngeas , Recurrencia Local de Neoplasia , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , China/epidemiología , Imagen por Resonancia Magnética , Carcinoma Nasofaríngeo/patología , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/diagnóstico por imagen , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/diagnóstico por imagen , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/patología , Radiómica , Estudios RetrospectivosRESUMEN
Mutations of the FBN1 gene lead to Marfan syndrome (MFS), which is an autosomal dominant connective tissue disorder featured by thoracic aortic aneurysm risk. There is currently no effective treatment for MFS. Here, we studied the role of mitochondrial dysfunction in the phenotypic transformation of human smooth muscle cells (SMCs) and whether a mitochondrial boosting strategy can be a potential treatment. We knocked down FBN1 in SMCs to create an MFS cell model and used rotenone to induce mitochondrial dysfunction. Furthermore, we incubated the shFBN1 SMCs with Coenzyme Q10 (CoQ10) to assess whether restoring mitochondrial function can reverse the phenotypic transformation. The results showed that shFBN1 SMCs had decreased TFAM (mitochondrial transcription factor A), mtDNA levels and mitochondrial mass, lost their contractile capacity and had increased synthetic phenotype markers. Inhibiting the mitochondrial function of SMCs can decrease the expression of contractile markers and increase the expression of synthetic genes. Imposing mitochondrial stress causes a double-hit effect on the TFAM level, oxidative phosphorylation and phenotypic transformation of FBN1-knockdown SMCs while restoring mitochondrial metabolism with CoQ10 can rapidly reverse the synthetic phenotype. Our results suggest that mitochondria function is a potential therapeutic target for the phenotypic transformation of SMCs in MFS.
Asunto(s)
Síndrome de Marfan , Enfermedades Mitocondriales , Ubiquinona/análogos & derivados , Humanos , Síndrome de Marfan/genética , Fenotipo , Miocitos del Músculo Liso/metabolismo , Enfermedades Mitocondriales/metabolismo , Fibrilina-1/metabolismo , Adipoquinas/metabolismoRESUMEN
The present study aimed to investigate the occurrence of ferroptosis in mouse hippocampal tissue and changes in related pathways after exposure to high-altitude hypoxia. A low-pressure hypoxia model was established using a high-altitude environment at 4 010 m. HE staining was used to observe morphological changes in mouse hippocampal tissue, immunohistochemical staining was used to observe lipid peroxidation levels in hippocampal tissue, and corresponding kits were used to measure malondialdehyde (MDA), reduced glutathione (GSH), and Fe2+ levels in hippocampal tissue. Western blot was used to detect glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), ferritin heavy chain 1 (FTH1), ferroportin 1 (FPN1), transferrin receptor 1 (TfR1), ferroptosis suppressor protein 1 (FSP1), and acyl-CoA synthase long chain family member 4 (ACSL4). The results showed that, compared with the plain control group, the mice exposed to high-altitude hypoxia for 1, 3, 7, and 14 d exhibited significant pathological damage, disordered arrangement, and obvious nuclear condensation in the dentate gyrus of the hippocampus. Compared with the plain control group, high-altitude hypoxia exposure increased 4-hydroxynonenal (4-HNE) content in the dentate gyrus and hippocampal MDA content, whereas significantly decreased hippocampal GSH content. Compared with the plain control group, the Fe2+ content in the hippocampus of mice exposed to high-altitude hypoxia for 14 d significantly increased. Compared with the plain control group, the protein expression levels of GPX4, FTH1, FPN1, TfR1, and FSP1 in the hippocampus of mice exposed to high-altitude hypoxia were significantly down-regulated (SLC7A11 was significantly down-regulated only in the 7-d high-altitude hypoxia exposure group), while the protein expression level of ACSL4 was only significantly up-regulated in the 14-d high-altitude hypoxia exposure group. These results suggest that exposure to high-altitude hypoxia for 14 d can reduce GSH synthesis in mouse hippocampus, down-regulate GPX4 expression, lead to GSH metabolism disorders, inhibit iron storage and efflux, promote lipid peroxidation reaction, and inhibit CoQ10H2's anti-lipid peroxidation effect, ultimately leading to ferroptosis.
Asunto(s)
Mal de Altura , Ferroptosis , Hipocampo , Hipoxia , Animales , Ferroptosis/fisiología , Hipocampo/metabolismo , Ratones , Hipoxia/metabolismo , Hipoxia/fisiopatología , Masculino , Mal de Altura/metabolismo , Mal de Altura/fisiopatología , Peroxidación de Lípido , Receptores de Transferrina/metabolismo , Altitud , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Glutatión/metabolismo , Malondialdehído/metabolismo , Hierro/metabolismo , Proteínas de Transporte de Catión/metabolismo , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genéticaRESUMEN
Diabetic retinopathy (DR) is one of the leading causes of blindness. However, because the data distribution of classes is not always balanced, it is challenging for automated early DR detection using deep learning techniques. In this paper, we propose an adaptive weighted ensemble learning method for DR detection based on optical coherence tomography (OCT) images. Specifically, we develop an ensemble learning model based on three advanced deep learning models for higher performance. To better utilize the cues implied in these base models, a novel decision fusion scheme is proposed based on the Bayesian theory in terms of the key evaluation indicators, to dynamically adjust the weighting distribution of base models to alleviate the negative effects potentially caused by the problem of unbalanced data size. Extensive experiments are performed on two public datasets to verify the effectiveness of the proposed method. A quadratic weighted kappa of 0.8487 and an accuracy of 0.9343 on the DRAC2022 dataset, and a quadratic weighted kappa of 0.9007 and an accuracy of 0.8956 on the APTOS2019 dataset are obtained, respectively. The results demonstrate that our method has the ability to enhance the ovearall performance of DR detection on OCT images.
Asunto(s)
Diabetes Mellitus , Retinopatía Diabética , Humanos , Retinopatía Diabética/diagnóstico por imagen , Teorema de Bayes , Tomografía de Coherencia Óptica/métodos , Aprendizaje AutomáticoRESUMEN
Autophagy is a multi-step catabolic process that delivers cellular components to lysosomes for degradation and recycling. The dysregulation of this precisely controlled process disrupts cellular homeostasis and leads to many pathophysiological conditions. The mechanistic target of rapamycin (mTOR) is a central nutrient sensor that integrates growth signals with anabolism to fulfil biosynthetic and bioenergetic requirements. mTOR nucleates two distinct evolutionarily conserved complexes (mTORC1 and mTORC2). However, only mTORC1 is acutely inhibited by rapamycin. Consequently, mTORC1 is a well characterized regulator of autophagy. While less is known about mTORC2, the availability of acute small molecule inhibitors and multiple genetic models has led to increased understanding about the role of mTORC2 in autophagy. Emerging evidence suggests that the regulation of mTORC2 in autophagy is mainly through its downstream effector proteins, and is variable under different conditions and cellular contexts. Here, we review recent advances that describe a role for mTORC2 in this catabolic process, and propose that mTORC2 could be a potential clinical target for the treatment of autophagy-related diseases. Video abstract.
Asunto(s)
Proteínas Proto-Oncogénicas c-akt , Serina-Treonina Quinasas TOR , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Sirolimus/farmacología , AutofagiaRESUMEN
INTRODUCTION: Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a rare genetic disease with diverse ocular malformations. This study aimed to investigate the disease-causing gene in members of a BPES pedigree presenting with the rare features of anisometropia, unilateral pathologic myopia (PM), and congenital cataracts. METHODS: The related BPES patients underwent a comprehensive ocular examination. Next, whole-exome sequencing (WES) was performed to screen for the disease-causing genetic variants. A step-wise variant filtering was performed to select candidate variants combined with the annotation of the variant's pathogenicity, which was assessed using several bioinformatic approaches. Co-segregation analysis and Sanger sequencing were then conducted to validate the candidate variant. RESULTS: The variant c.672_701dup in FOXL2 was identified to be the disease-causing variant in this rare BPES family. Combined with clinical manifestations, the two affected individuals were diagnosed with type II BPES. CONCLUSION: This study uncovered the variant c.672_701dup in FOXL2 as a disease causal variant in a rare-presenting BPES family with anisometropia, unilateral pathogenic myopia, and/or congenital cataracts, thus expanding the phenotypic spectrum of FOXL2.
Asunto(s)
Anisometropía , Blefarofimosis , Catarata , Miopía , Humanos , Mutación , Secuenciación del Exoma , Linaje , Síndrome , Proteína Forkhead Box L2/genéticaRESUMEN
Salidroside, a prominent active ingredient in traditional Chinese medicines, is garnering increased attention because of its unique pharmacological effects against ischemic heart disease via MAPK signaling, which plays a critical role in regulating the evolution of ventricular hypertrophy. However, the function of Salidroside on myocardial hypertrophy has not yet been elucidated. C57BL/6 mice were subjected to transverse aortic constriction (TAC), and treated with Salidroside (100 mg kg-1 day-1 ) by oral gavage for 3 weeks starting 1 week after surgery. Four weeks after TAC surgery, the mice were subjected to echocardiography and then sacrificed to harvest the hearts for analysis. For in vitro study, neonatal rat cardiomyocytes were used to validate the protective effects of Salidroside in response to Angiotensin II (Ang II, 1 µM) stimulation. Here, we proved that Salidroside dramatically inhibited hypertrophic reactions generated by pressure overload and isoproterenol (ISO) injection. Salidroside prevented the activation of the TAK1-JNK/p38 axis. Salidroside pretreatment of TAK1-inhibited cardiomyocytes shows no additional attenuation of Ang II-induced cardiomyocytes hypertrophy and signaling pathway activation. The overexpression of constitutively active TAK1 removed the protective effects of Salidroside on myocardial hypertrophy. TAC-induced increase of TLR4 protein expression was reduced considerably in the Salidroside treated mice. Transient transfection of small interfering RNA targeting TLR4 (siTLR4) in cardiomyocytes did not further decrease the activation of the TAK1/JNK-p38 axis. In conclusion, Salidroside functioned as a TLR4 inhibitor and displayed anti-hypertrophic action via the TAK1/JNK-p38 pathway.
Asunto(s)
Estenosis de la Válvula Aórtica , Cardiomegalia , Receptor Toll-Like 4 , Animales , Ratones , Ratas , Estenosis de la Válvula Aórtica/metabolismo , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/metabolismo , Cardiomegalia/patología , Células Cultivadas , Modelos Animales de Enfermedad , Quinasas Quinasa Quinasa PAM/genética , Quinasas Quinasa Quinasa PAM/metabolismo , Quinasas Quinasa Quinasa PAM/farmacología , Ratones Endogámicos C57BL , Miocitos Cardíacos , Transducción de Señal , Receptor Toll-Like 4/metabolismoRESUMEN
Vascular remodeling is a common pathological hallmark of many cardiovascular diseases. Vascular smooth muscle cells (VSMCs) are the predominant cell type lining the tunica media and play a crucial role in maintaining aortic morphology, integrity, contraction and elasticity. Their abnormal proliferation, migration, apoptosis and other activities are tightly associated with a spectrum of structural and functional alterations in blood vessels. Emerging evidence suggests that mitochondria, the energy center of VSMCs, participate in vascular remodeling through multiple mechanisms. For example, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)-mediated mitochondrial biogenesis prevents VSMCs from proliferation and senescence. The imbalance between mitochondrial fusion and fission controls the abnormal proliferation, migration and phenotypic transformation of VSMCs. Guanosine triphosphate-hydrolyzing enzymes, including mitofusin 1 (MFN1), mitofusin 2 (MFN2), optic atrophy protein 1 (OPA1) and dynamin-related protein 1 (DRP1), are crucial for mitochondrial fusion and fission. In addition, abnormal mitophagy accelerates the senescence and apoptosis of VSMCs. PINK/Parkin and NIX/BINP3 pathways alleviate vascular remodeling by awakening mitophagy in VSMCs. Mitochondrial DNA (mtDNA) damage destroys the respiratory chain of VSMCs, resulting in excessive ROS production and decreased ATP levels, which are related to the proliferation, migration and apoptosis of VSMCs. Thus, maintaining mitochondrial homeostasis in VSMCs is a possible way to relieve pathologic vascular remodeling. This review aims to provide an overview of the role of mitochondria homeostasis in VSMCs during vascular remodeling and potential mitochondria-targeted therapies.
Asunto(s)
Músculo Liso Vascular , Remodelación Vascular , Humanos , Músculo Liso Vascular/metabolismo , Mitocondrias/metabolismo , ADN Mitocondrial/metabolismo , Homeostasis , Dinámicas Mitocondriales/fisiologíaRESUMEN
Cerebral hypoxia often brings irreversible damage to the central nervous system, which seriously endangers human health. It is of great significance to further explore the mechanism of hypoxia-associated brain injury. As a programmed cell death, ferroptosis mainly manifests as cell death caused by excessive accumulation of iron-dependent lipid peroxides. It is associated with abnormal glutathione metabolism, lipid peroxidation and iron metabolism, and is involved in the occurrence and development of various diseases. Studies have found that ferroptosis plays an important role in hypoxia-associated brain injury. This review summarizes the mechanism of ferroptosis, and describes its research progress in cerebral ischemia reperfusion injury, neonatal hypoxic-ischemic brain damage, obstructive sleep apnea-induced brain injury and high-altitude hypoxic brain injury.
Asunto(s)
Lesiones Encefálicas , Ferroptosis , Hipoxia-Isquemia Encefálica , Daño por Reperfusión , Humanos , Recién Nacido , Apoptosis , HierroRESUMEN
OBJECTIVE: This study aimed to discuss the application value of an artificial intelligence-based diagnosis and recognition system (AIDRS) in the teaching activities for Bachelor of Medicine and Bachelor of Surgery (MBBS) in China. The learning performance of graduate students in gastroenterology during gastroscopy training with and without AIDRS was assessed. METHODS: The study recruited 32 graduate students of the gastroenterology program at Jiangsu province hospital of Chinese medicine and Xiangyang No. 1 People's Hospital from March 2018 to March 2022 and randomly divided them into AIDRS (nâ¯= 16) and non-AIDRS (nâ¯= 16) groups. The AIDRS software was used for real-time monitoring of blind spots of gastroscopy to aid in lesion diagnosis and recognition in the AIDRS group. Only a conventional gastroscopic procedure was implemented in the non-AIDRS group. The final performance score, success rate of gastroscopy, lesion detection rate, and pain score of patients were compared between the two groups during gastroscopy. A self-prepared teaching and learning satisfaction questionnaire was administered to the two groups of students. RESULTS: The AIDRS group had a higher final performance score (92.60⯱ 2.83 vs. 89.21⯱ 3.57, tâ¯= 2.98, Pâ¯< 0.05), a higher success rate of gastroscopy (448/480 vs. 417/480, χ2â¯= 11.23, Pâ¯< 0.05), and a higher detection rate of lesions (51/52 vs. 41/53, χ2â¯= 8.56, Pâ¯< 0.05) compared with the non-AIDRS group. The pain scores of patients were lower in the AIDRS group than in the non-AIDRS group (3.40 [2.23, 3.98] vs. 4.45 [3.72, 4.75], Zâ¯= 3.04, Pâ¯< 0.05). Besides, the average time for gastroscopy was lower in the AIDRS group than in the non-AIDRS group (7.15⯱ 1.24 vs. 8.21⯱ 1.26, tâ¯= 2.38, Pâ¯= 0.02). The overall satisfaction level with the teaching program was higher in the AIDRS group (43.51⯱ 2.29 vs. 40.93⯱ 2.07, tâ¯= 3.33, Pâ¯< 0.05). CONCLUSION: In the context of medicine-education cooperation, AIDRS offered valuable assistance in gastroscopy training and increased the success rate of gastroscopy and teaching and learning satisfaction. AIDRS is worthy of wider-scale promotion.
RESUMEN
The past decade witnessed remarkable success in synthetic molecular nanographenes. Encouraged by the widespread application of chiral nanomaterials, the design, and construction of chiral nanographenes is a hot topic recently. As a classic nanographene unit, hexa-peri-hexabenzocoronene generally serves as the building block for nanographene synthesis. This review summarizes the representative examples of hexa-peri-hexabenzocoronene-based chiral nanographenes.
RESUMEN
DNA methylation analysis holds great promise in the whole process management of cancer early screening, diagnosis, and prognosis monitoring. Nevertheless, accurate detection of target methylated DNA, especially its methylation ratio in the genome, remains challenging. Herein, we report for the first time an integrated strategy of target-induced nanoparticle-coupling and site-specific base oxidation damage for DNA methylation analysis with the assistance of well-designed nanosensors. The ultrahigh sensitivity for detecting target methylated DNA as low as 32 × 10-17 M and high specificity for distinguishing 0.001% methylation ratio are achieved by this proposed strategy without amplification operations. Notably, the precise quantification of target DNA methylation ratio has been achieved for the first time. Through quantitative detection of target methylated DNA and methylation ratio, this proposed strategy could reliably diagnose and monitor cancer progression and treatment responses for colorectal cancer, which is superior to the clinical Septin 9 kit. It is anticipated that the proposed strategy has attractive application prospects in early diagnosis and monitoring for colorectal cancer and other various diseases.
Asunto(s)
Neoplasias Colorrectales , Nanopartículas , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , ADN , Metilación de ADN , Humanos , Estrés OxidativoRESUMEN
Although the serum-abundant metal-binding protein transferrin (encoded by the Trf gene) is synthesized primarily in the liver, its function in the liver is largely unknown. Here, we generated hepatocyte-specific Trf knockout mice (Trf-LKO), which are viable and fertile but have impaired erythropoiesis and altered iron metabolism. Moreover, feeding Trf-LKO mice a high-iron diet increased their susceptibility to developing ferroptosis-induced liver fibrosis. Importantly, we found that treating Trf-LKO mice with the ferroptosis inhibitor ferrostatin-1 potently rescued liver fibrosis induced by either high dietary iron or carbon tetrachloride (CCl4) injections. In addition, deleting hepatic Slc39a14 expression in Trf-LKO mice significantly reduced hepatic iron accumulation, thereby reducing ferroptosis-mediated liver fibrosis induced by either a high-iron diet or CCl4 injections. Finally, we found that patients with liver cirrhosis have significantly lower levels of serum transferrin and hepatic transferrin, as well as higher levels of hepatic iron and lipid peroxidation, compared with healthy control subjects. Taken together, these data indicate that hepatic transferrin plays a protective role in maintaining liver function, providing a possible therapeutic target for preventing ferroptosis-induced liver fibrosis.
Asunto(s)
Ferroptosis/fisiología , Hierro/metabolismo , Cirrosis Hepática/metabolismo , Hígado/metabolismo , Transferrina/fisiología , Animales , Intoxicación por Tetracloruro de Carbono/tratamiento farmacológico , Intoxicación por Tetracloruro de Carbono/metabolismo , Intoxicación por Tetracloruro de Carbono/patología , Proteínas de Transporte de Catión/deficiencia , Proteínas de Transporte de Catión/genética , Ciclohexilaminas/farmacología , Citocinas/análisis , Eritropoyesis/fisiología , Eritropoyetina/análisis , Femenino , Ferroptosis/efectos de los fármacos , Hepatocitos/metabolismo , Homeostasis , Sobrecarga de Hierro/complicaciones , Hierro de la Dieta/toxicidad , Peroxidación de Lípido , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Musculares/análisis , Fenilendiaminas/farmacología , Transferrina/análisisRESUMEN
RATIONALE: Maintaining iron homeostasis is essential for proper cardiac function. Both iron deficiency and iron overload are associated with cardiomyopathy and heart failure via complex mechanisms. Although ferritin plays a central role in iron metabolism by storing excess cellular iron, the molecular function of ferritin in cardiomyocytes remains unknown. OBJECTIVE: To characterize the functional role of Fth (ferritin H) in mediating cardiac iron homeostasis and heart disease. METHODS AND RESULTS: Mice expressing a conditional Fth knockout allele were crossed with 2 distinct Cre recombinase-expressing mouse lines, resulting in offspring that lack Fth expression specifically in myocytes (MCK-Cre) or cardiomyocytes (Myh6-Cre). Mice lacking Fth in cardiomyocytes had decreased cardiac iron levels and increased oxidative stress, resulting in mild cardiac injury upon aging. However, feeding these mice a high-iron diet caused severe cardiac injury and hypertrophic cardiomyopathy, with molecular features typical of ferroptosis, including reduced glutathione (GSH) levels and increased lipid peroxidation. Ferrostatin-1, a specific inhibitor of ferroptosis, rescued this phenotype, supporting the notion that ferroptosis plays a pathophysiological role in the heart. Finally, we found that Fth-deficient cardiomyocytes have reduced expression of the ferroptosis regulator Slc7a11, and overexpressing Slc7a11 selectively in cardiomyocytes increased GSH levels and prevented cardiac ferroptosis. CONCLUSIONS: Our findings provide compelling evidence that ferritin plays a major role in protecting against cardiac ferroptosis and subsequent heart failure, thereby providing a possible new therapeutic target for patients at risk of developing cardiomyopathy.
Asunto(s)
Sistema de Transporte de Aminoácidos y+/metabolismo , Apoferritinas/deficiencia , Cardiomiopatías/etiología , Ferroptosis/fisiología , Hierro/metabolismo , Miocardio/metabolismo , Envejecimiento , Alelos , Animales , Apoferritinas/efectos adversos , Apoferritinas/genética , Cardiomiopatías/metabolismo , Cardiomiopatías/prevención & control , Cardiomiopatía Hipertrófica/etiología , Cardiomiopatía Hipertrófica/prevención & control , Cruzamientos Genéticos , Ciclohexilaminas/administración & dosificación , Glutatión/metabolismo , Insuficiencia Cardíaca/etiología , Homeostasis , Hipertrofia Ventricular Izquierda/etiología , Deficiencias de Hierro , Sobrecarga de Hierro , Hierro de la Dieta/efectos adversos , Peroxidación de Lípido , Masculino , Ratones , Ratones Transgénicos , Miocitos Cardíacos/metabolismo , Estrés Oxidativo , Fenilendiaminas/administración & dosificación , Especies Reactivas de Oxígeno/metabolismoRESUMEN
To improve the stability of magnetorheological jet polishing (MJP), a processing method of flow-focusing-assisted MJP is proposed in this paper. A relevant experimental setup was developed based on this method. The effects of the parameters (gas pressure drop, diameter of the small hole, and focusing distance) in the flow-focusing technique on the jet stability were studied by computational fluid dynamics simulation and experiment. The results show that the optimal gas pressure range is from 0.6 to 0.7 times the jet pressure, the optimal diameter of the small hole range is from 2.1 to 2.3 times the nozzle diameter, and the optimal focusing distance range is from 3.5 to 4.5 times the nozzle diameter. This is a preliminary attempt to provide a reference for future experimental studies of flow-focusing-assisted MJP.
RESUMEN
Aim: This study aimed to investigate the ability of ultrasound/magnetic resonance imaging (MRI) signature and clinical data-based model for preoperatively predicting the degree of placenta accreta spectrum disorders and develop combined prediction models. Methods: The clinicopathological characteristics, prenatal ultrasound images, and MRI features of 132 pregnant women with placenta accreta spectrum disorders at Xiangyang No. 1 People's Hospital were retrospectively reviewed from January 2016 to December 2020. In the training set of 99 patients, the ultrasound/MRI features model, clinical characteristics model, and combined model were developed by multivariate logistic regression analysis to predict the degree of placenta accreta spectrum disorders. The prediction performance of different models was compared using the Delong test. The developed models were validated by assessing their prediction performance in a test set of 33 patients. Results: The multivariate logistic regression analysis identified history of abortion, history of endometrial injury, and blurred boundary between the placenta and the myometrium/between the uterine serosa and the bladder to construct a combined model for predicting the degree of placenta accreta spectrum disorders (area under the curve (AUC) = 0.931; 95% confidence interval (CI): 0.882-0.980). The AUC of the clinical characteristics model and ultrasound/MRI features model was 0.858 (95% CI 0.794-0.921) and 0.709 (95% CI 0.624-0.798), respectively. The AUC of the combined model was significantly higher than that of the ultrasound/MRI features model (P < 0.001) or clinical characteristics model (P < 0.0015) in the training set. In the test set, the combined model also showed higher prediction performance. Conclusions: Ultrasound/MRI-based signature is a powerful predictor for the degree of placenta accreta spectrum disorders in an early stage. A combined model (constructed with history of abortion, history of endometrial injury, and blurred boundary between the placenta and the myometrium/between the uterine serosa and the bladder) can improve the accuracy for predicting the degree of placenta accreta spectrum disorders in an early stage.
Asunto(s)
Placenta Accreta , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Placenta/diagnóstico por imagen , Placenta/patología , Placenta Accreta/diagnóstico por imagen , Placenta Accreta/patología , Embarazo , Estudios Retrospectivos , UltrasonografíaRESUMEN
Objective: This study aimed to investigate the risk factors of reversible posterior leukoencephalopathy syndrome (RPLS) in pregnant women with severe preeclampsia or eclampsia (SPE/E) based on a predicting model and to analyze the perinatal outcomes. Methods: From January 2015 to March 2020, 78 pregnant women data diagnosed with severe preeclampsia or eclampsia with cranial magnetic resonance imaging (MRI) and transcranial Doppler (TCD) screening in Xiangyang No. 1 People's Hospital and Jiangsu Province Hospital of Chinese Medicine were analyzed retrospectively. They were divided into the RPLS group (n = 33) and non-RPLS group (n = 45) based on the MRI results. The general clinical data (blood pressure, BMI, symptoms, and so forth), laboratory examination, TCD results, and perinatal outcomes in the two groups were compared. The risk factors of severe preeclampsia or eclampsia complicated with RPLS were analyzed by multivariate logistic regression. The prediction model and decision curve (DCA) were established according to the clinical-imaging data. Results: The univariate analysis showed that poor placental perfusion, hypertension emergency, use of two or more oral antihypertensive drugs, headache, white blood cell (WBC) count, platelet (PLT) count, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), uric acid (UA), serum albumin (ALB), average flow velocity, and resistance index of the posterior cerebral and basilar arteries were significantly different in the RPLS group compared with the non-RPLS group (all P < 0.05). The multivariate logistic regression analysis showed that hypertensive emergency, headache, WBC, PLT, ALT, and average flow velocity of the basilar artery (BAAFV) were the risk factors in the RPLS group. The aforementioned clinical-imaging data modeling (general data model, laboratory examination model, TCD model, and combined model) showed that the combined model predicted RPLS better. DCA also confirmed that the net benefit of the combined model was higher. In addition, the incidence of postpartum hemorrhage, stillbirth, and preterm infants was higher in the RPLS group than in the non-RPLS group (all P < 0.05). Conclusions: More postpartum complications were detected in pregnant women with severe preeclampsia or eclampsia complicated with RPLS. Hypertensive emergency, headache, WBC, PLT, ALT, and BAAFV were the important risk factors for RPLS. The combined model had a better effect in predicting RPLS.