ABSTRACT
In this Letter, two relevant references were omitted; see the accompanying Amendment for details. The original Letter has not been corrected.
ABSTRACT
Persistent activation of estrogen receptor alpha (ERα)-mediated estrogen signaling plays a pivotal role in driving the progression of estrogen receptor positive (ER+) breast cancer (BC). In the current study, LINC00173, a long non-coding RNA, was found to bind both ERα and lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNFα) factor (LITAF), then cooperatively to inhibit ERα protein degradation by impeding the nuclear export of ERα. Concurrently, LITAF was found to attenuate TNFα transcription after binding to LINC00173, and this attenuating transcriptional effect was quite significant under lipopolysaccharide stimulation. Distinct functional disparities between estrogen subtypes emerge, with estradiol synergistically promoting ER+ BC cell growth with LINC00173, while estrone (E1) facilitated LITAF-transcriptional activation. In terms of therapeutic significance, silencing LINC00173 alongside moderate addition of E1 heightened TNFα and induced apoptosis, effectively inhibiting ER+ BC progression.
Subject(s)
Breast Neoplasms , Estrogen Receptor alpha , Estrone , RNA, Long Noncoding , Transcription Factors , Humans , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Breast Neoplasms/genetics , Estrogen Receptor alpha/metabolism , Estrogen Receptor alpha/genetics , Female , Estrone/metabolism , Estrone/pharmacology , Estrone/analogs & derivatives , Transcription Factors/metabolism , Transcription Factors/genetics , Tumor Necrosis Factor-alpha/metabolism , MCF-7 Cells , Cell Line, Tumor , Nuclear Proteins/metabolism , Nuclear Proteins/genetics , Apoptosis/drug effects , Cell Proliferation/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Proteolysis/drug effects , Animals , Mice , Gene SilencingABSTRACT
Covalent organic frameworks (COFs) offer a desirable platform to explore multichoromophoric arrays for photocatalytic conversion. Symmetric arrangement of choromophoric modules over π-extended frameworks enhances exciton delocalization while impairing excitation density and accordingly photochemical reactivity. Herein, a photoisomerization-driven strategy is proposed to break the excited-state symmetry of ketoenamine-linked COFs with multichoromophoric arrays. Incorporating electron-withdrawing benzothiadiazole facilitates the ultrafast excited-state intramolecular proton transfer (ESIPT) from enamine to keto within 140 fs, resulting in partially enolized COF isomers. The hybrid linkages containing imine and enamine bonds at the node of framework alter the symmetry of electronic structure and enforce the photoinduced charge separation. Increasing the imine-to-enamine ratio further promotes the electron transferred number in a long range, thereby affording the optimum photocatalytic hydrogen evolution rate. This work put forward an ESIPT-induced photoisomerization to build a symmetry-breaking COF with weakened exciton effect and enhanced photochemical reactivity.
ABSTRACT
MicroRNAs are essential in plant development and stress resistance, but their specific roles in drought stress require further investigation. Here, we have uncovered that a Populus-specific microRNAs (miRNA), miR6445, targeting NAC (NAM, ATAF, and CUC) family genes, is involved in regulating drought tolerance of poplar. The expression level of miR6445 was significantly upregulated under drought stress; concomitantly, seven targeted NAC genes showed significant downregulation. Silencing the expression of miR6445 by short tandem target mimic technology significantly decreased the drought tolerance in poplar. Furthermore, 5' RACE experiments confirmed that miR6445 directly targeted NAC029. The overexpression lines of PtrNAC029 (OE-NAC029) showed increased sensitivity to drought compared with knockout lines (Crispr-NAC029), consistent with the drought-sensitive phenotype observed in miR6445-silenced strains. PtrNAC029 was further verified to directly bind to the promoters of glutathione S-transferase U23 (GSTU23) and inhibit its expression. Both Crispr-NAC029 and PtrGSTU23 overexpressing plants showed higher levels of PtrGSTU23 transcript and GST activity while accumulating less reactive oxygen species (ROS). Moreover, poplars overexpressing GSTU23 demonstrated enhanced drought tolerance. Taken together, our research reveals the crucial role of the miR6445-NAC029-GSTU23 module in enhancing poplar drought tolerance by regulating ROS homeostasis. This finding provides new molecular targets for improving the drought resistance of trees.
Subject(s)
Drought Resistance , Glutathione Transferase , MicroRNAs , Plant Proteins , Populus , Reactive Oxygen Species , Adaptation, Physiological , Base Sequence , Free Radical Scavengers/metabolism , Gene Expression Regulation, Plant , Genes, Plant , Glutathione Transferase/genetics , Glutathione Transferase/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Plant Proteins/genetics , Plant Proteins/metabolism , Plants, Genetically Modified , Populus/genetics , Populus/physiology , Populus/enzymology , Promoter Regions, Genetic/genetics , Reactive Oxygen Species/metabolism , Stress, Physiological/geneticsABSTRACT
Low-cost nanocomposite metasurfaces have demonstrated attractive potential to replace the equivalent dielectric metasurfaces for light engineering. However, the resonance characteristics of embedded structures in nanocomposite metasurfaces have not been further analyzed beyond the effective refractive index. Herein, we have proposed customizable polarization-selective narrowband meta-filters using ultraviolet-curable (UV) nanocomposites. As an additional degree of freedom, near-field effects between highly concentrated doped nanoparticles can enhance the Mie resonance of the low aspect ratio (AR = 0.2) meta-units. The surface lattice resonances (SLRs) of meta-filters can be coupled with enhanced Mie resonances of individual meta-units to realize tunable narrowband (FWHM â¼0.007λ) reflections with intensities near unity. Meanwhile, the polarization-selective properties of the reflection peaks can be tuned by optimizing the asymmetric lattice. Such proposed new-generation customizable meta-filters will offer, to our knowledge, novel strategies for filtering specific near-infrared polarized fluorescence in the integrated imaging systems.
ABSTRACT
BACKGROUND: Lianhuaqingwen (LHQW) has been used in the treatment of chronic bronchitis, but the precise mechanism through which LHQW exhibits its anti-inflammatory effects in this context is not yet fully understood. The aim of this study was to investigate the active ingredients and signaling pathways responsible for LHQW's effectiveness in managing chronic bronchitis. METHODS: The research leveraged the TCMSP database to determine the active compounds and drug targets of LHQW. In parallel, the GeneCards, DrugBank, and PharmGkb databases were used to uncover targets pertinent to chronic bronchitis. To discern the potential mechanisms by which LHQW's active ingredients might treat chronic bronchitis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. Network pharmacology facilitated the construction of a drug-active ingredient-disease target network, aiding in forecasting the core targets for chronic bronchitis treatment by LHQW. Subsequently, molecular docking techniques alongside in vitro experiments were applied to confirm the interactions between the active ingredients and the primary targets. RESULTS: A total of 157 active ingredients, 225 potential drug targets, and 594 bronchitis-related targets were derived from various databases. Following this, 76 potential gene targets were pinpointed by integrating drug and related targets. GO and KEGG enrichment analyses were employed to identify key pathways involved in LHQW's mechanism for treating chronic bronchitis. By constructing a protein-protein interaction (PPI) network for the 76 potential gene targets, four core targets (TNF, IL6, IFNG, and STAT3) were identified as primarily involved in responses to lipopolysaccharide, the TNF pathway, and the JAK-STAT pathway. Molecular docking results revealed a favorable affinity between multiple active ingredients of LHQW and the four core targets, suggesting that the therapeutic effects are mediated through the inhibition of inflammatory responses and signaling pathways. Interestingly, quercetin, an active ingredient of LHQW, was observed to bind to all four core targets simultaneously. Furthermore, cell experiment and western blot analysis indicated that both LHQW and quercetin exhibit anti-inflammatory effects by targeting the four core proteins and the JAK-STAT pathways. CONCLUSION: This research emphasizes the diverse active ingredients, targets, channels, and pathways of LHQW in the treatment of chronic bronchitis, providing important perspectives for the creation of novel therapeutic drugs and clinical uses.
Subject(s)
Bronchitis, Chronic , Drugs, Chinese Herbal , Molecular Docking Simulation , Network Pharmacology , Bronchitis, Chronic/drug therapy , Bronchitis, Chronic/metabolism , Bronchitis, Chronic/genetics , Network Pharmacology/methods , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Drugs, Chinese Herbal/chemistry , Molecular Docking Simulation/methods , Humans , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Signal Transduction/drug effects , AnimalsABSTRACT
In view of the excellent prospects of gene therapy and the potential safety and immunogenicity issues challenged by viral vectors, it is of great significance to develop a nonviral vector with low toxicity and low cost. In this work, we report a chitosan nanoparticle (CSNP) to be used as a gene vector prepared through a facile solvent-exchange strategy. Chitosan is first dissolved in ionic liquid 1-ethyl-3-methylimidazolium acetate (EMIM Ac), and then, the solvent is exchanged with water/phosphate-buffered saline (PBS) to remove ionic liquid, forming a final CSNP dispersion after ultrasonication. The prepared CSNP shows a positive surface charge and can condense green fluorescent protein-encoding plasmid (pGFP) at weight ratios (CSNP/pGFP) of 5/1 or higher. Dynamic light scattering size and ζ-potential characterization and gel retardation results confirm the formation of CSNP/pGFP complexes. Compared with plain pGFP, efficient cellular internalization and significantly enhanced green fluorescent protein (GFP) expression are observed by using CSNP as a plasmid vector. Benefitting from the intrinsic biocompatibility, low cost, low immunogenicity, and abundant sources of chitosan, as well as the facile preparation and the efficient gene transfection capacity of CSNP, it is believed that this CSNP could be used as a nonviral gene vector with great clinical translational potentials.
Subject(s)
Chitosan , Green Fluorescent Proteins , Nanoparticles , Plasmids , Solvents , Chitosan/chemistry , Nanoparticles/chemistry , Green Fluorescent Proteins/chemistry , Green Fluorescent Proteins/genetics , Humans , Solvents/chemistry , Plasmids/chemistry , Plasmids/genetics , Gene Transfer Techniques , Transfection/methods , Particle Size , HeLa CellsABSTRACT
Tumour cells evade immune surveillance by upregulating the surface expression of programmed death-ligand 1 (PD-L1), which interacts with programmed death-1 (PD-1) receptor on T cells to elicit the immune checkpoint response1,2. Anti-PD-1 antibodies have shown remarkable promise in treating tumours, including metastatic melanoma2-4. However, the patient response rate is low4,5. A better understanding of PD-L1-mediated immune evasion is needed to predict patient response and improve treatment efficacy. Here we report that metastatic melanomas release extracellular vesicles, mostly in the form of exosomes, that carry PD-L1 on their surface. Stimulation with interferon-γ (IFN-γ) increases the amount of PD-L1 on these vesicles, which suppresses the function of CD8 T cells and facilitates tumour growth. In patients with metastatic melanoma, the level of circulating exosomal PD-L1 positively correlates with that of IFN-γ, and varies during the course of anti-PD-1 therapy. The magnitudes of the increase in circulating exosomal PD-L1 during early stages of treatment, as an indicator of the adaptive response of the tumour cells to T cell reinvigoration, stratifies clinical responders from non-responders. Our study unveils a mechanism by which tumour cells systemically suppress the immune system, and provides a rationale for the application of exosomal PD-L1 as a predictor for anti-PD-1 therapy.
Subject(s)
B7-H1 Antigen/immunology , Exosomes/metabolism , Immune Tolerance/immunology , Melanoma/immunology , Programmed Cell Death 1 Receptor/immunology , Tumor Escape/immunology , Animals , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/pharmacology , Antineoplastic Agents, Immunological/therapeutic use , B7-H1 Antigen/blood , B7-H1 Antigen/metabolism , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Case-Control Studies , Cell Line, Tumor , Disease Progression , Female , Humans , Immune Tolerance/drug effects , Interferon-gamma/blood , Interferon-gamma/immunology , Melanoma/drug therapy , Melanoma/pathology , Mice , Mice, Nude , Neoplasm Metastasis , Prognosis , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Tumor Escape/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Climate change and eutrophication are accelerating ocean deoxygenation, leading to a global decline in oxygen levels. The East China Sea, frequently experiencing deoxygenation events, harbors diverse microbial communities. However, the response of these communities to the changing deoxygenation dynamics remains poorly understood. Here, we explored the composition and function of microbial communities inhabiting seawaters of the Changjiang Estuary and offshore areas. Our findings suggested that neutral processes significantly influenced the assembly of these communities. The overall bacterial composition demonstrated remarkable high stability across the oxygen gradient. Salinity exhibited a significantly stronger correlation with bacterial community structure than dissolved oxygen. Both metagenomics and metaproteomics revealed that all of the samples exhibited similar functional community structures. Heterotrophic metabolism dominated these sites, as evidenced by a diverse array of transporters and metabolic enzymes for organic matter uptake and utilization, which constituted a significant portion of the expressed proteins. O2 was the primary electron acceptor in bacteria even under hypoxic conditions, evidenced by expression of low- and high-affinity cytochrome oxidases. Proteins associated with anaerobic processes, such as dissimilatory sulfite reductases, were virtually undetectable. Untargeted liquid chromatography with tandem mass spectrometry analysis of seawater samples revealed a diverse range of dissolved organic matter (DOM) components in amino acids, lipids, organic acids, peptides, and carbohydrates, potentially fueling dominant taxa growth. Despite fluctuations in the abundance of specific genera, the remarkable similarity in community structure, function, and DOM suggests that this ecosystem possesses robust adaptive mechanisms that buffer against abrupt changes, even below the well-defined hypoxic threshold in marine ecosystem.
ABSTRACT
The topically administered glaucoma medications usually encounter serious precorneal drug loss and low corneal penetration, leading to a low bioavailability. In addition, due to the complexity of glaucoma etiology, a single medication is often insufficient. In this work, we report a novel dendritic oligoethylenimine decorated liposome for codelivery of two antiglaucoma drugs, latanoprost and timolol. The liposome showed a uniform nanoscopic particle size, positive surface charge, and excellent dual-drug loading capacity. A prolonged precorneal retention is observed by using this liposomal delivery system. This liposomal delivery system presents increased cellular uptake and tight junctions opening capacity, contributing respectively to the transcellular and paracellular permeation, thereby enhancing the trans-corneal transportation. Following topical administration of one eye drop in brown Norway rats, the dual-drug-loaded liposome formulation resulted in a sustained and effective intraocular pressure reduction as long as 5 days, without inducing ocular inflammation, discomfort, and tissue damage.
Subject(s)
Glaucoma , Liposomes , Rats , Animals , Liposomes/therapeutic use , Antiglaucoma Agents , Glaucoma/drug therapy , Timolol/pharmacology , Timolol/therapeutic use , Administration, Topical , Drug Delivery SystemsABSTRACT
Multicolor two-photon endomicroscopy has become a highly competitive tool for functional imaging in biomedical researches. However, to make the imaging system miniature and applicable for freely behaving animal brain activity, metalenses have received much attention in compact imaging systems. For high resolution multicolor imaging and maximizing fluorescence collection, there is a challenge metalenses faced to achieve large numerical aperture (NA) and focus the NIR excitation and VIS emission lights of multiple fluorophores to the same distance simultaneously because of the limitation of the group delay range of the meta-units. In this paper, we proposed a high NA and polarization-insensitive ultra-broadband achromatic metalens specifically for achromatically focusing the excitation and emission light of multiple fluorophores commonly used in neuroscience studies. TiO2 and Si meta-unit libraries composed of heights, widths and the corresponding phase and group delay were constructed, and the optimal meta-units were selected by particle swarm optimization algorithm to engineer the dispersion of metalens in the VIS band and NIR band, respectively. Combining dispersion engineering with spatial multiplexing, the proposed metalens achieved the maximal effective NA up to 0.8 and large achromatic bandwidth ranging from 500â nm to 1050â nm, which exhibited the coefficient of variation of focal lengths was only 3.41%. The proposed achromatic metalens could successfully achromatically focus different fluorescence with any polarization, which was suitable for most fluorophores. Our results firmly establish that the proposed metalens can open the door to high resolution and minimally invasive multicolor two-photon functional imaging in intravital deep brain.
ABSTRACT
Targeted BRAF inhibition (BRAFi) and combined BRAF and MEK inhibition (BRAFi and MEKi) therapies have markedly improved the clinical outcomes of patients with metastatic melanoma. Unfortunately, the efficacy of these treatments is often countered by the acquisition of drug resistance. Here we investigated the molecular mechanisms that underlie acquired resistance to BRAFi and to the combined therapy. Consistent with previous studies, we show that resistance to BRAFi is mediated by ERK pathway reactivation. Resistance to the combined therapy, however, is mediated by mechanisms independent of reactivation of ERK in many resistant cell lines and clinical samples. p21-activated kinases (PAKs) become activated in cells with acquired drug resistance and have a pivotal role in mediating resistance. Our screening, using a reverse-phase protein array, revealed distinct mechanisms by which PAKs mediate resistance to BRAFi and the combined therapy. In BRAFi-resistant cells, PAKs phosphorylate CRAF and MEK to reactivate ERK. In cells that are resistant to the combined therapy, PAKs regulate JNK and ß-catenin phosphorylation and mTOR pathway activation, and inhibit apoptosis, thereby bypassing ERK. Together, our results provide insights into the molecular mechanisms underlying acquired drug resistance to current targeted therapies, and may help to direct novel drug development efforts to overcome acquired drug resistance.
Subject(s)
Drug Resistance, Neoplasm/drug effects , Melanoma/drug therapy , Melanoma/genetics , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Mutation , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/genetics , Signal Transduction/drug effects , p21-Activated Kinases/metabolism , Animals , Apoptosis/drug effects , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , Enzyme Activation/drug effects , Female , Humans , JNK Mitogen-Activated Protein Kinases/chemistry , JNK Mitogen-Activated Protein Kinases/metabolism , MAP Kinase Signaling System/drug effects , Melanoma/enzymology , Mice , Mitogen-Activated Protein Kinase Kinases/chemistry , Mitogen-Activated Protein Kinase Kinases/metabolism , Phosphorylation/drug effects , Proto-Oncogene Proteins c-raf/chemistry , Proto-Oncogene Proteins c-raf/metabolism , TOR Serine-Threonine Kinases/metabolism , beta Catenin/chemistry , beta Catenin/metabolism , p21-Activated Kinases/antagonists & inhibitors , p21-Activated Kinases/geneticsABSTRACT
Nuclear Factor-Y (NF-Y), composed of three subunits NF-YA, NF-YB and NF-YC, exists in most of the eukaryotes and is relatively conservative in evolution. As compared to animals and fungi, the number of NF-Y subunits has significantly expanded in higher plants. The NF-Y complex regulates the expression of target genes by directly binding the promoter CCAAT box or by physical interaction and mediating the binding of a transcriptional activator or inhibitor. NF-Y plays an important role at various stages of plant growth and development, especially in response to stress, which attracted many researchers to explore. Herein, we have reviewed the structural characteristics and mechanism of function of NF-Y subunits, summarized the latest research on NF-Y involved in the response to abiotic stresses, including drought, salt, nutrient and temperature, and elaborated the critical role of NF-Y in these different abiotic stresses. Based on the summary above, we have prospected the potential research on NF-Y in response to plant abiotic stresses and discussed the difficulties that may be faced in order to provide a reference for the in-depth analysis of the function of NF-Y transcription factors and an in-depth study of plant responses to abiotic stress.
Subject(s)
Gene Expression Regulation , Transcription Factors , Transcription Factors/metabolism , Promoter Regions, Genetic , Stress, Physiological/genetics , CCAAT-Binding Factor/geneticsABSTRACT
F-box proteins are important components of eukaryotic SCF E3 ubiquitin ligase complexes, which specifically determine protein substrate proteasomal degradation during plant growth and development, as well as biotic and abiotic stress. It has been found that the FBA (F-box associated) protein family is one of the largest subgroups of the widely prevalent F-box family and plays significant roles in plant development and stress response. However, the FBA gene family in poplar has not been systematically studied to date. In this study, a total of 337 F-box candidate genes were discovered based on the fourth-generation genome resequencing of P. trichocarpa. The domain analysis and classification of candidate genes revealed that 74 of these candidate genes belong to the FBA protein family. The poplar F-box genes have undergone multiple gene replication events, particularly in the FBA subfamily, and their evolution can be attributed to genome-wide duplication (WGD) and tandem duplication (TD). In addition, we investigated the P. trichocarpa FBA subfamily using the PlantGenIE database and quantitative real-time PCR (qRT-PCR); the results showed that they are expressed in the cambium, phloem and mature tissues, but rarely expressed in young leaves and flowers. Moreover, they are also widely involved in the drought stress response. At last, we selected and cloned PtrFBA60 for physiological function analysis and found that it played an important role in coping with drought stress. Taken together, the family analysis of FBA genes in P. trichocarpa provides a new opportunity for the identification of P. trichocarpa candidate FBA genes and elucidation of their functions in growth, development and stress response, thus demonstrating their utility in the improvement of P. trichocarpa.
Subject(s)
F-Box Proteins , Multigene Family , Droughts , Genome, Plant , Genes, Plant , F-Box Proteins/genetics , Stress, Physiological/genetics , Phylogeny , Plant Proteins/genetics , Gene Expression Regulation, PlantABSTRACT
In-plane ionic conduction over two-dimensional (2D) materials is desirable for flexible electronics. Exfoliating 2D covalent organic frameworks (COFs) towards a few layers is highly anticipated, whereas most examples remain robust via π-stacking against the interlayered dislocation. Herein, we synthesize a phosphine-amine-linked 2D COF by a nucleophilic substitution reaction of phosphazene with amines. The synthesized COF is crystalline, and stacks in an AB-staggered fashion, wherein the AB dual layers are interlocked by embedding P-Cl bonds from one to another layer, and the non-interlocked layers are readily delaminated. Therefore, in situ post-quaternization over phosphazene can improve the ionization of backbones, accompanied by layered exfoliation. The ultrathin nanosheets can decouple lithium salts for fast solid-state ion transport, achieving a high conductivity and low activation energy. Our findings explore the P-N substitution reaction for COF crystallization and demonstrate that the staggered stacking 2D COFs are readily exfoliated for designing solid electrolytes.
ABSTRACT
Two-dimensional covalent organic frameworks (2D COFs) offer a designable platform to explore porous polyelectrolyte frameworks with periodic ionic skeletons and uniform pore channels. However, the crystallinity of ionized 2D COF is often far from satisfactory as the electrostatic assembly of structures impedes the ordered layered arrangement. Here, a multivariate synthetic strategy to synthesize a highly crystalline squaraine (SQ)-linked zwitterionic 2D COF is proved. A neutral aldehyde monomer copolymerizes with squaric acid (SA) and amines in a controlled manner, resulting in the ionized COF with linkage heterogeneity in one tetragonal framework. Thus, the zwitterions of SQ are spatially isolated to minimize the electrostatic interaction and maintain the highly ordered layered stacking. With the addition of 85%-90% SA (relative to a total of aldehydes and SA), a fully SQ-linked zwitterionic 2D COF is achieved by the in-situ conversion of imine to SQ linkages. Such a highly crystalline SQ-linked COF promotes absorptivity in a full spectrum and photothermal conversion performances, and in turn, it exhibits enhanced solar-to-vapor generation with an efficiency of as high as 92.19%. These results suggest that synthetically regulating charge distribution is desirable to constitute a family of new crystalline polyelectrolyte frameworks.
Subject(s)
Metal-Organic Frameworks , Cyclobutanes , Imines/chemistry , Phenols , Polyelectrolytes , PorosityABSTRACT
BACKGROUND: Exercise boosts the health of some brain parts, such as the hippocampus and hypothalamus. Several studies show that long-term exercise improves spatial learning and memory, enhances hypothalamic leptin sensitivity, and regulates energy balance. However, the effect of exercise on the hippocampus and hypothalamus is not fully understood. The study aimed to find epigenetic modifications or changes in gene expression of the hippocampus and hypothalamus due to exercise. METHODS: Male C57BL/6 mice were randomly divided into sedentary and exercise groups. All mice in the exercise group were subjected to treadmill exercise 5 days per week for 1 h each day. After the 12-week exercise intervention, the hippocampus and hypothalamus tissue were used for RNA-sequencing or molecular biology experiments. RESULTS: In both groups, numerous differentially expressed genes of the hippocampus (up-regulated: 53, down-regulated: 49) and hypothalamus (up-regulated: 24, down-regulated: 40) were observed. In the exercise group, increased level of N6-methyladenosine (m6A) was observed in the hippocampus and hypothalamus (p < 0.05). Furthermore, the fat mass and obesity-associated gene (FTO) of the hippocampus and hypothalamus were down-regulated in the exercise group (p < 0.001). In addition, the Fto co-expression genes of the mouse brain were studied and analyzed using database to determine the potential roles of exercise-downregulated FTO in the brain. CONCLUSION: The findings demonstrate that long-term exercise might elevates the levels of m6A-tagged transcripts in the hippocampus and hypothalamus via down-regulation of FTO. Hence, exercise might be an effective intervention for epigenetic modification.
Subject(s)
Leptin , Animals , Epigenesis, Genetic , Hippocampus/metabolism , Hypothalamus/metabolism , Leptin/metabolism , Male , Mice , Mice, Inbred C57BL , RNA/metabolismABSTRACT
WHAT IS KNOWN AND OBJECTIVE: Olanzapine is an atypical antipsychotic drug used for mental disorders. There are limited studies providing sufficient pharmacokinetic data, thus the variability of concentrations of olanzapine used in Chinese paediatric patients aged 10 to 17 years remains to be evaluated. METHODS: Therapeutic drug monitoring data were collected from 151 paediatric patients aged 10 to 17 years who received olanzapine. The model was developed with a NONMEM software program. The final model validation and evaluation were assessed by bootstrap, diagnostic scatter plots, and normalized prediction distribution error (NPDE). Regimens of different dosages were simulated to reach the target concentration levels of 20 ng/ml, by using the final model with typical parameters. RESULTS: The one-compartment model was considered the best fit for the data. Typical estimates of the absorption rate constant (Ka), apparent clearance (CL/F), and apparent distribution volume (V/F) in the final model were 0.142 h-1 , 15.4 L/h, and 322 L, respectively. Sex and concomitant valproate (VPA) were included as significant predictors of olanzapine clearance, which was described by the following equation: CL/F = 15.4 × (1 + 0.546 × SEX) × (1 + 0.264 × VPA). Results of Monte-Carlo simulation suggested that male paediatric patients with concomitant VPA were advised to take no less than 15 mg per day of olanzapine orally, and in female paediatric patients with concomitant VPA, a dosing regimen of 10 mg may be sufficient to achieve the therapeutic range of olanzapine. WHAT IS NEW AND CONCLUSION: Our results identified concomitant valproate and sex as significant covariates in olanzapine population pharmacokinetics. Our model may be a useful tool for recommending dosage adjustments for physicians. The pharmacokinetics of olanzapine in patients aged 10 to 17 years was generally similar to that of adults and the elderly.
Subject(s)
Antipsychotic Agents , Valproic Acid , Adult , Child , Humans , Male , Female , Aged , Olanzapine , Antipsychotic Agents/therapeutic use , Kinetics , China , Models, BiologicalABSTRACT
NLRP3 inflammasome activation, which can be triggered by reactive oxygen species (ROS), contributes to nonalcoholic steatohepatitis (NASH) progression. Exercise is an effective therapeutic strategy for NASH. However, whether exercise prevents NLRP3 activation in NASH has not been investigated. Here, we investigated the effect of exercise on NLRP3 inflammasome in mice with high-fat diet (HFD)-induced or methionine and choine-deficient (MCD) diet-induced NASH and explored whether adropin, a metabolic peptide hormone shown to inhibit inflammation, mediates an exercise-induced benefit against NLRP3 inflammasome activation. Exercise alleviated diet-induced hepatic steatosis, inflammation, and fibrosis. Importantly, exercise significantly reduced the expression of NLRP3 inflammasome components, decreased Caspase-1 enzymatic activity, normalized IL-1ß production, and suppressed ROS overproduction in HFD-fed and MCD diet-fed mice. The exercise-elicited NLRP3 inflammasome inhibition was accompanied by increased adropin levels. Moreover, serum adropin levels were negatively correlated with serum IL-1ß levels. We further explored the effect of adropin on the NLRP3 inflammasome in palmitic acid (PA)-treated hepatocytes and Kupffer cells. Although adropin treatment did not significantly decrease the levels of all inflammasome components, it reduced the active Caspase-1 level, decreased Caspase-1 activity and downregulated IL-1ß expression in hepatocytes and Kupffer cells (KCs) treated with PA. Moreover, ROS levels in PA-stimulated hepatocytes and Kupffer cells were reduced upon adropin treatment. In summary, we demonstrated that the inhibitory effect of exercise on NLRP3 inflammasome activation was associated with adropin induction, resulting in NASH improvement.
Subject(s)
Inflammasomes/metabolism , Intercellular Signaling Peptides and Proteins/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Non-alcoholic Fatty Liver Disease/metabolism , Physical Conditioning, Animal/physiology , Animals , Diet, High-Fat/adverse effects , Male , Mice , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease/etiology , Reactive Oxygen Species/metabolismABSTRACT
Heat-stressed Arabidopsis plants release heterochromatin-associated transposable element (TE) silencing, yet it is not accompanied by major reductions of epigenetic repressive modifications. In this study, we explored the functional role of histone H1 in repressing heterochromatic TEs in response to heat stress. We generated and analyzed RNA and bisulfite-sequencing data of wild-type and h1 mutant seedlings before and after heat stress. Loss of H1 caused activation of pericentromeric Gypsy elements upon heat treatment, despite these elements remaining highly methylated. By contrast, nonpericentromeric Copia elements became activated concomitantly with loss of DNA methylation. The same Copia elements became activated in heat-treated chromomethylase 2 (cmt2) mutants, indicating that H1 represses Copia elements through maintaining DNA methylation under heat. We discovered that H1 is required for TE repression in response to heat stress, but its functional role differs depending on TE location. Strikingly, H1-deficient plants treated with the DNA methyltransferase inhibitor zebularine were highly tolerant to heat stress, suggesting that both H1 and DNA methylation redundantly suppress the plant response to heat stress.