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Neuroblastoma (NB) is one of the most common extracranial solid tumors in children. MYCN gene amplification is highly associated with poor prognosis in high-risk NB patients. In non-MYCN-amplified high-risk NB patients, the expression of c-MYC (MYCC) and its target genes is highly elevated. USP28 as a deubiquitinase is known to regulate the stability of MYCC. We show here USP28 also regulates the stability of MYCN. Genetic depletion or pharmacologic inhibition of the deubiquitinase strongly destabilizes MYCN and stops the growth of NB cells that overexpress MYCN. In addition, MYCC could be similarly destabilized in non-MYCN NB cells by compromising USP28 function. Our results strongly suggest USP28 as a therapeutic target for NB with or without MYCN amplification/overexpression.
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Células-Madre Neurales , Neuroblastoma , Niño , Humanos , Línea Celular Tumoral , Enzimas Desubicuitinizantes/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteína Proto-Oncogénica N-Myc/genética , Proteína Proto-Oncogénica N-Myc/metabolismo , Proteína Proto-Oncogénica N-Myc/uso terapéutico , Células-Madre Neurales/metabolismo , Neuroblastoma/patología , Factores de Transcripción/metabolismo , Ubiquitina Tiolesterasa/metabolismoRESUMEN
BACKGROUND: Cardiac-specific myosin light chain kinase (cMLCK), encoded by MYLK3, regulates cardiac contractility through phosphorylation of ventricular myosin regulatory light chain. However, the pathophysiological and therapeutic implications of cMLCK in human heart failure remain unclear. We aimed to investigate whether cMLCK dysregulation causes cardiac dysfunction and whether the restoration of cMLCK could be a novel myotropic therapy for systolic heart failure. METHODS: We generated the knock-in mice (Mylk3+/fs and Mylk3fs/fs) with a familial dilated cardiomyopathy-associated MYLK3 frameshift mutation (MYLK3+/fs) that had been identified previously by us (c.1951-1G>T; p.P639Vfs*15) and the human induced pluripotent stem cell-derived cardiomyocytes from the carrier of the mutation. We also developed a new small-molecule activator of cMLCK (LEUO-1154). RESULTS: Both mice (Mylk3+/fs and Mylk3fs/fs) showed reduced cMLCK expression due to nonsense-mediated messenger RNA decay, reduced MLC2v (ventricular myosin regulatory light chain) phosphorylation in the myocardium, and systolic dysfunction in a cMLCK dose-dependent manner. Consistent with this result, myocardium from the mutant mice showed an increased ratio of cardiac superrelaxation/disordered relaxation states that may contribute to impaired cardiac contractility. The phenotypes observed in the knock-in mice were rescued by cMLCK replenishment through the AAV9_MYLK3 vector. Human induced pluripotent stem cell-derived cardiomyocytes with MYLK3+/fs mutation reduced cMLCK expression by 50% and contractile dysfunction, accompanied by an increased superrelaxation/disordered relaxation ratio. CRISPR-mediated gene correction, or cMLCK replenishment by AAV9_MYLK3 vector, successfully recovered cMLCK expression, the superrelaxation/disordered relaxation ratio, and contractile dysfunction. LEUO-1154 increased human cMLCK activity ≈2-fold in the Vmax for ventricular myosin regulatory light chain phosphorylation without affecting the Km. LEUO-1154 treatment of human induced pluripotent stem cell-derived cardiomyocytes with MYLK3+/fs mutation restored the ventricular myosin regulatory light chain phosphorylation level and superrelaxation/disordered relaxation ratio and improved cardiac contractility without affecting calcium transients, indicating that the cMLCK activator acts as a myotrope. Finally, human myocardium from advanced heart failure with a wide variety of causes had a significantly lower MYLK3/PPP1R12B messenger RNA expression ratio than control hearts, suggesting an altered balance between myosin regulatory light chain kinase and phosphatase in the failing myocardium, irrespective of the causes. CONCLUSIONS: cMLCK dysregulation contributes to the development of cardiac systolic dysfunction in humans. Our strategy to restore cMLCK activity could form the basis of a novel myotropic therapy for advanced systolic heart failure.
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Insuficiencia Cardíaca Sistólica , Células Madre Pluripotentes Inducidas , Humanos , Ratones , Animales , Quinasa de Cadena Ligera de Miosina/genética , Quinasa de Cadena Ligera de Miosina/metabolismo , Fosforilación , Cadenas Ligeras de Miosina/genética , Cadenas Ligeras de Miosina/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Contracción Miocárdica/fisiología , ARN Mensajero/genética , Miosinas Cardíacas/genética , Miosinas Cardíacas/metabolismoRESUMEN
Rationally modulating the binding strength of reaction intermediates on surface sites of copper-based catalysts could facilitate C-C coupling to generate multicarbon products in an electrochemical CO2 reduction reaction. Herein, theoretical calculations reveal that cascade Ag-Cu dual sites could synergistically increase local CO coverage and lower the kinetic barrier for CO protonation, leading to enhanced asymmetric C-C coupling to generate C2H4. As a proof of concept, the Cu3N-Ag nanocubes (NCs) with Ag located in partial Cu sites and a Cu3N unit center are successfully synthesized. The Faraday efficiency and partial current density of C2H4 over Cu3N-Ag NCs are 7.8 and 9.0 times those of Cu3N NCs, respectively. In situ spectroscopies combined with theoretical calculations confirm that Ag sites produce CO and Cu sites promote asymmetric C-C coupling to *COCHO, significantly enhancing the generation of C2H4. Our work provides new insights into the cascade catalysis strategy at the atomic scale for boosting CO2 to multicarbon products.
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Breast cancer is the most commonly diagnosed cancer among women. The primary treatment options include surgery, radiotherapy, chemotherapy, targeted therapy and hormone therapy. The effectiveness of breast cancer therapy varies depending on the stage and aggressiveness of the cancer, as well as individual factors. Advances in early detection and improved treatments have significantly increased survival rates for breast cancer patients. Nevertheless, specific subtypes of breast cancer, particularly triple-negative breast cancer, still lack effective treatment strategies. Thus, novel and effective therapeutic targets for breast cancer need to be explored. As substrates of protein synthesis, amino acids are important sources of energy and nutrition, only secondly to glucose. The rich supply of amino acids enables the tumor to maintain its proliferative competence through participation in energy generation, nucleoside synthesis and maintenance of cellular redox balance. Amino acids also play an important role in immune-suppressive microenvironment formation. Thus, the biological effects of amino acids may change unexpectedly in tumor-specific or oncogene-dependent manners. In recent years, there has been significant progress in the study of amino acid metabolism, particularly in their potential application as therapeutic targets in breast cancer. In this review, we provide an update on amino acid metabolism and discuss the therapeutic implications of amino acids in breast cancer.
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Aminoácidos , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Inmunoterapia , Neoplasias de la Mama Triple Negativas/metabolismo , Microambiente TumoralRESUMEN
Diallyl disulfide (DADS), one of the main components of garlic, is well known to have anticancer effects on multiple cancers. However, its efficacy in treating multiple myeloma (MM) is yet to be determined. We explored the effects of DADS on MM cells and investigated the synergistic effects of DADS when combined with five anti-MM drugs, including melphalan, bortezomib, carfilzomib, doxorubicin, and lenalidomide. We analyzed cell viability, cell apoptosis, and DNA damage to determine the efficacy of DADS and the drug combinations. Our findings revealed that DADS induces apoptosis in MM cells through the mitochondria-dependent pathway and increases the levels of γ-H2AX, a DNA damage marker. Combination index (CI) measurements indicated that the combination of DADS with melphalan has a significant synergistic effect on MM cells. This was further confirmed by the increases in apoptotic cells and DNA damage in MM cells treated with the two drug combinations compared with those cells treated with a single drug alone. The synergy between DADS and melphalan was also observed in primary MM cells. Furthermore, mechanistic investigations showed that DADS decreases reduced glutathione (GSH) levels and increases reactive oxygen species (ROS) production in MM cells. The addition of GSH is effective in neutralizing DADS cytotoxicity and inhibiting the synergy between DADS and melphalan in MM cells. Taken together, our study highlights the effectiveness of DADS in treating MM cells and the promising therapeutic potential of combining DADS and melphalan for MM treatment.
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Ácido 4-Acetamido-4'-isotiocianatostilbeno-2,2'-disulfónico/análogos & derivados , Compuestos Alílicos , Disulfuros , Melfalán , Mieloma Múltiple , Humanos , Especies Reactivas de Oxígeno , Melfalán/farmacología , Mieloma Múltiple/tratamiento farmacológico , Daño del ADN , Apoptosis , Combinación de MedicamentosRESUMEN
Iron contributes to tumor initiation and progression; however, excessive intracellular free Fe2+ can be toxic to cancer cells. Our findings confirmed that multiple myeloma (MM) cells exhibited elevated intracellular iron levels and increased ferritin, a key protein for iron storage, compared with normal cells. Interestingly, Bortezomib (BTZ) was found to trigger ferritin degradation, increase free intracellular Fe2+, and promote ferroptosis in MM cells. Subsequent mechanistic investigation revealed that BTZ effectively increased NCOA4 levels by preventing proteasomal degradation in MM cells. When we knocked down NCOA4 or blocked autophagy using chloroquine, BTZ-induced ferritin degradation and the increase in intracellular free Fe2+ were significantly reduced in MM cells, confirming the role of BTZ in enhancing ferritinophagy. Furthermore, the combination of BTZ with RSL-3, a specific inhibitor of GPX4 and inducer of ferroptosis, synergistically promoted ferroptosis in MM cell lines and increased cell death in both MM cell lines and primary MM cells. The induction of ferroptosis inhibitor liproxstatin-1 successfully counteracted the synergistic effect of BTZ and RSL-3 in MM cells. Altogether, our findings reveal that BTZ elevates intracellular free Fe2+ by enhancing NCOA4-mediated ferritinophagy and synergizes with RSL-3 by increasing ferroptosisin MM cells.
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Bortezomib , Sinergismo Farmacológico , Ferritinas , Ferroptosis , Hierro , Mieloma Múltiple , Coactivadores de Receptor Nuclear , Humanos , Mieloma Múltiple/metabolismo , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Coactivadores de Receptor Nuclear/metabolismo , Coactivadores de Receptor Nuclear/genética , Bortezomib/farmacología , Ferritinas/metabolismo , Ferroptosis/efectos de los fármacos , Hierro/metabolismo , Línea Celular Tumoral , Autofagia/efectos de los fármacos , Antineoplásicos/farmacología , CarbolinasRESUMEN
This multicenter, open-label, single-arm trial (ClinicalTrials.gov, NCT05236621) was conducted to confirm the efficacy and safety of generic pomalidomide plus dexamethasone in Chinese patients with relapsed or refractory multiple myeloma (RRMM). Total 79 eligible RRMM patients were planned to be included. Patients were treated with generic pomalidomide (4 mg daily on days 1-21, orally) and low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22, orally; 20 mg for patients aged > 75 years) in 28-day cycles until disease progression with a maximum treatment duration of 2 years. The primary endpoint is the overall response rate (ORR) assessed by the independent review committee per the 2016 International Myeloma Working Group guidelines. A total of 85 eligible patients were included in this study from 32 centers in China, with a median age of 62.0 (range, 39-76) years, a median prior line of therapy of 4 (range, 1-16), and 41.2% patients with high-risk cytogenetics. The ORR was 38.8% (95% confidence interval (CI), 28.44-50.01). The disease control rate was 67.1% (95% CI, 56.02-76.87), meanwhile, the median progression-free survival was 5.55 months (95% CI, 3.68-7.52). Among the treatment-related adverse events (TRAEs), infective pneumonia (17.6%) was the most frequent non-hematologic adverse event, while a decrease in neutrophil count (52.9%) was the most common grade ≥ 3 TRAE. The study results indicated that the generic pomalidomide demonstrated consistent efficacy and a safety profile similar to the branded pomalidomide when combined with low-dose dexamethasone in Chinese RRMM patients.Registration number ClinicalTrials.gov NCT05236621, retrospectively registered on February 11, 2022.
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Mieloma Múltiple , Talidomida/análogos & derivados , Humanos , Adulto , Persona de Mediana Edad , Anciano , Mieloma Múltiple/tratamiento farmacológico , Dexametasona , Recurrencia Local de Neoplasia/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
INTRODUCTION: Growth hormone (GH) secreting pituitary adenoma is considered one of the most harmful types of Pituitary Neuroendocrine Tumors (PitNETs). Our previous research has found that high expression of Lysine methyltransferase 5A (KMT5A) is closely related to the proliferation of PitNETs. The aim of this study was to investigate the role and molecular mechanism of KMT5A in the progression of GH PitNETs. METHODS: Immunohistochemistry, qRT-PCR, and Western blot (WB) were used to assess the expression levels of KMT5A in human normal pituitary and GH PitNETs, as well as in rat normal pituitary and GH3 cells. Additionally, we utilized RNA interference technology and treatment with a selective KMT5A inhibitor to decrease the expression of KMT5A in GH3 cells. CCK-8, EdU, flow cytometry (FCM), clone formation, and WB assay were further employed to evaluate the impact of KMT5A on the proliferation of GH3 cells in vitro. A xenograft model was established to evaluate the role of KMT5A in GH PitNETs progression in vivo. RESULTS: KMT5A was highly expressed in GH PitNETs and GH3 cells. Moreover, the reduction of KMT5A expression led to inhibited growth of GH PitNETs and increased apoptosis of tumor cells, as indicated by the findings from CCK-8, EdU, clone formation, and FCM assays. Additionally, WB analysis identified the Wnt/ß-catenin signaling pathway as a potential mechanism through which KMT5A promotes GH PitNETs progression. CONCLUSION: Our research suggests that KMT5A may facilitate the progression of GH PitNETs via the Wnt/ß-catenin signaling pathway. Therefore, KMT5A may serve as a potential therapeutic target and molecular biomarker for GH PitNETs.
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Tumores Neuroendocrinos , Vía de Señalización Wnt , Adulto , Animales , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Ratas , Adenoma/metabolismo , Adenoma/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Progresión de la Enfermedad , Adenoma Hipofisario Secretor de Hormona del Crecimiento/metabolismo , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , N-Metiltransferasa de Histona-Lisina/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , Ratones Desnudos , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/patología , Neoplasias Hipofisarias/metabolismo , Neoplasias Hipofisarias/patología , Vía de Señalización Wnt/fisiología , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
BACKGROUND Nurses in the Intensive Care Unit (ICU) play a critical role in recognizing patients who are at risk of deterioration by conducting continual assessments and taking suitable measures in response to changing health status. The validity of the cluster nursing intervention has been studied previously, but its use among ICU patients with tracheal intubation and extubation has not been examined. This study assessed the effectiveness of cluster nursing intervention in ICU patients with tracheal intubation and extubation. MATERIAL AND METHODS In this retrospective study, 80 patients on mechanical ventilation in the ICU ward were randomly assigned to control and intervention groups (40 patients each). The control group received the routine nursing mode, while the intervention group was given 5 sessions of cluster nursing intervention. Tracheal intubation and extubation-associated complications, blood gas analysis, patient nursing satisfaction, and changes in patients' negative emotions were compared before and after the intervention. RESULTS After the nursing intervention, the levels of PaO2 were higher, while PaCO2 levels were lower in the intervention group compared to the control group (P<0.05). Importantly, anxiety and depression scores in the intervention group were lower than in the control group (P<0.05). Moreover, the overall incidence of complications in the intervention group was lower than in the control group, whereas patient satisfaction with nursing services was higher (P<0.05). CONCLUSIONS Cluster nursing intervention can effectively reduce the incidence of complications and improve patients’ physiological and psychological conditions. Moreover, it enhances patient satisfaction with nursing services, thus improving patients' clinical symptoms.
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Extubación Traqueal , Unidades de Cuidados Intensivos , Intubación Intratraqueal , Humanos , Masculino , Femenino , Intubación Intratraqueal/efectos adversos , Intubación Intratraqueal/métodos , Persona de Mediana Edad , Extubación Traqueal/métodos , Estudios Retrospectivos , Anciano , Respiración Artificial/efectos adversos , Respiración Artificial/métodos , Ansiedad , Adulto , Satisfacción del Paciente , Depresión , Bienestar PsicológicoRESUMEN
BACKGROUND: Hospital chief financial officer (CFO) contributes to improving health system performance. However, how to become an excellent hospital CFO has rarely been considered from a holistic perspective. This paper aims to identify competencies required by hospital CFO to fulfil the position's responsibilities and explore effective implementation pathways to generate high performance and improve healthcare service. METHODS: We conducted 61 semi-structured interviews with individuals in key leadership positions in China's hospitals and researchers focusing on healthcare system management to identify core competencies necessary for hospital CFO. Interviews were analysed through a multi-stage review process and modified via expert vetting using a national panel of 23 professors. Subsequently, interviews were conducted with 32 hospital CFOs from 14 provinces throughout September 2021 to May 2022. We scored the performance of 32 hospital CFOs in various aspects of competency and used the fuzzy-set qualitative comparative analysis to explore the competency configurations of excellent CFOs. RESULTS: We identify seven core competencies necessary for a hospital CFO to fulfil management practices, including personal morality, resource management, strategy management, learning ability, negotiating skill, leadership skill, and financial management. The findings indicate that a single competency factor is not a necessary condition to become an excellent hospital CFO. The results of qualitative comparative analysis then make it possible to propose four configurational paths, namely, supportive, interpersonal, all-around development, and technical, to become an excellent hospital CFO and achieve effective managerial performance. CONCLUSIONS: The responsibilities of hospital CFOs are complex and varied, hence, a better understanding of competencies required by CFO is essential to implement their responsibilities effectively. The identification in this study of the four effective implementation pathways to becoming an excellent hospital CFO enriches the literature on hospital management and provides implications for China's hospitals and their CFOs.
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Personal Docente , Hospitales Públicos , Humanos , Instituciones de Salud , China , LiderazgoRESUMEN
An electrochemical biosensor based on dual-amplified nucleic acid mode and biocatalytic silver deposition was constructed using catalytic hairpin assembly-hybrid chain reaction (CHA-HCR). The electrochemical detection of silver on the electrode by linear sweep voltammetry (LSV) can be utilized to quantitatively measure miR-205-5p since the amount of silver deposited on the electrode is proportional to the target nucleic acid. The current response values exhibit strong linearity with the logarithm of miR-205-5p concentrations ranging from 0.1 pM to 10 µM, and the detection limit is 28 fM. A consistent trend was found in the results of the qRT-PCR and electrochemical biosensor techniques, which were employed to determine the total RNA recovered from cells, respectively. Moreover, the constructed sensor was used to assess miR-205-5p on various cell counts, and the outcomes demonstrated the excellent analytical efficiency of the proposed strategy. The recoveries ranged from 97.85% to 115.3% with RSDs of 2.251% to 4.869% in human serum samples. Our electrochemical biosensor for miR-205-5p detection exhibits good specificity, high sensitivity, repeatability, and stability. It is a potentially useful sensing platform for tumor diagnosis and tumor type identification in clinical settings.
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Técnicas Biosensibles , Técnicas Electroquímicas , Límite de Detección , MicroARNs , Plata , Técnicas Biosensibles/métodos , Humanos , MicroARNs/sangre , MicroARNs/análisis , Plata/química , Técnicas Electroquímicas/métodos , Electrodos , Técnicas de Amplificación de Ácido Nucleico/métodosRESUMEN
This study aimed to explore the association between metabolic-associated fatty liver disease (MAFLD) and ulcer recurrence risk in patients with diabetic foot ulcers (DFUs) through an ambispective longitudinal cohort. From December 2013 to December 2022, a total of 482 inpatients with DFUs (PEDIS grade 3 and above with a severe infection) were eligible for inclusion in this study. This was an ambispective longitudinal cohort study. All participants were followed up every 6 months for 9 years with a median of 36 months. According to whether having MAFLD or not, all subjects were placed into two groups: non-MAFLD (n = 351) and MAFLD (n = 131). The association between MAFLD and ulcer recurrence in patients with DFUs was then evaluated through multivariate Cox regression analysis, stratified analyses and Kaplan-Meier survival analysis. Throughout the follow-up period, out of 482 subjects with DFUs, 68 had ulcer recurrence (14.1%). Three Cox regression models were established for data analyses. In the model I (unadjusted), MAFLD was significantly associated with the ulcer recurrence rate in patients with DFUs (HR = 1.79; 95% CI = 1.097-2.92; p = 0.02). Model II (adjusted model I with gender and age) (HR = 1.781; 95% CI = 1.09-2.912; p = 0.021) and model III (adjusted model II with CVD, duration of diabetes and Cr.) (HR = 1.743; 95% CI = 1.065-2.855; p = 0.027) also showed that MAFLD was significantly related to the ulcer recurrence risk in patients with DFUs, respectively. Stratified analysis indicated that subjects aged ≥60 had a greater risk of ulcer recurrence in MAFLD than in non-MAFLD (HR = 2.31; 95% CI = 1.268-4.206; p = 0.006). Kaplan-Meier survival curve analysis showed that ulcer recurrence rate had a significant association with MAFLD (log-rank, p = 0.018). This study indicated a close association between ulcer recurrence risk and MAFLD in patients with DFUs, especially in the elderly (aged ≥60). Therefore, special attention should be paid to the elderly with both DFUs and MAFLD because they have a higher ulcer recurrence rate than other general populations in routine clinical practice.
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Diabetes Mellitus , Pie Diabético , Hepatopatías , Anciano , Humanos , Pie Diabético/epidemiología , Pie Diabético/etiología , Estudios Longitudinales , Estudios de Cohortes , Hepatopatías/complicacionesRESUMEN
RNF7 has been reported to play critical roles in various cancers. However, the underlying mechanisms of RNF7 in glioma development remain largely unknown. Herein, the expression level of RNF7 was examined in tissues by quantitative real-time PCR, Western blotting and immunohistochemistry. The effect of RNF7 on glioma progression was measured by performing CCK-8 and apoptosis assays, cell cycle-related experiments and animal experiments. The effect of RNF7 on PI3K/AKT signalling pathway was tested by Western blotting. First, we found that RNF7 was upregulated in tumour tissue compared with normal brain tissue, especially in high-grade glioma, and the high expression of RNF7 was significantly related to tumour size, Karnofsky Performance Scale score and a poor prognosis. Second, RNF7 overexpression facilitated tumour cell cycle progression and cell proliferation and suppressed apoptosis. Conversely, RNF7 knockdown suppressed tumour cell cycle progression and cell proliferation and facilitated apoptosis. Furthermore, follow-up mechanistic studies indicated that RNF7 could facilitate glioma cell proliferation and cell cycle progression and inhibit apoptosis by activating the PI3K/AKT signalling pathway. This study shows that RNF7 can clearly promote glioma cell proliferation by facilitating cell cycle progression and inhibiting apoptosis by activating the PI3K/AKT signalling pathway. Targeting the RNF7/PI3K/AKT axis may provide a new perspective on the prevention or treatment of glioma.
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Glioma , Proteínas Proto-Oncogénicas c-akt , Animales , Apoptosis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Glioma/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Desmoglein-2, encoded by DSG2, is one of the desmosome proteins that maintain the structural integrity of tissues, including heart. Genetic mutations in DSG2 cause arrhythmogenic cardiomyopathy, mainly in an autosomal dominant manner. Here, we identified a homozygous stop-gain mutations in DSG2 (c.C355T, p.R119X) that led to complete desmoglein-2 deficiency in a patient with severe biventricular heart failure. Histological analysis revealed abnormal deposition of desmosome proteins, disrupted intercalated disk structures in the myocardium. Induced pluripotent stem cells (iPSCs) were generated from the patient (R119X-iPSC), and the mutated DSG2 gene locus was heterozygously corrected to a normal allele via homology-directed repair (HDR-iPSC). Both isogenic iPSCs were differentiated into cardiomyocytes [induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs)]. Multielectrode array analysis detected abnormal excitation in R119X-iPSC-CMs but not in HDR-iPSC-CMs. Micro-force testing of three-dimensional self-organized tissue rings (SOTRs) revealed tissue fragility and a weak maximum force in SOTRs from R119X-iPSC-CMs. Notably, these phenotypes were significantly recovered in HDR-iPSC-CMs. Myocardial fiber structures in R119X-iPSC-CMs were severely aberrant, and electron microscopic analysis confirmed that desmosomes were disrupted in these cells. Unexpectedly, the absence of desmoglein-2 in R119X-iPSC-CMs led to decreased expression of desmocollin-2 but no other desmosome proteins. Adeno-associated virus-mediated replacement of DSG2 significantly recovered the contraction force in SOTRs generated from R119X-iPSC-CMs. Our findings confirm the presence of a desmoglein-2-deficient cardiomyopathy among clinically diagnosed dilated cardiomyopathies. Recapitulation and correction of the disease phenotype using iPSC-CMs provide evidence to support the development of precision medicine and the proof of concept for gene replacement therapy for this cardiomyopathy.
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Cardiomiopatías/patología , Desmogleína 2/deficiencia , Miocitos Cardíacos/metabolismo , Calcio/metabolismo , Cardiomiopatías/metabolismo , Cardiomiopatía Dilatada/metabolismo , Diferenciación Celular , Desmogleína 2/metabolismo , Desmogleínas/genética , Desmogleínas/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Mutación , Miocardio/metabolismoRESUMEN
The neural mechanisms that support handwriting, an important mode of human communication, are thought to be controlled by a central process (responsible for spelling) and a peripheral process (responsible for motor output). However, the relationship between central and peripheral processes has been debated. Using functional magnetic resonance imaging, this study examined the neural mechanisms underlying this relationship in Chinese handwriting in 36 children (mean age = 10.40 years) and 56 adults (mean age = 22.36 years) by manipulating character frequency (a central variable). Brain network analysis showed that character frequency reconfigured functional brain networks known to underlie motor processes, including the somatomotor and cerebellar network, in both children and adults, indicating that central processing cascades into peripheral processing. Furthermore, the network analysis characterized the interaction profiles between motor networks and linguistic-cognitive networks, fully mapping the neural architecture that supports the interaction of central and peripheral processes involved in handwriting. Taken together, these results reveal the neural interface underlying the interaction between central and peripheral processes involved in handwriting in a logographic writing system, advancing our understanding of the neural basis of handwriting.
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Encéfalo , Pueblos del Este de Asia , Humanos , Adulto , Niño , Adulto Joven , Encéfalo/diagnóstico por imagen , Escritura Manual , Mapeo Encefálico , LenguajeRESUMEN
Multiple myeloma (MM) is the second largest hematological tumor with clonal proliferation of malignant plasma cells. Growing reports have revealed that the dysregulation of long non-coding RNA (lncRNA) is involved in the MM progression. Nevertheless, lncRNA FEZF1 antisense RNA 1 (FEZF1-AS1) remain not deeply explored. The RNA transcripts and protein level of MM-associated molecule were measured by quantitative real-time polymerase chain reaction or western blot assays, respectively. The clinical correlation was analyzed by Pearson analysis. Molecular interactions among lncRNA FEZF1-AS1, basic leucine zipper and W2 domain 2 (BZW2) and insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) were verified by RNA immunoprecipitation and RNA pull-down assays. The survival of MM cells was detected by cell counting kit-8 and flow cytometry assays. Xenograft tumor in vivo was performed to assess tumor growth. The RNA transcripts of lncRNA FEZF1-AS1, BZW2 and IGF2BP1 were upregulated in MM samples compared to those in healthy donors. Knockdown of lncRNA FEZF1-AS1 could inhibit the proliferation and induce cell apoptosis in vitro and in vivo. Besides, lncRNA FEZF1-AS1 could maintain the stability of BZW2 mRNA by interacting IGF2BP1. Moreover, BZW2 silence also downregulated the proliferation but enhanced apoptosis of MM cells, while BZW2 overexpression had an opposite role, which dramatically reversed the regulatory roles of lncRNA FEZF1-AS1. Altogether, lncRNA FEZF1-AS1 facilitated MM development by regulating IGF2BP1/BZW2 signaling, suggesting that lncRNA FEZF1-AS1 might be a candidate for MM treatment.
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Mieloma Múltiple , ARN Largo no Codificante , Humanos , ARN Largo no Codificante/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Mieloma Múltiple/genética , Transducción de Señal , ARN Mensajero , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismoRESUMEN
Fatigue has many negative effects on human health. As such, it is desirable to develop anti-fatigue foods and understand the mechanisms of their action. Based on a comprehensive review of the literature, this article discusses the important roles of gut microbiota in fatigue and anti-fatigue. Studies have shown that an increase in pathogenic bacteria and a decrease in beneficial bacteria co-exist when fatigue is present in both rodents and humans, whereas changes in gut microbiota were reported after intervention with anti-fatigue foods. The roles of gut microbiota in the activities of anti-fatigue foods can also be explained in the causes and the effects of fatigue. Among the causes of fatigue, the accumulation of lactic acid, decrease of energy, and reduction of central nervous system function were related to gut microbiota metabolism. Among the harmful effects of fatigue, oxidative stress, inflammation, and intestinal barrier dysfunction were related to gut microbiota dysbiosis. Furthermore, gut microbiota, together with anti-fatigue foods, can inhibit pathogen growth, convert foods into highly anti-oxidative or anti-inflammatory products, produce short-chain fatty acids, maintain intestinal barrier integrity, inhibit intestinal inflammation, and stimulate the production of neurotransmitters that regulate the central nervous system. Therefore, it is believed that gut microbiota play important roles in the activities of anti-fatigue foods and may provide new insights on the development of anti-fatigue foods.
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Enfermedades Gastrointestinales , Microbioma Gastrointestinal , Humanos , Intestinos/microbiología , Inflamación , Bacterias/metabolismo , DisbiosisRESUMEN
Obesity is a serious health problem in modern life and increases the risk of many comorbidities including iron dyshomeostasis. In contrast to malnourished anemia, obesity-related iron dyshomeostasis is mainly caused by excessive fat accumulation, inflammation, and disordered gut microbiota. In obesity, iron dyshomeostasis also induces disorders associated with gut microbiota, neurodegenerative injury, oxidative damage, and fat accumulation in the liver. Selenium deficiency is often accompanied by obesity or iron deficiency, and selenium supplementation has been shown to alleviate obesity and overcome iron deficiency. Selenium inhibits fat accumulation and exhibits anti-inflammatory activity. It regulates gut microbiota, prevents neurodegenerative injury, alleviates oxidative damage to the body, and ameliorates hepatic fat accumulation. These effects theoretically meet the requirements for the inhibition of factors underlying obesity-related iron dyshomeostasis. Selenium supplementation may have a potential role in the alleviation of obesity-related iron dyshomeostasis. This review verifies this hypothesis in theory. All the currently reported causes and results of obesity-related iron dyshomeostasis are reviewed comprehensively, together with the effects of selenium. The challenges and strategies of selenium supplementation are also discussed. The findings demonstrate the possibility of selenium-containing drugs or functional foods in alleviating obesity-related iron dyshomeostasis.
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Deficiencias de Hierro , Selenio , Humanos , Hierro , Selenio/farmacología , Selenio/uso terapéutico , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Hígado , Dieta Alta en GrasaRESUMEN
OBJECTIVE: Environmental contaminants such as cadmium (Cd) may have a deleterious impact on sperm and reduce male fertility by compromising the blood-testis barrier (BTB). Hence, the effects of the traditional Chinese medicine Qiangjing tablet (QJP) on sperm quality and BTB alterations induced by Cd in mouse testes were examined. METHODS: Adult KM mice challenged with Cd chloride were examined, QJP was administered to mice as an oral drug by gavage, and the experiments lasted 2 weeks. Testicular and epididymal weights, sperm quality, anti-sperm antibodies (AsAb), hormone levels, and histology were evaluated. Changes in the levels of N-cadherin, occludin, ZO-1, claudin-11, F-actin, and ß-tubulin and their mRNAs were evaluated. The effects of QJP on the PI3K/Akt/Rictor pathway were evaluated. RESULTS: CdCl2 decreased reproductive organ weight, sperm quality, and testosterone (T) levels; increased AsAb, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels; induced structural damage in testicles with BTB disruption; increased BTB permeability; and decreased N-cadherin, occludin, ZO-1, claudin-11, F-actin, and ß-tubulin expression. After treatment, QJP blocked the effects of Cd on reproductive organ weight, sperm quality, and T; mitigated germinal epithelium compartment alterations; decreased AsAb, FSH, and LH levels; and preserved BTB ultrastructure and function. In addition, QJP induced increases in N-cadherin, occludin, ZO-1, claudin-11, F-actin, and ß-tubulin levels and the expression of their mRNAs through the PI3K/Akt/Rictor pathway. After the application of JRAB2011, the levels of a specific mTORC2 suppressor, Rictor, and the BTB-protective effect of QJP were greatly reduced. CONCLUSIONS: We demonstrated the effect of QJP against Cd-induced damage to the BTB, and the results indicate that QJP may play a significant role in opposing the effects of Cd through the PI3K/Akt/Rictor pathway.
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Barrera Hematotesticular , Fosfatidilinositol 3-Quinasas , Ratones , Masculino , Animales , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Cadmio/metabolismo , Actinas/metabolismo , Tubulina (Proteína)/metabolismo , Tubulina (Proteína)/farmacología , Ocludina/metabolismo , Medicina Tradicional China , Testículo , Transducción de Señal , Factores de Transcripción/metabolismo , Cadherinas/metabolismo , Hormona Folículo Estimulante/metabolismo , Claudinas/metabolismo , EspermatogénesisRESUMEN
BACKGROUND: Pulmonary neuroendocrine tumors (pNETs) include typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung carcinoma (SCLC). The optimal treatment strategy for each subtype remains elusive, partly due to the lack of comprehensive understanding of their molecular features. We aimed to explore differential genomic signatures in pNET subtypes and identify potential prognostic and therapeutic biomarkers. METHODS: We investigated genomic profiles of 57 LCNECs, 49 SCLCs, 18 TCs, and 24 ACs by sequencing tumor tissues with a 520-gene panel and explored the associations between genomic features and prognosis. RESULTS: Both LCNEC and SCLC displayed higher mutation rates for TP53, PRKDC, SPTA1, NOTCH1, NOTCH2, and PTPRD than TC and AC. Small cell lung carcinoma harbored more frequent co-alterations in TP53-RB1, alterations in PIK3CA and SOX2, and mutations in HIF-1, VEGF and Notch pathways. Large cell neuroendocrine carcinoma (12.7 mutations/Mb) and SCLC (11.9 mutations/Mb) showed higher tumor mutational burdens than TC (2.4 mutations/Mb) and AC (7.1 mutations/Mb). 26.3% of LCNECs and 20.8% of ACs harbored alterations in classical non-small cell lung cancer driver genes. The presence of alterations in the homologous recombination pathway predicted longer progression-free survival in advanced LCNEC patients with systemic therapy (P = .005) and longer overall survival (OS) in SCLC patients with resection (P = .011). The presence of alterations in VEGF (P = .048) and estrogen (P = .018) signaling pathways both correlated with better OS in patients with resected SCLC. CONCLUSION: We performed a comprehensive genomic investigation on 4 pNET subtypes in the Chinese population. Our data revealed distinctive genomic signatures in subtypes and provided new insights into the prognostic and therapeutic stratification of pNETs.