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Bile cell-free DNA (cfDNA) has been reported as a promising liquid biopsy tool for cholangiocarcinoma (CCA), however, the whole-genome mutation landscape and structural variants (SVs) of bile cfDNA remains unknown. Here we performed whole-genome sequencing on bile cfDNA and analyzed the correlation between mutation characteristics of bile cfDNA and clinical prognosis. TP53 and KRAS were the most frequently mutated genes, and the RTK/RAS, homologous recombination (HR), and HIPPO were top three pathways containing most gene mutations. Ten overlapping putative driver genes were found in bile cfDNA and tumor tissue. SVs such as chromothripsis and kataegis were identified. Moreover, the hazard ratio of HR pathway mutations were 15.77 (95% CI: 1.571-158.4), patients with HR pathway mutations in bile cfDNA exhibited poorer overall survival (P = 0.0049). Our study suggests that bile cfDNA contains genome mutations and SVs, and HR pathway mutations in bile cfDNA can predict poor outcomes of CCA patients.
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Osmotic energy from the ocean has been thoroughly studied, but that from saline-alkali lakes is constrained by the ion-exchange membranes due to the trade-off between permeability and selectivity, stemming from the unfavorable structure of nanoconfined channels, pH tolerance, and chemical stability of the membranes. Inspired by the rapid water transport in xylem conduit structures, we propose a horizontal transport MXene (H-MXene) with ionic sequential transport nanochannels, designed to endure extreme saline-alkali conditions while enhancing ion selectivity and permeability. The H-MXene demonstrates superior ion conductivity of 20.67 S m-1 in 1 M NaCl solution and a diffusion current density of 308 A m-2 at a 10-fold salinity gradient of NaCl solution, significantly outperforming the conventional vertical transport MXene (V-MXene). Both experimental and simulation studies have confirmed that H-MXene represents a novel approach to circumventing the permeability-selectivity trade-off. Moreover, it exhibits efficient ion transport capabilities, addressing the gap in saline-alkali osmotic power generation.
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Introduction: Osteoporosis is a prevalent challenge in clinical orthopedics, affecting a significant percentage of individuals aged 50 and above. The goal of this study was to comprehensively understand the relationships between a specialized dietary regimen and the risk of developing osteoporosis. Methods: This study employed extensive genome-wide association study (GWAS) summary statistics derived from the UK Biobank. It encompassed 8 kinds of special diets and 7 datasets pertaining to osteoporosis and associated symptoms. The principal analytical approach employed was the inverse-variance weighted method. Additionally, sensitivity analysis was employed to elucidate the diverse multiplicity patterns observed in the final model. Results: Our results showed that there is significant evidence that a gluten-free diet is associated with osteoporosis [odds ratio (OR): 1.080, 95% confidence interval (CI): 1.048-1.112, p = 4.23E-07)]. Furthermore, there exists a suggestive link between the three distinct dietary approaches and osteoporosis [(OR: 0.949, 95%CI: 0.929-0.970, p = 3.00E-06) for comprehensive consumption; (OR: 1.053, 95%CI: 1.018-1.089, p = 2.23E-03) for abstaining from wheat consumption; (OR: 1.036, 95%CI: 1.005-1.068, p = 1.97E-02) for abstaining from sugar consumption]. No additional correlation between the special dietary regimens and osteoporosis has been observed. Conclusion: Our research has uncovered a notable correlation between a gluten-free diet and the occurrence of osteoporosis. Furthermore, it exerts a promoting influence on the onset of osteoporosis, which stands in direct contradiction to the therapeutic principles for Celiac Disease's complications. As such, a novel association among these three elements is postulated.
Subject(s)
Genome-Wide Association Study , Mendelian Randomization Analysis , Osteoporosis , Humans , Osteoporosis/epidemiology , United Kingdom/epidemiology , Incidence , Female , Male , Middle Aged , Diet, Gluten-Free/statistics & numerical data , Risk Factors , Aged , Diet/statistics & numerical dataABSTRACT
Soft actuators, pivotal for converting external energy into mechanical motion, have become increasingly vital in a wide range of applications, from the subtle engineering of soft robotics to the demanding environments of aerospace exploration. Among these, electrochemically-driven actuators (EC actuators), are particularly distinguished by their operation through ion diffusion or intercalation-induced volume changes. These actuators feature notable advantages, including precise deformation control under electrical stimuli, freedom from Carnot efficiency limitations, and the ability to maintain their actuated state with minimal energy use, akin to the latching state in skeletal muscles. This review extensively examines EC actuators, emphasizing their classification based on diverse material types, driving mechanisms, actuator configurations, and potential applications. It aims to illuminate the complicated driving mechanisms of different categories, uncover their underlying connections, and reveal the interdependencies among materials, mechanisms, and performances. We conduct an in-depth analysis of both conventional and emerging EC actuator materials, casting a forward-looking lens on their trajectories and pinpointing areas ready for innovation and performance enhancement strategies. We also navigate through the challenges and opportunities within the field, including optimizing current materials, exploring new materials, and scaling up production processes. Overall, this review aims to provide a scientifically robust narrative that captures the current state of EC actuators and sets a trajectory for future innovation in this rapidly advancing field.
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In the clinical diagnosis and treatment of children with short stature, mental health issues merit special attention. It is widely acknowledged that the psychological well-being of children with short stature is lower than that of their peers with normal height. Therefore, during the diagnosis, treatment, and care of short stature, it is crucial to actively monitor the mental health of these children, promptly identify potential psychological and behavioral issues, and intervene accordingly. Such measures play a positive role in enhancing the quality of life of these children and improving their physical and mental health. This article analyses and discusses the current state of psychological assessment and psycho-behavioral interventions for children with short stature, aiming to provide insights for improving their mental health.
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Mental Health , Humans , Child , Body HeightABSTRACT
Cancer stem cells (CSCs) play a pivotal role in the pathogenesis of human cancers. Previous studies have highlighted the role of long non-coding RNA (lncRNA) in modulating the stemness of CSCs. In our investigation, we identified an upregulation of lncRNA FOXD1-AS1 in CSCs. The enforced expression of lncRNA FOXD1-AS1 promotes tumorigenesis and self-renewal in pancreatic cancer CSCs. Conversely, the knockdown of lncRNA FOXD1-AS1 inhibits tumorigenesis and self-renewal in pancreatic cancer CSCs. Furthermore, our findings reveal that lncRNA FOXD1-AS1 enhances self-renewal and tumorigenesis in pancreatic cancer CSCs by up-regulating osteopontin/secreted phosphoprotein 1(SPP1) and acting as a ceRNA to sponge miR-570-3p in pancreatic cancer (PC) CSCs. Additionally, lncRNA FOXD1-AS1 depleted pancreatic cancer cells exhibit heightened sensitivity to 5-FU-indued cell growth inhibition and apoptosis. Analysis of patient-derived xenografts (PDX) indicates that a low level of lncRNA FOXD1-AS1 may serve as a predictor of 5-FU benefits in PC patients. Moreover, the introduction of SPP1 can reverse the sensitivity of lncRNA FOXD1-AS1-knockdown PC cells to 5-FU-induced cell apoptosis. Importantly, molecular studies have indicated that the elevated levels of lncRNAFOXD1-AS1 in PC are facilitated through METTL3 and YTHDF1-dependent m6A methylation. In summary, our results underscore the critical functions of lncRNA FOXD1-AS1 in the self-renewal and tumorigenesis of pancreatic cancer CSCs, positioning lncRNA FOXD1-AS1 as a promising therapeutic target for PC.
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Background: High mobility group box 2 (HMGB2) is abnormally expressed in human cancers and participated in multiple biological behaviors, such as proliferation, invasion and prognosis. However, its role in hepatocellular carcinoma (HCC) is largely unknown. Methods: In clinical sample analysis, 62 HCC patients were enrolled in this study. The expression of HMGB2 was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical method, clinical prognosis data were analyzed by Kaplan-Meier analysis. In cellular and molecular biology experiments, HMGB2 expression was analyzed in HCC cells. HMGB2 knockdown model was constructed by small interfering RNA (siRNA). Cell counting kit-8 (CCK-8) and cell migration & invasion assay were used to evaluate cell proliferative potential and motility. Recombinant human vimentin protein was used to partially restore the expression and function of vimentin. Western blot and immunochemical staining were performed to detect HMGB2 protein, zinc finger E-box binding homeobox 1 (ZEB1) and vimentin. Flow cytometry analyses were performed to determine the alteration of cell cycle in different groups. Results: HMGB2 was abnormally overexpressed in HCC. HMGB2 knockdown reduced malignant behaviors especially the proliferative potential and motility of HCC cells. The inhibition of HCC cells proliferation and mobility could be partially restored via treatment with recombinant vimentin protein. Our findings confirmed abnormal activation of HMGB2-ZEB1 vimentin axis facilitates HCC malignant proliferation and motility. The elevated HMGB2 expression in clinical samples was related to postoperative survival time of HCC patients. It indicated HMGB2 promotes the proliferation and motility potential of HCC via HMGB2-ZEB1-vimentin axis activation. Conclusions: HMGB2 is up-regulated in HCC and affects the malignant transformation by modulating HMGB2-ZEB1-vimentin signaling pathway, which may provide a research basis for evaluating the disease progression and developing clinical treatment strategies of HCC.
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Sarcopenia, as an increasingly pressing clinical issue, can be ameliorated through employment of traditional Chinese medicines. However, the current lack of specific pharmacological interventions for Sarcopenia necessitates further exploration of novel possibilities in traditional Chinese medicine for the treatment of this condition, utilizing advanced methodologies such as web pharmacology and data mining. Screening the essential targets of Sarcopenia, conducting matching between target and active molecules, as well as active molecules and herbs. Employing data mining techniques to analyze the screening outcomes, and molecular docking to compare the binding activities of active molecules with target proteins. The approach of using herbs for the treatment of Sarcopenia involves 13 targets, with 414 active compounds and 367 types of herbs. Data mining reveals that the herbs used in treating Sarcopenia are primarily characterized by their bitter taste, exerting their effects through dispelling dampness and promoting blood circulation. Moreover, 2 new formulas are postulated. Furthermore, molecular docking analysis indicates that the main active components of the herbs can be observed to tightly bind with the targets. Through network pharmacology and molecular docking, our findings reveal that herbs contain 15 key active components and 5 key targets, which correspond to 7 major herbs and 2 new formulas. Academically, these findings hold significant reference value for the development of novel drugs targeting Sarcopenia.
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Drugs, Chinese Herbal , Sarcopenia , Humans , Medicine, Chinese Traditional/methods , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Drugs, Chinese Herbal/chemistry , Network Pharmacology , Molecular Docking Simulation , Sarcopenia/drug therapy , Data MiningABSTRACT
Ferroptosis is a form of regulated cell death induced by iron-dependent lipid peroxidation, and it has been studied extensively since its discovery in 2012. Induced by iron overload and ROS accumulation, ferroptosis is modulated by various cellular metabolic and signaling pathways. The GSH-GPX4 pathway, the FSP1-CoQ10 pathway, the GCH1-BH4 pathway, the DHODH-CoQH2 system and the sex hormones suppress ferroptosis. Mitochondrial iron metabolism regulates ferroptosis and mitochondria also undergo a morphological change during ferroptosis, these changes include increased membrane density and reduced mitochondrial cristae. Moreover, mitochondrial energy metabolism changes during ferroptosis, the increased oxidative phosphorylation and ATP production rates lead to a decrease in the glycolysis rate. In addition, excessive oxidative stress induces irreversible damage to mitochondria, diminishing organelle integrity. ROS production, mitochondrial membrane potential, mitochondrial fusion and fission, and mitophagy also function in ferroptosis. Notably, some ferroptosis inhibitors target mitochondria. Ferroptosis is a major mechanism for cell death associated with the progression of cancer. Metastasis-prone or metastatic cancer cells are more susceptible to ferroptosis. Inducing ferroptosis in tumor cells shows very promising potential for treating drug-resistant cancers. In this review, we present a brief retrospect of the discovery and the characteristics of ferroptosis, then we discuss the regulation of ferroptosis and highlight the unique role played by mitochondria in the ferroptosis of cancer cells. Furthermore, we explain how ferroptosis functions as a double-edged sword as well as novel therapies aimed at selectively manipulating cell death for cancer eradication.
Subject(s)
Ferroptosis , Neoplasms , Reactive Oxygen Species/metabolism , Mitochondria/metabolism , Oxidative Stress , Iron/metabolism , Neoplasms/metabolismABSTRACT
Hepatocellular carcinoma (HCC) is an intractable malignant disease with high incidence rate annually. LincRNA PRNCR1 has been confirmed as a tumor supporter, while its functions in HCC remain unclear. This study aims to explore the mechanism of LincRNA PRNCR1 in hepatocellular carcinoma. The qRT-PCR was applied to the quantification of non-coding RNAs. Cell counting Kit-8 (CCK-8), Transwell assay and flow cytometry assay were applied to reflect the change in the phenotype of HCC cells. Moreover, the databases including Targetscan and Starbase and dual-luciferase reporter assay were applied to investigate the interaction of the genes. The western blot was applied to detect the abundance of proteins and the activity of the related pathways. Elevated LincRNA PRNCR1 was dramatically upregulated in HCC pathological samples and cell lines. MiR-411-3p served as a target of LincRNA PRNCR1, and decreased miR-411-3p was found in the clinical samples and cell lines. LincRNA PRNCR1 downregulation could induce the expression of miR-411-3p, and LincRNA PRNCR1 silence could impede the malignant behaviors via increasing the abundance of miR-411-3p. Zinc finger E-box binding homeobox 1 (ZEB1) was confirmed as a target of miR-411-3p, which remarkably upregulated in HCC cells, and ZEB1 upregulation could significantly rescue the effect of miR-411-3p on malignant behaviors of HCC cells. Moreover, LincRNA PRNCR1 was confirmed to involve the Wnt/ß-catenin pathway via regulating miR-411-3p/ZEB1 axis. This study suggested that LincRNA PRNCR1 could drive the malignant progression of HCC via regulating miR-411-3p/ZEB1 axis.
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Sichuan hotpot oil is a distinctive traditional Chinese cuisine, and chili pepper is an essential material for its flavor formation. In this study, the effect of chili pepper cultivars on capsaicinoids as well as Sichuan hotpot oil volatile compounds were examined. Gas chromatography-mass spectrometry (GC-MS) and chemometrics were employed to ascertain the differences between volatile components and flavor. The results showed that the EJT hotpot oil had the highest color intensity of 34.8, and the SSL hotpot oil had the highest capsaicinoids content of 1.536 g/kg. The results of QDA showed distinct differences among hotpot oils in terms of all sensory properties. A total of 74 volatile components were detected. Aldehydes, ketones, esters, and acids were the dominant volatile compounds formed in 18 hotpot oil samples and showed a significant difference, suggesting that they played a key role in flavor contribution and distinguishing the flavor differences between different hotpot oils. The PCA results well distinguished 18 kinds of hotpot oil.
Subject(s)
Capsicum , Aldehydes , Camphor , Esters , Menthol , OilsABSTRACT
Extramedullary infiltration (EMI) is a concomitant manifestation that may indicate poor outcome of acute myeloid leukemia (AML). The underlying mechanism remains poorly understood and therapeutic options are limited. Here, we employed single-cell RNA sequencing on bone marrow (BM) and EMI samples from a patient with AML presenting pervasive leukemia cutis. A complement C1Q+ macrophage-like leukemia subset, which was enriched within cutis and existed in BM before EMI manifestations, was identified and further verified in multiple patients with AML. Genomic and transcriptional profiling disclosed mutation and gene expression signatures of patients with EMI that expressed high levels of C1Q. RNA sequencing and quantitative proteomic analysis revealed expression dynamics of C1Q from primary to relapse. Univariate and multivariate analysis demonstrated adverse prognosis significance of C1Q expression. Mechanistically, C1Q expression, which was modulated by transcription factor MAF BZIP transcription factor B, endowed leukemia cells with tissue infiltration ability, which could establish prominent cutaneous or gastrointestinal EMI nodules in patient-derived xenograft and cell line-derived xenograft models. Fibroblasts attracted migration of the C1Q+ leukemia cells through C1Q-globular C1Q receptor recognition and subsequent stimulation of transforming growth factor ß1. This cell-to-cell communication also contributed to survival of C1Q+ leukemia cells under chemotherapy stress. Thus, C1Q served as a marker for AML with adverse prognosis, orchestrating cancer infiltration pathways through communicating with fibroblasts and represents a compelling therapeutic target for EMI.
Subject(s)
Complement C1q , Leukemia, Myeloid, Acute , Humans , Proteomics , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Bone Marrow/metabolism , Prognosis , Chronic Disease , RecurrenceABSTRACT
The altitudinal patterns of soil fungi have attracted considerable attention; however, few studies have investigated the diversity and community assembly of fungal functional guilds along an altitudinal gradient. Here, we explored ectomycorrhizal (EcM) and saprotrophic (SAP) fungal diversity and community assembly along a 470 m vertical gradient (ranging from 830 to 1300 m) on Oakley Mountain, sampling bulk soils in the 0-10 cm and 10-20 cm soil layers of Larix gmelinii-dominated forests. Illumina MiSeq sequencing of the ITS genes was employed to explore the fungal community composition and diversity. The relative abundance of EcM and SAP fungi showed a divergent pattern along an altitudinal gradient, while we observed a consistent altitudinal tendency for EcM and SAP fungal diversity and community assembly. The diversity of both fungal guilds increased with increasing altitude. Altitude and soil moisture were the key factors affecting the community composition of both fungal guilds. In addition, the plant community composition significantly affected the EcM fungal community composition, whereas the dissolved organic nitrogen and ammonium nitrogen contents were the driving factors of SAP fungal community. Despite the effects of vegetation and soil factors, EcM and SAP fungal communities were mainly governed by stochastic processes (especially drift) at different altitudes and soil depths. These results shed new light on the ecology of different fungal functional guilds along an altitudinal gradient, which will provide a deeper understanding of the biogeography of soil fungi.
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The hydrolysis time is directly related to the flavor of the Maillard reaction, but existing proxy models cannot simulate and model the variation curves of vital volatile components. This study developed a predictive model for modelling and simulating key volatile compounds of Maillard reaction products (MRPs) derived from beef tallow residue hydrolysate. Results showed the degree of hydrolysis increased with hydrolysis time, and the most significant improvement in the roast flavor and overall acceptance was when hydrolyzing 4 h. Based on flavor dilution value and the relative odor activity value, nine key volatile components were identified, and 2-ethyl-3,5-dimethylpyrazine with roast flavor was the highest. Compared with Polynomial Curve Fitting (PCF) and Cubic Spline Interpolation (CSI), key volatile compounds of MRPs could be better modeled and simulated by the Curve Prediction Model (CPM). All results suggested that CPM could predict the changes in key volatile components produced by MRPs.
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The beef flavor of beef tallow residue was improved by enzymatic hydrolysis followed by the Maillard reaction, and the flavor could be predicted using an artificial neural network. Five beef tallow residue hydrolysates were prepared using different enzymes. The Flavourzyme and Papain (FP) hydrolysate had low molecular weight peptides and high degree of hydrolysis and free amino acid content. We identified 49 main compounds, including aldehydes, pyrazines, and furan. Furan and pyrazine were the dominant volatile compounds in the five beef tallow residue-derived Maillard reaction products (MRPs), and their profiles and levels in the FP MRPs were high. The FP MRPs had the best sensory characteristics. The artificial neural network analysis revealed that the multiple input single output model had a better performance than the single input single output model, and the prediction accuracy was>90%, indicating that the MRPs sensory evaluation scores could be accurately predicted.
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Objectives: This study aimed to examine the incidence of bifid pancreatic duct (BPD) in pancreaticoduodenectomy (PD) and clarify its impact on clinically relevant postoperative pancreatic fistula (CR-POPF). Background: Until now, all the literature about BPD during PD are published as case reports, and the incidence of BPD in PD and its impact on CR-POPF remain unknown. Results: A total of 438 consecutive PDs were divided into two groups: the former year group and the latter year group. The former year group included 215 consecutive PDs, while the latter year group included 223. In the latter year group, we found 16 BPDs during PD (O-BPD); the incidence of O-BPD is 7.17%. Of them, there were eight patients who had BPD in the preoperative imaging (I-BPD). All the I-BPDs are O-BPDs; which means that 50% of O-BPDs were a single pancreatic duct in the preoperative imaging (I-SPD). There were 17 I-BPDs in the 438 consecutive PDs; the incidence of I-BPD is 3.88%. In the former year group, the rate of severe complications of I-BPD and I-SPD is 77.78% and 27.18%, respectively (p = 0.003); the rate of CR-POPF of I-BPD is higher than I-SPD, 55.56% vs. 27.18%, but there were no statistically significant differences. In the latter year group, the rate of severe complications of O-BPD and O-SPD is 50% and 18.36%, and the rate of CR-POPF of O-BPD and O-SPD is 37.5% and 22.22%, respectively; both of them have statistically significant differences, and the p-value is 0.003 and 0.006, respectively. In the subgroup analysis, both the rate of severe complications and the rate of CR-POPF of I-BPD were higher than O-BPD, 77.78% vs. 50%, and 55.56% vs. 37.5%, but there were no statistically significant differences in both of them; the p-value is 0.174 and 0.434, respectively. Univariate and multivariate analyses showed that BPD was an independent risk factor of CR-POPF. Conclusions: The incidence of O-BPD in PD is 7.17%, 50% of O-BPDs were I-SPD, and the incidence of I-BPD is 3.88%. BPD is an independent risk factor of CR-POPF. The suture closure method may be a simple, safe, and effective method in dealing with BPD in PD.
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Drought is a critical and increasingly common abiotic factor that has impacts on plant structures and functioning and is a challenge for the successful management of forest ecosystems. Here, we test the shifts in leaf morpho-anatomical or hydraulic traits and plant growth above ground caused by drought. A factorial experiment was conducted with two gymnosperms (Larix gmelinii and Pinus koraiensis) and two angiosperms (Fraxinus mandshurica and Tilia amurensis), tree species grown under three varying drought intensities in NE China. Considering all the species studied, the plant height (PH), root collar diameter (RCD), and plant biomass (PB) were significantly decreased by drought. The leaf thickness (LT) increased, while the leaf area (LA) decreased with drought intensity. In the gymnosperms, the mesophyll thickness (MT) increased, and the resin duct decreased, while in the angiosperms the palisade mesophyll thickness (PMT), the spongy mesophyll thickness (SMT), and the abaxial (ABE) and adaxial epidermis (ADE) thickness were increased by drought. The correlation analysis revealed that P. koraiensis and F. mandshurica had the higher RMF and total plant biomass, but the least LMF, suggesting drought tolerance. In contrast, the L. gmelinii had the least RMF and higher LMF, suggesting vulnerability to drought. Similarly, T. amurensis had the higher leaf size, which increased the evaporative demand and depleted the soil water quickly relative to the other species. The interrelation among the morpho-anatomical leaf traits was equally affected by drought across all the studied species, suggesting that there is no clear evidence to differentiate the taxa based on drought resistance vs. drought tolerance. Thus, we have identified some easily measurable traits (i.e., LMF, RMF, and PB) which evidenced the seedling's ability to cope with drought and which therefore could be used as proxies in the selection of drought tolerant species for reforestation in the temperate forest.
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Increasing upconversion luminescence (UCL) to overcome the intrinsically low conversion efficiency of upconversion nanoparticles (UCNPs) poses a fundamental challenge. Photonic nanostructures are the efficient approaches for UCL enhancement by tailoring the local electromagnetic fields. Unfortunately, such nanostructures are sensitive to environmental conditions, and the regulation strength is varied in flexible applications. Here, we report giant UCL enhancement from a flexible UCNP-embedded film coupled with a microsphere photonic superlens (MPS), by which the enhancement ratio of UCL is over 104-fold under 808 nm excitation down to 0.72 mW. The enhancement pathways of MPS-enhanced UCL are attributed to Mie-resonant nanofocusing for high excitation-photon density, optical whispering-gallery modes (WGMs) for fast radiative decay, and the directional antenna effect for far-field emission confinement. The contribution of optical resonance in the MPS to suppressing the phonon-induced nonradiative transition and thermal quenching is experimentally validated. The UCL quantum yield is therefore improved by 3-fold to 4.20% under 120 mW/cm2 near-infrared excitation, consistent with the enhancement ratio via the Purcell effect of WGMs. Furthermore, the MPS demonstrates the robust optical regulation capability toward flexible applications, opening up new opportunities for facilitating multiphoton upconversion in wearable optoelectrical devices for nanoimaging, biosensing, and energy conversion in the future.
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Chronic myeloid leukemia (CML) are initiated and sustained by self-renewing malignant CD34+ stem cells. Extensive efforts have been made to reveal the metabolic signature of the leukemia stem/progenitor cells in genomic, transcriptomic, and metabolomic studies. However, very little proteomic investigation has been conducted and the mechanism regarding at what level the metabolic program was rewired remains poorly understood. Here, using label-free quantitative proteomic profiling, we compared the signature of CD34+ stem/progenitor cells collected from CML individuals with that of healthy donors and observed significant changes in the abundance of enzymes associated with aerobic central carbonate metabolic pathways. Specifically, CML stem/progenitor cells expressed increased tricarboxylic acid cycle (TCA) with decreased glycolytic proteins, accompanying by increased oxidative phosphorylation (OXPHOS) and decreased glycolysis activity. Administration of the well-known OXPHOS inhibitor metformin eradicated CML stem/progenitor cells and re-sensitized CD34+ CML cells to imatinib in vitro and in patient-derived tumor xenograft murine model. However, different from normal CD34+ cells, the abundance and activity of OXPHOS protein were both unexpectedly elevated with endoplasmic reticulum stress induced by metformin in CML CD34+ cells. The four major aberrantly expressed protein sets, in contrast, were downregulated by metformin in CML CD34+ cells. These data challenged the dependency of OXPHOS for CML CD34+ cell survival and underlined the novel mechanism of metformin. More importantly, it suggested a strong rationale for the use of tyrosine kinase inhibitors in combination with metformin in treating CML.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Metformin , Animals , Antigens, CD34/metabolism , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Metformin/pharmacology , Mice , Neoplastic Stem Cells/metabolism , Oxidative Phosphorylation , Protein Kinase Inhibitors/pharmacology , ProteomicsABSTRACT
The Fenton-like reaction has great potential in water treatment. Herein, an efficient and reusable catalytic system is developed based on atomically dispersed Fe catalyst by anchoring Fe atoms on nitrogen-doped porous carbon (Fe SA/NPCs). The catalyst of Fe SA/NPCs exhibits enhanced performance in activating peroxymonosulfate (PMS) for organic pollutant degradation and bacterial inactivation. The Fe SA/NPCs + PMS system demonstrates a high turnover frequency of 39.31 min-1 in Rhodamine B (RhB) degradation as well as a strong bactericidal activity that can completely sterilize an Escherichia coli culture within 5 min. Meanwhile, the degradation activity of RhB by Fe SA/NPCs is improved up to 28 to 371-fold in comparison with the controls. Complete degradation of RhB can be achieved in 30 s by the Fe SA/NPCs + PMS system, demonstrating an efficiency much higher than most traditional Fenton-like processes. Experiments with different radical scavengers and density functional theory calculations have revealed that singlet oxygen (1 O2 ) generated on the N-coordinated single Fe atom (Fe-N4 ) sites is the key reactive species for the effective and rapid pollutant degradation and bacterial inactivation. This work innovatively affords a promising single-Fe-atom catalyst/PMS system for applying Fenton-like reactions in water treatment.