ABSTRACT
Although high titers of neutralizing Abs in human serum are associated with protection from reinfection by SARS-CoV-2, there is considerable heterogeneity in human serum-neutralizing Abs against SARS-CoV-2 during convalescence between individuals. Standard human serum live virus neutralization assays require inactivation of serum/plasma prior to testing. In this study, we report that the SARS-CoV-2 neutralization titers of human convalescent sera were relatively consistent across all disease states except for severe COVID-19, which yielded significantly higher neutralization titers. Furthermore, we show that heat inactivation of human serum significantly lowered neutralization activity in a live virus SARS-CoV-2 neutralization assay. Heat inactivation of human convalescent serum was shown to inactivate complement proteins, and the contribution of complement in SARS-CoV-2 neutralization was often >50% of the neutralizing activity of human sera without heat inactivation and could account for neutralizing activity when standard titers were zero after heat inactivation. This effect was also observed in COVID-19 vaccinees and could be abolished in individuals who were undergoing treatment with therapeutic anti-complement Abs. Complement activity was mainly dependent on the classical pathway with little contributions from mannose-binding lectin and alternative pathways. Our study demonstrates the importance of the complement pathway in significantly increasing viral neutralization activity against SARS-CoV-2 in spike seropositive individuals.
Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Vaccines , COVID-19 , Complement Pathway, Classical , Neutralization Tests , SARS-CoV-2 , Humans , SARS-CoV-2/immunology , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/blood , COVID-19/immunology , Antibodies, Viral/immunology , Antibodies, Viral/blood , Complement Pathway, Classical/immunology , COVID-19 Vaccines/immunology , Male , Female , Middle Aged , Adult , Convalescence , Aged , Complement System Proteins/immunologyABSTRACT
Glutamate (Glu) is the major excitatory transmitter in the nervous system. Impairment of its vesicular release by ß-amyloid (Aß) oligomers is thought to participate in pathological processes leading to Alzheimer's disease. However, it remains unclear whether soluble Aß42 oligomers affect intravesicular amounts of Glu or their release in the brain, or both. Measurements made in this work on single Glu varicosities with an amperometric nanowire Glu biosensor revealed that soluble Aß42 oligomers first caused a dramatic increase in vesicular Glu storage and stimulation-induced release, accompanied by a high level of parallel spontaneous exocytosis, ultimately resulting in the depletion of intravesicular Glu content and greatly reduced release. Molecular biology tools and mouse models of Aß amyloidosis have further established that the transient hyperexcitation observed during the primary pathological stage is mediated by an altered behavior of VGLUT1 responsible for transporting Glu into synaptic vesicles. Thereafter, an overexpression of Vps10p-tail-interactor-1a, a protein that maintains spontaneous release of neurotransmitters by selective interaction with t-SNAREs, resulted in a depletion of intravesicular Glu content, triggering advanced-stage neuronal malfunction. These findings are expected to open perspectives for remediating Aß42-induced neuronal hyperactivity and neuronal degeneration.
Subject(s)
Alzheimer Disease , Glutamic Acid , Mice , Animals , Glutamic Acid/metabolism , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Neurons/metabolism , Brain/metabolism , Peptide Fragments/metabolismABSTRACT
BACKGROUND: MicroRNA (miRNA) has been shown to play a key role in the occurrence and progression of diseases, making uncovering miRNA-disease associations vital for disease prevention and therapy. However, traditional laboratory methods for detecting these associations are slow, strenuous, expensive, and uncertain. Although numerous advanced algorithms have emerged, it is still a challenge to develop more effective methods to explore underlying miRNA-disease associations. RESULTS: In the study, we designed a novel approach on the basis of deep autoencoder and combined feature representation (DAE-CFR) to predict possible miRNA-disease associations. We began by creating integrated similarity matrices of miRNAs and diseases, performing a logistic function transformation, balancing positive and negative samples with k-means clustering, and constructing training samples. Then, deep autoencoder was used to extract low-dimensional feature from two kinds of feature representations for miRNAs and diseases, namely, original association information-based and similarity information-based. Next, we combined the resulting features for each miRNA-disease pair and used a logistic regression (LR) classifier to infer all unknown miRNA-disease interactions. Under five and tenfold cross-validation (CV) frameworks, DAE-CFR not only outperformed six popular algorithms and nine classifiers, but also demonstrated superior performance on an additional dataset. Furthermore, case studies on three diseases (myocardial infarction, hypertension and stroke) confirmed the validity of DAE-CFR in practice. CONCLUSIONS: DAE-CFR achieved outstanding performance in predicting miRNA-disease associations and can provide evidence to inform biological experiments and clinical therapy.
Subject(s)
MicroRNAs , Humans , MicroRNAs/genetics , Computational Biology/methods , Algorithms , Genetic Predisposition to DiseaseABSTRACT
Cytarabine (Ara-C) is widely used in the induction chemotherapy for acute myeloid leukemia (AML). Association between LncRNA GAS5 genetic polymorphism and the recovery of hematopoietic function after Ara-C-based chemotherapy is observed. This study aimed to identify whether intervention of GAS5 expression and GAS5 genotype affect Ara-C-induced inhibition of hematopoietic stem cells (HSCs) differentiation. In this study, cord blood-derived CD34+ cells were cultured in vitro, and a cell model of myelosuppression was established by treatment of CD34+ cells with Ara-C. The effect of GAS5 overexpression, Ara-C treatment, and GAS5 rs55829688 genotype on the hematopoietic colony-forming ability of CD34+ cells was assessed using methylcellulose-based colony forming unit assay. GAS5 overexpression slowed down the proliferation of cord blood-derived CD34+ cells significantly (p < 0.05) and decreased their ability to form hematopoietic colonies in vitro. Ara-C significantly reduced the hematopoietic colony-forming ability of CD34+ cells in vitro (p < 0.0001), and overexpressing GAS5 further decreased the number of hematopoietic colonies. GAS5 expression was higher in CD34+ cells than in CD34- cells, and positively correlated with GATA1 mRNA expression in CD34+ cells in vitro culture. However, GAS5 genotype had no effect on the total number of hematopoietic colonies formed from cord blood-derived CD34+ cells. In conclusion, our study highlights that GAS5 inhibited the in vitro proliferation and reduced the hematopoietic colony-forming ability of cord blood-derived CD34+ cells, with the most pronounced effect observed on CFU-GEMM formation. GAS5 also enhanced the inhibitory effect of Ara-C on the in vitro hematopoietic ability of CD34+ HSCs.
Subject(s)
Cytarabine , Leukemia, Myeloid, Acute , Humans , Cytarabine/toxicity , Cytarabine/metabolism , Hematopoietic Stem Cells , Hematopoiesis , Antigens, CD34 , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Cell DifferentiationABSTRACT
Herein, visible light-induced, nickel-catalyzed direct functionalization of the Hantzsch esters (HEs) with readily accessible alkyl bromides has been successfully achieved by taking advantage of HE as the reductant and substrate through an aromatization-dearomatization process. In this strategy, the single electron reduction of alkyl bromides by reactive Ni(I) species is essential for the success of this late-stage transformation. A wide range of 4-alkyl-1,4-dihydropyridines were rapidly assembled in moderate to good yields under mild conditions, rendering this photoinduced approach attractive for synthetic and medicinal chemistry.
ABSTRACT
Nickel/photoredox catalysis has emerged as a powerful platform for exploring nontraditional and challenging cross-couplings. Herein, a metallaphotoredox catalytic protocol has been developed on the basis of a tertiary amine-ligated boryl radical-induced halogen atom transfer process under blue-light irradiation. A wide variety of aryl and heteroaryl bromides featuring different functional groups and pharmaceutical moieties were facilely coupled to rapidly install C(sp3)-enriched aromatic scaffolds. The compatibility of Lewis base-ligated borane with nickel catalysis was well exemplified to extend the chemical space for Ni-catalyzed cross-electrophile coupling.
ABSTRACT
Interlayered thin-film nanocomposite (TFN) membranes have shown the potential to boost nanofiltration performance for water treatment applications including the removal of organic micropollutants (OMPs). However, the effects of substrates have been overlooked when exploiting and evaluating the efficacy of certain kinds of interlayers in tailoring membrane performance. Herein, a series of TFN membranes were synthesized on different porous substrates with identical interlayers of metal-organic framework nanosheets. It was revealed that the interlayer introduction could narrow but not fully eliminate the difference in the properties among the polyamide layers formed on different substrates, and the membrane performance variation was prominent in distinct aspects. For substrates with small pore sizes exerting severe water transport hindrance, the introduced interlayer mainly enhanced membrane water permeance by affording the gutter effect, while it could be more effective in reducing membrane pore size by improving the interfacial polymerization platform and avoiding PA defects when using a large-pore-size substrate. By matching the selected substrates and interlayers well, superior TFN membranes were obtained with simultaneously higher water permeance and OMP rejections compared to three commercial membranes. This study helps us to objectively understand interlayer efficacies and attain performance breakthroughs of TFN membranes for more efficient water treatment.
Subject(s)
Filtration , Membranes, Artificial , Nylons , Water Pollutants, Chemical , Water Purification , Nylons/chemistry , Water Purification/methods , Water Pollutants, Chemical/chemistry , Nanocomposites/chemistryABSTRACT
Mechanotransduction is the essential process that cells convert mechanical force into biochemical responses, and electrochemical sensor stands out from existing techniques by providing quantitative and real-time information about the biochemical signals during cellular mechanotransduction. However, the intracellular biochemical response evoked by mechanical force has been poorly monitored. In this paper, we report a method to apply local stretch on single cell and simultaneously monitor the ensuing intracellular biochemical signals. Specifically, a ferromagnetic micropipette was fabricated to locally stretch a single cell labeled with Fe3O4 nanoparticles under the external magnetic field, and the SiC@Pt nanowire electrode (SiC@Pt NWE) was inserted into the cell to monitor the intracellular hydrogen peroxide (H2O2) production induced by the local stretch. As a proof of concept, this work quantitatively investigated the elevated amount of H2O2 levels in single endothelial cell under different stretching amplitudes. This work puts forward a new research modality to manipulate and monitor the mechanotransduction at the single-cell level.
Subject(s)
Hydrogen Peroxide , Mechanotransduction, Cellular , Nanowires , Single-Cell Analysis , Hydrogen Peroxide/analysis , Single-Cell Analysis/methods , Mechanotransduction, Cellular/physiology , Nanowires/chemistry , Biosensing Techniques/methods , Biosensing Techniques/instrumentation , Humans , Electrochemical Techniques/methods , Electrochemical Techniques/instrumentation , Platinum/chemistry , ElectrodesABSTRACT
Myocardial ischemia/reperfusion injury (MIRI) is an irreversible adverse event during the management of coronary heart disease that lacks effective controls. The underlying mechanism of MIRI still requires further investigation. Recent studies have suggested that overexpression of ATF3 protects against MIRI by regulating inflammatory responses, ferroptosis, and autophagy. The downstream target of ATF3, EGR1, also showed cardioprotective properties against MIRI by promoting autophagy. Therefore, further investigating the effect of ATF3/EGR1 pathway on MIRI-induced inflammation and autophagy is needed. Cardiomyocyte MIRI model was established by challenging H9C2 cells with hypoxia/reoxygenation (H/R). The ATF3 overexpression-H/R cell model by transfecting ATF3 plasmid into the H9C2 cell line. The transcription levels of ATF3 and EGR1 were determined using RT-qPCR, the levels of TNF-α and IL-6 were determined using ELISA kits, the protein expression of LC3 I, LC3 II, and P62 was determined via WB, and microstructure of H9C2 cell was observed by transmission electron microscopy (TEM). Overexpression of ATF3 significantly downregulated Egr1 levels, indicating that EGR1 might be the target of ATF3. By upregulating ATF3 levels, the extracellular levels of the inflammatory cytokines TNF-α and IL-6 significantly decreased, and the protein expression of the autophagy markers LC3 I, LC3 II, and P62 significantly increased. TEM results revealed that the cell line in the H/R-ATF3 group exhibited a higher abundance of autophagosome enclosures of mitochondria. The results indicated that ATF3/EGR1 may alleviate inflammation and improve autophagy in an H/R-induced MIRI model of cardiomyocytes.
Subject(s)
Activating Transcription Factor 3 , Autophagy , Early Growth Response Protein 1 , Inflammation , Myocardial Reperfusion Injury , Myocytes, Cardiac , Tumor Necrosis Factor-alpha , Activating Transcription Factor 3/metabolism , Activating Transcription Factor 3/genetics , Autophagy/genetics , Early Growth Response Protein 1/metabolism , Early Growth Response Protein 1/genetics , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Animals , Inflammation/metabolism , Inflammation/pathology , Inflammation/genetics , Rats , Cell Line , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/pathology , Myocardial Reperfusion Injury/genetics , Tumor Necrosis Factor-alpha/metabolism , Tumor Necrosis Factor-alpha/genetics , Interleukin-6/metabolism , Interleukin-6/genetics , Microtubule-Associated Proteins/metabolism , Microtubule-Associated Proteins/genetics , Signal Transduction , Sequestosome-1 Protein/metabolism , Sequestosome-1 Protein/geneticsABSTRACT
BACKGROUND: Obesity is a serious public health issue worldwide, which is a risk factor of cardiovascular disorders. Obesity has been shown to be associated with subclinical myocardial injury, increasing the risk of heart failure. Our study aims to explore novel mechanisms underlying obesity-induced myocardial injury. METHODS: Mice were fed a high-fat diet (HFD) to establish a mouse model of obesity, and serum levels of TG, TCH, LDL, CK-MB, LDH, cTnI and BNP were examined. Inflammatory response was evaluated by determining the expression and secretion of proinflammatory cytokines IL-1ß and TNF-α. Macrophage infiltration in the heart was examined by IHC staining, and H&E staining was applied to evaluate myocardial injury. Primary peritoneal macrophages were isolated from mice and treated with palmitic acid (PA). Macrophage polarization was evaluated by determine the expression of CCL2, iNOS, CD206 and arginase I via Western blot, RT-qPCR, and flow cytometry. Co-IP assays were performed to examine the interaction between LEAP-2, GHSR and ghrelin. RESULTS: Hyperlipidemia, increased proinflammatory cytokines and myocardial injury were observed in mice with obesity, and silencing of LEAP-2 ameliorated HFD-induced hyperlipidemia, inflammation, and myocardial injury. Moreover, HFD-induced macrophage infiltration and M1 polarization were reversed by LEAP-2 knockdown in mice. Furthermore, silencing of LEAP-2 suppressed PA-induced M1 polarization but enhanced M2 polarization in vitro. LEAP-2 interacted with GHSR in macrophages, and knockdown of LEAP-2 promoted the interaction of GHSR and ghrelin. Overexpression of ghrelin enhanced LEAP-1 silencing-mediated suppression of inflammatory response and upregulation of M2 polarization in PA-induced macrophages. CONCLUSION: Knockdown of LEAP-2 ameliorates obesity-induced myocardial injury via promoting M2 polarization.
Subject(s)
Ghrelin , Macrophages , Animals , Mice , Cytokines/metabolism , Ghrelin/metabolism , Inflammation/metabolism , Macrophages/metabolism , Obesity/complications , Obesity/geneticsABSTRACT
Analysis of molecular aberrations across multiple cancer types, known as pan-cancer analysis, identifies commonalities and differences in key biological processes that are dysregulated in cancer cells from diverse lineages. Pan-cancer analyses have been performed for adult but not paediatric cancers, which commonly occur in developing mesodermic rather than adult epithelial tissues. Here we present a pan-cancer study of somatic alterations, including single nucleotide variants, small insertions or deletions, structural variations, copy number alterations, gene fusions and internal tandem duplications in 1,699 paediatric leukaemias and solid tumours across six histotypes, with whole-genome, whole-exome and transcriptome sequencing data processed under a uniform analytical framework. We report 142 driver genes in paediatric cancers, of which only 45% match those found in adult pan-cancer studies; copy number alterations and structural variants constituted the majority (62%) of events. Eleven genome-wide mutational signatures were identified, including one attributed to ultraviolet-light exposure in eight aneuploid leukaemias. Transcription of the mutant allele was detectable for 34% of protein-coding mutations, and 20% exhibited allele-specific expression. These data provide a comprehensive genomic architecture for paediatric cancers and emphasize the need for paediatric cancer-specific development of precision therapies.
Subject(s)
Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Genome, Human/genetics , Leukemia/genetics , Mutation/genetics , Neoplasms/genetics , Alleles , Aneuploidy , Child , DNA Copy Number Variations , Exome/genetics , Humans , Mutation/radiation effects , Mutation Rate , Oncogenes/genetics , Precision Medicine/trends , Ultraviolet Rays/adverse effectsABSTRACT
Segmental bone defects, arising from factors such as trauma, tumor resection, and congenital malformations, present significant clinical challenges that often necessitate complex reconstruction strategies. Hydrogels loaded with multiple osteogenesis-promoting components have emerged as promising tools for bone defect repair. While the osteogenic potential of the Piezo1 agonist Yoda1 has been demonstrated previously, its hydrophobic nature poses challenges for effective loading onto hydrogel matrices.In this study, we address this challenge by employing Yoda1-pretreated bone marrow-derived mesenchymal stem cell (BMSCs) exosomes (Exo-Yoda1) alongside exosomes derived from BMSCs (Exo-MSC). Comparatively, Exo-Yoda1-treated BMSCs exhibited enhanced osteogenic capabilities compared to both control groups and Exo-MSC-treated counterparts. Notably, Exo-Yoda1-treated cells demonstrated similar functionality to Yoda1 itself. Transcriptome analysis revealed activation of osteogenesis-associated signaling pathways, indicating the potential transduction of Yoda1-mediated signals such as ErK, a finding validated in this study. Furthermore, we successfully integrated Exo-Yoda1 into gelatin methacryloyl (GelMA)/methacrylated sodium alginate (SAMA)/ß-tricalcium phosphate (ß-TCP) hydrogels. These Exo-Yoda1-loaded hydrogels demonstrated augmented osteogenesis in subcutaneous ectopic osteogenesis nude mice models and in rat skull bone defect model. In conclusion, our study introduces Exo-Yoda1-loaded GELMA/SAMA/ß-TCP hydrogels as a promising approach to promoting osteogenesis. This innovative strategy holds significant promise for future widespread clinical applications in the realm of bone defect reconstruction.
Subject(s)
Exosomes , Hydrogels , Mesenchymal Stem Cells , Osteogenesis , Osteogenesis/drug effects , Animals , Exosomes/metabolism , Mesenchymal Stem Cells/metabolism , Hydrogels/chemistry , Mice , MAP Kinase Signaling System/drug effects , Signal Transduction/drug effects , Calcium Phosphates/chemistry , Calcium Phosphates/pharmacology , Rats , Male , Alginates/chemistry , Gelatin/chemistry , Cell Differentiation/drug effects , Bone Regeneration/drug effects , Cells, CulturedABSTRACT
Emerging findings point to a role for C1q/TNF-related protein 4 (CTRP4) in feeding in mammals. However, it remains unknown whether CTRP4 regulates feeding in fish. This study aimed to determine the feeding regulation function of CTRP4 in Siberian sturgeon (Acipenser baerii). In this study, the Siberian sturgeon ctrp4 (Abctrp4) gene was cloned, and Abctrp4 mRNA was shown to be highly expressed in the hypothalamus. In the hypothalamus, Abctrp4 mRNA decreased during fasting and reversed after refeeding. Subsequently, we obtained the AbCTRP4 recombinant protein by prokaryotic expression and optimized the expression and purification conditions. Siberian sturgeon (81.28 ± 14.75 g) were injected intraperitoneally using 30, 100, and 300 ng/g Body weight (BW) AbCTRP4 to investigate its effect on feeding. The results showed that 30, 100, and 300 ng/g BW of the AbCTRP4 significantly reduced the cumulative food intake of Siberian sturgeon at 1, 3, and 6 h. Finally, to investigate the potential mechanism of CTRP4 feeding inhibition, 300 ng/g BW AbCTRP4 was injected intraperitoneally. The findings demonstrated that AbCTRP4 treatment for 1 h significantly promoted the mRNA levels of anorexigenic peptides (pomc, cart, and leptin) while suppressing the mRNA abundances of orexigenic peptides (npy and agrp).In addition, the jak2/stat3 pathway in the hypothalamus was significantly activated after 1 h of AbCTRP4 treatment. In conclusion., this study confirms the anorexigenic effect of CTRP4 in Siberian sturgeon.
Subject(s)
Appetite , Complement C1q , Animals , Appetite/genetics , Complement C1q/metabolism , Complement C1q/pharmacology , Eating/physiology , Fishes/physiology , Peptides/genetics , Peptides/pharmacology , Peptides/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Mammals/metabolismABSTRACT
BACKGROUND: Previous studies on the effects of microplastics (MPs) on bone in early development are limited. This study aimed to investigate the adverse effects of MPs on bone in young rats and the potential mechanism. METHODS: Three-week-old female rats were orally administered MPs for 28 days, and endoplasmic reticulum (ER) stress inhibitor salubrinal (SAL) and ER stress agonist tunicamycin (TM) were added to evaluate the effect of ER stress on toxicity of MPs. The indicators of growth and plasma markers of bone turnover were evaluated. Tibias were analyzed using micro-computed tomography (micro-CT). Histomorphological staining of growth plates was performed, and related gene expression of growth plate chondrocytes was tested. RESULTS: After exposure of MPs, the rats had decreased growth, shortened tibial length, and altered blood calcium and phosphorus metabolism. Trabecular bone was sparse according to micro-CT inspection. In the growth plate, the thickness of proliferative zone substantial reduced while the thickness of hypertrophic zone increased significantly, and the chondrocytes were scarce and irregularly arranged according to tibial histological staining. The transcription of the ER stress-related genes BIP, PERK, ATF4, and CHOP dramatically increased, and the transcription factors involved in chondrocyte proliferation, differentiation, apoptosis, and matrix secretion were aberrant according to RT-qPCR and western blotting. Moreover, the addition of TM showed higher percentage of chondrocyte death. Administration of SAL alleviated all of the MPs-induced symptoms. CONCLUSION: These results indicated that MPs could induce growth retardation and longitudinal bone damage in early development. The toxicity of MPs may attribute to induced ER stress and impaired essential processes of the endochondral ossification after MPs exposure.
Subject(s)
Endoplasmic Reticulum Stress , Growth Plate , Microplastics , Polystyrenes , Animals , Endoplasmic Reticulum Stress/drug effects , Growth Plate/drug effects , Growth Plate/pathology , Female , Rats , Microplastics/toxicity , Polystyrenes/toxicity , Rats, Sprague-Dawley , Osteogenesis/drug effects , Chondrocytes/drug effects , Tibia/drug effects , Tibia/pathologyABSTRACT
A chemical investigation of Anthriscus sylvestris roots led to the isolation and characterization of two new nitrogen-containing phenylpropanoids (1-2) and two new phenol glycosides (8-9), along with fifteen known analogues. Structure elucidation was based on HRESIMS, 1D and 2D NMR spectroscopy, and electronic circular dichroism (ECD). In addition, compounds 3, 6, 9-10, 12, and 17 exhibited inhibitory effects against the abnormal proliferation of pulmonary arterial smooth muscle cells with IC50 values ranging from 10.7 ± 0.6 to 57.1 ± 1.1 µM.
Subject(s)
Cell Proliferation , Myocytes, Smooth Muscle , Plant Roots , Pulmonary Artery , Plant Roots/chemistry , Cell Proliferation/drug effects , Myocytes, Smooth Muscle/drug effects , Pulmonary Artery/cytology , Pulmonary Artery/drug effects , Animals , Molecular Structure , Plant Extracts/pharmacology , Plant Extracts/chemistry , Glycosides/pharmacology , Glycosides/chemistry , Glycosides/isolation & purification , Rats , Magnetic Resonance SpectroscopyABSTRACT
It is widely known controversies about the results of violent video game increase aggression. However, the role of competitive video games, has received less research attention, and the underlying mechanisms of their influence are unknown. This study aimed to expand the existing literature by systematically exploring the effects of competitive video game exposure on adolescent aggression and the mediating role of impulsivity. In so doing, three types of studies (collectively N = 2919, mean age varied from 13.75 to 15.44 years, with a balanced gender) combining cross-sectional, experimental, and longitudinal approaches, were conducted. The findings consistently show that competitive video game exposure increased adolescents' aggression and impulsivity. Also, impulsivity mediated the correlation and long-term effect of competitive video game exposure on aggression. However, the experimental study did not confirm the short-term mediating effect of impulsivity, which may be related to the type of aggression measured in the study. The results indicate that competitive video game exposure is an important antecedent factor for adolescent aggression, and impulsivity is the key underlying mechanism.
Subject(s)
Adolescent Behavior , Aggression , Competitive Behavior , Impulsive Behavior , Video Games , Humans , Video Games/psychology , Aggression/psychology , Adolescent , Male , Female , Adolescent Behavior/psychology , China , Cross-Sectional Studies , Longitudinal Studies , East Asian PeopleABSTRACT
Gastrin is an important intragastrointestinal hormone, but reports on its regulation of feeding behavior in fish are still scarce. This study aimed to determine the feeding regulatory function of gastrin in sturgeon. In this study, a gastrin/cholecystokinin-like peptide was identified in the genomes of sturgeon and proved to be gastrin by evolutionary tree analysis. Tissue distribution of gastrin and its receptor, cholecystokinin receptor B (CCKRB), showed that both had high mRNA abundance in the hypothalamus and gastrointestinal tract. In the duodenum, gastrin and CCKRB mRNAs were reduced at 1 h of fasting, and both were also observed in the stomach and hypothalamus in response to changes in feeding status. Sulfated gastrin 17 is the major form of gastrin in vivo. Therefore, we investigated the effect of sulfated gastrin 17 on feeding by intraperitoneal injection into Siberian sturgeon using sulfated gastrin 17. The results showed that gastrin 17 significantly reduced the cumulative feeding of Siberian sturgeon in the short term (1, 3 and 6 h) and long term (1, 2, 3, 4, 5 and 7 days). Finally, we explored the potential mechanism of feeding inhibition after intraperitoneal injection of gastrin 17 for 7 consecutive days. The results showed that gastrin 17 treatment significantly increased the mRNA levels of anorexigenic peptides (cart, cck and pyy), while it had no significant effect on the mRNA abundance of orexigenic peptides (npy and agrp). In addition, gastrin 17 treatment significantly affected the expression of appetite signaling pathways in the hypothalamus, such that the mRNA expression of ampkα1 was significantly reduced, whereas the mRNA abundance of stat3, mtor and s6k was significantly increased. In conclusion, the present study confirmed the anorectic effect of gastrin on Siberian sturgeon.
Subject(s)
Fishes , Gastrins , Receptor, Cholecystokinin B , Animals , Gastrins/metabolism , Fishes/physiology , Fishes/metabolism , Receptor, Cholecystokinin B/metabolism , Receptor, Cholecystokinin B/genetics , Feeding Behavior/drug effects , RNA, Messenger/metabolism , RNA, Messenger/genetics , Hypothalamus/metabolismABSTRACT
The study investigated the protective effect and mechanism of 2-phenylethyl-beta-glucopyranoside(Phe) from Huaizhong No.1 Rehmannia glutinosa on hypoxic pulmonary hypertension(PH), aiming to provide a theoretical basis for clinical treatment of PAH. Male C57BL/6N mice were randomly divided into normal group, model group, positive drug(bosentan, 100 mg·kg~(-1)) group, and low-and high-dose Phe groups(20 and 40 mg·kg~(-1)). Except for the normal group, all other groups were continuously subjected to model induction in a 10% hypoxic environment for 5 weeks, with oral administration for 14 days starting from the 3rd week. The cardiopulmonary function, right ventricular pressure, cough and asthma index, lung injury, cell apoptosis, oxidative stress-related indicators, immune cells, and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR)/hypoxic inducible factor 1α(HIF-1α) pathway-related proteins or mRNA levels were examined. Furthermore, hypoxia-induced pulmonary arterial smooth muscle cell(PASMC) were used to further explore the mechanism of Phe intervention in PH combined with PI3K ago-nist(740Y-P). The results showed that Phe significantly improved the cardiopulmonary function of mice with PH, decreased right ventricular pressure, cough and asthma index, and lung injury, reduced cell apoptosis, oxidative stress-related indicators, and nuclear levels of phosphorylated Akt(p-Akt) and phosphorylated mTOR(p-mTOR), inhibited the expression levels of HIF-1α and PI3K mRNA and proteins, and maintained the immune cell homeostasis in mice. Further mechanistic studies revealed that Phe significantly reduced the viability and migration ability of hypoxia-induced PASMC, decreased the expression of HIF-1α and PI3K proteins and nuc-lear levels of p-Akt and p-mTOR, and this effect was blocked by 740Y-P. Therefore, it is inferred that Phe may exert anti-PH effects by alleviating the imbalance of oxidative stress and apoptosis in lung tissues and regulating immune levels, and its mechanism may be related to the regulation of the PI3K/Akt/mTOR/HIF-1α pathway. This study is expected to provide drug references and research ideas for the treatment of PH.
Subject(s)
Glucosides , Hypertension, Pulmonary , Hypoxia-Inducible Factor 1, alpha Subunit , Hypoxia , Mice, Inbred C57BL , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Rehmannia , TOR Serine-Threonine Kinases , Animals , Male , TOR Serine-Threonine Kinases/metabolism , TOR Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/genetics , Mice , Hypertension, Pulmonary/drug therapy , Hypertension, Pulmonary/physiopathology , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Rehmannia/chemistry , Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol 3-Kinases/genetics , Glucosides/pharmacology , Hypoxia/drug therapy , Hypoxia/physiopathology , Hypoxia/metabolism , Signal Transduction/drug effects , Humans , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/chemistry , Apoptosis/drug effectsABSTRACT
Exocytosis involving the fusion of intracellular vesicles with cell membrane, is thought to be modulated by the mechanical cues in the microenvironment. Single-cell electrochemistry can offer unique information about the quantification and kinetics of exocytotic events; however, the effects of mechanical force on vesicular release have been poorly explored. Herein, we developed a stretchable microelectrode with excellent electrochemical stability under mechanical deformation by microfabrication of functionalized poly(3,4-ethylenedioxythiophene) conductive ink, which achieved real-time quantitation of strain-induced vesicular exocytosis from a single cell for the first time. We found that mechanical strain could cause calcium influx via the activation of Piezo1 channels in chromaffin cell, initiating the vesicular exocytosis process. Interestingly, mechanical strain increases the amount of catecholamines released by accelerating the opening and prolonging the closing of fusion pore during exocytosis. This work is expected to provide revealing insights into the regulatory effects of mechanical stimuli on vesicular exocytosis.
Subject(s)
Chromaffin Cells , Exocytosis , Chromaffin Cells/metabolism , Microelectrodes , Animals , Microtechnology/methods , Calcium/metabolism , Stress, Mechanical , Polymers/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistryABSTRACT
Recently, the prevalence of Aeromonas hydrophila antibiotic-resistant strains has been reported in aquaculture, but its intrinsic antibiotic resistance mechanisms are largely unknown. In the present study, a label-free proteomics technology was used to compare the differential protein abundances in response to norfloxacin (NOR) stress in A. hydrophila. The results showed that there were 186 proteins decreasing and 220 proteins increasing abundances in response to NOR stress. Bioinformatics analysis showed that the differentially expressed proteins were enriched in several biological processes, such as sulfur metabolism and homologous recombination. Furthermore, the antibiotic sensitivity assays showed that the deletion of AHA_0904, cirA, and cysI significantly decreased the resistance against NOR, whereas ΔAHA_1239, ΔcysA, ΔcysD, and ΔcysN significantly increased the resistance against NOR. Our results provide insights into NOR resistance mechanisms and indicate that AHA_0904, cirA, AHA_1239, and sulfur metabolism may play important roles in NOR resistance in A. hydrophila.