ABSTRACT
Enteritis posed a significant health challenge to golden pompano (Trachinotus ovatus) populations. In this research, a comprehensive multi-omics strategy was implemented to elucidate the pathogenesis of enteritis by comparing both healthy and affected golden pompano. Histologically, enteritis was characterized by villi adhesion and increased clustering after inflammation. Analysis of the intestinal microbiota revealed a significant increase (P < 0.05) in the abundance of specific bacterial strains, including Photobacterium and Salinivibrio, in diseased fish compared to the healthy group. Metabolomic analysis identified 5479 altered metabolites, with significant impacts on terpenoid and polyketide metabolism, as well as lipid metabolism (P < 0.05). Additionally, the concentrations of several compounds such as calcitetrol, vitamin D2, arachidonic acid, and linoleic acid were significantly reduced in the intestines of diseased fish post-enteritis (P < 0.05), with the detection of harmful substances such as Efonidipine. In transcriptomic profiling, enteritis induced 68 upregulated and 73 downregulated genes, predominantly affecting steroid hormone receptor activity (P < 0.05). KEGG pathway enrichment analysis highlighted upregulation of SQLE and CYP51 in steroidogenesis, while the HSV-1 associated MHC1 gene exhibited significant downregulation. Integration of multi-omics results suggested a potential pathogenic mechanism: enteritis may have resulted from concurrent infection of harmful bacteria, specifically Photobacterium and Salinivibrio, along with HSV-1. Efonidipine production within the intestinal tract may have blocked certain calcium ion channels, leading to downregulation of MHC1 gene expression and reduced extracellular immune recognition. Upregulation of SQLE and CYP51 genes stimulated steroid hormone synthesis within cells, which, upon binding to G protein-coupled receptors, influenced calcium ion transport, inhibited immune activation reactions, and further reduced intracellular synthesis of anti-inflammatory substances like arachidonic acid. Ultimately, this cascade led to inflammation progression, weakened intestinal peristalsis, and villi adhesion. This study utilized multi-level omics detection to investigate the pathological symptoms of enteritis and proposed a plausible pathogenic mechanism, providing innovative insights into enteritis verification and treatment in offshore cage culture of golden pompano.
Subject(s)
Enteritis , Fish Diseases , Gastrointestinal Microbiome , Animals , Enteritis/veterinary , Enteritis/immunology , Enteritis/microbiology , Fish Diseases/immunology , Gene Expression Profiling/veterinary , Perciformes/immunology , Perciformes/genetics , Transcriptome , Metabolomics , MultiomicsABSTRACT
The Chinese government promotes nuclear energy development in the context of mitigating climate change. However, the large-scale development is still facing challenges related to the knowledge gap among the general public and the potential "not-in-my-back-yard" objection. Based on a representative national survey, we analyze Chinese people's knowledge and perceptions of nuclear energy and estimate their willingness-to-accept the potential risks of new nuclear programs in neighborhoods via the Contingent Valuation Method. Generally, more than half of people do not know anything about nuclear energy. The main factors influencing public knowledge are identified, such as the residential distance to existing nuclear power stations and the frequency of internet use. Moreover, approximately 12% of individuals with some knowledge seem to be willing to accept new nuclear power plants in their neighborhoods with no compensation needed. Specifically, the perceptions of nuclear risks and pollution from fossil fuels are significant factors influencing people's acceptance of nuclear energy. Although public knowledge does not directly influence acceptance, more knowledge seems to reduce risk perception and increase benefit perception. The residential distance to exiting nuclear stations has limited effects on people's acceptance of newly planned nuclear programs for those living in the same county with some knowledge. In general, a typical Chinese household is willing to accept USD $5.66 every month or USD $67.97 every year to bear the potential risks of the new nuclear program in neighborhoods. Significant practical implications that can be transferable to other new energy technologies and countries or regions are provided.
Subject(s)
Nuclear Energy , China , Humans , Surveys and Questionnaires , Knowledge , Nuclear Power Plants , Perception , Climate Change , Public OpinionABSTRACT
INTRODUCTION: Coronavirus disease-2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. It was initially detected in Wuhan, China, in December 2019. In March 2020, the World Health Organization (WHO) declared COVID-19 a global pandemic. Compared to healthy individuals, patients with IgA nephropathy (IgAN) are at a higher risk of SARS-CoV-2 infection. However, the potential mechanisms remain unclear. This study explores the underlying molecular mechanisms and therapeutic agents for the management of IgAN and COVID-19 using the bioinformatics and system biology way. METHODS: We first downloaded GSE73953 and GSE164805 from the Gene Expression Omnibus (GEO) database to obtain common differentially expressed genes (DEGs). Then, we performed the functional enrichment analysis, pathway analysis, protein-protein interaction (PPI) analysis, gene regulatory networks analysis, and potential drug analysis on these common DEGs. RESULTS: We acquired 312 common DEGs from the IgAN and COVID-19 datasets and used various bioinformatics tools and statistical analyses to construct the PPI network to extract hub genes. Besides, we performed gene ontology (GO) and pathway analyses to reveal the common correlation between IgAN and COVID-19. Finally, on the basis of common DEGs, we determined the interactions between DEGs-miRNAs, the transcription factor-genes (TFs-genes), protein-drug, and gene-disease networks. CONCLUSION: We successfully identified hub genes that may act as biomarkers of COVID-19 and IgAN and also screened out some potential drugs to provide new ideas for COVID-19 and IgAN treatment.
Subject(s)
COVID-19 , Glomerulonephritis, IGA , MicroRNAs , Humans , COVID-19/genetics , SARS-CoV-2 , Glomerulonephritis, IGA/genetics , Computational Biology , Gene Regulatory Networks , Gene Expression ProfilingABSTRACT
Nur77 modulators have emerged as a promising therapeutic approach for hepatocellular carcinoma. In this study, a structure-based rational drug design approach was used to design and synthesise a series of 4-((8-hydroxy-2-methylquinolin-4-yl)amino)benzoylhydrazone derivatives based on the binding characteristics of our previously reported 10g and the native ligand 3NB at the binding Site C of Nur77. Cell-based cytotoxicity assays revealed that compound TMHA37 demonstrated the highest cytotoxicity against all tested cancer cells. The induced fit docking and binding pose metadynamics simulation suggested that TMHA37 was the most promising Nur77 binder at Site C. Molecular dynamics simulation validated the stable binding of TMHA37 to Nur77's Site C but not to Sites A or B. Specifically, TMHA37 bound strongly to Nur77-LBD (KD = 445.3 nM) and could activate Nur77's transcriptional activity. Furthermore, TMHA37 exhibited antitumor effects by blocking the cell cycle at G2/M phase and inducing cell apoptosis in a Nur77-dependent manner.
Subject(s)
Antineoplastic Agents , Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Apoptosis , Binding Sites , Cell Division , Antineoplastic Agents/pharmacology , Molecular Docking Simulation , Drug Screening Assays, Antitumor , Cell Proliferation , Cell Line, TumorABSTRACT
The systemic review and meta-analysis aimed to identify the predictors for short-term successful weaning from CRRT in severe AKI patients. PubMed, Embase, the Cochrane Library, and grey literature were searched for relevant studies investigating variables for short-term successful weaning from CRRT to August 2022. Our criteria included patients with AKI who required CRRT but excluded patients with kidney failure. The pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated using fixed-effect (I2≤50% and P-value of the Q statistic > 0.1) or random-effect models (I2>50% or p-value of the Q statistic ≤ 0.1) as appropriate. Our search yielded 11 studies and described 11 variables. The pooled analysis showed that chronic kidney disease (OR = 0.638, 95% CI: 0.491-0.829), CRRT duration (OR = 0.913, 95% CI: 0.882-0.946), and urine output at the cessation of CRRT (per 100 mL/day increase) (OR = 1.084, 95% CI: 1.061-1.108) were predictive factors for short-term successful weaning from CRRT. Male (OR = 0.827, 95% CI: 0.627-1.092), diabetes mellitus (OR = 0.970, 95% CI: 0.761-1.237), and sepsis (OR = 0.911, 95% CI: 0.717-1.158) were unrelated to the short-term weaning from CRRT. The relationship between hypertension, use of vasopressors or inotropes at the starting of CRRT, use of vasopressors or inotropes at the cessation of CRRT, use of diuretics at the cessation of CRRT, serum creatinine at the cessation of CRRT, and short-term weaning from CRRT remains unclear. Additional prospective studies are needed to evaluate this relationship further.
Subject(s)
Acute Kidney Injury , Continuous Renal Replacement Therapy , Humans , Male , Renal Replacement Therapy , Weaning , Acute Kidney Injury/therapy , Diuretics , Retrospective StudiesABSTRACT
With the increase in urban rail transit construction, instances of tunnel disease are on the rise, and cracks have become the focus of tunnel maintenance and management. Therefore, it is essential to carry out crack detection in a timely and efficient manner to not only prolong the service life of the tunnel but also reduce the incidence of accidents. In this paper, the design and structure of a tunnel crack detection system are analyzed. On this basis, this paper proposes a new method for crack identification and feature detection using image processing technology. This method fully considers the characteristics of tunnel images and the combination of these characteristics with deep learning, while a deep convolutional network (Single-Shot MultiBox Detector (SSD)) is proposed based on deep learning for object detection in complex images. The experimental results show that the test set accuracy and training set accuracy of the support vector machine (SVM) in the classification comparison test are up to 88% and 87.8%, respectively; while the test accuracy of Alexnet's deep convolutional neural network-based classification and identification is up to 96.7%, and the training set accuracy is up to 97.5%. It can be seen that this deep convolutional network recognition algorithm based on deep learning and image processing is better and more suitable for the detection of cracks in subway tunnels.
Subject(s)
Railroads , Neural Networks, Computer , Algorithms , Image Processing, Computer-Assisted/methods , Support Vector MachineABSTRACT
BACKGROUND: Renal fibrosis is a common outcome of various renal damage, including diabetic nephropathy (DN), the leading cause of end-stage renal disease. Currently, there are no effective therapies for renal fibrosis. The present study aimed to determine whether pentosan polysulphate sodium (PPS), a FDA approved medication for interstitial cystitis, protects diabetic renal fibrosis. METHODS: Cell viability and apoptosis were evaluated in mouse mesangial cells (SV40-MES13) after incubating with the advanced glycation end products (AGEs), which play important roles in the pathogenesis of DN. Western blot and ELISA were performed to determine the expression of transforming growth factor-beta1 (TGF-ß1) and fibronectin (FN), two biomarkers of renal fibrosis, as well as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα), two biomarkers of inflammation. The miRNA-mRNA regulatory network involved in the phosphatidylinositol 3-kinase (PI3K)/Ser and Thr Kinase (AKT) signalling was investigated by miRNA deep sequencing and validated by RT-PCR and miRNA transfection. RESULTS: AGEs significantly inhibited cell proliferation and promoted cell apoptosis, which was associated with the overexpression of TGF-ß1, FN, IL-6, and TNFα. PPS almost completely reversed AGEs-induced biomarkers of fibrosis and inflammation, and significantly altered the miRNA expression profile in AGEs-treated cells. Notably, the PI3K/AKT signalling was one of the most significantly enriched pathways targeted by PPS-related differentially expressed miRNAs. PPS significantly up-regulated miR-466a-3p, which was shown to target PIK3CA, and mediated the inhibitory effect of PPS on AGEs-induced activation of PI3K/AKT pathway. CONCLUSIONS: The treatment of PPS protected against AGEs-induced toxicity in SV40 MES13 cells via miR-466a-3p-mediated inhibition of PI3K/AKT pathway.
Subject(s)
Diabetic Nephropathies , MicroRNAs , Animals , Biomarkers , Diabetic Nephropathies/pathology , Fibrosis , Inflammation/complications , Inflammation/drug therapy , Interleukin-6 , Mice , MicroRNAs/genetics , Pentosan Sulfuric Polyester/pharmacology , Phosphatidylinositol 3-Kinase , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Transforming Growth Factor beta1/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Zhibaidihuang Decoction (ZBDHD) is a traditional Chinese medicine with immense potential to treat IgA nephropathy. However, its core ingredients and representative mechanism remain unclear. In this study, we uncovered the key component and underlying mechanisms of ZBDHD for IgA nephropathy by applying network pharmacology and molecular docking approaches. This was done by first identifying the active ingredients and, subsequently, their corresponding gene targets in ZBDHD with the help of the Traditional Chinese Medicine Systems Pharmacology and analysis platform (TCMSP) database, thereby constructing the drug-compound-target network. The IgA nephropathy-associated genes were then identified using GeneCards, Drugbank, and OMIM databases. The overlapped targets were later obtained to establish Protein-Protein Interaction (PPI) networks, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Finally, we performed molecular docking among active compounds and hub genes, and thereby verified the key compound of ZBDHD. The drug-compound-gene network consisted of 289 nodes and 1,113 edges. The top four active ingredients were beta-sitosterol, kaempferol, quercetin and stigmasterol. The top five hub genes in the PPI network were AKT1, ILB1, IL-6, TNF, and TP53. Molecular docking results could demonstrate that there was high affinity among active compounds and the core targets, while quercetin may possibly be the key compound of ZBDHD. We first identified the positive compound and the candidate molecular mechanisms of ZBDHD in an IgA nephropathy treatment and discovered that quercetin might be the core compound of ZBDHD in the treatment of IgA nephropathy.
Subject(s)
Drugs, Chinese Herbal , Glomerulonephritis, IGA , Humans , Molecular Docking Simulation , Glomerulonephritis, IGA/drug therapy , Glomerulonephritis, IGA/genetics , Network Pharmacology , Quercetin , Protein Interaction Maps/genetics , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic useABSTRACT
Taking variations in PM2.5 as indicators for assessing the performance of authority in air quality management will probably lead to misjudgment, as PM2.5 concentration is affected not only by anthropogenic emissions but also by uncontrollable circumstances. To solve this problem, we proposed a decomposition method to attribute the variations in PM2.5 to the contributions of meteorological conditions, cross-regional transports of pollutants, secondary aerosols, and local emissions. This method estimated the relationship between PM2.5 concentration and the various influencing factors using a semi-parametric generalized additive model. A case study was conducted in Shenyang, a heavily polluted city in northeast China, based on up to 595,000 hourly data samples from 2014 to 2017. The decomposition results indicated that the average PM2.5 in 2017 decreased by 39.80% compared with 2014, far exceeding the government's target of 15%, but only 11.79% of the decrease was benefited from the control of local emissions. The severe pollution event that occurred in November 2015 was induced by the combination of massive emissions from heating and meteorological conditions conducive to pollutant accumulation. Furthermore, the approach we proposed can be extended to any location that has monitoring data on air pollutant concentrations and meteorological conditions.
Subject(s)
Air Pollutants , Air Pollution , Aerosols/analysis , Air Pollutants/analysis , Air Pollution/analysis , China , Environmental Monitoring/methods , Particulate Matter/analysis , SeasonsABSTRACT
This systematic review and meta-analysis aimed to assess the predictive value of diabetic retinopathy (DR) on further diabetic nephropathy (DN) risk in patients with type 2 diabetes (T2D) based on the prospective cohort studies. PubMed, Embase, and the Cochrane Library were systematically searched for eligible prospective cohort studies through March 2020. The predictive value of DR was assessed using sensitivity, specificity, positive likelihood ratio (PLR) and negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the receiver operating characteristic curve (AUC) through the bivariate generalized linear mixed model and the random-effects model. Ten prospective cohort studies recruited 635 patients with T2D. The pooled sensitivity and specificity of DR for predicted DN were noted to be 0.64 (95% CI, 0.54-0.73) and 0.77 (95% CI, 0.60-0.88), respectively. The pooled PLR and NLR of DR for predicted DN were 2.72 (95% CI, 1.42-5.19) and 0.47 (95% CI, 0.33-0.67), respectively. The summary DOR for the relationship between DR and subsequent DN for T2D patients was 5.53 (95% CI, 2.00-15.30), and the AUC of DR for predicted DN was 0.73 (95% CI, 0.69-0.77). This study found significant associations between DR and subsequent DN risk for patients with T2D. Moreover, the predictive value of DR on subsequent DN risk was relatively lower.
Subject(s)
Diabetes Mellitus, Type 2/complications , Diabetic Nephropathies/diagnosis , Diabetic Retinopathy/diagnosis , Humans , Prospective Studies , ROC Curve , Sensitivity and SpecificityABSTRACT
Gastric cancer is one of the four major tumors in the world and the second leading cause of cancer-related death. It was reported that Substance P (SP), as an oncogenic factor, could regulate the expression of miRNAs in gastric cancer progression. Here, we focused on the role of miR-877-5p in gastric cancer development and the miR-877-5p involvement in the SP-mediated gastric cancer development. The mRNA expression level and cell proliferation were assessed by quantitative real-time PCR and cell counting kit-8 assay, respectively. Flow cytometry was conducted to detect apoptosis, followed by assessing the expression of related apoptosis factors. Dual-luciferase reporter assay was performed to validate the interaction between miR-877-5p and Forkhead cassette M1 (FOXM1). Our results showed that SP treatment significantly increased cell proliferation in gastric cancer. Moreover, the miR-877-5p expression was dose-dependently decreased by SP, whereas FOXM1 expression was markedly increased by SP in gastric cancer cells. miR-877-5p negatively regulated gastric cancer development via inhibiting cell proliferation and promoting apoptosis accompanied by increased cleaved caspase-3, cleaved caspase-9, and Bax protein levels and decreased Bcl-2 level. We confirmed that miR-877-5p could target FOXM1 and negatively regulate its expression. Furthermore, we demonstrated that SP could promote cell proliferation and inhibit apoptosis, while miR-877-5p overexpression reversed the effect of SP on cell proliferation and apoptosis. These results suggest that miR-877-5p overexpression can antagonize the promoting effect of SP on the development of gastric cancer, indicating that miR-877-5p may serve as a promising therapeutic target for gastric cancer.
Subject(s)
MicroRNAs/genetics , Stomach Neoplasms , Substance P/genetics , Cell Line, Tumor , Forkhead Box Protein M1/genetics , Gene Expression Regulation, Neoplastic , Humans , Stomach Neoplasms/geneticsABSTRACT
Alzheimer's disease (AD) is a progressive neurodegenerative disease leading to the irreversible loss of brain neurons and cognitive abilities, and the vicious interplay between oxidative stress (OS) and tauopathy is believed to be one of the major players in AD development. Here, we demonstrated the capability of the small molecule N-(1,3-benzodioxol-5-yl)-2-[5-chloro-2-methoxy(phenylsulfonyl)anilino]acetamide (LX2343) to ameliorate the cognitive dysfunction of AD model rats by inhibiting OS-induced neuronal apoptosis and tauopathy. Streptozotocin (STZ) was used to induce OS in neuronal cells in vitro and in AD model rats that were made by intracerebroventricular injection of STZ (3 mg/kg, bilaterally), and Morris water maze test was used to evaluate the cognitive dysfunction in ICV-STZ rats. Treatment with LX2343 (5-20 µmol/L) significantly attenuated STZ-induced apoptosis in SH-SY5Y cells and mouse primary cortical neurons by alleviating OS and inhibiting the JNK/p38 and pro-apoptotic pathways. LX2343 was able to restore the integrity of mitochondrial function and morphology, increase ATP biosynthesis, and reduce ROS accumulation in the neuronal cells. In addition, LX2343 was found to be a non-ATP competitive GSK-3ß inhibitor with IC50 of 1.84±0.07 µmol/L, and it potently inhibited tau hyperphosphorylation in the neuronal cells. In ICV-STZ rats, administration of LX2343 (7, 21 mg·kg-1·d-1, ip, for 5 weeks) efficiently improved their cognitive deficits. LX2343 ameliorates the cognitive dysfunction in the AD model rats by suppressing OS-induced neuronal apoptosis and tauopathy, thus highlighting the potential of LX2343 for the treatment of AD.
Subject(s)
Acetamides/therapeutic use , Alzheimer Disease/drug therapy , Apoptosis/drug effects , Cognitive Dysfunction/drug therapy , Nootropic Agents/therapeutic use , Oxidative Stress/drug effects , Sulfonamides/therapeutic use , Tauopathies/drug therapy , Animals , Cells, Cultured , Disease Models, Animal , Male , Maze Learning/drug effects , Neurons/drug effects , Rats , Rats, Sprague-DawleyABSTRACT
Considering the complicated pathogenesis of Alzheimer's disease (AD), multi-targets have become a focus in the discovery of drugs for treatment of this disease. In the current work, we established a multi-target strategy for discovering active reagents capable of suppressing both Aß level and Tau hyperphosphorylation from natural products, and found that the ethanol extract of Thamnolia vermicularis (THA) was able to improve learning ability in APP/PS1 transgenic mice by inhibiting both Aß levels and Tau hyperphosphorylation. SH-SY5Y and CHO-APP/BACE1 cells and primary astrocytes were used in cell-based assays. APP/PS1 transgenic mice [B6C3-Tg(APPswe, PS1dE9)] were administered THA (300 mg·kg-1·d-1, ig) for 100 d. After the administration was completed, the learning ability of the mice was detected using a Morris water maze (MWM) assay; immunofluorescence staining, Congo red staining and Thioflavine S staining were used to detect the senile plaques in the brains of the mice. ELISA was used to evaluate Aß and sAPPß contents, and Western blotting and RT-PCR were used to investigate the relevant signaling pathway regulation in response to THA treatment. In SH-SY5Y cells, THΑ (1, 10, 20 µg/mL) significantly stimulated PI3K/AKT/mTOR and AMPK/raptor/mTOR signaling-mediated autophagy in the promotion of Aß clearance as both a PI3K inhibitor and an AMPK indirect activator, and restrained Aß production as a suppressor against PERK/eIF2α-mediated BACE1 expression. Additionally, THA functioned as a GSK3ß inhibitor with an IC50 of 1.32±0.85 µg/mL, repressing Tau hyperphosphorylation. Similar effects on Aß accumulation and Tau hyperphosphorylation were observed in APP/PS1 transgenic mice treated with THA. Furthermore, administration of THA effectively improved the learning ability of APP/PS1 transgenic mice, and markedly reduced the number of senile plaques in their hippocampus and cortex. The results highlight the potential of the natural product THA for the treatment of AD.
Subject(s)
Amyloid beta-Protein Precursor/genetics , Lichens/chemistry , Maze Learning/drug effects , Plant Extracts/pharmacology , Plaque, Amyloid/metabolism , Presenilin-1/genetics , Tauopathies/drug therapy , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/metabolism , Animals , Brain/metabolism , Cells, Cultured , Cricetinae , Dose-Response Relationship, Drug , Mice, Transgenic , Phosphorylation/drug effects , Plant Extracts/chemistry , Primary Cell Culture , Signal Transduction/drug effects , tau Proteins/metabolismABSTRACT
AIM: Streptozotocin (STZ) is widely used to induce oxidative damage and to impair glucose metabolism, apoptosis, and tau/Aß pathology, eventually leading to cognitive deficits in both in vitro and in vivo models of Alzheimer's disease (AD). In this study, we constructed a cell-based platform using STZ to induce stress conditions mimicking the complicated pathologies of AD in vitro, and evaluated the anti-amyloid effects of a small molecule, N-(1,3-benzodioxol-5-yl)-2-[5-chloro-2-methoxy(phenylsulfonyl)anilino]acetamide (LX2343) in the amelioration of cognitive deficits in AD model mice. METHODS: Cell-based assays for screening anti-amyloid compounds were established by assessing Aß accumulation in HEK293-APPsw and CHO-APP cells, and Aß clearance in primary astrocytes and SH-SY5Y cells after the cells were treated with STZ in the presence of the test compounds. Autophagic flux was observed using confocal laser scanning microscopy. APP/PS1 transgenic mice were administered LX2343 (10 mg·kg-1·d-1, ip) for 100 d. After LX2343 administration, cognitive ability of the mice was evaluated using Morris water maze test, and senile plaques in the brains were detected using Thioflavine S staining. ELISA assay was used to evaluate Aß and sAPPß levels, while Western blot analysis was used to measure the signaling proteins in both cell and animal brains. RESULTS: LX2343 (5-20 µmol/L) dose-dependently decreased Aß accumulation in HEK293-APPsw and CHO-APP cells, and promoted Aß clearance in SH-SY5Y cells and primary astrocytes. The anti-amyloid effects of LX2343 were attributed to suppressing JNK-mediated APPThr668 phosphorylation, thus inhibiting APP cleavage on one hand, and inhibiting BACE1 enzymatic activity with an IC50 value of 11.43±0.36 µmol/L, on the other hand. Furthermore, LX2343 acted as a non-ATP competitive PI3K inhibitor to negatively regulate AKT/mTOR signaling, thus promoting autophagy, and increasing Aß clearance. Administration of LX2343 in APP/PS1 transgenic mice significantly ameliorated cognitive deficits and markedly ameliorated the Aß pathology in their brains. CONCLUSION: LX2343 ameliorates cognitive dysfunction in APP/PS1 transgenic mice via both Aß production inhibition and clearance promotion, which highlights the potential of LX2343 in the treatment of AD.
Subject(s)
Acetamides/therapeutic use , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/metabolism , Neuroprotective Agents/therapeutic use , Nootropic Agents/therapeutic use , Plaque, Amyloid/drug therapy , Sulfonamides/therapeutic use , Acetamides/pharmacology , Animals , CHO Cells , Cricetulus , Drosophila melanogaster , HEK293 Cells , Humans , Mice , Mice, Transgenic , Neuroprotective Agents/pharmacology , Nootropic Agents/pharmacology , Plaque, Amyloid/chemically induced , Streptozocin , Sulfonamides/pharmacologyABSTRACT
Alzheimer's disease (AD) is a progressively neurodegenerative disease that eventually leads to the irreversible loss of neurons and intellectual abilities, including cognition and memory. AD has become the most common cause of dementia in aged people, and the ill-defined pathogenesis of AD is seriously impeding the current drug discovery against this disease. To date, there is still a lack of etiologically therapeutic drugs for AD, although some symptomatic treatments have been successfully developed. The ß-amyloid (Aß)-induced neurodegeneration is determined as the main pathogenesis of AD, and by targeting the regulation of Aß in production inhibition or clearance promotion, many active agents have been designed potentially for AD treatment, but no drug has yet been approved in clinical use. Actually, AD has a complex pathogenic mechanism that involves multiple aberrant signaling genes and pathways, and the idea of 'single target' for anti-AD drug research is thus full of challenges. Recently, with a deep understanding of AD pathogeneses and the development of advanced pharmacological techniques, 'multiple target'-based strategy has been widely applied for the drug discovery against this disease, and many promising results have been achieved. Here, we review the recent multitarget strategies for the drug discovery in the treatment of AD by focusing on the involvement of Aß regulation.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid beta-Peptides/drug effects , Drug Discovery/methods , Alzheimer Disease/genetics , Amyloid beta-Peptides/genetics , Amyloid beta-Peptides/metabolism , Animals , Gene Expression Regulation , Humans , Tauopathies/genetics , Tauopathies/metabolism , tau Proteins/genetics , tau Proteins/metabolismABSTRACT
OBJECTIVE: To investigate the precise locations of the blood vessels and nerves surrounding the seminal vesicles (SV) in men and provide some anatomical evidence for SV-related minimally invasive surgery. METHODS: We observed the courses and distribution of the blood vessels and nerves surrounding SVs and obtained the data for positioning the SV neuroplexes in 20 male pelvises. RESULTS: One branch of the neuroplexes was distributed to the SVs bilaterally with the neurovascular bundles, (2.85 ± 0.18) cm from the median sulcus of the prostate (MSP), while another branch ran through the Denonvillier fascia behind the SV, (0.81 ± 0.06) cm from the MSP. The arterial SVs (ASV) originated from the inferior vesical artery and fell into 4 types, 55% going directly to the SVs as one branch, 15% running between the SV and the ampulla of the deferent duct as another branch, 25% downward as 2 branches to the SV and between the SV and the ampulla of the deferent duct respectively, and 5% as the other ASVs. The shortest distance from the ASV through the prostatic neuroplexus to the posterior SV was (1.08 ± 0.09) cm. CONCLUSION: In SV resection, neuroplexus injury can be reduced with a bilateral distance of < 2.85 cm and a posterior distance of < 0.81 cm from the MSP, and so can bleeding by vascular ligation between the SV and the ampulla of the deferent duct.
Subject(s)
Seminal Vesicles/blood supply , Seminal Vesicles/innervation , Biopsy , Humans , Male , Prostate/blood supply , Prostate/innervation , Vas Deferens/blood supply , Vas Deferens/innervationABSTRACT
This study adopts a new approach to reassess the factors influencing urban energy intensity in China. Initially, the factors impacting energy intensity are classified into controllable and uncontrollable categories. Subsequently, employing a single-factor multi-stage method combined with the Adaboost method, 289 Chinese cities are categorized based on uncontrollable factors to eliminate the influence of inherent differences on energy intensity. Finally, panel data regression analyses are conducted using data from 289 Chinese cities between 2005 and 2016, individually for each city type, to evaluate the extent to which controllable factors contribute to energy intensity. The findings indicate that (1) heightened energy prices, an increased share of electricity consumption, and a greater proportion of centralized heating significantly influence the reduction of energy intensity across all city types; (2) to optimize energy consumption, each city type should adopt specific strategies. For instance, cities located in resource-rich heating regions with low economic outputs can reduce their energy intensity by increasing electricity consumption, while cities with high economic outputs can decrease their energy intensity by increasing natural gas consumption. The findings of this study carry substantial implications for the Chinese government in shaping targeted energy policies tailored to different city types.
Subject(s)
Cities , China , Electricity , Energy-Generating Resources , Natural GasABSTRACT
Polycystic ovary syndrome (PCOS), a common endocrine disorder affecting premenopausal women, is associated with various metabolic consequences such as insulin resistance, hyperlipidemia, obesity, and type 2 diabetes mellitus (T2DM). Insulin sensitizers, such as metformin and pioglitazone, though effective, often leads to significant gastrointestinal adverse effects or weight gain, limiting its suitability for women with PCOS. There is an urgent need for safe, effective and affordable agents. Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, enhances glucose elimination through urine, thereby reducing body weight and improving glucose and lipid metabolism. Nevertheless, it is not currently recommended as a therapeutic option for PCOS in clinical guidelines. In this study, we systematically examined the impact of dapagliflozin on an obese PCOS mouse model, focusing on alterations in glucose metabolism, adipose tissue morphology, and plasma lipid profile. Obese PCOS was induced in mice by continuous dihydrotestosterone (DHEA) injections over 21 days and high-fat diet (HFD) feeding. PCOS mice were then orally gavaged with dapagliflozin (1 mg/kg), metformin (50 mg/kg), or vehicle daily for 8 weeks, respectively. Our results demonstrated that dapagliflozin significantly prevented body weight gain and reduced fat mass in obese PCOS mice. Meanwhile, dapagliflozin treatment improved glucose tolerance and increased insulin sensitivity compared to the control PCOS mice. Furthermore, dapagliflozin significantly improved adipocyte accumulation and morphology in white adipose tissue, resulting in a normalized plasma lipid profile in PCOS mice. In conclusion, our results suggest that dapagliflozin is an effective agent in managing glucose and lipid metabolism disorders in obese PCOS mice.
Subject(s)
Benzhydryl Compounds , Glucosides , Insulin Resistance , Obesity , Polycystic Ovary Syndrome , Animals , Polycystic Ovary Syndrome/drug therapy , Polycystic Ovary Syndrome/metabolism , Glucosides/pharmacology , Glucosides/therapeutic use , Benzhydryl Compounds/pharmacology , Benzhydryl Compounds/therapeutic use , Female , Mice , Obesity/drug therapy , Obesity/metabolism , Obesity/complications , Diet, High-Fat/adverse effects , Disease Models, Animal , Mice, Obese , Adipose Tissue/drug effects , Adipose Tissue/metabolism , Metformin/pharmacology , Metformin/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Lipid Metabolism/drug effects , Mice, Inbred C57BL , Blood Glucose/drug effects , Blood Glucose/metabolismABSTRACT
China has announced a target of achieving carbon peaking by 2030 and carbon neutrality by 2060. Therefore, it is important to assess the economic impacts and emission reduction effects of China's low-carbon policies. In this paper, a multi-agent dynamic stochastic general equilibrium (DSGE) model is established. We analyze the effects of carbon tax and carbon cap-and-trade policies under both deterministic and stochastic conditions, as well as their ability to cope with stochastic shocks. We found that (1) from a deterministic perspective, these two policies have the same effect. Every 1% cut in CO2 emissions will bring a 0.12% output loss, a 0.5% drop in demand for fossil fuels, and a 0.05% rise in demand for renewable energy; (2) from a stochastic perspective, effects of these two policies are different. This is mainly because economic uncertainty does not change the cost of CO2 emissions under a carbon tax policy, but it does change the price of CO2 quotas and the emission reduction behaviors under a carbon cap-and-trade policy; (3) from an economic volatility perspective, both two policies can act as automatic stabilizers. Compared to a carbon tax, a cap-and-trade policy can better ease economic fluctuations. The results of this study provide implications for policy-making.