ABSTRACT
Acute myeloid leukemia (AML) is an aggressive hematological malignancy. Nearly 50% of patients who receive the most intensive treatment inevitably experience disease relapse, likely resulting from the persistence of drug-resistant leukemia stem cells (LSCs). AML cells, especially LSCs, are highly dependent on mitochondrial oxidative phosphorylation (OXPHOS) for survival, but the mechanism involved in OXPHOS hyperactivity is unclear, and a noncytotoxic strategy to inhibit OXPHOS is lacking. To our knowledge, this study is the first to demonstrate that ZDHHC21 palmitoyltransferase serves as a key regulator of OXPHOS hyperactivity in AML cells. The depletion/inhibition of ZDHHC21 effectively induced myeloid differentiation and weakened stemness potential by inhibiting OXPHOS in AML cells. Interestingly, FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD)-mutated AML cells expressed significantly higher levels of ZDHHC21 and exhibited better sensitivity to ZDHHC21 inhibition. Mechanistically, ZDHHC21 specifically catalyzed the palmitoylation of mitochondrial adenylate kinase 2 (AK2) and further activated OXPHOS in leukemic blasts. Inhibition of ZDHHC21 arrested the in vivo growth of AML cells and extended the survival of mice inoculated with AML cell lines and patient derived xenograft AML blasts. Moreover, targeting ZDHHC21 to suppress OXPHOS markedly eradicated AML blasts and enhanced chemotherapy efficacy in relapsed/refractory leukemia. Together, these findings not only uncover a new biological function of palmitoyltransferase ZDHHC21 in regulating AML OXPHOS but also indicate that ZDHHC21 inhibition is a promising therapeutic regimen for patients with AML, especially relapsed/refractory leukemia.
Subject(s)
Leukemia, Myeloid, Acute , Oxidative Phosphorylation , Animals , Humans , Mice , Cell Differentiation , fms-Like Tyrosine Kinase 3/metabolism , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Mutation , Protein Kinase Inhibitors/therapeutic useABSTRACT
The discovery of effective therapeutic treatments for cancer via cell differentiation instead of antiproliferation remains a great challenge. Cyclin-dependent kinase 2 (CDK2) inactivation, which overcomes the differentiation arrest of acute myeloid leukemia (AML) cells, may be a promising method for AML treatment. However, there is no available selective CDK2 inhibitor. More importantly, the inhibition of only the enzymatic function of CDK2 would be insufficient to promote notable AML differentiation. To further validate the role and druggability of CDK2 involved in AML differentiation, a suitable chemical tool is needed. Therefore, we developed first-in-class CDK2-targeted proteolysis-targeting chimeras (PROTACs), which promoted rapid and potent CDK2 degradation in different cell lines without comparable degradation of other targets, and induced remarkable differentiation of AML cell lines and primary patient cells. These data clearly demonstrated the practicality and importance of PROTACs as alternative tools for verifying CDK2 protein functions.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Differentiation/drug effects , Gene Expression Regulation, Leukemic/drug effects , Myeloid Progenitor Cells/drug effects , Proteolysis/drug effects , Triazoles/pharmacology , Antineoplastic Agents/chemical synthesis , Aurora Kinase A/genetics , Aurora Kinase A/metabolism , Cell Line, Tumor , Cell Proliferation , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Cyclin-Dependent Kinase 2/genetics , Cyclin-Dependent Kinase 2/metabolism , Drug Design , Drug Discovery , Humans , Ikaros Transcription Factor/genetics , Ikaros Transcription Factor/metabolism , Inhibitory Concentration 50 , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/enzymology , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Myeloid Progenitor Cells/enzymology , Myeloid Progenitor Cells/pathology , Piperazines/pharmacology , Primary Cell Culture , Pyridines/pharmacology , Pyrimidines/pharmacology , Quinazolines/pharmacology , Signal Transduction , Structure-Activity Relationship , Transcriptome , Triazoles/chemical synthesisABSTRACT
The mechanism by which psoralen is transported across the placenta was investigated in the BeWo human placental cell line derived from choriocarcinoma in a transwell assay system using liquid chromatography-mass spectrometry/mass spectrometry detection. Psoralen uptake by BeWo cells increased linearly over the concentration range of 0.01 µM to 100 µM (r (2) = 0.997) and was not saturable. Psoralen uptake by BeWo cells was not affected by temperature (4â°C, room temperature, and 37â°C; p > 0.05). Psoralen transport increased linearly over 180 min (r (2) = 0.988) with 3.08 ± 0.26â%, 5.47 ± 0.21â%, 7.54 ± 0.06â%, 9.40 ± 0.37â%, 11.49 ± 0.31â%, and 12.46 ± 0.61â% transferred from the apical chamber to the basolateral chamber in the transwell assays at 30, 60, 90, 120, 150, and 180 min, respectively. The rate of transport showed the same tendency, increasing linearly from 0.13 ± 0.01 pmol/s to 0.58 ± 0.03 pmol/s over the concentration range of 25 µM to 100 µM (r (2) = 0.989). The apparent permeability coefficient for psoralen (100 µM) was 5.62 ± 0.24 × 10(-6) cm/s and 5.53 ± 0.47 × 10(-6) cm/s before and after treatment with verapamil (100 µM), respectively (p > 0.05). The efflux value for psoralen was approximately 1. These data show that psoralen is well absorbed and crosses the placental barrier via passive diffusion in the BeWo cell line.
Subject(s)
Ficusin/metabolism , Biological Transport , Cell Line, Tumor , Female , Humans , Placenta/cytology , Placenta/metabolism , PregnancyABSTRACT
Platinum-tin (Pt/Sn) binary nanoparticles are active electrocatalysts for the ethanol oxidation reaction (EOR), but inactive for splitting the C-C bond of ethanol to CO2. Here we studied detailed structure properties of Pt/Sn catalysts for the EOR, especially CO2 generation in situ using a CO2 microelectrode. We found that composition and crystalline structure of the tin element played important roles in the CO2 generation: non-alloyed Pt46-(SnO2)54 core-shell particles demonstrated a strong capability for C-C bond breaking of ethanol than pure Pt and intermetallic Pt/Sn, showing 4.1 times higher CO2 peak partial pressure generated from EOR than commercial Pt/C.
Subject(s)
Ethanol/chemistry , Platinum/chemistry , Tin Compounds/chemistry , Alloys/chemistry , Catalysis , Electrochemistry , Oxidation-ReductionABSTRACT
This study addresses a gap in the literature by exploring the longitudinal effects of hassles in mediating the relationship between neuroticism and the tripartite model of depression and anxiety. The research investigates these associations in a large sample of university students, utilising baseline and 6-month follow-up data. Initial assessments involved participants completing measures for neuroticism, depression and anxiety symptoms, and the occurrence of stress, followed by monthly assessments of stress, anxiety symptom and mood symptoms over a 6-month period. Our results illuminate the mediating role of daily hassles in the relationship between neuroticism and various dimensions of anxiety and depression, including general distress, specific depression, and anxiety symptoms. These findings underscore the significant impact of neuroticism and hassles on a broad spectrum of mood symptoms, offering valuable insights for both research and clinical practice. Discussions around the implications of these findings are provided in the our paper, where we also outline potential directions for future research and clinical applications.
ABSTRACT
Currently, it remains challenging to balance intrinsic stiffness with programmability in most vitrimers. Simultaneously, coordinating materials with gel-like iontronic properties for intrinsic ion transmission while maintaining vitrimer programmable features remains underexplored. Here, we introduce a phase-engineering strategy to fabricate bicontinuous vitrimer heterogel (VHG) materials. Such VHGs exhibited high mechanical strength, with an elastic modulus of up to 116 MPa, a high strain performance exceeding 1000%, and a switchable stiffness ratio surpassing 5 × 103. Moreover, highly programmable reprocessing and shape memory morphing were realized owing to the ion liquid-enhanced VHG network reconfiguration. Derived from the ion transmission pathway in the ILgel, which responded to the wide-span switchable mechanics, the VHG iontronics had a unique bidirectional stiffness-gated piezoresistivity, coordinating both positive and negative piezoresistive properties. Our findings indicate that the VHG system can act as a foundational material in various promising applications, including smart sensors, soft machines, and bioelectronics.
ABSTRACT
Through theoretical calculations, we show that integrating Pd with WO3 nanomaterials can trigger the interfacial electron transfer from Pd to WO3, thus upshifting the d-band center (εd) of Pd to optimize toxic hexavalent chromium (Cr(VI)) reduction. The elevated εd can derive stronger chemisorption capability toward crucial formic acid molecules, notably lowering the thermodynamic energy barrier and speeding up the kinetics process. In order to realize this concept, we synthesized unique Pd/WO3 nanofibers by loading Pd nanoparticles onto electrospun WO3 nanofibers through an in situ photodeposition technique. Extensive structural, morphological, and X-ray photoelectron spectrometer (XPS) characterizations confirm the successful formation of the above nanofibers. As anticipated, the as-designed Pd/WO3 nanofibers exhibit enhanced catalytic performance in the Cr(VI) reduction with a high turnover frequency (TOF) value of 62.12 min-1, surpassing a series of reported Pd-based catalysts. Such nanofibrous WO3-induced electronic modification of Pd with a high specific area leads to catalytic enhancement, providing a novel model for catalyst design.
ABSTRACT
Tacrolimus is the principal immunosuppressive drug which is administered after heart transplantation. Managing tacrolimus therapy is challenging due to a narrow therapeutic index and wide pharmacokinetic (PK) variability. We aimed to establish a physiologically based pharmacokinetic (PBPK) model of tacrolimus in adult heart transplant recipients to optimize dose regimens in clinical practice. A 15-compartment full-PBPK model (Simbiology® Simulator, version 5.8.2) was developed using clinical observations from 115 heart transplant recipients. This study detected 20 genotypes associated with tacrolimus metabolism. CYP3A5*3 (rs776746), CYP3A4*18B (rs2242480), and IL-10 G-1082A (rs1800896) were identified as significant genetic covariates in tacrolimus pharmacokinetics. The PBPK model was evaluated using goodness-of-fit (GOF) and external evaluation. The predicted peak blood concentration (Cmax) and area under the drug concentration-time curve (AUC) were all within a two-fold value of the observations (fold error of 0.68-1.22 for Cmax and 0.72-1.16 for AUC). The patients with the CYP3A5*3/*3 genotype had a 1.60-fold increase in predicted AUC compared to the patients with the CYP3A5*1 allele, and the ratio of the AUC with voriconazole to alone was 5.80 when using the PBPK model. Based on the simulation results, the tacrolimus dosing regimen after heart transplantation was optimized. This is the first PBPK model used to predict the PK of tacrolimus in adult heart transplant recipients, and it can serve as a starting point for research on immunosuppressive drug therapy in heart transplant patients.
ABSTRACT
Feline calicivirus (FCV) is one of the most important pathogens causing upper respiratory tract diseases in cats, posing a serious health threat to these animals. At present, FCV is mainly prevented through vaccination, but the protective efficacy of vaccines in China is limited. In this study, based on the differences in capsid proteins of isolates from different regions in China, as reported in our previous studies, seven representative FCV epidemic strains were selected and tested for their viral titers, virulence, immunogenicity, and extensive cross-protection. Subsequently, vaccine strains were selected to prepare inactivated vaccines. The whole-genome sequencing and analysis results showed that these seven representative FCV strains and 144 reference strains fell into five groups (A, B, C, D, and E). The strains isolated in China mainly fall into groups C and D, exhibiting regional characteristics. These Chinese isolates had a distant evolutionary relationship and low homology with the current FCV-255 vaccine strain. The screened FCV-HB7 and FCV-HB10 strains displayed desirable in vitro culture characteristics, with the highest virus proliferation titers (109.5 TCID50/mL) at 36 h post inoculation at a dose of 0.01 MOI. All five cats infected intranasally with FCV-HB7 or FCV-HB10 strains showed obvious clinical symptoms of FCV. The symptoms of cats infected with the FCV-HB7 strain were more severe than those infected with the FCV-HB10 strain. Both the single-strain inactivated immunization and combined bivalent inactivated vaccine immunization of FCV-HB7 and FCV-HB10 induced high neutralizing antibody titers in five cats immunized. Moreover, bivalent inactivated vaccine immunization protected cats from FCV-HB7 and FCV-HB10 strains. The cross-neutralizing antibody titer against seven representative FCV epidemic strains achieved by combined bivalent inactivated vaccine immunization was higher than that achieved by single-strain immunization, which was much higher than that achieved by commercial vaccine FCV-255 strain immunization. The above results suggest that the FCV-HB7 and FCV-HB10 strains screened in this study have great potential to become vaccine strains with broad-spectrum protective efficacy. However, their immune protective efficacy needs to be further verified by multiple methods before clinical application.
ABSTRACT
The long-distance transport of iron (Fe) in the xylem is critical for maintaining systemic Fe homeostasis in plants. The loading form of Fe(II) into the xylem and the long-distance translocation form of Fe(III)-citrate have been identified, but how Fe(II) is oxidized to Fe(III) in the xylem remains unknown. Here, we showed that the cell wall-resided ferroxidases LPR1 and LPR2 (LPRs) were both specifically expressed in the vascular tissues of Arabidopsis thaliana, while disruption of both of them increased Fe(II) in the xylem sap and caused excessive Fe deposition in the xylem vessel wall under Fe-sufficient conditions. As a result, a large amount of Fe accumulated in both roots and shoots, hindering plant growth. Moreover, under low-Fe conditions, LPRs were preferentially induced in old leaves, but the loss of LPRs increased Fe deposition in the vasculature of older leaves and impeded Fe allocation to younger leaves. Therefore, disruption of both LPRs resulted in severer chlorosis in young leaves under Fe-deficient conditions. Taken together, the oxidation of Fe(II) to Fe(III) by LPRs in the cell wall of vasculature plays an important role in xylem Fe allocation, ensuring healthy Fe homeostasis for normal plant growth.
ABSTRACT
Acute promyelocytic leukemia (APL) is driven by the oncoprotein PML/RARα, which destroys the architecture of PML nuclear bodies (NBs). PML NBs are critical to tumor suppression, and their disruption mediated by PML/RARα accelerates APL pathogenesis. However, the mechanisms of PML NB disruption remain elusive. Here, we reveal that the failure of NB assembly in APL results from neddylation-induced aberrant phase separation of PML/RARα. Mechanistically, PML/RARα is neddylated in the RARα moiety, and this neddylation enhances its DNA-binding ability and further impedes the phase separation of the PML moiety, consequently disrupting PML NB construction. Accordingly, deneddylation of PML/RARα restores its phase separation process to reconstruct functional NBs and activates RARα signaling, thereby suppressing PML/RARα-driven leukemogenesis. Pharmacological inhibition of neddylation by MLN4924 eradicates APL cells both in vitro and in vivo. Our work elucidates the neddylation-destroyed phase separation mechanism for PML/RARα-driven NB disruption and highlights targeting neddylation for APL eradication.
Subject(s)
Leukemia, Promyelocytic, Acute , Humans , Leukemia, Promyelocytic, Acute/genetics , Leukemia, Promyelocytic, Acute/pathology , Nuclear Bodies , Promyelocytic Leukemia Nuclear Bodies , Promyelocytic Leukemia Protein/genetics , Signal Transduction , Tretinoin/pharmacologyABSTRACT
In most acute promyelocytic leukemia (APL) cells, promyelocytic leukemia (PML) fuses to retinoic acid receptor α (RARα) due to chromosomal translocation, thus generating PML/RARα oncoprotein, which is a relatively stable oncoprotein for degradation in APL. Elucidating the mechanism regulating the stability of PML/RARα may help to degrade PML/RARα and eradicate APL cells. Here, we describe a deubiquitinase (DUB)-involved regulatory mechanism for the maintenance of PML/RARα stability and develop a novel pharmacological approach to degrading PML/RARα by inhibiting DUB. We utilized a DUB siRNA library to identify the ovarian tumor protease (OTU) family member deubiquitinase YOD1 as a critical DUB of PML/RARα. Suppression of YOD1 promoted the degradation of PML/RARα, thus inhibiting APL cells and prolonging the survival time of APL cell-bearing mice. Subsequent phenotypic screening of small molecules allowed us to identify ubiquitin isopeptidase inhibitor I (G5) as the first YOD1 pharmacological inhibitor. As expected, G5 notably degraded PML/RARα protein and eradicated APL, particularly drug-resistant APL cells. Importantly, G5 also showed a strong killing effect on primary patient-derived APL blasts. Overall, our study not only reveals the DUB-involved regulatory mechanism on PML/RARα stability and validates YOD1 as a potential therapeutic target for APL, but also identifies G5 as a YOD1 inhibitor and a promising candidate for APL, particularly drug-resistant APL treatment.
ABSTRACT
Ethanol is a promising fuel for low-temperature direct fuel cell reactions due to its low toxicity, ease of storage and transportation, high-energy density, and availability from biomass. However, the implementation of ethanol fuel cell technology has been hindered by the lack of low-cost, highly active anode catalysts. In this paper, we have studied Iridium (Ir)-based binary catalysts as low-cost alternative electrocatalysts replacing platinum (Pt)-based catalysts for the direct ethanol fuel cell (DEFC) reaction. We report the synthesis of carbon supported Ir(71)Sn(29) catalysts with an average diameter of 2.7 ± 0.6 nm through a "surfactant-free" wet chemistry approach. The complementary characterization techniques, including aberration-corrected scanning transmission electron microscopy equipped with electron energy loss spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy, and X-ray absorption spectroscopy, are used to identify the "real" heterogeneous structure of Ir(71)Sn(29)/C particles as Ir/Ir-Sn/SnO(2), which consists of an Ir-rich core and an Ir-Sn alloy shell with SnO(2) present on the surface. The Ir(71)Sn(29)/C heterogeneous catalyst exhibited high electrochemical activity toward the ethanol oxidation reaction compared to the commercial Pt/C (ETEK), PtRu/C (Johnson Matthey) as well as PtSn/C catalysts. Electrochemical measurements and density functional theory calculations demonstrate that the superior electro-activity is directly related to the high degree of Ir-Sn alloy formation as well as the existence of nonalloyed SnO(2) on surface. Our cross-disciplinary work, from novel "surfactant-free" synthesis of Ir-Sn catalysts, theoretical simulations, and catalytic measurements to the characterizations of "real" heterogeneous nanostructures, will not only highlight the intriguing structure-property correlations in nanosized catalysts but also have a transformative impact on the commercialization of DEFC technology by replacing Pt with low-cost, highly active Ir-based catalysts.
Subject(s)
Ethanol/chemistry , Iridium/chemistry , Nanoparticles/chemistry , Tin Compounds/chemistry , Tin/chemistry , Catalysis , Electrochemistry , Oxidation-Reduction , Particle Size , Quantum Theory , Surface PropertiesABSTRACT
Although molecular targeted therapies have recently displayed therapeutic effects in acute myeloid leukemia (AML), limited response and acquired resistance remain common problems. Numerous studies have associated autophagy, an essential degradation process involved in the cellular response to stress, with the development and therapeutic response of cancers including AML. Thus, we review studies on the role of autophagy in AML development and summarize the linkage between autophagy and several recurrent genetic abnormalities in AML, highlighting the potential of capitalizing on autophagy modulation in targeted therapy for AML.Abbreviations: AML: acute myeloid leukemia; AMPK: AMP-activated protein kinase; APL: acute promyelocytic leukemia; ATG: autophagy related; ATM: ATM serine/threonine kinase; ATO: arsenic trioxide; ATRA: all trans retinoic acid; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; BET proteins, bromodomain and extra-terminal domain family; CMA: chaperone-mediated autophagy; CQ: chloroquine; DNMT, DNA methyltransferase; DOT1L: DOT1 like histone lysine methyltransferase; FLT3: fms related receptor tyrosine kinase 3; FIS1: fission, mitochondrial 1; HCQ: hydroxychloroquine; HSC: hematopoietic stem cell; IDH: isocitrate dehydrogenase; ITD: internal tandem duplication; KMT2A/MLL: lysine methyltransferase 2A; LSC: leukemia stem cell; MDS: myelodysplastic syndromes; MTORC1: mechanistic target of rapamycin kinase complex 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NPM1: nucleophosmin 1; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PML: PML nuclear body scaffold; ROS: reactive oxygen species; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SAHA: vorinostat; SQSTM1: sequestosome 1; TET2: tet methylcytosine dioxygenase 2; TKD: tyrosine kinase domain; TKI: tyrosine kinase inhibitor; TP53/p53: tumor protein p53; ULK1: unc-51 like autophagy activating kinase 1; VPA: valproic acid; WDFY3/ALFY: WD repeat and FYVE domain containing 3.
Subject(s)
Autophagy , Leukemia, Myeloid, Acute , Autophagy/physiology , Autophagy-Related Proteins/metabolism , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/geneticsABSTRACT
Checkpoint kinase 1 (CHK1) plays an important role in the DNA damage response pathway, being a potential anti-cancer drug target. In this study, we used a strategy for trifluoromethyl substitution to obtain orally bioavailable CHK1 inhibitors to overcome the limitations of lead compound 1, which can only be administered intravenously. After detailed investigation, we identified compound 6c as an oral CHK1 inhibitor, which demonstrated a considerably higher plasma exposure in mice. Compound 6c also showed good kinase selectivity. Moreover, it exhibited a significant antiproliferative effect in MV-4-11 cells singly and a synergistic effect in combination with gemcitabine in HT-29, A549, and RPMI-8226 cells. Additionally, compound 6c could inhibit tumor growth in the MV-4-11 xenograft mouse model. The combination of 6c and gemcitabine exhibited synergistic effect in the HT-29 xenograft mouse model. Thus, compound 6c was found to be a selective and oral potential anticancer CHK1 inhibitor.
Subject(s)
Antineoplastic Agents/pharmacology , Checkpoint Kinase 1/antagonists & inhibitors , Drug Development , Protein Kinase Inhibitors/pharmacology , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Biological Availability , Cell Line , Cell Proliferation/drug effects , Checkpoint Kinase 1/metabolism , Dose-Response Relationship, Drug , Humans , Mice , Mice, Nude , Models, Molecular , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
We have reported the synthesis of Au(25)Pt(75) and Au(48)Pt(52) alloyed ultrathin nanowires with average widths of less than 3 nm via a wet chemistry approach at room temperature. Using a combination of techniques, including scanning transmission electron microscopy equipped with X-ray energy dispersive spectroscopy, ultraviolet-visible spectroscopy, and X-ray absorption near-edge structure and extended X-ray absorption fine structure spectroscopies, we identified the stoichiometry-dependent heterogeneous crystalline structures, as well as electronic structures with respect to the charge transfer between Pt and Au within both nanowires. In particular, we observed d-charge depletion at the Au site and the d-charge gain at the Pt site in Au(48)Pt(52) nanowires, which accounted for its ferromagnetic magnetic behavior, in contrast to the paramagnetism and diamagnetism appearing respectively in bulk Pt and Au.
Subject(s)
Alloys/chemistry , Electrons , Gold/chemistry , Magnetics , Nanowires/chemistry , Platinum/chemistry , Alloys/chemical synthesis , Materials Testing , Nanotechnology , Particle Size , Surface Properties , TemperatureABSTRACT
Environment-friendly medium-density fiberboards (MDFs) prepared using sodium lignosulfonate/chitosan adhesives (L/C) show potential in environment-friendly wood-based panel application. However, the synthesis mechanism of this adhesive and the relationships between synthesis mechanism and bonding performance were not discussed in depth. Herein, the synthesis mechanism of L/C was explored in detail based on characterizations of L/C with different mass ratios of sodium lignosulfonate to chitosan by Fourier-transform infrared spectroscopy, thermogravimetric analysis, and X-ray diffraction. For L/C with different mass ratios of sodium lignosulfonate to chitosan, the corresponding bonding performance was also determined based on characterizations of mechanical and dimensional performance of MDFs. Results showed a 3D network structure of L/C formed through the hydrogen linkages among hydroxyl groups in sodium lignosulfonate and hydroxyl and amino groups in chitosan, amide linkages resulted from reaction between carbonyl groups in sodium lignosulfonate and amino groups in chitosan, and sulfonamide linkages originated from reaction between sulfonic groups in sodium lignosulfonate and amino groups in chitosan. The mechanical performance of MDF was closely related to the 3D network and amino groups of L/C, while the dimensional performance of MDF was negatively affected by sodium lignosulfonate. The MDFs with 1:3 and 1:2 mass ratios of sodium lignosulfonate to chitosan showed superior mechanical properties and comparable dimensional performance with a commercial panel.
ABSTRACT
Activated nuclear factor-κB (NF-κB) plays an important role in the development of cardiovascular disease (CVD) through its regulated genes and microRNAs (miRNAs). However, the gene regulation profile remains unclear. In this study, primary mouse vascular endothelial cells (pMVECs) were employed to detect CVD-related NF-κB-regulated genes and miRNAs. Genechip assay identified 77 NF-κB-regulated genes, including 45 upregulated and 32 downregulated genes, in tumor necrosis factor α (TNFα)-treated pMVECs. Ten of these genes were also found to be regulated by NF-κB in TNFα-treated HeLa cells. Quantitative real-time PCR (qRT-PCR) assay confirmed the up-regulation of Egr1, Tnf, and Btg2 by NF-κB in the TNFα-treated pMVECs. The functional annotation revealed that many NF-κB-regulated genes identified in pMVECs were clustered into classical NF-κB-involved biological processes. Genechip assay also identified 26 NF-κB-regulated miRNAs, of which 21 were upregulated and 5 downregulated, in the TNFα-treated pMVECs. Further analysis showed that nine of the identified genes are regulated by seven of these miRNAs. Finally, among the identified NF-κB-regulated genes and miRNAs, 5 genes and 12 miRNAs were associated with CVD by miRWalk and genetic association database analysis. Taken together, these findings show an intricate gene regulation network raised by NF-κB in TNFα-treated pMVECs. The network provides new insights for understanding the molecular mechanism underlying the progression of CVD.
Subject(s)
Cardiovascular Diseases/genetics , Endothelial Cells/drug effects , Gene Regulatory Networks , MicroRNAs/physiology , NF-kappa B/physiology , Tumor Necrosis Factor-alpha/pharmacology , Animals , Cardiovascular Diseases/etiology , Cells, Cultured , MiceSubject(s)
Core Binding Factor Alpha 2 Subunit , Leukemia, Myeloid, Acute , Humans , Core Binding Factor Alpha 2 Subunit/genetics , Gene Expression Regulation, Leukemic , Gene Fusion , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Neoplasm Recurrence, Local/genetics , Nuclear Pore Complex Proteins/genetics , Oncogene Proteins, Fusion/genetics , Translocation, GeneticABSTRACT
This communication reports the first example of cyclic ferric clusters with an odd number of iron atoms capped by phosphonate ligands, namely, [Fe9(mu-OH)(7)(mu-O)2(O3PC6H9)8(py)12]. The magnetic studies support a S = 1/2 ground state with an exchange coupling constant of about J approximately equal to -30 K.